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Prosthetic Aortic Heart Valves

Prosthetic Aortic Heart Valves In this review, the anatomy and structure of the aortic valve and its prostheses are comprehensively discussed. Cardiac anatomy and function, human heart valves and their prostheses are also extensively discussed. The current status of prosthetic heart valves along with the next generation of these devices is broadly deliberated. Ather promising options such astranscatheter technologies (percutaneous valves), minimally invasive techniques, and the construction of prosthetic valves using tissue engineering as futureristic areas of research are brought into conclusion. Keywords: Aortic Valve, Prosthetic Valve, Mechanical Heart Valves, Bioprostheic Valves, Hydrogel Biomaterials, Surgical Tools Background downwardsto the left. It sits between the lungs and behind Cardiac Anatomy and Function the ribcage for safety and protection. The cavity in which the The heart is undoubtedly one of the most dynamic organs in heart is locatedis known as the thoracic cavity, which is behind the human body. The main function of the human heart is to the breastbone, also known as the sternum, in front of trachea circulate the blood, acting as a synchronized reciprocating and esophagus, and above the diaphragm [3]. The diaphragm double-pump. In every heartbeat, blood is squeezed into the is a curved-shaped membrane made of muscle that is located arteries from the heart, and then returns back to the heart in a between the chest and the abdomen as a separator. Since it is one-way circuit through the veins. The delivery of the oxygen placed in the thoracic cavity, it also has another name which is and nutrients takes place in the connection between arteries the thoracic diaphragm. The main axis of the heart is aligned and veins, known as the capillary network, which are known as along the body’s midline, while the apex is inclined slightly micro vessels [1,2]. Blood flows through the circulation system towards the left side. Due to the inclination of the heart towards due to the continuous rhythmic heart muscle contractions. the left, about %65 of its mass is on the left side of the body However, the form, function and complexity of the heart arenot while the remaining %35 is on the right side [4]. the same in different animals. In some animals it is similar to a A thin layer of tissue, known as the pericardium, covers the beating tube as observed in fish, spiders and worms.In some outside of the myocardium. Pericardium is a strong two-layered other animals, it may have a more complex structure as ob- membrane that shields the heart. There are two sub-layers in the served in birds and reptiles. In humans and pigs, the heart is pericardial membrane: the outermost fibrous pericardium and much more developed as asignificant evolution from a single the inner serous pericardium. The serous pericardium, is further to a double pump is observed. It should be noted that the pig separated into two sub-layers: the parietal pericardium, which heart is the closest to the human heart in shape, function and is connected to and inseparable from the fibrous pericardium, complexity [1]. and the visceral pericardium, which is a segment of the epi- In general, the heart is made of active muscles known as cardium. The epicardium is the layer directly outside of the myocardium and is as big as a closed fist (Figure 1). The average myocardium. The heart is not attached to any other organs dimensions of an adult heart are 130×95×65 mm with a weight and issuspended in the pericardium. The firm outer segment of 300 g. It is a somewhat conic structure, with the wide base of the sac, or fibrous pericardium, is strongly connected to the oriented towards the right and the head, the apex oriented diaphragm under the mediastinal pleura on the side and the © 2017 Mohammadi et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 that carry oxygen-rich blood. All of the collected blood in the left atrium then goes directly to the left ventricle [4]. The left ventricle then pumps it to the systemic circulation system through the aorta to deliver oxygen to the remainder of the body. It should be noted that in the right half of the heart, the wall is thinner and the heart valves have lessconcentra- tion and density of collagen fibers whencompared to the left side. It is observed that these two pumps (halves), which are completely separate, work simultaneously together in a very effective way. In fact, each pump is responsible for driving the blood into a distinct circuit, either the pulmonary circuit or the systemic circuit. The pulmonary circulation is the circuit by which blood is oxygenated and requires a much lower driving force than the systemic circulation. This is mainly because of the much lower resistance between the blood and vessels. Thisalsoexplains why the left part of the heart has a stronger and thicker structure than the right side, and why the blood pressure at the onset of the systemic circuitis much higher than that of the pulmonary circuit (Figure 2) [6]. Figure 1. Diagram of a porcine heart model. sternum in front [5]. It progressively becomes the coatings of the superior vena cava and the pulmonary arteries and veins. The serous membrane lines the fibrous pericardium and covers the heart wall. The segment of membrane lining the fibrous pericardium is known as the parietal serous layer or parietal pericardium, and the segment coating the heart is known asthe visceral serous layer, visceral pericardium or epicardium. There is a gap between these two layers of serous membrane known as the precardial cavity. This cavity is filled by 10 to 15 ml of pericardial fluid, which is secreted by the serous membranes. The pericardial fluid is responsible Figure 2. The horizontal section of the heart [7]. for the lubrication of the two membranes during the cardiac cycle so that the energy loss due tofriction is almost zero [6]. The human heart has four chambers (or cavities) known The heart wall is composed of three identifiable layers, the as ventricles (bottom chambers) and atria (top chambers). epicardium, the myocardium, and the endocardium. Coronary Blood flows from all regions of the body intothe vena cava arteries and veins are imbedded within the epicardium and vein, which empties into the right atrium that collects all of the the myocardium. The epicardium (or visceral pericardium) deoxygenated blood. The inferior vena cava is responsible for is made of a surface of compacted epithelial cells covering collecting deoxygenated blood from the lower body, including the connective tissues. The myocardial layer is made of the the legs, back, abdomen and pelvis.The superior vena cava contractile bundles of striated muscle fibres. These bundles is responsible for collecting deoxygenated blood from the are constructed in a branching-like pattern and cause a wring- upper body, including the brain, neck, arms, and chest. All ingmovement thatproficiently squeeze the heart champers of the collected blood in the right atrium then goes directly on each cardiac cycle. The thickness of the myocardium is to the right ventricle, whichpumps it to the main pulmonary not constant and highly depends on the pressure required artery and subsequently the lungs. This is where the blood to move the blood in each cardiac chamber. Also, the atrial receives fresh oxygen and releases its carbon dioxide [3]. The walls are much thinner when compared to the ventricular power needed to pump the deoxygenated blood to the lung walls. The myocardium is made of muscle fibres which are is considerably less than that required for systemic circulation. then broken down into smaller structurescalled cardiac The pulmonary veins connect the lungs to the left atrium and muscle cells. Each cardiac muscle cell is then subdivided into bring oxygenated blood from the lungs back to the left atrium. smaller structures known as myofibrils. Myofibrils are made In fact, the pulmonary veins are the only veins in the body of smaller unites known as sarcomeres. A sarcomere is the 2 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 fundamental unit of cardiac muscle and is highly responsible In normal conditions, there is absolutely no contribution from for the contractibility of cardiac muscle [8]. The length of the neural system or any external regulatory mechanisms to sarcomeres is approximately a few microns and theyhave stimulate the regular cardiac muscle. In fact, the root of this very complicated structures. The cardiac sarcomere is an rhythmic mechanism is in the cardiac muscle. Thisoriginates extremely organized cytoskeletal structure made mainly of during the cardiac development in the embryo long before myosin, actin and a set of regulatory giant proteins known as various levels of the neural systemhave developed. Each sub- titin. Myosin is known to be the cytoskeletal motor protein in segment of the heart structure has the beating property where the muscle cell thatis directly accountable for converting small cardio-myofibril in a tissue culture continuously contract chemical energy (ATP) into mechanical force and eventually rhythmically. It should be noted that the regular contraction muscle contraction. Myosin is the thick filament while actin in cardio-myofibrils is either maximum (100% contraction) is called the thin filament. Myosinbinds to actin through its or nothing(0% contraction),unlike skeletal muscle cells. This long, fibrous tail and a globular head. Its globular head is strongly indicatesthe lack of neural network contribution to also attached to ATP, which is the main provider of energy the regular heart construction. If more or less blood is required for muscle activities. Actin molecules are attached to the Z to be circulated through the body (depending on the physi- line, which are limits of the sarcomere unit andmyosin is at- cal or mental conditions), the heart rate needs to increase or tached to the Z line through titin. The space in which titin is decrease [10]. The regulation of heart rate is directlycontrolled located is called the I-band and the space between the two by the neural network,which is achieved specifically by the actin filaments in a sarcomere is called H zone (Figure 3) [8]. sympathetic nerves and the parasympathetic fibres in the vagus nerve. The sympathetic nerves serve as a cardiac accelerator and the parasympathetic nerves act as a cardiac decelerator. If the vagus nerve is stimulated, it reduces the heart rate [11]. Consequently, the atrial contractility is also reduced and the cardiac output is decreased. If parasympathetic nerves are stimulated, the contractility of the atria and ventricles as well asheart rate is increased. The effect of the sympathetic and parasympathetic nerves is similar to an analog system, meaning that the heart rate (or cardiac muscle contraction) highly depends on the degree of stimulation. The period of one full contraction and relaxation of the heart is defined as the cardiac cycle, which includes the relaxation phase (diastole) and the contraction phase (systole). The pressure Figure 3. Structure of a sarcomere. developed at the beginning of the systemic circulation var- ies during these two periods. The normal diastolic pressure Cardiac muscle and skeletal muscles have similar proper- is between60 to 80 mmHg and the normal systolic pressure ties. The heart containspacemaker cells that generate the is between 90 to 120 mmHg [12]. depolarization and action potentials to cause cardiac cells The systole phase normally takes between 0.3 to 0.4 seconds, to contract. Regularheart contraction is self-driven,which is in which 80 cc to 100 cc is pumped to the systemic and the not based on neuron stimulations. Cardiac muscle cells are pulmonary circulation systems together. In the beginning of positioned next to each other with gap junctions in between. this phase, the systemic blood pressure is maximum with a This allows action potentials to quickly spread from one cell value of 90 to 120 mmHg. The ventricle pressure is slightly to another to connect all the cardiac cells in a very organized higher due to: (1) the pressure drop through the aortic valve, way. Another role of gap junctions is to let the sinoatrial node and (2) the compliance of the aortic root. In fact, atrial systole cells generate the action potential, which is communicated follows at the end of ventricular diastole in which the ventricles via the gap junctions throughout the heart. This helps heart are relaxed and filled for the next cardiac cycle. In the begin- contract and relax in a very controlled way [6,8]. Cardiac muscle ning of the cardiac cycle, both atria and ventricles are in the cells in atria and ventricles are different. Some are called the diastolic phase [13]. There is a period of quick relaxation of pacemaker cells, which are in the sinoatrial node, and some the ventricles followed by a quick atrial systole. Simultane- are called the atrial and ventricular cells that cause the con- ously, the arterial blood pressure falls to its minimum, known traction only. Nevertheless, all share the same mechanisms of as the diastolic blood pressure (approximately 80 mmHg). excitation-contraction coupling; however, there are certain Ventricular relaxation again takes place after the blood has features thatdistinguish the sinoatrial cells [9]. been pumped during ventricular systole out of the heart. The muscle contraction mechanism leads to a beating The heart myocardium is known to be active as there are heart. Regular heartbeat is a self-driven mechanism that is electrical stimulations which cause the myocardial tissue to completely due to the inherent rhythmicity of cardiac muscle. contract. The key factor for the heart to act like a pump is 3 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 the myocardial contraction and relaxation. The contraction larger than that of the right coronary artery (Figure 4) [15,18]. of myocardium causes a high pressure in each chamber and The lumen diameter of the main branch of the right coronary the relaxation causes the pressure to drop. The periods of artery is approximately 2.5 mm. The areas covered by the right relaxation and contraction are called diastole and systole, coronary artery system are as follows: the right ventricular respectively. These electrical stimulations are initiated in outflow area, the atrioventricular node, the sinoatrial node, and the sinoatrial (SA) node, which is locatedin the right atrium wall. Through an impulse started from the SA node and then propagated in the entire atrium wall, the two atria contract. There is another node in the ventricle chambers where electri- cal impulses initiate, causing them to contract. This node is known as the atrioventricular (AV ) node, which is locatedat the interface of the two atria. The period of diastole is longer than that of systole, which is the time for heart to relax between two consecutive contractions. A healthy human heart beats around 100,000 times every day, almost 70 beats per minute. The total amountof blood pumped by an adult heart every day is about 7,500 liters [14]. One of the main features of the cardiovascular system through which the performance of the heart is evaluated is the cardiac output. Cardiac output is the amount of blood pumped by the two ventricular chambers. It is typically con- sidered as the volume of blood per minute or litres of blood Figure 4. The diagram of the human per minute. If the stroke volume,also known as the heart coronary arteries [19]. output, in each cardiac cycle is multiplied by the number of beats per minute (heart rate), the cardiac output can be calculated [10,12]. It should be noted that the levelof cardiac the bulk of the right ventricle. Also, the right coronary artery output is directly proportional to the entire body’s need for has branches that spread into the interventricular septum and oxygen and other nutrients. In normal conditions, the cardiac merge with arteriolar branches from the left coronary artery output at rest (or sleeping) is evaluated to be approximately at the border of the two ventricles. The lumen diameter of the 5 litres per minute. It is typically increased upon the initiation main branch of the left coronary artery is approximately 3.5 of any types of physical or mental activities by 50% to 500%, mm with a length between 10 mm and 20 mm [12,20]. The depending on the person [15]. subdivisions of the main left coronary are two smaller arteries, called the anterior descending and the circumflex arteries. Coronary Arteries The areas covered by the left coronary artery are mainly the The mechanism by which oxygen and nutrientsare delivered left ventricle and the interventricular septum [15-21]. The to the heart is, somewhat surprisingly, not by diffusion. It is left circumflex artery is positioned along the atrioventricular actually achieved though the coronary artery vascular network. groove, which is then divided into an arterialand the obtuse This network consists of two main coronary arteries, known marginal branch. The arterial branch is then connected to as the right and the left coronary artery. Generally, the left the sinoatrial node and the obtuse marginal branch covers coronary artery has a Y-shape structure,and it branches to the posterior left ventricular wall towards the apex. It should two major smaller arteries. These are called the left anterior be noted that veins usually follow the same pattern as the descending and the circumflex coronary arteries. The left distribution of the distal arteries [22]. anterior descending and the circumflex coronary arteries are divided to many smaller arteries that cover the entire Review cardiac surface [17]. Human Heart Valves The right and left coronary arteries originate from the To regulate the precise blood flow within the heart, there aortic root, or more specifically, from the right and left aortic are four unidirectional valves in the heart. These valves are sinuses. These are better known as the right coronary sinus categorized as:(1) the atrioventricular valves or tricuspid and and the left coronary sinus, respectively. The other aortic sinus mitral valves, and (2) the semilunar valves or pulmonary and is called the non-coronary sinus of Valsalva, simply because aortic valves. The atrioventricular valves are known to have there is no coronary artery that originates from there. The very thin structures thatare positioned between the atria and left coronary arterial system is said to be more vital than the the ventricles. The right atrioventricular valve is called the right arterial system, simply because it covers a larger area. tricuspid valve because of its three unequally shaped leaflets. This explains why the size of the main left coronary artery is The leaflets are covered by the endocardium and are strength- 4 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ened with a layer of compact connective tissue. The chordae valves and how they are positioned and oriented within the tendineae which is a connective tissue (similar to a tendon)is heart. In a healthy human heart, the location and orientation coated by endocardium and connects the papillary muscles of the valves is much more complicated, but the following and the ventricular surface of the middle layer of each cusp. diagram makes it easier to understand. The cardiac valves are The left atrioventricular orifice is the location of the mitral positioned in between the chambers of the heart and at the valve. The mitral valve is connected in the same way as the onset of the aorta and pulmonary artery. The role of valves is tricuspid, but it has a stronger and thicker structure because acritical component inproviding the proper direction for the the operational pressure around the mitral valve is much flow of blood through the heart and thereafter. All of the valves, higher. First, blood is pumped through the tricuspid and mitral in normal physiological condition, perform as unidirectional valves as the atria contract. Following the ventricle contrac- check-valves thatallow blood to flow in only one direction (i.e., tion, blood is pushed backward, flowing between the flaps from one chamber to another, or letting blood flow to the and walls of the ventricles [20-23]. The flaps are consequently lungs or to the systemic circulation of body in only one direc- pushed upward sothat the valvesare closed completely. In tion) [24]. The valves control the direction and the rate of the this case, a complete separator is formed between the atria blood flow through the heart in a timely manner by opening and the ventricles. The motion of the leaflets is controlled by and closing the leaflets during diastolic and systolic phases. the chordae tendineae and papillary muscles so as to prevent The mechanism by which valves open and close during the the leaflets from opening into the atria. The semilunar valves, cardiac cycle is known to be almost passive as the pressure known as the pulmonary and aortic valves, are pocket-like gradient before and after the valves is the driving force. This structures positioned where the pulmonary artery and the pressure gradient is generated within the heart and highly aorta are connected to the ventricles. The pulmonary valve is depends on the compliance of the heart and arteries [10-25]. positionedat the orifice between the right ventricle and the However,in the mitral valve, the opening and closing phases pulmonary artery. The aortic valve is positioned between the are not completely passive as the papillary muscles and the left ventricle and aorta. The three leaflets of the pulmonary chordae tendineaelocated within the left ventricle partly valves arethinner than that of the aortic valve, but in both contribute, as mentioned before. valves there is no connective tissue of chordae tendineae. Due In summary, the four heart valves are known as: (1) the to this, the motion of the leaflets isnot restricted by any cords tricuspid valve, (2) the pulmonary valve, (3) the mitral valve, during the opening and closing phases. The closing phase of and (4) the aortic valve. the heart valves is associated with an audible sound, known • Tricuspid valve: located between the right atrium and as the heartbeat. The first sound is because of the closure of the right ventricle  the mitral and tricuspid valves, and the second one is when • Pulmonary valve: located between the right ventricle the pulmonary and aortic valves close [18-22]. and the pulmonary artery  The following diagram (Figure 5) shows the four cardiac • Mitral valve: located between the left atrium and the left ventricle  • Aortic valve: located between the left ventricle and the aorta As the heart muscle contracts and relaxes, the valves open and close, letting blood flow into the ventricles and atria at alternate times.As to the stages ofhow the valves function normally in the left ventricle: (1) after the left ventricle con- tracts, the aortic valve closes and the mitral valve opens. This allows blood flow from the left atrium into the left ventricle, (2) once the left atrium contracts, more blood flows into the left ventricle, and (3) when the left ventricle contracts again, the mitral valve closes and the aortic valve opens, and blood flows into the aorta [24-27]. The aortic valve, located at the onset of the aorta, is the por- tion of the aortic root thatconnects the heart to the systemic circulation of the body. It plays a key role in the function of the heart and the cardiovascular system. It also preserves optimal Figure 5. The structure of heart and coronary perfusion and plays a significant role in providing a heart valves, four chambers (atriums non-turbulent flow in the vascular system. Each component and ventricles) and four heart valves: of the aortic root has its own individual histological features pulmonary valve, mitral valve, aortic and anatomical construction. The specific shape of the an- valve and tricuspid valve are shown clearly [26]. nulus, including the three aortic sinuses’ interleaflet triangles, 5 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 the sinotubular junction, commissures, and the aortic valve microstructure provides an ideal transferal of force from the leaflet tissue interrelate with each other in a very precise leaflet tissue to the base (attachment) and eventually, to the way in order to preserve ideal function. This harmonized ac- aortic wall [35-36]. tive behaviour has been demonstrated to be significantfor coronary perfusion, especific flow characteristics, and left Interleaflet Triangles ventricular function [28]. These interleaflet triangles are basically the three regions between the apex of the crown-like annulus and the anatomic Annulus boundary. In fact, the interleaflet triangles and the ventricular The aortic valve cusps are connected to the sinuses’ wall by outflow area are on the same extension and the sinotubular a very solid collagenous network known asthe annulus. The junction in the region of the commissures and interleaflet word annulus indicates a circular structure of the aortic ring triangles are at the same level. The triangle formed by the which is not accurate. In fact, the only circular component of right- and the left-coronary sinuses is positioned towards the aortic root is the region where the left ventricle and the the pulmonary valve, whose base is located on the septal fibroelastic wall of the arterial trunk intersect. The annulus section of the right ventricular outflow area. Attachment to has a crown-like shape thatis located on the interface of the the pulmonary artery is attained in almost half of cases by left ventricle and the aortic root. It is made up of a fibrous the ligament of the infundibulum. The triangle formed by the structure thatis strongly connected to the media of the aortic right- and non-coronary sinuses is positioned towards the sinuses distally and also to the muscular and the membranous right atrium and is in direct connection with the membranous septa anteriorly and proximally. The three superior portions of septum. The close communication between the conduction the annulus are known as commissures.In the non-coronary system and the aortic root occurs in this region. Lastly, the sinus of the annulus, there are regions in which no myocardial triangle formed by the left- and non-coronary sinuses is in muscle exists and instead havea cartilaginous structure. These direct connection inferiorly with the aortic or anterior cusp of regions are the locations where the layers of the cusps exhibit the mitral valve. These three triangles separate and indicate a specific arrangement. The ventricular and arterial layers the three sinuses in the healthy valve (Figure 6) [34-40]. become separate, and the middle collagenous layer exhibits The three intraleaflet triangles are attached by a delicate a cuneiform structure. The ventricular layer blends into the fibrous membrane of the aorta between the extended sinuses. endocardial layer gradually and the arterial layer blends to The triangle formed by the left-coronary and non-coronary the sinus wall. Small arteries and veins are positioned in the sinus becomes a portion of the aortic–mitral valvular curtain. connective tissue layer [29-34]. Elastic and collagen fibers as Its structure is mainly fibrous tissue, which is similar to the well asneuronal structures are present in the annulus. mitral valve cusp structure. The triangle formed by the non- coronary and the right-coronary aortic sinus is merged in the Commissures membranous portion of the septum and is made up of fibrous The apex of annulus in the region where the lannula of two tissue. However, the triangle formed by the right-coronary cusps are connected to the aortic wall. This occurs at the height and left-coronary sinus in the region of the subpulmonary of the sinotubular junction and is known as a commissure. In infundibulum is different. This triangle is mainly reinforced by this region, two cusps are attached to the aortic wall in paral- lel for a short distance, which makes three commissures. The first one is formed by the right- and left-coronary cusps and is oriented anteriorly. Itis relatively opposite to the equiva- lent commissure of the pulmonary valve. The second one is formed by the right and non-coronary cusps and is on the right anterior. Finally, the third one is formed by the left- and non-coronary cusps, typically on the right posterior aspect of the aortic root. The commissures are made up of fibres and structurally support the valve cusps. They arepositioned above three triangular regions known as the interleaflet triangles [35]. The pressure load on the leaflets is transferred to the an- nulus, mostly by a network of collagen fibers in the closing phase. The majority of these fibers appear to originate at the commissure level. The collagen fibers of the middle layer are positioned inthe radial direction in the region close to the commissures. At one end, these fibers penetrate to the in- Figure 6. Schematic diagram of the aortic root (cut and open tima layer of the aortic root and atthe other end, they blend longitudinally) [41]. to the media layer in which they are fixed. This particular 6 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 muscular tissue except for its apex, which is a fibrous structure. tubular junction. The transition from the aortic root to the The interleaflet triangles may contain a variety of contractile ascending aorta takes place in this region. The sinotubular and cytoskeletal proteins such as desmin, vimentin, and junction passes through the upper part of each individual smooth muscle α-actin, signifying that these structures may commissure and subsequently indicates the upper end of the play a major role in the regulation of aortic root function [40-44]. connection of each valve cusp. It should be noted that dilation of the aortic root at this level canlead to aortic insufficiency Aortic Sinuses [48-50]. The sinotubular junction has similar microstructure In the aortic root right after the valve, there are three nearly to the sinuses and the ascending aorta. The sinus wall is symmetrical lumpsor bulges,which are also known as aortic significantly thinner than the wall thatrepresents the fold as sinuses. They are located between the attachments of the the higher portion of the aortic root. valve cusps and the sinotubular junction. At the base of the aortic root, it is partly made up of ventricular musculature Leaflets but the sinus wall is mainly made up of the aortic wall and The native aortic valve has three semi-lunar soft-tissue leaflets is thinner than the healthy aorta. Two of the sinuses make or cusps: the left coronary leaflet, the right coronary leaflet and connections to the coronary arteries at very specific spots the non-coronary leaflet, following the names of the sinuses and have a significant impact on coronary flow. Generally, they correspond to. The basal attachment region of the leaflets the sinuses are named according to their connection to the forms the annular ring of the aortic valve, which is located coronary arteries (coronary ostia) resulting in the right, left, between the left ventricle and the ascending aorta. In the fully and non-coronary sinus. The non-coronary sinus is the largest closed position, the three leaflets come into contact on their one in healthy conditions, which has no connection to any free edge to a nodulus known as the coaptation zone. Each arteries. The location of coronary ostia is not the same for all leaflet includes outer endothelial layers and interstitial cells cases,as the left coronary ostium is located inside the sinus scattered in the matrix, known as the interstitium [41,49]. The in 70% of cases, slightly above the sinotubular junction in matrix is located between the endothelial layers. Interstitial almost 22% of cases, and at the level of the junction in 9% cells are spindle shaped and are composed of a variety of of cases. The right coronary ostium is located in 78% of cases fibroblasts, smooth muscle cells and myofibroblasts. Further- inside the sinus, 13% slightly above the junction and 10% at more, endothelial cells have a cobblestone-like structure. The the level of the junction. Also, there is an additional segment fibrosa, suggested to be the major structural layer, is located to the right coronary ostium in 75% of cases [42-45]. on the aortic side and has considerable surface rippling due The attachment of arteries tothe heart is through a fibrous to the presence of collagen in the form of thick and long tissue known as arterial fibre-rings. The structure of this tissue is bundles and fibers. These collagen bundles and fibers are similar to connective tissue (such as tendons), which have non- embedded within an elastin matrix. The orientation of these distinct boundaries in the region of structural and anatomical fibers and bundles are in thecircumferential direction, which attachment of the heart and the aorta. The sinuses hold very results in a soft structure. It is noticeably stiffer and stronger dissimilar constituents, but the largest portion of them and in the circumferential direction when compared to the radial the three corresponding layers of the aortic wall (known as direction. The ventricularis, which is located on the ventricular tunica intima, tunica media and tunica externa (also known side, is smooth and mainly made up of elastin and collagen. as adventitia)) have similar structures. The internal layer of the However, it is moderately flabby and soft due to the absence of intima is made up of endothelial cells thatare oriented in the structural organization, unlike fibrosa. Spongiosa is the central longitudinal direction of the vessel [46]. The subendothelial layer andis mainly made of water similar to hydrogels. This connective tissue is positioned inthe same direction as the layer also contains glycosaminoglycans and a small amount endothelial cells. This layer is separated from the intima by of elastin and collagen fibres [50-53]. the membrana elastica interna. The media is made up of The leaflet layers are highly heterogenous and there is con- ring-shape structures such as elastic fibres, smooth muscle siderable blending of these layers with each other and with cells, collagen fibres (mostly type II and III) and proteoglycans the extracellular matrix. The fibrosa covers the whole leaflet (PGs). The adventitia is the outer layer, which is detached from and consists of almost 50% collagen (90% Type I collagen) by the intima by the membrana elastica externa. The elements dry weight and 10% elastin. The ventricularis covers all but the of the externa are similar to theintima, which are oriented coaptation region where two adjacent leaflets contact and longitudinally and are made up of collagen fibres (mostly consists of almost 50% collagen (90% Type I collagen), 20% type I). The wall of the sinuses has the same microstructure elastin. The fibrosa’s structure is oriented in the circumferential whose wall thickness is considerably thinner than that of the direction shown in Figure 7 [54]. ascending aorta [47]. Available thickness data for aortic valve leaflets shows con- siderable inconsistency between various studies. The mean Sinotubular Junctions thickness has been reported to range from 0.57 mm at the The easily identifiable fold at the top of the sinus is the sino- leaflet edge to 1.20 mm at the leaflet base in healthy human 7 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ventricular side (i.e., ventricularis) and multiple rims on the arterial side, (i.e., fibrosa). The endothelial cells on the cusps and the entirety of the vascular systems are connected to each other in a similar fashion. The only difference is that the endothelial cells on the leaflets are aligned in the direction of flow. This is unlike the endothelial lining pattern in the other locations of the vascular system wherethe cells are aligned perpendicular to the direction of flow. This particu- Figure 7. The leaflet anatomy. lar arrangement of the endothelial cells is due to a biaxial pressure load on the leaflet tissue and wall shear stresses in all blood vessels. Between the ventricularis and fibrosa (i.e., tissues. The thickness was found usingdifferent techniques ventricular and aortic surfaces), five layers of connective such as scanning acoustic microscopy, X-ray attenuation tissue are identifiable: lamina radialis, lamina ventricularis, technique, etc. When using the X-ray attenuation technique lamina fibrosa, lamina spongiosa, and lamina arterialis. The on the porcine valve, mean thickness has been reported to lamina ventricularis is considered as a supplementary layer be nearly 0.8 mm at the base and 0.4 mm in the rest of the that is found between the ventricular endothelium and the leaflet. Also, there is a correlation between the leaflet thickness lamina radialis [63]. Generally, three discrete layers, the lamina and the hydration level of the tissue sothat the mass of the radialis, lamina spongiosa and the lamina fibrosa are easily leaflet highly depends on the time during which the tissue identifiable. The connective tissuesare mechanically attached is exposed to. An example of this would be dextran solutions to each other and forma well-defined sponge-like structure. with varying concentrations. In this case, immersionof the It has been suggested that this special microstructure is ef- tissue in high-concentration dextran solutions decreases fective inreorganizingcollagen’sintial construction after the the mass of the tissue, whereasimmersion of the tissue in external pressure load is removed. The arterial layer holdsgrainy low-concentration solutions increases the tissue mass. This bundles of collagen fibres thatare oriented circumferentially. indicatesthat the aortic valve leaflet tissue willingly obtains or These construct the macroscopical folds analogous to the loses fluid volume by osmosis. The change in fluid volume in free edge of the cusps. This optimal arrangement of fibresis fibrosa and ventricularis is not as much as that of in spongiosa. is highlyeffective in transferring the externalload of the cusps In fact, significant amount of this change in fluid volume to the base and eventually to the wall of the aortic root. The occurs in spongiosa. It is suggested that the source of this main cells in the leaflet tissue are known as interstitial cells, osmotic pressure gradient is because of the high concentra- which are located in the extracellular matrix. These cells are tion of glycosaminoglycans, known as GAGs. GAG fibers are originallyconsidered as smooth muscle cells and exhibitfeatures hydrophilic polysaccharides placed in the ECM of spongiosa. of both fibroblasts and smooth muscle cells (myofibroblasts). The GAG content of bioprosthetic aortic valve leaflets, such It should be noted that they have similar mechanical proper- as porcine valves, is decreased during implant preparation. ties to fibroblasts or smooth muscle cells. As well, they are However, lack of GAG fibers may result in failure of prosthetic significantly effective in the regular function of the aortic valve leaflets. The estimation of glycosaminoglycan content valve and undertakedimensionalchanges during the closing during bioprosthetic valve preparation can be attained by and opening phases [64-69]. measuring osmotic swelling using a high-frequency ultra- sound, which is non-destructive [55-61]. Dynamics of Cardiac Aortic Valve In ultrasound-basedtechniques, the main source of ambigu- The aortic heart valve is a unidirectional valve thathas two ity in the leaflet tissue thickness evaluation is the unknown primary functions. The first is that it allows a pressure dif- speed of sound in the tissue. Using scanning acoustic micros- ferential to form between the left ventricle and the aorta copy, it has been foundthat the speed of sound is nearly 1620, when it is closed. When ventricular systole takes place, the −1 1550 and 1590 ms for fibrosa, spongiosa and ventricularis, pressure in the left ventricle is increased due to contraction respectively, in a normal, formalin fixed human aortic valve of the myocardium in the left ventricle. The increase of the leaflet tissue. It should be noted that fresh leaflet tissues ventricular pressure continuesto the point whereit exceeds are better hydrated than fixed tissues, and the speed of the pressure in the aorta. In this stage, the high ventricular −1 sound in 20°C water is 1480 ms . If the leaflet is considered pressure causes the aortic valve to open, which normally takes as a monolayer and homogenous structure, the pulse–echo between 20 to 30 ms. The second is that in the opening phase, measurement method can be implemented to assess the the valve controls the direction of blood flow to be in only average sound speed in the tissue. However, the sound speed one direction. It also controls the passive transport due to can vary in different layers by a factor of 5% [62]. the pressure differential, which allows the oxygenated blood The aortic valve cusps are covered by a continuous layer to enter the aorta and the systemic circulation of the body. of endothelial cells which provide a smooth surface on the The closing phase starts at the beginning of diastole when 8 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 the left ventricle dilates and fills from the left atrium. These valve leaflet tissue repair and therefore helps determine the opening and closing phases of the native aortic valve are vital structural integrity and/or durability of the aortic heart valve for theproper dynamic transport of oxygenated blood [70]. leaflet tissue. It has been suggested that heart valve interstitial Due to the pulsatile nature of the blood flowing through cells preserve valve tissue homeostasis through a controlled the valve, the blood reaches its maximum velocity after the extracellular matrix, mostly by collagen biosynthesis. It is leaflets have fully opened in the first half of the systolic phase. importantto understandthe relation between the oxygen During the second half, the flow rate decreases quickly. The tension in the valve tissue and the leaflet cells biosynthetic small pressure gradient that is developed affects the low activity. The existence of a blood supply and capillary network momentum fluid near the wall of the aortic root more than within aortic valve leaflet tissue suggests that oxygen deliv- that at the centerline. This causes a reverse flow in the sinus ered to the tissue by diffusion is not enough. More oxygen is region, which has an irregular concaved-like morphology. This delivered to the cusps by microcirculation [70-73]. reverse flow increases during the closing phase and impacts It is known that aortic valves possess significant mechani- the valve at the start of diastole, as shown in Figure 8 [71]. cal properties in order to function.A large cellular population, including mostlyfibroblasts and myofibroblasts, are present in the leaflet tissue. This implies that oxygen factors, such as consumption (VO ) or diffusion (DO ), of the valve leaflet 2 2 tissue need to be taken into consideration. Unfortunately, for different vascular structures, these values are not available as they have not been measured. For example these values for the dog femoral artery at body temperature (37°C) is –4  –1  –1  VO  =1.8×10 mL O ×mL O · mL tissue · s and the for dog 2 2 2  –6  2  –1 aorta adventitia DO =11.4×10 cm · s . Also, as an impor- tant oxygen parameter in the leaflet tissue, the solubility of oxygen within the tissue needs to be taken into account.The solubility of blood in plasma at body temperature (37°C) is –5  –1 –1 2.82×10 mL O · mL tissue · mm Hg . In addition, water con- 2  tent of the valve leaflet tissue is 90%, sosolubility of oxygen in the valve leaflet is then calculated to be 90% of that for –5  –1  –1 plasma, k=2.54×10 mL O · mL tissue · mm Hg . On the basis 2  of these oxygen transport factors and assuming that PaO is 2  100 mm Hg, the assessed maximum distance that oxygen Figure 8. Typical flow curve for the aortic valve showing can be supplied from the leaflet surface into the tissue is various events during diastole [71]. nearly 0.2 mm. The significant amount of oxygen delivered through the vascular supply of the aortic valve is located- During systole, vortices and secondary circulation zones de- mainly at the valve base. This is because tissue thickness is velop in all three sinuses right behind the leaflets of the aortic high,ranging from 0.692 to 0.860 mm. It is assumedthat the valve, which significantly assists in a quick and efficient valve oxygen transport properties,such as diffusivity and solubility closure. The backflow volume (or the regurgitation flow during of oxygen within the tissue,and the metabolic requirements closure) has been shown to be less than 5% of the forward flow of the valve are closeto those of other vascular structures. in native valves, more for prosthetic valves. This period of re- By assuming this,is clear that an oxygen supply route, such verse flow can be measured using experimental means, such as as microcirculation,in addition to that of diffusion from the Doppler ultrasound techniques or computational methods [72]. leaflet surfaces is required for places where the leaflet tissue In each cycle atthe end of the closing phase, there is a massive thickness is higher than a certain value [73]. impact, known as hammer pressure, which is applied on the Given that the thickness of the leaflet tissue is highly aortic side of the valve, i.e., fibrosa. This pressure is a typical variable, the largest part of the leaflet receives the necessary force experienced by a valve in the aortic position and is similar oxygen by diffusion from the blood stream surrounding the to the water hammer effect. This load is a pressure induced valves. However,if the thickness is higher than a given value, force caused by the kinetic energy of moving blood when it the leaflet tissue may need an additional oxygen supply route. is forcedto stop or change direction rapidly. For native aortic This route would be through the microcirculation and micro cardiac valves, this closing phase takes about 35 ms and the arteries in the tissue. This is due to the collagen content in the impact lasts foralmost 5.8 ms. leaflet, which changes the thickness of the leaflet locally. The area of the leaflet is comprised of large amount of collagen Heart Valve Tissue Oxygenation fibers in the form of bundles that reach an average thickness The partial pressure of oxygen has a controlling effect on the of 0.2 mm. The corrugated surface of the leaflets due thepres- 9 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ence of collagen bundles also provides a larger surface, which pulmonary valve. Since the pulmonary valve leaflets are thin- can increase the available surface for oxygen to be delivered ner, that they can function well within the high-pressure and to the tissue via diffusion. Also, when a leaflet is loaded or oxygen-rich environment of the left ventricle and the aortic unloaded due to systolic and diastolic pressures, it will affect root, in spite of the loss of blood supply. This is because of the tissue thickness. The change in thickness is not prevalent the pulmonary valve’s capability to receive enough oxygen in the base regions, but can be up to 40% in the other regions through diffusion only from its surfaces in the new position. of the leaflet tissue. This relatively high thickness change in Also, the new environment has a higher partial pressure of the areas far from the base region explains why oxygen is oxygen compared to the previous i.e., native PO environ- 2  supplied only by diffusion there and that microcirculationand ment in the pulmonary circulation is 40 mm Hg whereas the presence of micro arteries is not required. Another point to pressure in the aortic root is 100 mm Hg. Valve leaflets are take into consideration is when two adjacent leaflets come to complicated structures with a precise balance of components, contact at the end of systole, one side of the leaflets becomes soa slight change in geometry and composition can lead to passive and would no longer be able to receive oxygen from significant functional effects. Due to this,tissue characteristics, both sides of the tissue via diffusion [74]. cellular density,oxygen consumption and diffusion properties The microcirculation components and micro arteries thatare must be well understood. This is essential for the application present close to the base are mostly capillaries and areknown of tissue engineering of the heart valve leaflet tissue [77]. as the capillary bed.However, the presence of arterioles and venules has been also reported. This bed is located mostly Mechanical Characterization of Aortic Valves in the spongiosa layer, which is almost in the middle of the The aortic valve is a unidirectional and almost passive check- leaflet. The presence of the microcirculation at any location valve that controls the direction of blood flow from the left in the leaflet indicates that the partial pressure of oxygen due ventricle to the rest of the body through the systemic circula- to diffusion is considerably low. As such, micro arteries are tion. Mechanical stresses such as tensile, shear and bending required to supply additional oxygen to the tissue. In addition, stresses are high and time-dependent as they change very the density of the micro arteries may vary from location to quickly during the opening and closing phases. Each heart location in the leaflet tissue,enough that almost 30% of the beat, known as a cardiac cycle, causes one time opening and base region and nearly 3% of other leaflet areas are vascular- one time closing on the aortic valve. This takes almost 0.83 ized. It has been shown that the density of the micro vessels seconds. This cycle repeats approximately 100,000 times a day 3, in the base of the left coronary leaflet is 4.9 vessels/mm and almost 3.72 billion times in an average lifetime. A cascade whereas in the other layers, such as the noncoronary and right of biochemical and biomechanical events at the molecular coronary leaflets,it is almost the same at5.1 vessels/mm In and cellular leveloccurin order for the aortic valve to maintain the regions relatively far from the base, the density of micro its function. In fact, any types of valve abnormality (which vessels decreases to approximately0.66 vessels/mm [70-75]. could be congenital or due to disease or trauma) affect its Given that the major factor in oxygen supply and demand function in a substantial way.The extracellular matrix (ECM), is the thickness of the leaflet tissue, it should be noted that the main portion of the leaflet tissue, is the extracellular part the metabolic rate within the tissue is just as important. The of multicellular structure that provides structural, biochemical metabolic rate of the tissue depends on the state of the and biomechanical support to the tissue cells. Asmulticellu- tissue,as damage and repair may significantly affect the larity evolved independently in different multicellular roots, metabolic rate. Therefore, metabolic rate plays a major role the composition of the ECM differs between multicellular in the oxygen supply to the tissue and the tissue composi- structures; however, cell-to-cell communication, cell adhesion tion, including the formation of microcirculation and micro and differentiation are common functions of the ECM. The vessels [76]. ECM within the heart valve leaflet tissue mainly consists of These factors are extremely important in tissue engineering collagen, elastin, proteoglycans (PGs), and glycosaminoglycans of heart valve leaflet tissue. Given the porous structure of a (GAGs). The ECM plays a major role in the unique mechanical scaffold and cells sitting sporadically within the scaffold, a full properties of the valve tissue and the overall valve function. understanding of leaflet function, anatomy, state, and oxygen Within the ECM, there is another protein known as pericellular demand and supply for cells is necessary. In general conditions metrics (PCM). PCM bonds with and immediately surrounds with a normal metabolic rate, an overall thickness of nearly the cells. The role of PCM is to serve as a source of ligands 0.4 mm is enough for a leaflet to obtain its essential oxygen for cells receptors. When the leaflet tissue is under external via diffusion. A good example is the comparison between loads, PCM transfers these mechanical forces to the cells and the aortic valve and the pulmonary valve in the Ross Proce- develops intracellular signaling pathways. There are multiple dure. The Ross Procedure is a particular aortic valve surgery types of ECM with different distinctive mechanical proper- in which the patient’s diseased aortic valve is replaced with ties so that a variety of micromechanical environments are his or her own pulmonary valve. The pulmonary valve is then available for the tissue cells. This is significant because there replaced with a xenograft valve or a cryopreserved cadaveric is strong hypothesis that the tissue cells react to mechanical 10 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 signals and consequently adapt gene expression and protein production. Also, ECM can easily link with soluble molecules in the ECM, e.g., growth factors, so it can host variety of bioactive factors which are influential on cell behavior. Any changes in the composition of the ECM are significant because it may lead to heart valve disease and/or majorly affect the valve functions [78]. The valve leaflet is soft and flexible andhas a layered, com- plex and heterogeneous architecture. Three distinct layers Figure 9. (a) Mechanical behavior of collagen and elastin fibers during the cardiac cycle and (b) the morphology of the aortic are identifiable, two of which are known as structural layers: leaflet during the opening and closing phases, i.e., systole and fibrosa and ventricularis. The third layer is a non-structural diastole [81]. layer which is located in between fibrosa and ventricularis, known as spongiosa. Like other tissues, the leaflet tissue has an extremely specialized, functionally adapted extracellular bundles in the fibrosa layer, and in addition forms a three- matrix. The mechanical properties of the valve tissue have dimensional interconnected network in the spongiosa layer. direct impact with the composition of the matrix, including When the tissue is unloaded, these networks cause the col- collagen, elastin and PGs. It is important for the heart valve lagen fibers to return to their wavy and crimped shape in the leaflet tissue to be soft and flexible when unloaded, but nearly three layers of the valve tissue. The particular roll of each layer inextensible, strong and stiff when fully loaded. The design is varying. Fibrosa is thought to be load bearing due to the features of the leaflet tissue include a rippling surface, which presence of collagen fibers. The role of spongiosa is conferring is like an array of collagen fibers and bundles in fibrosa elon- flexibility, dampening vibrations from closing, and resisting gated from one commissure to the other commissure. Elastin delamination due to the presence of glycosaminoglycans and collagen are the main proteins that provide mechanical and proteoglycans. The role of ventricularis is restoration of characteristics of aortic heart valves. Elastin is a protein which the wavy and crimped state of collagen fibers in ventricularis is structurally available in sheets, tubes or fibers. It is highly due to its high amount of elastin [82]. extensible and elastic, having a stiffness of almost 2100 times Aortic heart valve leaflet tissues are highly nonlinear, less than collagen fibers. Given that elastin has a relatively low anisotropic and heterogeneous. These properties have been mechanical stiffness, its energy loss in cyclic loading conditions developed according to the physiological conditions of the is extremely low. It is so low that that it is considered to be the valve and are consistent with the mechanical environment in purest natural elastic material. The maximum load and force which the valve functions. The two main directions in which on the leaflets is when the valve is fully closed, which happens the mechanical properties of the valve leaflet tissue are fo- in the diastolic phase. In the very early stages where load is cusedare the commissure-to-commissure direction (known small, the tissue offers a very small resistance to elongation. as the circumferential direction) and the radial direction In this stage, only elastin fibers provide mechanical strength (perpendicular to circumferential). During diastole, when the and force transmission. In this stage, elongation of the tissue load applied on the tissue is maximum, collagen fibers and is relatively high and collagen fibers are coil-like structures. bundles in the fibrosa layer are the layer responsible fortoler- Upon load increase, the collagen fibers start to uncoil and ating nearly 80 mmHg pressure. In order for the leaflet tissue gradually stretch. As the strength and stiffness of the tissue to withstand such a high tensile load, collagen fibers bond increases, the amount of force on the tissue also increases, and together. They formparallel collagen bundles that are aligned accordingly more collagen fibersuncoil. In this stage, elastin in the circumferential direction. Although the collagen fibers fibers do not contribute to the mechanical characteristics of have nearly 1-2% yield strain, the crimping and waviness of the the tissue.In addition, elongation of the tissue is consistently fibers allows the fibrosa to tolerate approximately 40% strain low and the main elements providing mechanical strength in when fully loaded. Flattening of wavy fibers provides nearly are collagen fibers. In excessive loading conditions, when the 17% strain capacity, whereas the waviness allows additional force would further increase,the tissue cannot tolerate it and nearly 23% strain capacity. During the opening phase, leaflets eventually ruptures. When the tissue tears apart, the corruga- are relaxed and elastin maintains the mechanical strength of tions completely flatten and the crimps of the collagen fibers the leaflet tissue. In this phase, collagen fibers return back to become oriented in the radial direction. In a complete cardiac their original wavy and crimped shape and the surface area cycle, the leaflet dimensions changes between the systolic of the tissue isdecreased. Spongiosa, which mainly consists anddiastolic phases, but there is no change in dimensions of GAG fibers, enables the rearrangement of the collagen and during systole or diastole (Figure 9) [70-80]. elastic fibers, diminishes vibration, dissipates energy from The attachments of the three layers are made ofelastin closing, provides a smooth contact between the leaflets, and fibers that are distributed in the entire leaflet tissue. Elastin prevents delamination between layers [80]. also provides intrafibrillar binds between collagen fibers and In case of diseased aortic valves, for example; the calcific 11 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 aortic valve, collagen fibers and bundles as well aselastin fibers est on the endothelium layer in the noncoronary sinus of the in the fibrosa layer are disrupted and disordered. Due to this root. This is due to drag force being less due to hemodynamic proteoglycan deposition is increased. ECM remodeling occurs conditions around the coronary outlets, which justifies why because of matrix metalloproteinases and the potent elastase the noncoronary leaflet is affected more intensely than the cathepsin S, which are composed ofmacrophages. Also, in other two leaflets. Also, if two of the leaflets fuse together, calcific fibrosa, osteocalcin and osteonectin, which are bone the calcification process is accordingly affected. Patients with proteins, are found in the tissue. These proteins accelerate bicuspid valves are subjected to higher shear and normal mineralization and cause the osteoblastic differentiation of stresses, which lowers the calcification process considerably. valvular interstitial cells [81]. However, almost all patients with bicuspid valves develop significant hemodynamic complications over time leading Calcification of the Heart Valve Tissue to aortic stenosis, which is not the case for patientswith a Aortic valve calcification is a condition where calcium depos- trileaflet valve (Figure 10) [80-82]. its accumulateon the aortic valve. These deposits can cause (1) weakening of the structure of the leaflet tissue, and (2) narrowing at the opening of the aortic valve. This narrowing can become significant enough that it may reduce blood flow through the aortic valve, a condition called aortic valve stenosis.Aortic valve calcification may be an early sign for a heart disease, even if the patient does not have any other heart disease symptoms. Generally, calcification and stenosis affect patients who are 65+ in age. However, when it occurs in younger patients, the reason might be acongenital heart diseaseor kidney failure. Calcification is one of the significant issues leading to the mechanical failure of tissue heart valve replacements. After treating tissue valves with glutaraldehyde, calcification originates primarily within remainingcells that Figure 10. Histology of a calcified leaflet tissue in the early have been devitalized. In this process, the tissue is covered and late lesions. Early lesion determines accumulation of with calcium phosphate mineraldeposits through a reac- cells, extracellular lipid, and matrix in the sub-endothelial region on fibrosa, which is characterized by movement of tion of calcium-rich extracellular fluid with phosphorusin normal sub-endothelial elastic lamina. In the late lesion the tissue. Calcification of the heart valve leaflet tissue and however, accumulation of lipid, cells, and extracellular matrix mineralization of bone are precisely the same concept. There is more significant. Elastic lamina is considerably moved and have been many studies as to how to prevent calcification discontinued. (Adopted from Verhoeff-van Gieson stain, original magnification ×100) [83]. in the heart valve leaflet tissue, which are summarized into 4 categories: (1) Making a stable link between calcification- inhibitors and glutaraldehyde fixed tissue, (2) Removing ormodifying calcifiable agents, (3) Modifying glutaraldehyde In the early stages, extracellular lipid accumulation is ob- fixation, and (4) Usinganother tissue cross-linker other than served in several minor regionsunder the endothelial layer, glutaraldehyde [80-82]. also known as sub-endothelial level. In this stage, the elastic Calcification ofthe aortic valve is a slow process. Itwas lamina is displaced and extended into the nearby layer, i.e., initially thought to be a deteriorating mechanism because fibrosa. There is histological evidence indicating that plasma of the vigorous wearandtear of the leaflet structures. In this lipoproteins are the source of these lipids. The formation of mechanism, calcium is passively deposited on the leaflets. foam cells takes place whenadapted low density lipoprotein Based oncomprehensive histopathological and clinical data,it (LDLs), which are related to proinflammatory and growth- is known that calcification process in aortic valves is an active stimulatory properties, are taken up by macrophages. disease similar to atherosclerosis with chronic inflammation, In the early stages, inflammatory cells includingT lympho- lipoprotein deposition, and active leaflet calcification. In the cytes and macrophagesplay a major role in the calcification early stages, variation of mechanical forces, such as shear stress, process. Macrophages are differentiated from monocytes, may form a notch on the aortic valve leaflets as a result of which have been penetrated to the endothelial layer by adhe- endothelial disruption. The state of normal and shear stresses sion molecules. T lymphocytes are activated within the sub- is influential on the calcification initiation and progression endothelium and fibrosa and then release cytokines. Cytokines on the tissue. Normal stresses are highest on fibrosa near include transforming growth factor-β1and interleukin-1β, the attachment of the leaflets and the root at the beginning which is a proinflammatory cytokine related to matrix metal- of the systolic phase, simply because the leaflets act like a loproteins. All of these proteins contribute to the formation of cantilever beam. Among the three sinuses, shear stress is low- extracellular matrix, remodeling, and focal calcification [72]. 12 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 Angiotensin-converting enzyme (ACE)is also identifiable in may be congenital or due to other causes later in life. the calcification process. It can be formed locally or extracel- lularly and colocalized with apolipoprotein B. The colocalized Congenital Valve Disease  ACE with apolipoprotein B is a module of taken LDL particles, This type of valve disease most often affects the aortic or which implies that the ACE could be carried into the lesion via pulmonary valve due to geometrical issues. These include LDL cholesterol particles. Moreover, angiotensin II, which is an abnormal size of the valve, the issues with the leaflet the promoted version of monocyte infiltration and the uptake geometry or the way they are attached [75-77]. of modified LDL within atherosclerotic lesions, is observed In the aortic valve, two of the leaflets may fuse together in the early stages of the calcification process. This suggests and play the role of one, which is known as bicuspid aortic that ACE is active enzymatically. Also, a fraction of fibroblasts valve disease. In this case, instead of the normal three leaf- within the fibrosa is transformed into myofibroblasts, which lets or cusps, the aortic valve has only two leaflets. This can are similar to smooth muscle cells with expression of α-actin, reduce the compliance of the valve and leaflets, which in desmin, and vimentin. In advanced stages, angiotensin type-1 turn negatively affects the dynamics of the valve in the clos- receptors form on a fraction of the myofibroblasts that ex- ing and opening phases. One of the issues of bicuspid aortic press α-actin, further reinforcing that ACE detected is active valve diseases is the leakage due to the non-parallel contact enzymatically [72-75]. between the two leaflets [75-77]. In the early stages of the calcification progression, the pro- cess is active and quick,which essentially leads to the leaflet Acquired Valve Disease hardening and severe stenosis. In areas where lipoprotein is A range of diseases and infections, such as endocarditis or built-up and inflammatory cells are infiltrated, microscopic rheumatic fever, may affect the structure and composition of regions of calcification are observed. Matrix vesicles (the loca- normal valves which is also known as acquired valve disease tion of calcification) are released when valvular fibroblasts are (Figure 11). stimulated by oxidized LDL. A protein which participates in bone formation, osteopontin, is expressed by macrophagesin A B which the level of mRAN expression is proportional to the level and location of calcification. A portion of myofibroblasts consists of osteoblast phenotypes,which participate inthe de- velopment of calcific nodules. The formation of these nodules is increased once the myofibroblasts are exposed to oxidized LDL and transforming growth factor-β1.During the calcification progression, deposition of calcium on the leaflet continues in a rapid way,which is the same as bone formation. For sig- Figure 11. Diseased aortic valve: (A) Rheumatic Fever, and nificant number of patients (~85%) ,the type of calcification (B) Endocarditis [84]. is dystrophic.For the remaining 15% of patients, it is lamellar or endochondral bone tissue where hematopoietic marrow and remodeling are evidenced. Bone tissues on the leaflets An untreated bacterial infection, which is usually strep throat, lead to expression of factors promoting osteogenesis. In pa- might be the reason for rheumatic fever. The initial infection tients with increased bone demineralization or osteoporosis, typically happens in children and is the origin of inflammation the occurrence of calcification is higher. This is thought to be of the heart valves. However, symptoms associated with the related to ectopic calcification or an increased body mineral inflammation may become apparent 20-40 years later. Also, turnover. The calcification progression may be controlled by the presence of bacteria in the bloodstream for whatever factors such asconnective tissue growth factor, polymorphisms reason may cause endocarditis. This may cause growths and of interleukin-10, and chemokine receptor-5 [76]. holes in the valves and scarring, which in turn causes leakage Calcification is also an issue with bioprosthetic valves. in the closing phase [78]. However, the occurrence of calcification innative valve failure Some of the geometrical or structural issues associated with appears to increase with age, which is in contrast to tissue the diseased valves are: (1) the chordae tendinae or papillary native valves. This inconsistencyproposes that the calcification muscles may stretch or tear, (2) the annulus of the valve can process of bioprosthetic valves is unlike the process perceived dilate and become wide due to structural deficiencies, and in native valves [77]. (3) the valve leaflets can become stiff, fibrotic and calcific [85]. Mitral valve prolapse (MVP) is a geometrical and con- Aortic Valve Disease structional deficiency of the mitral valve which affects 1% Valvular heart disease is any disease involving one or more to 2% of the population. While the mitral valve cannot hold heart valves (the aortic and mitral valves on the left and the its structural integrity, the leaflets flop back into the left pulmonary and tricuspid valves on the right). Valve problems atrium during diastole (the heart’s contraction).In turn, the 13 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 back flow rate and static leakage significantly increases. MVP motion affects around 25% of the population above the age also causes the tissues of the valve to become abnormal and of 65. Calcific aortic stenosis, however, affects roughly 2% to stretchy, which specifically occurs in the anterior-posterior 3% of the population above the age of 75. Congenital bicuspid direction, perpendicular to the transverse direction of the aortic valve stenosis is known to be the main source of aortic valve (Figure 12). stenosis; the estimated overall occurrence of an anatomic bicuspid aortic valve is around 1% to 2% of the population. Of these, about 50% are prone to develop aortic stenosis and up to 30% will develop aortic regurgitation. Aortic stenosis due to a congenital bicuspid aortic valve is more frequent in men compared to women, but later life calcific disease of the aortic valve affects both genders similarly. Congenital aortic stenosis is typically caused by failure of the valve commis- sures that causes aortic stenosis, mostly in young adults or children [72-76]. Aortic valve disease such as calcific disease, calcification of the congenital bicuspid valve, and congenital aortic stenosis can be mostly diagnosed clinically by the evaluation of echo- cardiography data. Calcific aortic stenosis, which is known as degenerative or senile form, involves patients with other risk Figure 12. Mitral valve prolapse: side view of the factors for atherosclerotic disease. The progression of aortic normal valve on left and the diseased valve on right valve disease is a dynamic process, with inflammation, lipid [86]. deposition, and calcification. This type of aortic stenosis pro- Treatment may be with medication but often (depending on gresses gradually for the patients between the ages of 70 and the severity) involves valve repair or replacement. The aortic 90. Echocardiography is usually effective in finding varying valve is the heart valve that is the most susceptible to diseases degrees of nodular thickening and calcification of the leaflets as it sustains the largest pressure difference between the left with limited systolic motion. Adult patients with congenital ventricle and the main aorta. This is neccessary to ensure the bicuspid valves (also known as heart murmur) are mainly oxygenated blood is distributed effectively throughout the men and and is most commonly found in patients between arterial system [71]. the ages of 40 and 60. In bicuspid valves, two of the leaflets There are two major diseases that can affect the aortic are typically merged together. This can be diagnosed using valve: (1) aortic stenosis, in which the valve fails to open fully, electrocardiography by the presence of a raphe, eccentric thereby obstructing blood flow out from the heart, and (2) closure, leaflet doming, and fish mouth orifice during sys- aortic insufficiency (also known as aortic regurgitation) in tole. Congenital aortic stenosis in which the valve is either which the aortic valve is incompetent and blood flows pas- unicuspid or bicuspid typically occurs in children and infants sively back to the heart in the wrong direction. These two and can be diagnosed using echocardiography data. Minor conditions frequently co-exist. Whatever the cause of valvular causes of aortic stenosis includerheumatic disease, radiation disease, it burdens the heart with an increased work rate to heart disease, and homozygous hypercholesterolemia [76]. maintain stroke volume. This could lead to: (1) heart muscle Aortic stenosis may cause chronic left ventricular hyper dysfunction (including left ventricular hypertrophy), and (2) pressure. In all ages, the natural history of aortic stenosis potential congestive heart failure [72]. and the functional integrity of the mitral valve are related to one another. As long as sufficient mitral valve function Aortic Stenosis is preserved, the pulmonary bed will not be affected by the Aortic stenosis is mainly due to obstruction of blood flow systolic hyper pressure caused by aortic stenosis. Contrary at the aortic valve and does not includethe subvalvular and to mitral valve disease, in which the pulmonary circulation is supravalvular types of this disease. Aortic valve stenosis is typi- directly influenced, compensatory concentric left ventricular cally characterized by restricted systolic opening of the valve hypertrophy permits the hyper-pressurized ventricle to sustain leaflets, in which the mean transvalvular pressure gradient stroke volume with slight growths in diastolic pressure. In some is at least 10 mm Hg. The reason of the stenosis can be also cases, patients may stay asymptomatic for several years [76]. characterized by the anatomy and disease process affecting Ultimately, however, left ventricular hypertrophy leads to the valve tissue [72-75]. either diastolic dysfunction with the initiation of congestive Two of the major aortic stenosis cases are calcific aortic and symptoms or myocardial oxygen requirements exceeding congenital bicuspid aortic stenoses. Minor cases include rheu- supply, causing the initiation of angina. In some patients, matic aortic and congenital aortic stenoses. Minor thickening exertional syncope can occur, possibly reflecting the incapa- and/or calcification of the aortic valve without limited leaflet bility to increase cardiac output and sustain blood pressure 14 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 as a reaction to vasodilation [76]. Aortic Regurgitation or Aortic Insufficiency Aortic regurgitation is characterized by the ineffectiveness of the aortic valve, causing a portion of the left ventricular forward stroke volume to returnto the left ventricle during diastole. The reason of the regurgitation, as for aortic stenosis, can be further characterized due to the anatomy of the valve, aortic root, and the disease process influencing the valve [77]. Aortic regurgitation is mainly a product of leaflet pathol- ogy or aortic root disease,but alsocould also be caused by a congenital unicuspid or bicuspid aortic valve often due to leaflet prolapse. Infective endocarditis affecting the aortic valve may lead to aortic regurgitation because of lack of coaptation, Figure 13. Heart valve disease and available options. perforation, or leaflet retraction. In fact, aortic root dilation and loss of leaflet coaptation due to any pathological process can lead to aortic regurgitation. As to the related diseases of ally worldwide. The age range of the majority of patients with the aortic root leading to aortic regurgitation, the following aortic valve pathology in need of replacement is between 60 diseases can be outlined: annuloaortic ectasia, familial aortic and 80. Among the two main aortic valve diseases, replacement aneurysmal disease, long standing hypertension, hereditable for aortic insufficiency, aortic stenosis of ~15% is performed diseases of connective tissue (e.g., Marfan syndrome), and much less frequently than for aortic stenosis of~85% [1]. As ventricular septal defects as observed in tetralogy of Fallot. of the related diseases to aortic stenosis, there are several of Minor conditions includeEhlers-Danlos syndrome, radiation note, including congestive heart failure, syncope,angina, or a heart disease, inflammatory aortitis, aortic valvulitis developed combination of these. If left untreated, the life expectancy of by giant cell aortitis, syphilitic aortitis, ankylosing spondylitis, patients reduces significantly. For instance, it would be a 50% reactive arthritis, and rheumatoid arthritis. Chronic aortic re- reduction over a period of 5 years for angina, over a period of gurgitation leads to volume overloading of the left ventricle 3 years for syncope, and over a period of 2 years for conges- and, unlike mitral regurgitation, also leads to an increase of tive heart failure. Also, these diseases in a small percentage of pressure in the left ventricle. The volume overload could be patients may cause sudden death. Aortic insufficiency has a insignificantand thereforecause no important symptoms slower progress rate than the aortic stenosis as it can normally for possibly decades [77]. The consequence of aortic regur- be diagnosed by fatigue symptoms. In some cases, it can be gitation is an intense diastolic leak, left ventricular dilation diagnosed by the slow development of congestive heart failure, and hypertrophy, where the left ventricle becomes a more and in these patients typically angina pectoris and syncope spherical shape. The ejection fraction generally is conserved don’t occur often. In order to diagnose these diseases, normally untilthe final stages of the disease. Since patients may resist echocardiography is implemented to assess ventricular func- against severe aortic regurgitation with minimal symptoms, tion, the severity of stenosis, and insufficiency. Also, cardiac constant careful monitoring of left ventricular dimensions and catheterization is performed to evaluate cardiac output and systolic function should occur. This is because the aortic root estimate aortic valve area. An image-based method can be and proximal ascending aortic dilation can happen together. implemented in the coronary arteries to check for any major Aortic valve replacement is in order if a patient is sympto- lesions. To predict postoperative prosthetic valve infection, a matic from either aortic insufficiency or aortic regurgitation, precise dental or oral examination is usually performed [1-5]. or if the heart begins to expand as tested by echocardiogram. There are a number of options for repairing or replacing Other types of valve disease consist of: (1) coronary artery the diseased valves. Although surgery is a common solution, disease, (2) myocardial infarction, (3) cardiomyopathy (heart there are novel non-surgical procedures under developed muscle disease), (4) syphilis, (5) hypertension, (6) aortic aneu- nowadays. Some available surgical techniques include [2-7]: rysms, and (7) connective tissue diseases. Rare cases include • A commissurotomy surgery is applied to diseased valves tumors, some types of drugs, and radiation. There are two with thickened and fused leaflets. This surgery, known main options available to remedy the diseased valve: (1) heart as valvuloplasty or valvular reconstructing procedure, is valve repair, which leads to tissue engineering and regenera- done by cutting the spots in which the cusps are stuck tive medicine, and (2) heart valve replacement, which leads together. to medical devices (Figure 13). • In some other cases, if the issue is with the annulus, the required surgery is called annuloplasty. In this surgery, Prosthetic Heart Valves sutures are sewn around a circle so that the opening There are nearly 350,000 valve replacement procedures annu- becomes smaller. In more severe cases, a well-designed 15 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ring (known as an annuloplasty ring) holds the original ge- mitral valves. In general, there are two types of valves that ometry of the healthy annulus. It is applied to reconstruct are considered for valve replacement: the annulus back to its original shape. The annuloplasty (1) Mechanical valves must be made up of durable bio- ring provides more mechanical support to the valve so it materials such as metals, carbon, ceramics and polymers. A can function more effectively. A surgeon may reconstruct sewing ring wrapped with a biomaterial is used to attach a valve by removing some abnormal segments (such as the valve to the tissues in the patient’s heart. The major ad- fatty bulges or calcified nodules) off the diseased cusps vantage is durability. However, anticoagulant therapy (blood and sewing it back together. diluter) must be taken the rest of the patient’s life to prevent • If the issue is with the deposition of calcium on the valve thromboembolism (blood clots). tissue, decalcification surgery is applied and calcium (2) Biological or tissue valves (known as xenograph) which buildups from the leaflets are removed.  are made up of animal tissue such as pig (known as porcine • The Mitral and tricuspid valves are supported by cords, valves) valve or a pericardial tissue of cow (known as bovine known as chordae tendineae, and papillary muscles. If valves). the issue with the diseased valve has to do with the cords, (3) Human tissues donated from a cadaver (known as al- i.e., stretched or weakened cords, which may lead to the lograft or homograft) are also an option. valve ineffectiveness, the surgery required would replace (4) The replacement can be harvested from patient’s own or shorten the cords.   tissues (known as autograft), which is through a surgery • If there are holes or tears in the cusps, a tissue patch known as the Ross procedure (also called switch procedure). may be applied. In this surgery, the valve is taken from the patient’s normally There are fairly new techniques (to be discussed later) where functioning pulmonary valve and is replaces the diseased the surgical process is done but with much less damage on aortic valve. The pulmonary valve is then replaced with a patients. These approaches are collectively known as minimally prosthetic valve, such as homograft or porcine valve. Biologi- invasive surgery (MIS). In MIS, surgeons monitor the heart cal valves are not mechanically efficient and have durability using an appropriate imaging technique and operate using issues, unlike mechanical valves, and need to be replaced a new class of surgical tools inserted through small incisions. every 10 to 15 years. Also, anticoagulant therapy may be Minimally invasive valve repair is a developing technique that needed for these patients for a short duration. Bioprosthetic is also known as endoscopic or robotic heart surgery [18]. valves are mostly recommended for young patients, while Furthermore, there areother techniques under development mechanical valves are recommended for the elderly. This is highly regarded asreplacements to conventional surgeries, mainly because older patients may not be able to afford a known as non-surgical therapy. These techniques are called new open heart surgery [45-51]. percutaneous or catheter-based surgeries thatdo not require any chest incisions and patients do not need the heart-lung Indication for replacement surgery machine during the procedure. A thin elastic tube (known as Heart valve replacement was first initiated in the early 1960s a catheter) is inserted into the body through a blood vessel and is now a normal surgical procedure. It employs devices and is then directed tothe intended destination in the heart. made of nonliving, nonresorbable biomaterials for used to Percutaneous or balloon valvuloplasty is applied in patients substitute the valvular mechanical functions. Replacement with calcifies or stenosed valves, which is more common for of heart valves offers a large improvement in the quality of the mitral valve than the aortic valve. An inflatable balloon life for thousands of patients and can be considered one of tip on the end of the catheter is situated in the stenosed valve the major accomplishments of biomedical engineering. It is and inflated to expand the opening,completely crushing the estimated that more than 280,000 replacement heart valves calcified tissue.  are implanted annually worldwide, makingthe social and For the mitral valve, multiple methods of percutaneous economic impact of heart valveresearch and development valve repair are in the development phase. If the gap between considerable [1-5]. the anterior and the posterior leaflets is large, it can be re- There is no assurance that a surgical procedure or medical paired using a technique known as edge-to-edge repair. In treatment canprevent or defer valve disease. Procedures such this surgery, a delivery catheter equipped with a clip is sent as balloon valvotomy could be applied as a bridge to surgery, through the femoral vein from the groin into the left part of with a temporary relief of symptoms beingprovided. Patients the heart. The clip is situated beyond the diseased valve in with symptomatic severe aortic stenosis, who may also have an open location and then pulled back so that it hooks the undergoneother cardiac procedures like coronary artery by- leaflets. Once closed, the leaflets are held together and the pass graft surgery, have a poor prognosis and are considered valve leakage is fixed [27-33]. for aortic valve replacement. The severity of aortic stenosis If repair is not sufficient for the patient, then replacement is assessed by diagnostic physical measurements,where could be an option. Replacement is more generally applied the effective orifice area (EOA), the hemodynamic features for the treatment of aortic valves or extensively damaged such as jet velocity, turbulence, the ejection fraction and the 16 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 transvalvular pressure drop are evaluated. EOA is generally Advent of caged ball valves was a major innovation in the measured by the Gorlin formula as follows: Orifice Area = CO/ treatment of patients with valvular heart disease. The place (HR.SEP. 44.3C. SQR(deltaP) where CO is the cardiac output, of caged ball valves in history remains undisturbed, as they HR is the heart rate, and SEP is systolic ejection period. 44.3C continue to serve as a benchmark against which the newer is a constant thatis assumed to be 0.1 for the aortic valve. In tilting disc and bileaflet designs are evaluated. It is also clear this formula,the unit of time is min, the unit of length is cm, from information in literature that these mechanical valves delta P is the pressure drop across the valve with the unit of comewith a number of complications, the majority of which are mmHg [21-32]. related to higher pressure drops and poor hemodynamics [87]. Mechanical heart valves are used to replace diseased hu- In 1952, Dr. Charles Hufnagel, implanted the first ever man heart valves in approximately 50% of cases. Bioprosthetic ball and cage valve,which was named after himself as the heart valves are used in the other 45% of cases. Pulmonary Hufnagel’s valve (Figure 14). This valve was a unique design autograft valves and human cryopreserved homograft valves of a ball entrapped in a transparent glassy type cage. The represent the remainder of implanted valves. Autografts and ball was made of methacrylate covered by silicon rubber homografts exhibit excellent durability after implantation, and the cage made of methacrylate. This material was the but are not readily available for all patients. first implanted in an animal model to test a tube made of methacrylate for arterial replacement in late 1940’s. The mate- Mechanical Heart Valves rial for the ball was immediately modified; instead, a hollow Mechanical heart valves (MHV ) are artificial valves made of nylon ball covered by silicon rubber was implemented. It was synthetic biomaterials that are developed to replace diseased thought that a smaller ball with smaller momentum could valves.They are designed to provide the same function as the reduce noise and enhance dynamic behaviour of the valve, natural valves of the human heart. This is applicable to the four such as the regurgitation flow and the impact force between human cardiac valves: tricuspid, pulmonic, mitral, and aortic the case and the ball. More than 200 of Hufnagel’s valves were valves, as discussed in the previous chapter. The main function implanted for patients with aortic insufficiency [87]. of the prosthetic valves is to preserve unidirectional forward In the early designs of caged ball valves, the issue was flow, which in turn regulates the flow of the oxygenated and with the contact that the ball could make with the aortic wall deoxygenated blood through the systemic and pulmonary during the systolic phase, which could lead to hemodynamic systems. These systems are connected to the heart by the vena complications in those regions. In order to address this issue, cava veins, pulmonary artery, pulmonary vein, and the aorta. the idea was to improve the cage by giving the floating ball Numerous cardiac valve disease processes, (explained briefly in a larger, yet controlled space. In this design, a second outer the previous chapter) of both acquired and congenital causes, concentric cagethat slightly penetrates the left ventricle may lead to one of the four heart valves diseases. They are in chamber was added to the valve. This model was implanted the form of stenosis, known as obstructed forward flow, and/ or increased backward flow, known as regurgitation/dynamic backflow. Each of the mentioned conditions would burden the heart with extra work andwould lead to serious complica- tions in the patients, such as heart failure [1]. In general, the durability of mechanical heart valves is long enough that the patient would not need another open heart and/or valve replacement surgeries. The issue with mechanical valves is that the patient would need to take anticoagulation therapy for the rest of their life. The main types of mechanical heart valves are considered as follows: (1) The ball and cage valves, (2) Disc and cage valves, (3) Tilt- ing disc valves, (4) Bileaflet valves, (5) Polymeric valves and (6) Percutaneous valves. Ball and Cage or Caged Ball Valves The first open heart surgery to repair a stenotic aortic valve took place in 1912. In this procedure, the aortic root wall was invaginated with a finger and the aorta was pushed through the valve. The next registered open heart surgery took place in 1914, which was about the dilation of a calcified aortic valve. This was achieved with apparatuses passed from the Figure 14. Hufnagel’s caged ball valve [88]. innominate artery or another arterial source [87]. 17 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 in 7 patients, two of which survived. The patients that survived damaged by the stellite ball. Model 2400, also known as the needed following valve replacements, one for a perivalvular track valve, was developed for the aortic position in 1972 leak after 3 years and one for bacterial endocarditis after 22 and the covering fabric of the stent was eliminated. There years. In these models, the ball (which was made of silicon) were other Edwards-Starr Models thatwere developed for showed excellent structural integrity as it had not deteriorated the aortic position, such as model 1260, and for the mitral after 22 years implantation [89]. position,such as models 6000 and 6120. In these models, the The next model of the the ball and cage valve was designed cage was fabric free and made of stellite and the ball made by M. Lowell Edwards, a retired engineer, and Dr. Albert Starr, of silastic rubber. These models were implanted more than a young cardiac surgeon, in the early 1960’s. The valve was 300,000 times worldwide with almostno issues with the ball commercially branded as the Edwards-Starr ball and cage due tothe postmold silicone rubber heat cure process. The valve. It was a bulky valve (Figure 15) where the ball was made last models of Edwards-Starr valves contained the stent or of elastomer rubber and the cage was made of methacrylate. strut with no cloth and the ball made of heat-cured silicon These were also known as Lucite (methacrylate) valves. This elastomer, which lasted until early 2000 [89]. valve was implanted in a 50 years old patient who was diag- nosed with calcific mitral stenosis and the patient survived Magovern-Cromie Ball and Cage Valve for several years. There was animmediate improvement on Other ball and cage models were developed as well in the the Lucite valves byswitching from methacrylate to stellite 1960’s. Dr. Magovern, a cardiothoracic surgeon, and Harry metal for the cage [89]. Cromie, an engineer,designed a ball and cage valve for the aortic position. It possessed a unique feature for fixation without suturing. Following their names, it was branded as the Magovern-Cromie ball and cage valve. In this model, the ball was made of heat-cured silicon rubber and the cage was made of titanium. For implantation, a rotating tool was de- signed in order to insert the valve into position and engage it with several vertical pins in the aortic annulus. This model had significant advantage over other available models at the time simply because the implantation process was quick. Thisremovedthe need for the cardiopulmonary bypass,which was not as safe and reliable as it is today. This valve was im- planted in aortic position in ~7300 patients and in the mitral position in ~200 patient till 1988. The issue with this valve was structural defect of the ball after some time, which was reported in 2%of patients. This was also the main issue with the Edwards-Starr valves, which was addressed properly later with the post-mold heat cure process of the ball (Figure 16-1). Figure 15. Edwards-Starr caged ball valve, ball is made of plastic and metal and stent (cage) made of sterile cases [90]. In the Edwards’ laboratory,several ball and cage models were developed for both the aortic and mitral positions over almost 10 years. A number of models of Edwards-Starr valves were commercialized and named as the Edwards-Starr 1000, 1200, Figure 16. (1) McGovern-Cromie caged ball valve designed 1250, 2300, 2400, etc. Model 1000 was developed for the aortic in ~1965, (2) Smeloff-Cutter caged ball valve designed in ~1966, (3) Debakey-Surgitool caged ball valve designed in position in the early 1960’s. In the1200 model, the cage was 1969, and (4) Braunwald-Cutter caged ball valve designed in made of heavy stellite, the annulus covered by Teflon fabric, 1968 [90]. and the ball a hollow stellite ball. The silicon rubber ball was no longerused because lipids could be absorbed, leading to fast deterioration. In the model 1250, the ball was made of Smeloff-Cutter ball and cage valve hollow stellite, and was little different from model 1200. The The next idea for a caged ball valve was to provide a full-flow issue with models 1200 and 1250 was that they were noisy. orifice model, which was commercialized as the Smeloff-Cutter Model 2300 was developed in 1967 where whole stent was ball and cage valve in 1966. This valve followed the name of covered by cloth. This could control the noise issue to some Dr. Edward Smeloff, a cardiac surgeon, and the Cutter labo- extent; however, the new issue was that the fabric could be ratory at the University of California, Berkeley. In this model, 18 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 two titanium cages were addedon each side of the valve and valve in 1965. This design was for the mitral position with the ball was made of heat-cured silastic. The effective design the cage made of stellite and the ball made of silastic. The of the cage allowed the silicon ball to sit on the smaller cage wear was still a major issue with the disc in this model,and in the closing phase. This valve was implanted in ~72,000 shortly after in 1975 the material used for disc was modified patients in both aortic and mitral positions (Figure 16-2) [89]. to Derlin. This model was implanted in 12,000 patients until 1980 when the manufacturing of these valves was stopped. Debakey-Surgitool ball and cage valve The Kay-Shiley disc and cage valve was probably one of the Dr. DeBakey and Harry Cromie of Surgitool proposed a new most widely used mitral valve prostheses from 1965 to 1980. design for a ball and cage valve, commercialized as Debakey- Later on, Dr. Kay improved the design of his valve by adding Surgitool caged ball valve in 1967. In this design, the cage was a muscle-guard in order to prevent disc impingement. This made of titanium and the ball was made of high molecular model was never marketed and was never used by any other weight polyethylene instead of heat-cured silicon rubber. surgeons other than himself [89]. However, the material for the ball was soon changed to a hollow pyrolytic carbon ball. This was the first ever valve in Beall-Surgitool Disc and Cage Valve which a new carbon-based material was implemented. The In 1971, Dr. Arthur Beall, a cardiologist, and Mr. Howard Cro- idea was to improve the quality of the ball to be more resist- mie of Surgitool designed a disc and cage valve where the ant against any structural defects. However, to some degree disc was fairly flat and made of Teflonwiththe cage made of hard the ball and soft titanium cage caused structural defects Titanium. A few design modifications were implemented on and rapid wear rate in the cage.Strut and cage fracture was this model such as: (1)a velour fabric was used to cover the reported in multiple occasions (Figure 16-3). [89]. annular apron, (2) the Teflon disc was replaced by Pyrolyte, etc. This model was implanted in nearly 5,000 patients in Braunwald-Cutter ball and cage valve the aortic position until 1985. The production of this model Drs. Braunwald and Morrow proposed a new model of ball was stopped mainly due tofabric wear on the annular apron. and cage valve wherethe cage was made of titanium and the ball was made of silicon rubber. In this model, the cage and Cooley-Cutter biconical disc and cage valve annulus werecovered by a flexible polyurethane-Dacron fabric. Similar to a biconical ball and cage valve, a biconical disc and This valve was used in the mitral position with attached Teflon- cage was proposed by Dr. Denton Cooley, a cardiac surgeon, ropefor chordae tendoneae. Later on, it was observed that the and his engineering colleagues at the Cutter laboratory in fabricwas penetrated by fibrous connective tissue,leading to late 1960’s, In this model, the disc was made of Titanium and the idea that covering the titanium cage with the ball and cage the cage was biconical and made of Pyrolyte. This model was valve fabric might decrease thrombus formation (Figure 16-4). conceptually very similar to the Smeloff-Cutter valvewherefull- The development of the cloth for covering the cage was flow orificewas achievable due to a double strut cage. This continued. In a new design, the cagewas covered with knit valve was implanted in nearly 3000 patients in both the mitral Dacron tubes and the inflow ring with an ultrathin polypropyl- and the aortic positions. ene mesh fabric, which led to low incidences of valve-related The major advantage of the caged ball and cageddisk problems. However, the main issue with this model was with valves over others isthat theymaintain a very simple design. the fabric. As itwas not mechanically stable, fabric wear and In fact, in these models,the onlymoving part is a ball or a disc silicon ball structural defect were reported frequently. in the most simplistic way. The major drawback of these valves, however, is that they have a poor hemodynamic performance. Disc and Cage Valves As theblood must flow around the ball, this lead to a higher From an engineering standpoint, it makes sense if the ball pressure drop across the valve and caused the heart to per- in the traditional ball and cage valve was replaced by a disc. form extra work. The disc cage valve is much worse than the For a heart valve, a lighter and more agile disc could be more ball and cage valves, which makes these valve have a higher effective (e.g., quicker dynamic response) than a heavy ball. rate of thromboembolism (Figure 17). This is because dynamic stresses on the occluder (disc or ball) and the cage could be reduced, the regurgitation flow could Tilting Disc Valves be lessened, and the overall dimensions of the valve could be From an engineering standpoint, if the motion of the disc in much smaller with a disc. The main question; however, was a disc and cage valve could be controlled by a mechanism, if disc and cage valves could offer a better hemodynamic it follows that the hemodynamics of the valve may improve performancethan ball and cage valves. significantly. One of the obvious disadvantages of the design of the disc and cage valve is the high pressure-drop across Kay-Shiley Disc and Cage Valve the disc. Also, the blood flow is easily disturbed due to the Dr. James Kay a professor of cardiac surgery, and Donald Shiley, geometry of the disc,which may lead to turbulent flow down- an engineer, proposed the first ever design of a disc and cage stream of the valve. This disadvantage can be addressed to 19 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 Figure 17. (1) Kay-Shileycaged disk valve designed in 1966, (2) Beall-Surgitool caged disk valve designed in 1974, and (3) Cooley-Cuttercaged disk valve designed in 1974 [90,91]. Figure 18. (1) Bjork-Shiley flat disk valve designed in 1960, (2) Bjork-Shiley convexo-concave tilting disc valve some point by improving the design of the cage and disc designed in 1975 [90,91]. valve by replacingthe floating disc with a tilting disc. Bjork-Shiley Flat Disc Valve disc was made of Pyrolyte and the strut was made of Titanium. in 1960, Dr. Viking Bjork, a cardiac surgeon, and Donald Shiley, The major feature of this model was the design of the strut an engineer,proposed the first tilting disc valve. In this model, wherethe motion of the flat disc of valve wasregulated by the disc was made of Derlin polymer, and instead of a cage, two protuberant side-prongs. This model was successful to they designed a strut. The strut was made of stellite, which some extent and was implanted in almost 55,000 patients in was intended to control the motion of the disc in both the both the aortic and the mitral positions. The fabrication of this opening and closing phases. This model was considered for valve was stopped in 1976 simply because it was replaced by both the aortic and the mitral positions and was implanted the consecutive models, the Omniscience tilting disc valves. in almost 300,000 patients until 1986. Derlin polymer was not an appropriate biomaterial for this application because Omniscience Tilting Disc Valve it absorbs water, which can cause defects in the structure of This model was a modification to the Lillehei-Kaster tilting disc the disc. In the later models of this valve, the material for the valve by Robert Kaster where the profile of the protuberant disc was changed to Pyrolyte in order to address this issue. prongs on the annulus was improved. Also, the disc of the Lillehei-Kaster valve was no longer flat. A slight curvilinear Bjork-Shiley Convexo-Concave Tilting Disc Valve profile in the Omniscience valve was incorporated to the In 1975, the geometry of the strut and the disc in the flat disk disc. In this model, the strut was made of Titanium and the Bjork-Shiley valve was significantly improved in order to pro- disc was made of Pyrolyte. This model has been implanted vide a better hemodynamic performance. In this model, the in almost 75,000 patients in the aortic position and in nearly two struts (inlet strut and outlet strut) were made of stellite 25,000 patients in the mitral position. The major feature of and the disc was made of Pyrolyte. The struts were welded this model compared to other available tilting disc valves to the annulus. The idea was to design a 3D structure for was its curvilinear disc. the strut to allow the disc to slide forward and downward by approximately 2 mm more, compared to the standard Omnicarbon Tilting Disc Valve Bjork-Shiley model. Also, the disc was no longer flat as it was The Omnicarbon and Omniscience valves were designed and replaced by a convexo-concavedisc. This model improved manufactured around the same time. The major advantage of the hemodynamics of the Bjork-Shiley valve significantly and the Omnicarbon over Omniscience was the material used for was implanted in almost 85,000 patients in both the aortic the strut, which was Pyrolyte rather than Titanium. The other and mitral positions. The main issue with this valve was the design features were basically identical. These two models fracture of the struts,and in particular, the outlet strut. This were very successful, possessing outstanding durability and malfunction was reported in almost 2% of the patients. Due structural integrity properties. to this issue, the manufacturing of this model stopped in 1986. It should be noted that a mono-strut tilting disc Bjork-Shiley Hall-Kaster and Medtronic-Hall Tilting Disc Valves valve,whereonly one strut is attached to the annulus without In 1977, Robert Kaster and Dr. Karl Victor Hall, a cardiac surgeon, welding, was implanted in more than 100,000 patients with designed a new tilting valve which was named first as the no structural failure reports (Figure 18). Hall-Kaster and later as the Medtronic-Hall tilting disc valves. In this model, the strut plays the role of thedisc’s guide. In the Lillehei-Kaster Tilting Disc Valve centre of the disc, there is a hole through which the guide is In 1970, Dr. C. Walton Lillehei, a cardiac surgeon, and Ms. passed. The strut is made of Titanium and the disc is made of Robert Kaster, an engineer, designed a new tilting disc valve Pyrolyte. This model was implanted in almost 190,000 patients named the Lillehei-Kaster tilting disc valve. In this model, the in the aortic position and in nearly 125,000 patients in the 20 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 mitral position with no structural failure reports. There are still was that a well-polished Pyrolyte surface and heparin will some hospitals in the world where this model is implanted not bind. Nowadays, it is well established that the Bokros in patients (Figure 19). material was the most blood compatible material (thrombo resistant, nonheparinized material) that had been developed until that point. This material was applied to the ball in the DeBakey-Surgitoolball and valve model.This was the model he was focused on previously. This model was implanted in almost 300 patients in the aortic position and in 200 patients in the mitral position with fairly good clinical results. This model, however, had a major drawback.There was rather stagnant blood flow in the region of the super-strut imple- mented to capture the flexible leaflets. This region was often Figure 19. (1) Lillehei-Kaster tilting disk designed in 1970, (2) Omniscience tilting disk, and (3) Hall-Kaster the location of thrombus; however, no clinical episodes of and Medtronic-Hall tilting disk designed in 1977 [90,91]. thromboembolism were observed. From an engineering perspective, if the disc in a disc and cage Kalke-Lillehei Bileaflet Valve valve is broken down into two pieces, each engaged within In 1964, Drs. Bhagabant Kalke and C. Walton Lillehei proposed the ring by hinges,this could provide a central blood stream a new design for mechanical heart valves. They came up through the valve. In fact, the hemodynamics in bileaflet valves with the first ever design of bileaflet mechanical valves with must be better compared to previous models, as listed: ball a pivot mechanism. They designed a bileaflet mechanical and cage valves, disc and cage valves, and tilting disc valves. valve in which the pivot sites for the two solid leaflets were This is simply because the central area of the valve, where located at the equator of the housing or annulus. In their initial the velocity of blood could be maximum, is wide open to the model, they used an overriding semicircular strut/brace to blood flow. The bileaflet concept, a hinge mechanism, and a avoid leaflet escapement. Later on, after Dr. Kalke joined Dr. low profile are some of the basic design features of bileaflet Lillehei’s laboratory, together they proposed a design wherea heart valve prosthesis. They have two semicircular leaflets pivot mechanism for the two leaflets was considered (first engaged within the ring by hinges. The leaflet hinge is located ever design of the pivot mechanism) so that the overriding at the center of the valve annulus, and leaflets open and close strut/bracewas no longer necessary. Only a few of these Kalke- similar to a butterfly’s wings. The relation between the leaflet Lillehei valves were fabricated and only one was implanted in motion and the flow through the valve is: (1) Leaflets open a patient who died after 48 hours in 1968. The cause of death rapidly when the forward flow starts, (2) around peak flow, was advanced rheumatic mitral disease, so the fabrication of the leaflets remain stable at the maximumopening position, the Kalke-Lillehei valves wasstopped mainly because of the and (3) leaflets maintain the opening position while the flow lack of an appropriate biomaterial for this model. rate decreases slowly after the peak flow. Leaflets are still in the open position as the flow rate drops to almost zero. Finally, St. Jude Medical Bileaflet Valves the leaflets start to close when backflow happens. Bileaflet The design of the St. Jude Medical bileaflet valve was concep- valves are the most protected as the leaflets hardly protrude tually similar to the design of the Kalke-Lillehei valve and was from the valve ring, even during maximum opening. first introduced in 1977. In the design of the St. Jude valve, however, the focus was more on the improvement of the Gott-Daggett Bileaflet Valve pivot hinge. In this model, both the leaflets and the housing In 1969, the application of a hollow ball made of Pyrolyte (also were made of Pyrolyte, which made the St. Jude valve the first known as pyrolytic carbon) in a ball and cage valve (used in ever valve made entirely of carbon. Xinon Posis, an engineer, the DeBakey-Surgitool valve) was a further evolution in the proposed the first design of a St. Jude valve in 1976 wherethe design of mechanical valves. Drs. Vincent L Gott and Ronald pivots werenear the periphery, providing a central opening. Daggett, a professor of polymer engineering, designed the Xinon Posis,with Dr. Demetre Nicoloff, a cardiac surgeon, and Gott-Daggett bileaflet valve in 1963. In this model, the housing Donald Hunson, an engineer, redesigned the St. Jude Medical (annulus) was made of carbon coated Lexanand the leaflets valve multiple times.The focus was mostly on a modification were made of silicon coated Teflon fabric. In fact, the valve of the hinge design. Posis, Jack Bokros, the initiator of the idea was flexible, and was branded as the Gott-Daggett bileaflet of using carbon in valve construction, and Hanson improved valve. The housing also had a graphite-benzalkonium-heparin the design of the hinge and introduced the new concept of a coating,making this the first ever prosthetic valve with car- leaflet-tab spinning in a butterfly-recessinsideof the housing bon coating. Dr. Bokros, who was the initiator of this idea, wall. The design of this model was a success and soon became suggested that binding of heparin andPyrolyte could offer a major alternative for the replacement of the diseased valves. excellent blood compatibility properties.However, the issue This valve has been implanted millions of times in patients in 21 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 both the aortic and the mitral positions. ATS Bileaflet Valves The ATS bileaflet valve, similar to the St. Jude medical valve, Carbomedics bileaflet valves was a new design of bileaflet heart valve that was made of In 1986, Dr Bokros designed a similar valve to the St. Jude Pyrolyte in 1994. This model was branded as the ATS Open where was made of Pyrolyte both the leaflets and the hous- Pivot valve prosthesis. The main feature of the ATS prosthesis ing were made of Pyrolyte. In this model, the main feature was the design of the hinge,where a ball hinge was propo- was the housing that could rotate with respect to the sewing sedinstead of a cavity hinge. Since this model’s pivot areas ring. This valve was marketed as the Carbomedics bileaflet are fully exposed to the blood stream, the hinge area can valve and was implanted in more than 350,000 patients in the be washed out effectively. The sewing cuff is attachedto a aortic position and in 250,000 patients in the mitral position. titanium ring in a way a rotation during implantation. Radi- opacity is also provided, which is helpful for visualization by On-X bileaflet valves roentgenography. The radiopacity is possible in this model Dr. Bokros introduced a new design for bileaflet mechanical because of the presence of 20% tungsten in the leaflet con- heart valves in 1996. This model was an overall improvement struction. The ATS bileaflet valve is thought to provide a better on St. Jude medical bileaflet valves and was branded as the hemodynamics and less noise compared to other bileaflet On-X valve. The surfaces of the leaflets and the housing were valves. The ATS bileaflet valve has been implanted in nearly coated with pure carbon and extremely polished to provide 1200 patients in both the aortic and the mitral positions from high quality surface properties. In the On-X valves, silicon 1994 to 2000 (Figure 20). had been completely removed from its structure, unlike conventional models. This is because silicone embedded carbon may lead to a low surface quality, which in turn increases chance of blood damage near the surfaces of the leaflets and housing. That was the case in the regions close to the hinges. The most significant design feature of this model was that itaddressed insufficient hemodynamics in small aortas. Periodic incidents ofhemolytic anemia, extreme pannus overgrowth or tissue interference, and thrombogenic complications are the issues associated with hemodynamics of bileaflet mechanical valves, especially in small sizes. Low profile valves (low length to diameter ratio) are prone to tissue ingrowth (pannus). The profile (length to diameter ratio) of the On-X valve is designed to be similar to that of thenative Figure 20. (1) Gott-Daggett bileaflet valve designed in aortic valve,therefore providing unique protection from tissue 1969, (2) Kalke-Lillehei bileaflet valve designed in 1964, (3) damages on both the inflow and outflow sides. An inlet flare, St. Jude Medical valves designed in 1977, (4) Carbomedics valves designed in 1986, (5), On-X valve designed in 1994, full annulus support, and leaflet guards are allcomponents in and (6) ATS valve designed in 1994 [90,91]. the design. The opening angle is considered to be 90º (> 80º in SJM), which is thought to improve the hemodynamics of the valve significantly. The design of the pivot hinge is also Sorin Bileaflet Valves improved, which may in turn lead to more stability of the The idea behind the Sorin bileaflet valves was to design and hinges and less thromboembolic complications. Pivots are fabricate an advanced version of the original bileaflet model, high potential sites of clot formation,due to the possibility of which would overcome some of its inherent deficiencies and flow stagnation (stasis). In the On-X design, the location and surpass its performance. In order to improve the bileaflet the geometry of the hinges were designed so they are being valves available at the end of the penultimate decade of the constantly washed out in every cardiac cycle more efficiently last century, Sorin Biomedica (Saluggia, Italy) focused on three compared to conventional valves. This is done to eliminate main points: hemocompatibility (minimal damage to blood possible flow stagnant regions around the hinges. The backflow components and prevention of thrombotic deposits); hemo- channels are sensibly designed in order toavoid hemolysis dynamics (low resistance flow pattern similar to that in natural by allowing blood flow to penetrate tthe pivot areas. The im- valves); and durability. Experience with the Sorin tilting disc proved hemodynamics provided in the On-X valve is thought valve clearly indicated that the most biocompatible material to decreasethe anticoagulation therapy in low-riskpatients. for blood contacting surfaces is pyrolytic carbon, whether it This valve has been implanted in so many patients so far in is solid or used as a coating. Maximal hemodynamic perfor- both the aortic and the mitral positions and together with mance was achievedwith the design of the curved leaflets St. Jude Medical valve are the most widespread prosthetic and the aerofoil inner housing profile. Structural stability and valves alternative considered by cardiac surgeons globally. excellent mechanics resulted from the choice of a titanium 22 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 alloy for the housing when combined with the decreased the leaflets are made of pericardium, which will be attached thrombogenicity of the pyrolitic carbon coating. The hinge later on to a synthetic stent. In terms of the design procedure, design was based on the principle of rolling without sliding. porcine valves are one step ahead of bovines, simply because Consequently, uninterrupted washing of the hinge surfaces porcine valves are already a valve, whereas bovine valves is achieved at each point of the cardiac cycle with controlled should be designed and fabricated in a form of a valve. Al- blood leakage. The housing is rotatable within the sewing ring. lografts are those harvested from cadaver. They are excellent Short-term results were reported by Casselman and Goldsmith, alternatives for bioprosthetic valves, but are not readily avail- andintermediate results were subsequently presented in a able at the right size and time when needed. Autogratfs are large cohort of 1350 patients. harvested from a patient’s own body, in which the patient’s pulmonary valve is moved to the aortic position through the Elliptic St. Jude Medical Valves Ross Procedure. The Ross procedure, also known as a pulmo- In 2014, the Heart Valve Performance laboratory at the Univer- nary autograft, is a cardiac surgery in which a diseased aortic sity of British Columbia (the authors) published a manuscript valve is substituted with the patient’s own pulmonary valve. in the Journal of Biomechanics. They suggested a new design A pulmonary allograft or any other prosthetic valve is then for the stent (housing) of SJM valves in which 15% ovality was used as the patient’s pulmonary valve. This operation is applied to the stent whileits perimeter remains constant. In a more often recommended in infants and children, but is not pilot study, the hemodynamic performance of the proposed uncommon in adults as well. design was analyzed in the closing phase and then compared The arrival of tissue valves is associated with the introduc- to that of conventional SJM models. Results showed that while tion of glutaraldehyde for the fixation of biological tissue by Dr. the elliptic SJM model offers a shorter closing phase (9.7% Carpentier in 1969. The tissue treatment with glutaraldehyde shorter), the regurgitation flow remains almost unchanged. is essential for the design and fabrication of bioprosthetic In other words, even though the dynamic response of the valves, including porcine and bovine pericardium valves, valve improved, the regurgitation flow did not decrease. Thus, which are made of animal tissues. The main issue with the a more efficient and effective orifice area (EOA) was provided animal tissues used in the structure of prosthetic valves is by the proposed model. The elliptic concept can be applied the potential of thrombogenic complications. In 1970, the to the On-X valve as well and improved hemodynamics are Hancock standard porcine BHV was implanted in the aortic expected in the elliptic On-X valve compared to the conven- position. After a while, the Hancock modified orifice (MO) BHV tional On-X models (Figure 21). was introduced in order to addressthe high post-implantation gradients associated with small-size valves in the aortic posi- tion. The issue was due to the bulky muscle under the right coronary leaflet. In this model, a composite valve is designed where the right coronary leaflet is replaced with a leaflet from another valve,with the muscle bar already removed. After this model, the Carpentier-Edwards standard porcine BHV was in- troduced in 1975.The consecutive generationsof BHVsconsist of the Carpentier-Edwards supraannular (SAV ) porcine model, which was introduced in 1981; the Hancock II porcine model, Figure 21. (1) Sorin bileaflet valves [90,91], and (2) the elliptic St. Jude Medical valve designed in 2014. which has been available since 1982; and the Medtronic intact porcine model, which was introduced in 1985. These BHV Tissue Valves or Bioprosthetic Heart Valves (BHVs) models are known to offer improved zero-pressure fixation Bioprosthetic heart valves, which are also known as tissue that maintainsdelicate but significant histologic features of valves, are the prostheses made entirely of animal or human the valve leaflets, along with anti-mineralization treatments tissues. BHVs are divided into 3 groups: xenograft, allograft to decreasecalcification-oriented deterioration of the valve and autograft. Xenograts are those made of animal tissues. tissue. The idea is to provide the new designs with a more Two candidate animals, pigs and cows, are commonly used for flexible, lower-profile stent and smaller sewing rings,which bioprosthetic aortic valves. Xenograft valves harvested from can essentially lead to a larger orifice area. pigs are known as porcine, and those harvested from cows The first bovine BHV model was the Ionescu-Shiley valve are known as bovine valves. Porcine valves are basically the introduced in 1971. 10 years later, the first improvement aortic valve harvested from pigs and have similar structure to on that model was made, and a low-profile model was de- nd that of humans. This is simply because several components of signed where the rate of failure was much higher. On the 2 the cardiovascular system in pigs, such as the heart structure, attempt on that model, a final model III was developed and systemic pressure, aortic heart valve, mitral valve, and aortic implemented clinically. This was before the Shiley model was root is similar to those of humans. Bovine valves are made withdrawn off the market, and the production of pericardial of the precordium tissue harvested from cows. In fact, only valves was officially terminated in 1977. The Mitroflow pericar- 23 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 dial valve was introduced and first was implanted clinically in 1982. The most commonly used pericardial BHV presently is theCarpentier-Edwards pericardial valve, which was designed and clinically implanted in 1980. There are modified versions of this valve available on the market, which are known as the Perimount RSR37 and Magna series (Figure 22). Figure 23. (1) Hancock porcine valve and (2) Carpentier- Edwards pericardium bioprosthetic heart valve (Edwards LifeSciences Ltd.) [92]. Following the same concept as natural valves, the function of BHVs is pressure-driven. Ifthere is a pressure gradient across the valve (or the blood pressure before the valve Figure 22. (1) Ionescu-Shiley BHV designed and fabricated becomeslarger than the pressure after), the cusps are forced in 1971, (2) The Mitroflow pericardial valve designed and fabricated in 1982, and (3) Toronto SPV valve designed and towards the outside by reversing their curvature. This causes fabricated in 1991 [90,91]. the valve to open. When the blood pressure after the valve becomeslarger than the pressure before, the valve closes by The first clinically approvedBHV stentless model for the aortic pushing the cusps toward the center. As the total surface area position was the Toronto stentless porcine valve,also known of the cuspsis more than that of the orifice, the two adjacent as the SPV valve, which wasdesigned and fabricated in 1991. cusps overlap in the center.This is known as the coaptation In this design, the available orifice area was significant, which area,which plays a major role in complete closure of the valve originated in the concept of stentless BHV models. To reach without leakage or dynamic backflow (regurgitation flow). such a remarkable effective orifice area, the sewing ring The main issue with the BHVs is thatcross-species implanta- was minimized and the supporting struts were eliminated. tion of animal tissues causes an immune rejection and therefore In the design of the SPV valve, a native porcine valve that quick tissue deterioration. For this reason, bovine or porcine was reinforced by a small quantity of fabric was considered. valves are treated with glutaraldehyde. Glutaraldehyde is The fabric wasthen sewn to the patient’s annulus in a planar regularly implemented in biomaterialsas an amine-reactive fashion. Then a small amount of porcine aorta around the homo-dual-functional cross-linker.For instance, it is used to valve commissures was implanted straight into the patient’s determine theoligomeric state of proteins. Glutaraldehyde is native aorta. to for other conventional stentless BHV models, also implemented in polyacrylamide gel electrophoresis(SDS- the Edwards Prima Plus porcine BHV model, the 3F Therapeu- PAGE) to fix peptides and proteins before staining. In fact, the tics stentless equine BHV model, and the Medtronic Freestyle objective of SDS-PAGE is to distinguish certainproteins based porcine BHV model are quality considerations. on their size only. Usually, a gel is treated with a 5% solution for The first experimental animal studies that includedauto- nearly 30 minutes. It is then completely washed to eliminate graftof the aortic tissue were performed in 1952. In this study, the yellow stain caused by reacting with free hydroxylmethy an allograft aortic valve was implanted into the descending laminomethane. In general, a cross-link is a bond between two aorta of a dog. A few years later, an allograft aortic valve polymeric chains, including long molecules, etc. This bond was implanted into the human descending aorta in 1955. may be ionic or covalent, and these polymeric chains may The method for subcoronary implantation of allografttissue be synthetic, such as rubber, like materials, or natural,such via the single-suture technique was initiated and applied in as proteins. The concept of ”cross-linking” for proteins typically 1962 in patients with a freeze-dried aortic valve, a feat imple- refers to the use of cross-links to improve the targeted protein’s mented shortly afterward byBarrett-Boyes. There have been physical properties. In biomaterials, crosslinkingrefers to the multiple revolutionary techniques which were used for the use of a concept or method to link proteins together,which is sterilization of homograft valves, such as (a) formaldehyde, implemented for protein–protein interactions studies. (b) chlorhexidine, (c) propiolactone, (d) methylene oxide, (e) Glutaraldehyde is a water-soluble cross-linker, which com- gamma radiation, and (f ) storage using a carbon dioxide pletely decreases tissue antigenicity. Furthermore, glutar- freezer at -70ºC. Presently, most homograft valves are (g) aldehyde devitalizes tissues and destroys all existing cells, cryopreserved with low-dose antibiotics. therefore preventing degradation by host enzymes, and steri- Porcine aortic valves or bovine pericardial sheets can be lizes the tissue for implantation. BHVs are less thrombogenic mounted on supports to make a valve with stent,which is to than mechanical heart valves and do not need long-term mimic the valvular architecture, or they can be left un-mounted anticoagulation. to make a stentless valve (Figure 23). In general, BHVs’performancein both hemodynamics and 24 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 structure is excellent for many years after implantation, but valve decomposition. Also, the absence of an intact layer of their long-term durability is an issue. Clinical reportsshow that endothelial cells may let free influx of blood components more than 50% of patients with a BHV replacement develop and could also contribute to valve-related thrombogenicity. complications within 10 years, which suggests that the ma- Finally, the majority of conventional BHVs, except for newer jority of implanted BHV valves need to be explanted after 20 stentless models, do not uphold their cardiac skeleton-valve years. It is known that a second open-heart surgery to recover continuity and thus may increasingly influence heart func- and replace the defective valve is prone to high clinical risks, tion negatively. and therefore is not recommended. The absence of long- BHVs gained extensive use during the mid-1970s. The term valve durability is particularly significant in the case of major advantage of bioprosthetic valves compared to me- pediatric patients, where additional surgical procedures are chanical valves is that bioprosthetic valves are less prone to needed to accommodate the natural growth of the patients. thromboembolic complications. Consequently, most patients The choice between BHVs and MHVs depends highly on receiving bioprosthetic valves do not need to take anticoagu- individualpatient features. MHVs are more durable but need lation therapy. The main disadvantage ofbioprosthetic valves, life-long anticoagulant therapy, whereasBHVs are prone to particularly in small valve sizes, is large pressure drops (albeit deterioration more quickly but do not need anticoagulation their excellent hemodynamics) compared to some mechanical therapy. The major reasons for BHV failure are (1) structural valvesof the same size. Complications, such as jet-like flow destruction and (2) calcification of the tissue constituent. through the existing gaps between the valve leaflets, ma- Analysis of failed BHVs naturally discloses the coexistence of terial fatigue and/or wear, and calcification of value cusps, structural deteriorationand calcification. Structural failuremay particularly in children and young adults are of the issues not be associated with calcification, so it can be a purely associated with BHVs. Valve deterioration, however, typically stress-induced disruption of fiber architecture, or induced by takes place gradually in these valves. The main advantage enzymatic deterioration. Mechanical stresses/deformationsof of the conventional mechanical valves is their long-term the tissue were thought to effectivelyaccelerate calcification durability. Conventional mechanical valves are manufac- and vice versa, calcium deposits intensely affect mechanical tured from a variety of biomaterials, includingPyrolyte and properties. These progressions may be synergistic, but based Titanium. Structural failure of mechanical valves is not usual, on comprehensive studies on the subject, is it thought that butwhen it happens, it is catastrophic. One main disadvan- each may happen independently. It is also suggested that the tage of the use of mechanical valves is the need for life-long geometrical design factors of the prosthetic valves are highly anticoagulation therapy to lessenthe risk of thrombosis and influential in the mechanical deterioration rate of the valve. thromboembolic complications. Since the anticoagulation It should be noted that the calcification process in native therapy may result in bleeding complications, careful control aortic valves and bioprosthetic tissue valves follow dissimilar of anticoagulation medication is necessaryfor the patient’s concepts. In general, the calcification process of BHVs is as- well-being and quality of life. sociated with a cascade of bioelectrochemical and bioelectro- The choice of an appropriate BHV for the patient is deter- mechanical events are yet to be understood. However, tissue mined by the patient’s age, since BHVs have a relatively short composition and the glutaraldehyde tissue treatment seem to lifespan. There are significant differences between BHVs be two important factors. In most studiesreportedsofar, the and MHVs. MHVs are extremely durable, but require lifelong mineral phase consists of bone-like hydroxyapatite linked anticoagulation therapy. They are often recommended for with collagen and elastin, which then chemically devitalizes younger patients in order to avoid the need for a second cells. One of the suggested methods to prevent calcification open heart surgery or valve replacement procedure. Their in BHVs is to remove, devitalize or extract inhabitant cells, use also appears to be reasonable when the patient already modify the structure of collagen and elastin fibers, and add must take anticoagulation therapy for other medical reasons. natural inhibitors. In some cases, MHVs are preferred if the patient has a very It is well known that mechanical and biological factors narrow aortic basebecause their effective opening area is contribute considerably to failure of BHVs. Even though BHVs’ larger than BHVs with the same size. The risk of prosthesis performance in hemodynamics and structure is excellent, they endocarditis is similarly significant in the two types of pros- do not havesatisfactory biological factors thatare necessaryfor theses.The conventionalBHVsexhibit acceptable long-term true biomimetic valves. Their absence of biologic properties results in the aortic and mitral positions. For older patients may justify their insufficient durability after implantation. As (65+), the degeneration rate of BHVsat 15 years is reported BHVs lack living cells, unlike native valves,they are incapable to be between 10% and 35%. If a consecutive valve replace- of maintaining and adapting with the valvular matrix com- ment procedure is required, the operative mortality is almost position or maintaining an adequate calcium homeostasis. In 5%. The degeneration rate of BHVs is inversely proportional fact, degenerative processes pushedby mechanical fatigue, to the age of the patient at the time of implantation, so BH- proteolytic enzymes, and calcium deposition gradually dete- Vsare normally recommended for patients who are the age riorate the structural components and result in progressive of 65+. If a concurrent surgical procedure is necssary, such as 25 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 correcting a cardiac arrhythmia by surgery during the valve valve, causing stented BHVsto bemore desirable than stent- replacement, this may influence the choice of BHVs for the less. It should be noted thatstented BHVs’ also have better patient. In contrast, if the patient is already taking anticoagula- long-term resultsand their implantation is associated with tion therapy because of, for instance, chronic atrial fibrillation, consistently lower risk. However, stentless valves hold certain an MHV should not necessarily be selected for the patient. clinical advantages, such as their excellent hemodynamic properties. The preliminary reports of 10-year studies show The choice of a prosthetic valve in the aortic position that stentless valves have similar deterioration, rateswhich The implantation of BHVs in the aortic position is desirable if is ~20%, compared to conventional stented valves. Patients the lifespan of the prosthetic is not an issue. Recent report- with a narrow aortic base and a high risk of inconsistency sindicate that the new generation of BHVsare more durable between the size of the valve and aortic base may benefit than earlier models. In addition, since the age limit is taken from stentless valves. Also, autograft valves hold the same into consideration, re-operation rates have decreased signifi- degeneration rates as xenografts, which has been extensively cantly. There are the reasons that the implantation of BHVs is reported in long-term follow-up studies. recommended for more elderly patients nowadays. BHVs are known for their risk of degeneration and their The choice of a prosthetic valve for the mitral position need for re-operation 10-20 years after implantation; however, and ablative surgery in atrial fibrillation they are still recommended for the patients under the age of Prosthetic valves for the mitral position are chosen based on 60. Also, in young patients who are taking oral anticoagula- similar same criteria as the aortic position. The rate of deterio- tion therapy, BHVs are a considerable alternative. The risks ration of the BHVs, however, is higher in the mitral position. involved in the second valve replacement surgery havebeen It is normally recommended that BHVs not be implanted in considerably reduced, which is mostly due to the advances patients less than 65 years oldin the mitral position unless it in cardioprotection. Consequently, BHVs are recommended is absolutely necessary.The following conditions are consid- for younger patients; however,a second valve replacement ered for the choice of prosthetic valves in the mitral position: surgery with an acceptable degree of risk may be required • BHVs for patients of any age who are taking oral antico- after 10+ years after implantation. Also, patients who have agulation therapy and for whom oral anticoagulation is a lower life expectancy due to chronic health issues, such unconditionally prescribed as coronary heart disease, are considered for BHVs and not • MHVs for patients who are under the age of 65 with MHVs. The following conditions are considered for the choice longstanding atrial fibrillation of prosthetic valves in the aortic position: • BHVs for patients over the age of 65 • MHVs for patients who already have an MHV in their • BHVs for patients under the age of 65 due to a personal mitral or tricuspid positions decision - after enough discussion with the patients about • BHVs for patients of any age who are taking oral antico- the risks of anticoagulation therapy and the need for a agulation therapy and for whom oral anticoagulation is second valve replacement surgery unconditionally prescribed If the patient also suffers from atrial fibrillation along with a • MHVs for patients under the age of 65 for whom oral valvular heart disease, the approach is to perform both abla- anticoagulation is not prescribed tive methods to attain sinus rhythm and valvular replacement • BHVs for patients under the age of 65 due to a personal during the same procedure. If the valve can be repaired or decision - after enough discussion with the patients about a BHV is implanted, then oral anticoagulation therapy may the risks of the anticoagulation therapy and the need for be stopped. It is reasonable to implant MHVs in those pa- a second valve replacement surgery tients since they would require the anticoagulation therapy • BHVs for patientsover the age of 65 if the risk of throm- postoperatively regardless. Nearly 75% to 90% of patients boembolism is consistently low undergoing the rhythm surgery and mitral valve replacement • A secondary valve replacement surgery with a autograft surgery concurrently may still be in sinus rhythm for up to six is recommended for patients with active prosthesis months after. The success rate of ablative surgery is known to endocarditis be higher if the patient has atrial fibrillation for less than one • BHVs for young female patientsif the patient is consider- year. Also, ablative surgery may decrease the incidence of a ing having childrenin future. heart stroke. BHVs are considered an appropriate choice for There are some regulations and platforms available from those patients who cannot be permanently converted to sinus clinical trials for surgeons to choose the right prosthetic rhythm, and consequently still need the oral anticoagulation valve and replacement surgery. However,currently personal therapy. This is because if a BHV was implanted (as oppose to experience and individual assessment play a vital role in these an MHV ), a lower target INR would be required. decisions. This is often the case if the patient suffers from difficult anatomy and/or substantial comorbidity. Other Cases Ease of surgery is also important in the choice of the right MHVs were recommended for patients associated with 26 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 dialysis-dependent renal failure. In this situation, if BHVs were valve tissue, and easily permits contraction and expansion. used, their abnormal metabolic situation couldincrease the This is consistent with the aortic root’s movement during degeneration rate. Recently, long-life studies suggest that cardiac cycle; hence, it provides natural hemodynamics. Also, BHVs can also be implanted for those patients as their life it is also likely that polymeric biomaterials can be treated to expectancy is already reduced.The degeneration rate due to enhanceblood-compatibility. Research on prosthetic heart BHVs implantation is oftenlonger than their remaining lifetime. valves made of flexible polymers is not recent, as it has been Since oral anticoagulation therapy is more problematic in ongoing for more than 45 years. Biomaterials tested include: dialysis patients than in others, MHVs are not recommended silicone rubber, poly-carbonateurethane,Silastic, poly-olefin for these patients even though MHVs have longer durabil- (PO), poly-tetrafluoroethylene (PTFE), SR-impregnated Dacron, ity. Recently, prosthetic valves were not recommended for and poly-urethane (PU). PU is known to have good consistency patients with end-stage renal failure because of the risks of with blood, life-long durability, and thrombogenic resistance. systemic anticoagulation. However, calcification is a major issue with PU. Mechanical In the case of patients that are young women desiring to properties of the polymeric material are a significant concern have children, there is no appropriate type of prosthetic valves in the effective formation of a polymer based prosthetic valve. that can be recommended yet. In general, pregnant women In the past two decades, growing insight has been obtained with prosthetic valves are prone to heart failure, arrhythmia, into the significance of optimal hemodynamic performance or maternal endocarditis with high degree of propensity. of elastomeric valves for their durability. Presently, some PVs Pregnancy decreases the life-span of BHVs significantly,and have shown their efficacy in assist devices for short-term use it is strongly recommended that the female patients manage [93-98]. their pregnancy period to be within the first five years after the The advent of the PVs was perhaps in the late 1950’s. A implantation. It should be noted that pregnant women with trileaflet PV made of silicone rubber (SR) was designed and MHVs hold the highest rate of maternal and fetal complica- fabricated, and then was implanted in several patients in the tions. In patients under treatment with phenprocoumone, the aortic position in 1960 and 1962. The main issue with all of miscarriage rate is ~70%, which can be improved to ~20% if these valves was thromboembolic complications. Certainly, oral anticoagulation is replaced by heparin. The rate of chronic the choice of material is a major factor in the development cardiac complications in pregnant female patients with MHVs of PVs. Acceptable characteristics with regard to blood- is ~20%, which is almost twice as high as the rate with BHVs. compatibility, anti-thrombogenicity, resistance to calcification Age is a dominant factor for the choice of the best prosthetic and degradation,as well as excellent mechanical and material valve. For patients over the age of 65, it is understandable that properties are significant factors for the chosen polymers to a BHV be recommended. This is because these patients’ life be considered for a prosthetic valve. expectancy is decreased by comorbidity. For patients under Silicone has great mechanical properties and is considered the age of 65, MHVs are highly recommended, specifically as a blood-compatible biomaterial. It was first used in 1960 for for the mitral position. If a patient in this age group shows prosthetic valves. The issue with silicone is the formation of chronic issues to anticoagulation, then BHVs are recommended. thrombosis and stiffening of valve leaflets,which was found Patients with chronic atrial fibrillation cannot be perma- in long-term clinical studies. This was enough evidence for nently converted to a sinus rhythm by an ablative procedure. silicone not to be considered as a blood-compatible bioma- For patientswith mild arterial fibrillation, permanent oral terial for PVs in 1966. Also, mechanical properties of silicone, anticoagulation therapy can be stopped by implantation of such as low stiffness and strength, failure and short durabil- a BHValong with ablative surgery. For patients with a narrow ity were other reasons against its use. Short life-span and aortic base, a stentless BHV is recommended, even though durability was reported for silicone and poly-olefin rubbers the implantation surgery is more difficult and more time- in vivo in 1980. PVs made of PTFE or Teflon showed excellent consuming. For patients with endocarditis, mainly BHVs are hemodynamics properties at first. However, its low resistance proposed. For patients with prosthesis endocarditis, mainly to thromboembolism, calcification and leaflet thickening were stented or stentless MHVs are recommended. the major issues with these materials, preventing them from further application in 1990. Polymeric Valves (PVs) Segmented Poly-Urethane (SPU) was introduced for PVs as Polymeric valves (PVs)are those made of flexible and synthetic an excellent biocompatible material in 1982. Medical grade biomaterials. PVs may have geometry similar to that of the SPU has been used effectively in numerous cardiovascular native aortic heart valve. This design is a response to the un- devices, including artificial hearts, ventricle assist devices similar geometry of the MHVs, which are made of stiff materials ( VAD) and blood pumps and cannulas. The trileaflet PV made (Pyrolyte) with leaflets protruding in front of the blood flow. of SPU, which was designed similar to the native aortic valve, The capacity of polymeric materials to preserve or closely showed excellent hemodynamic characteristics. It reduced simulate normal hemodynamics is because they hold a soft turbulence and blood trauma,showedgreat flexure durabil- texture. This structure mimics the stiffness of native heart ity, high strength and intrinsic non-thrombogenic features. 27 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 PU has numerous applications in medical devicesfor a variety mechanical properties, superior surface quality and refusal of purposes. Ithas multiple constructive properties due to its to platelet adhesion. The mechanical properties of POSSPCU two-phased microstructure,which includes hard crystalline are comparable to that of commercially available products, segments and soft elastomeric segments. The hard segment e.g., Estane, Elasteon, and Chronoflex C. It was suggested to makes forthe structural strength, whereas the soft segment reinforce POSSPCU by adding POSS nano-particles into the provides the flexibility and complianceto the material. PU polymer matrix in order to improve its tensile strength and elastomers are copolymers encompassing polyethers that hardness. The hydrophobic properties of the nanocomposite are connected together by a urethane group or blocks of low polymer reduce its tendency to adsorption of blood proteins, molecular weight polyesters. There are 3 monomers forming which is essential in avoiding thrombosis and calcification on these elastomers, namely an isocyanate source, which is ei- the polymer surfaces. ther aromatic or aliphatic, a chain extender or curative,and a In 2014, the author and his colleagues developed and dem- macroglycol. One application of aromatic isocyanate, which onstrated a novel one-piece, tricuspid valve made completely is very reactive, is methylene diphenyl diisocyanate (MDI). of polyvinyl alcohol cryogel reinforced by bacterial cellulose If a diamine chain extender is applied, typically it does not natural nanofibers (PVA-BC). The mechanical properties of need a catalyst for synthesis. Oneapplication of an aliphatic the valve were effectively improved with decrease in flexural isocyanate is the cyclo-aliphatic diisocyanate H12MDI, which stresses of the leaflets. The stress concentrations at the com- contains polymers that change color to yellow if exposed to missural areas where the leaflets are connected to the stent ultraviolet radiation and some aromatic PUs. Aromatic PUs were also avoided. However, further studies are neededto are the polymerswhich are made of methylene dianiline evaluate the potential of the PVA-BC valve as an effective (MDA),are known carcinogens and display instant cell toxicity. alternative to the conventional PVs (Figure 24). The hard segments are formed by the reaction of a diisocyn- ate with a short chain diamine or diol, which are known as chain extenders. Normal extenders for medical application are 1,4 butane diol or ethylene diamine. The soft segments are formed by the reaction of the diisocynate with higher molecular weight polyols, e.g., polyesther or polycarbonate. In recent years, notable progress has been made in poly- mer synthesis,which has resulted in a more bio-stable PU. A broader range of SPUs for PV leaflets is available now, such as polyester urethane, polycarbonate urethane (PCU), and polyether urethane (PEU). The issue with PEU is that it is unsuit- able for long-term implants,mainly because of the hydrolytic degradation. In fact, inin vivo conditions, it is susceptible to Figure 24. A one-piece, tricuspid valve made completely of polyvinyl alcohol cryogel reinforced oxidative degradation. Also, PCU holds a higher oxidative by bacterial cellulose natural nanob fi ers (PVA-BC). stability, and its biodegradation rate compared to PEU is considerably lower and is restricted to a thinner surface layer. If PU is chain extended with ethylene diamine (PEUE), its A polymeric MHV suitable for long-term implantation is yet to biostability is improved and can be used in the leaflets of be found due to a combination of valve design and material PVs. This is because of its good rubbery characteristics, which problems. This is currently an active area in the heart valve improves the durability of the valve. PU can also be promoted performance laboratory at the University of British Columbia. to PCU and polyhedral oligomeric silsesquioxanes(POSS), which improves the thromboresistance property of the new Percutaneous Valves nanocomposite PU polymers. In 2007, POSSPCU was shown This type of valve is currently under development for older to have decreased inflammation and capsular development adults. It is also known as a transcatheter aortic valve,which is in a sheep model, and no degradation was reported within 3 applied for patients with severe symptomatic aortic stenosis. years after implantation. The high fibrinogen adsorption on Moreimportantly, it is for those who are high-risk operable POSSPCU and significant contact-angle hysteresis indicated candidates and are not considered suitable for traditional that adsorbing and inactivating fibrinogen on its surface al- open heart surgery. This technology is performed on a beat- lows POSSPCU to prevent inflammation. This new composite ing heart and does not needa heart-lung machine.Percuta- polymer offered a better blood-compatibility and a superior neous heart valve replacement or transcatheter devices are biological stability than other conventional silicone based a relatively innovative technology involving the insertion of biomaterials. an artificial heart valve (or a device) using a catheter, rather The POSSPCU nanocomposite polymer has great poten- than through the conventional open heart surgery. The por- tial for cardiovascular applications because of its excellent tal of entry could be either via the femoral artery or vein, or 28 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 directly through the myocardium tissue around the apical Conclusion section of the heart. An expandable (or self-expandable) In order to expand the patients’ options for the implantation prosthetic heart valve is delivered and positioned at the site of BHVs, which are believed to have better performance than of the diseased native valve, which is already crushed back by MHVs, the durability of stented BHVs should be improved. This an inflatable transcatheter balloon. Similar to angioplasty, a lies in in methods of BHVs’ construction and preservation. The catheter is positioned in the femoral artery and then is guided main issue with stentless BHVs is the complications associ- into the left ventricle. Alternatively, it can be sent through ated with the implantation process, which are not desirable the left ventricle through the apex of the heart. An inflatable by surgeons. There is a clear link between the conventional balloon is then sent in place to crush the diseased valve, and BHVs and the next generation of prosthetic valves. Also, other then a percutaneous valve (which is compressed in a tiny options such astranscatheter technologies (percutaneous tube) is placed on the balloon catheter and is guided directly valves), minimally invasive techniques, and the construction inside the crushed valve. The valve’s frame is inflated (or the of prosthetic valves using tissue engineering seem to be frame opens itself if self-expandable) to secure the valve in promising options for the future. place. This surgery is executed with general anaesthesia in a hybrid suite in which both catheterization and surgical capa- Competing interests The authors declare that they have no competing interests. bilities are available. To proceed with this procedure, a team of cardiologists and imaging specialists, heart surgeons and Authors’ contributions cardiac anaesthesiologists are needed to simultaneously utilize Authors’ contributions HM GF echocardiography and fluoroscopy. The percutaneous heart Research concept and design ✓ ✓ valve replacement procedure is considered a quick surgery Collection and/or assembly of data ✓ -- and is significantly less invasive than the conventional open Data analysis and interpretation ✓ ✓ heart surgery. Potential benefits of percutaneous valves Writing the article ✓ -- are reduced recovery time and lower surgical risk. Potential Critical revision of the article ✓ ✓ drawbacks are valve migration simply because the valve is Final approval of article ✓ ✓ not sewn into place, issuesrelated to catheter-based delivery, Statistical analysis ✓ ✓ and valve durability. Acknowledgement In available percutaneous valves, such as Edwards SAPIEN NSERC DG Program and the University of British Columbia for XT, the frame (inflatable) is made of cobalt chromium and the financial support. leaflets are made of animal tissues, such as bovine pericardium. The frame could be self-expandable and made of Nitinol, such Publication history Senior Editor: Juan Jose Badimon, Mount Sinai School of Medicine, USA. as in Medtronic CoreValve. Potential advantages of percutane- Received: 01-May-2017 Final Revised: 14-Aug-2017 ous valves include decreased recovery time and lower surgical Accepted: 06-Sep-2017 Published: 21-Sep-2017 risk. Potential disadvantages include a greater risk for valve migration (since the valve is not sewn into place), complications associated with catheter-based delivery, and uncertain valve References durability. Also, similar to bioprosthetic valves, these valves 1. Mohammadi H and Mequanint K. Prosthetic aortic heart valves: modeling and design. Med Eng Phys. 2011; 33:131-47. | Article | are highly associated with thrombogenic complications and PubMed calcification (Figure 25). 2. Taber, Clarence Wilbur and Venes, Donald. Taber’s cyclopedic medical dictionary. F a Davis Co . 2009; 1018-23. 3. Keith L. Moore, Arthur F. 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Nazari S, Carli F, Salvi S, Banfi C, Aluffi A, Mourad Z, Buniva P and Rescigno G. Paerns of s tt ystolic stress distribution on mitral valve anterior leaflet chordal apparatus. A structural mechanical theoretical analysis. J Cardiovasc Surg (Torino). 2000; 41:193-202. | PubMed 94. Schoenwolf Gary C et al. Development of the Urogenital system”. Larsen’s human embryology (4th ed.). Philadelphia: Churchill Livingstone/Elsevier. 2009; 177-179. 95. Britton, the editors Nicki R. Colledge, Brian R. Walker, Stuart H. Ralston and illustrated by Robert. Davidson’s principles and practice of medicine. (21st ed.). Edinburgh: Churchill Livingstone/Elsevier. 2010; 612-628. 96. Mitchell RS, Kumar V, Robbins SL, Abbas AK and Fausto N. Robbins Basic http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiovascular System Unpaywall

Prosthetic Aortic Heart Valves

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Abstract

In this review, the anatomy and structure of the aortic valve and its prostheses are comprehensively discussed. Cardiac anatomy and function, human heart valves and their prostheses are also extensively discussed. The current status of prosthetic heart valves along with the next generation of these devices is broadly deliberated. Ather promising options such astranscatheter technologies (percutaneous valves), minimally invasive techniques, and the construction of prosthetic valves using tissue engineering as futureristic areas of research are brought into conclusion. Keywords: Aortic Valve, Prosthetic Valve, Mechanical Heart Valves, Bioprostheic Valves, Hydrogel Biomaterials, Surgical Tools Background downwardsto the left. It sits between the lungs and behind Cardiac Anatomy and Function the ribcage for safety and protection. The cavity in which the The heart is undoubtedly one of the most dynamic organs in heart is locatedis known as the thoracic cavity, which is behind the human body. The main function of the human heart is to the breastbone, also known as the sternum, in front of trachea circulate the blood, acting as a synchronized reciprocating and esophagus, and above the diaphragm [3]. The diaphragm double-pump. In every heartbeat, blood is squeezed into the is a curved-shaped membrane made of muscle that is located arteries from the heart, and then returns back to the heart in a between the chest and the abdomen as a separator. Since it is one-way circuit through the veins. The delivery of the oxygen placed in the thoracic cavity, it also has another name which is and nutrients takes place in the connection between arteries the thoracic diaphragm. The main axis of the heart is aligned and veins, known as the capillary network, which are known as along the body’s midline, while the apex is inclined slightly micro vessels [1,2]. Blood flows through the circulation system towards the left side. Due to the inclination of the heart towards due to the continuous rhythmic heart muscle contractions. the left, about %65 of its mass is on the left side of the body However, the form, function and complexity of the heart arenot while the remaining %35 is on the right side [4]. the same in different animals. In some animals it is similar to a A thin layer of tissue, known as the pericardium, covers the beating tube as observed in fish, spiders and worms.In some outside of the myocardium. Pericardium is a strong two-layered other animals, it may have a more complex structure as ob- membrane that shields the heart. There are two sub-layers in the served in birds and reptiles. In humans and pigs, the heart is pericardial membrane: the outermost fibrous pericardium and much more developed as asignificant evolution from a single the inner serous pericardium. The serous pericardium, is further to a double pump is observed. It should be noted that the pig separated into two sub-layers: the parietal pericardium, which heart is the closest to the human heart in shape, function and is connected to and inseparable from the fibrous pericardium, complexity [1]. and the visceral pericardium, which is a segment of the epi- In general, the heart is made of active muscles known as cardium. The epicardium is the layer directly outside of the myocardium and is as big as a closed fist (Figure 1). The average myocardium. The heart is not attached to any other organs dimensions of an adult heart are 130×95×65 mm with a weight and issuspended in the pericardium. The firm outer segment of 300 g. It is a somewhat conic structure, with the wide base of the sac, or fibrous pericardium, is strongly connected to the oriented towards the right and the head, the apex oriented diaphragm under the mediastinal pleura on the side and the © 2017 Mohammadi et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 that carry oxygen-rich blood. All of the collected blood in the left atrium then goes directly to the left ventricle [4]. The left ventricle then pumps it to the systemic circulation system through the aorta to deliver oxygen to the remainder of the body. It should be noted that in the right half of the heart, the wall is thinner and the heart valves have lessconcentra- tion and density of collagen fibers whencompared to the left side. It is observed that these two pumps (halves), which are completely separate, work simultaneously together in a very effective way. In fact, each pump is responsible for driving the blood into a distinct circuit, either the pulmonary circuit or the systemic circuit. The pulmonary circulation is the circuit by which blood is oxygenated and requires a much lower driving force than the systemic circulation. This is mainly because of the much lower resistance between the blood and vessels. Thisalsoexplains why the left part of the heart has a stronger and thicker structure than the right side, and why the blood pressure at the onset of the systemic circuitis much higher than that of the pulmonary circuit (Figure 2) [6]. Figure 1. Diagram of a porcine heart model. sternum in front [5]. It progressively becomes the coatings of the superior vena cava and the pulmonary arteries and veins. The serous membrane lines the fibrous pericardium and covers the heart wall. The segment of membrane lining the fibrous pericardium is known as the parietal serous layer or parietal pericardium, and the segment coating the heart is known asthe visceral serous layer, visceral pericardium or epicardium. There is a gap between these two layers of serous membrane known as the precardial cavity. This cavity is filled by 10 to 15 ml of pericardial fluid, which is secreted by the serous membranes. The pericardial fluid is responsible Figure 2. The horizontal section of the heart [7]. for the lubrication of the two membranes during the cardiac cycle so that the energy loss due tofriction is almost zero [6]. The human heart has four chambers (or cavities) known The heart wall is composed of three identifiable layers, the as ventricles (bottom chambers) and atria (top chambers). epicardium, the myocardium, and the endocardium. Coronary Blood flows from all regions of the body intothe vena cava arteries and veins are imbedded within the epicardium and vein, which empties into the right atrium that collects all of the the myocardium. The epicardium (or visceral pericardium) deoxygenated blood. The inferior vena cava is responsible for is made of a surface of compacted epithelial cells covering collecting deoxygenated blood from the lower body, including the connective tissues. The myocardial layer is made of the the legs, back, abdomen and pelvis.The superior vena cava contractile bundles of striated muscle fibres. These bundles is responsible for collecting deoxygenated blood from the are constructed in a branching-like pattern and cause a wring- upper body, including the brain, neck, arms, and chest. All ingmovement thatproficiently squeeze the heart champers of the collected blood in the right atrium then goes directly on each cardiac cycle. The thickness of the myocardium is to the right ventricle, whichpumps it to the main pulmonary not constant and highly depends on the pressure required artery and subsequently the lungs. This is where the blood to move the blood in each cardiac chamber. Also, the atrial receives fresh oxygen and releases its carbon dioxide [3]. The walls are much thinner when compared to the ventricular power needed to pump the deoxygenated blood to the lung walls. The myocardium is made of muscle fibres which are is considerably less than that required for systemic circulation. then broken down into smaller structurescalled cardiac The pulmonary veins connect the lungs to the left atrium and muscle cells. Each cardiac muscle cell is then subdivided into bring oxygenated blood from the lungs back to the left atrium. smaller structures known as myofibrils. Myofibrils are made In fact, the pulmonary veins are the only veins in the body of smaller unites known as sarcomeres. A sarcomere is the 2 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 fundamental unit of cardiac muscle and is highly responsible In normal conditions, there is absolutely no contribution from for the contractibility of cardiac muscle [8]. The length of the neural system or any external regulatory mechanisms to sarcomeres is approximately a few microns and theyhave stimulate the regular cardiac muscle. In fact, the root of this very complicated structures. The cardiac sarcomere is an rhythmic mechanism is in the cardiac muscle. Thisoriginates extremely organized cytoskeletal structure made mainly of during the cardiac development in the embryo long before myosin, actin and a set of regulatory giant proteins known as various levels of the neural systemhave developed. Each sub- titin. Myosin is known to be the cytoskeletal motor protein in segment of the heart structure has the beating property where the muscle cell thatis directly accountable for converting small cardio-myofibril in a tissue culture continuously contract chemical energy (ATP) into mechanical force and eventually rhythmically. It should be noted that the regular contraction muscle contraction. Myosin is the thick filament while actin in cardio-myofibrils is either maximum (100% contraction) is called the thin filament. Myosinbinds to actin through its or nothing(0% contraction),unlike skeletal muscle cells. This long, fibrous tail and a globular head. Its globular head is strongly indicatesthe lack of neural network contribution to also attached to ATP, which is the main provider of energy the regular heart construction. If more or less blood is required for muscle activities. Actin molecules are attached to the Z to be circulated through the body (depending on the physi- line, which are limits of the sarcomere unit andmyosin is at- cal or mental conditions), the heart rate needs to increase or tached to the Z line through titin. The space in which titin is decrease [10]. The regulation of heart rate is directlycontrolled located is called the I-band and the space between the two by the neural network,which is achieved specifically by the actin filaments in a sarcomere is called H zone (Figure 3) [8]. sympathetic nerves and the parasympathetic fibres in the vagus nerve. The sympathetic nerves serve as a cardiac accelerator and the parasympathetic nerves act as a cardiac decelerator. If the vagus nerve is stimulated, it reduces the heart rate [11]. Consequently, the atrial contractility is also reduced and the cardiac output is decreased. If parasympathetic nerves are stimulated, the contractility of the atria and ventricles as well asheart rate is increased. The effect of the sympathetic and parasympathetic nerves is similar to an analog system, meaning that the heart rate (or cardiac muscle contraction) highly depends on the degree of stimulation. The period of one full contraction and relaxation of the heart is defined as the cardiac cycle, which includes the relaxation phase (diastole) and the contraction phase (systole). The pressure Figure 3. Structure of a sarcomere. developed at the beginning of the systemic circulation var- ies during these two periods. The normal diastolic pressure Cardiac muscle and skeletal muscles have similar proper- is between60 to 80 mmHg and the normal systolic pressure ties. The heart containspacemaker cells that generate the is between 90 to 120 mmHg [12]. depolarization and action potentials to cause cardiac cells The systole phase normally takes between 0.3 to 0.4 seconds, to contract. Regularheart contraction is self-driven,which is in which 80 cc to 100 cc is pumped to the systemic and the not based on neuron stimulations. Cardiac muscle cells are pulmonary circulation systems together. In the beginning of positioned next to each other with gap junctions in between. this phase, the systemic blood pressure is maximum with a This allows action potentials to quickly spread from one cell value of 90 to 120 mmHg. The ventricle pressure is slightly to another to connect all the cardiac cells in a very organized higher due to: (1) the pressure drop through the aortic valve, way. Another role of gap junctions is to let the sinoatrial node and (2) the compliance of the aortic root. In fact, atrial systole cells generate the action potential, which is communicated follows at the end of ventricular diastole in which the ventricles via the gap junctions throughout the heart. This helps heart are relaxed and filled for the next cardiac cycle. In the begin- contract and relax in a very controlled way [6,8]. Cardiac muscle ning of the cardiac cycle, both atria and ventricles are in the cells in atria and ventricles are different. Some are called the diastolic phase [13]. There is a period of quick relaxation of pacemaker cells, which are in the sinoatrial node, and some the ventricles followed by a quick atrial systole. Simultane- are called the atrial and ventricular cells that cause the con- ously, the arterial blood pressure falls to its minimum, known traction only. Nevertheless, all share the same mechanisms of as the diastolic blood pressure (approximately 80 mmHg). excitation-contraction coupling; however, there are certain Ventricular relaxation again takes place after the blood has features thatdistinguish the sinoatrial cells [9]. been pumped during ventricular systole out of the heart. The muscle contraction mechanism leads to a beating The heart myocardium is known to be active as there are heart. Regular heartbeat is a self-driven mechanism that is electrical stimulations which cause the myocardial tissue to completely due to the inherent rhythmicity of cardiac muscle. contract. The key factor for the heart to act like a pump is 3 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 the myocardial contraction and relaxation. The contraction larger than that of the right coronary artery (Figure 4) [15,18]. of myocardium causes a high pressure in each chamber and The lumen diameter of the main branch of the right coronary the relaxation causes the pressure to drop. The periods of artery is approximately 2.5 mm. The areas covered by the right relaxation and contraction are called diastole and systole, coronary artery system are as follows: the right ventricular respectively. These electrical stimulations are initiated in outflow area, the atrioventricular node, the sinoatrial node, and the sinoatrial (SA) node, which is locatedin the right atrium wall. Through an impulse started from the SA node and then propagated in the entire atrium wall, the two atria contract. There is another node in the ventricle chambers where electri- cal impulses initiate, causing them to contract. This node is known as the atrioventricular (AV ) node, which is locatedat the interface of the two atria. The period of diastole is longer than that of systole, which is the time for heart to relax between two consecutive contractions. A healthy human heart beats around 100,000 times every day, almost 70 beats per minute. The total amountof blood pumped by an adult heart every day is about 7,500 liters [14]. One of the main features of the cardiovascular system through which the performance of the heart is evaluated is the cardiac output. Cardiac output is the amount of blood pumped by the two ventricular chambers. It is typically con- sidered as the volume of blood per minute or litres of blood Figure 4. The diagram of the human per minute. If the stroke volume,also known as the heart coronary arteries [19]. output, in each cardiac cycle is multiplied by the number of beats per minute (heart rate), the cardiac output can be calculated [10,12]. It should be noted that the levelof cardiac the bulk of the right ventricle. Also, the right coronary artery output is directly proportional to the entire body’s need for has branches that spread into the interventricular septum and oxygen and other nutrients. In normal conditions, the cardiac merge with arteriolar branches from the left coronary artery output at rest (or sleeping) is evaluated to be approximately at the border of the two ventricles. The lumen diameter of the 5 litres per minute. It is typically increased upon the initiation main branch of the left coronary artery is approximately 3.5 of any types of physical or mental activities by 50% to 500%, mm with a length between 10 mm and 20 mm [12,20]. The depending on the person [15]. subdivisions of the main left coronary are two smaller arteries, called the anterior descending and the circumflex arteries. Coronary Arteries The areas covered by the left coronary artery are mainly the The mechanism by which oxygen and nutrientsare delivered left ventricle and the interventricular septum [15-21]. The to the heart is, somewhat surprisingly, not by diffusion. It is left circumflex artery is positioned along the atrioventricular actually achieved though the coronary artery vascular network. groove, which is then divided into an arterialand the obtuse This network consists of two main coronary arteries, known marginal branch. The arterial branch is then connected to as the right and the left coronary artery. Generally, the left the sinoatrial node and the obtuse marginal branch covers coronary artery has a Y-shape structure,and it branches to the posterior left ventricular wall towards the apex. It should two major smaller arteries. These are called the left anterior be noted that veins usually follow the same pattern as the descending and the circumflex coronary arteries. The left distribution of the distal arteries [22]. anterior descending and the circumflex coronary arteries are divided to many smaller arteries that cover the entire Review cardiac surface [17]. Human Heart Valves The right and left coronary arteries originate from the To regulate the precise blood flow within the heart, there aortic root, or more specifically, from the right and left aortic are four unidirectional valves in the heart. These valves are sinuses. These are better known as the right coronary sinus categorized as:(1) the atrioventricular valves or tricuspid and and the left coronary sinus, respectively. The other aortic sinus mitral valves, and (2) the semilunar valves or pulmonary and is called the non-coronary sinus of Valsalva, simply because aortic valves. The atrioventricular valves are known to have there is no coronary artery that originates from there. The very thin structures thatare positioned between the atria and left coronary arterial system is said to be more vital than the the ventricles. The right atrioventricular valve is called the right arterial system, simply because it covers a larger area. tricuspid valve because of its three unequally shaped leaflets. This explains why the size of the main left coronary artery is The leaflets are covered by the endocardium and are strength- 4 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ened with a layer of compact connective tissue. The chordae valves and how they are positioned and oriented within the tendineae which is a connective tissue (similar to a tendon)is heart. In a healthy human heart, the location and orientation coated by endocardium and connects the papillary muscles of the valves is much more complicated, but the following and the ventricular surface of the middle layer of each cusp. diagram makes it easier to understand. The cardiac valves are The left atrioventricular orifice is the location of the mitral positioned in between the chambers of the heart and at the valve. The mitral valve is connected in the same way as the onset of the aorta and pulmonary artery. The role of valves is tricuspid, but it has a stronger and thicker structure because acritical component inproviding the proper direction for the the operational pressure around the mitral valve is much flow of blood through the heart and thereafter. All of the valves, higher. First, blood is pumped through the tricuspid and mitral in normal physiological condition, perform as unidirectional valves as the atria contract. Following the ventricle contrac- check-valves thatallow blood to flow in only one direction (i.e., tion, blood is pushed backward, flowing between the flaps from one chamber to another, or letting blood flow to the and walls of the ventricles [20-23]. The flaps are consequently lungs or to the systemic circulation of body in only one direc- pushed upward sothat the valvesare closed completely. In tion) [24]. The valves control the direction and the rate of the this case, a complete separator is formed between the atria blood flow through the heart in a timely manner by opening and the ventricles. The motion of the leaflets is controlled by and closing the leaflets during diastolic and systolic phases. the chordae tendineae and papillary muscles so as to prevent The mechanism by which valves open and close during the the leaflets from opening into the atria. The semilunar valves, cardiac cycle is known to be almost passive as the pressure known as the pulmonary and aortic valves, are pocket-like gradient before and after the valves is the driving force. This structures positioned where the pulmonary artery and the pressure gradient is generated within the heart and highly aorta are connected to the ventricles. The pulmonary valve is depends on the compliance of the heart and arteries [10-25]. positionedat the orifice between the right ventricle and the However,in the mitral valve, the opening and closing phases pulmonary artery. The aortic valve is positioned between the are not completely passive as the papillary muscles and the left ventricle and aorta. The three leaflets of the pulmonary chordae tendineaelocated within the left ventricle partly valves arethinner than that of the aortic valve, but in both contribute, as mentioned before. valves there is no connective tissue of chordae tendineae. Due In summary, the four heart valves are known as: (1) the to this, the motion of the leaflets isnot restricted by any cords tricuspid valve, (2) the pulmonary valve, (3) the mitral valve, during the opening and closing phases. The closing phase of and (4) the aortic valve. the heart valves is associated with an audible sound, known • Tricuspid valve: located between the right atrium and as the heartbeat. The first sound is because of the closure of the right ventricle  the mitral and tricuspid valves, and the second one is when • Pulmonary valve: located between the right ventricle the pulmonary and aortic valves close [18-22]. and the pulmonary artery  The following diagram (Figure 5) shows the four cardiac • Mitral valve: located between the left atrium and the left ventricle  • Aortic valve: located between the left ventricle and the aorta As the heart muscle contracts and relaxes, the valves open and close, letting blood flow into the ventricles and atria at alternate times.As to the stages ofhow the valves function normally in the left ventricle: (1) after the left ventricle con- tracts, the aortic valve closes and the mitral valve opens. This allows blood flow from the left atrium into the left ventricle, (2) once the left atrium contracts, more blood flows into the left ventricle, and (3) when the left ventricle contracts again, the mitral valve closes and the aortic valve opens, and blood flows into the aorta [24-27]. The aortic valve, located at the onset of the aorta, is the por- tion of the aortic root thatconnects the heart to the systemic circulation of the body. It plays a key role in the function of the heart and the cardiovascular system. It also preserves optimal Figure 5. The structure of heart and coronary perfusion and plays a significant role in providing a heart valves, four chambers (atriums non-turbulent flow in the vascular system. Each component and ventricles) and four heart valves: of the aortic root has its own individual histological features pulmonary valve, mitral valve, aortic and anatomical construction. The specific shape of the an- valve and tricuspid valve are shown clearly [26]. nulus, including the three aortic sinuses’ interleaflet triangles, 5 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 the sinotubular junction, commissures, and the aortic valve microstructure provides an ideal transferal of force from the leaflet tissue interrelate with each other in a very precise leaflet tissue to the base (attachment) and eventually, to the way in order to preserve ideal function. This harmonized ac- aortic wall [35-36]. tive behaviour has been demonstrated to be significantfor coronary perfusion, especific flow characteristics, and left Interleaflet Triangles ventricular function [28]. These interleaflet triangles are basically the three regions between the apex of the crown-like annulus and the anatomic Annulus boundary. In fact, the interleaflet triangles and the ventricular The aortic valve cusps are connected to the sinuses’ wall by outflow area are on the same extension and the sinotubular a very solid collagenous network known asthe annulus. The junction in the region of the commissures and interleaflet word annulus indicates a circular structure of the aortic ring triangles are at the same level. The triangle formed by the which is not accurate. In fact, the only circular component of right- and the left-coronary sinuses is positioned towards the aortic root is the region where the left ventricle and the the pulmonary valve, whose base is located on the septal fibroelastic wall of the arterial trunk intersect. The annulus section of the right ventricular outflow area. Attachment to has a crown-like shape thatis located on the interface of the the pulmonary artery is attained in almost half of cases by left ventricle and the aortic root. It is made up of a fibrous the ligament of the infundibulum. The triangle formed by the structure thatis strongly connected to the media of the aortic right- and non-coronary sinuses is positioned towards the sinuses distally and also to the muscular and the membranous right atrium and is in direct connection with the membranous septa anteriorly and proximally. The three superior portions of septum. The close communication between the conduction the annulus are known as commissures.In the non-coronary system and the aortic root occurs in this region. Lastly, the sinus of the annulus, there are regions in which no myocardial triangle formed by the left- and non-coronary sinuses is in muscle exists and instead havea cartilaginous structure. These direct connection inferiorly with the aortic or anterior cusp of regions are the locations where the layers of the cusps exhibit the mitral valve. These three triangles separate and indicate a specific arrangement. The ventricular and arterial layers the three sinuses in the healthy valve (Figure 6) [34-40]. become separate, and the middle collagenous layer exhibits The three intraleaflet triangles are attached by a delicate a cuneiform structure. The ventricular layer blends into the fibrous membrane of the aorta between the extended sinuses. endocardial layer gradually and the arterial layer blends to The triangle formed by the left-coronary and non-coronary the sinus wall. Small arteries and veins are positioned in the sinus becomes a portion of the aortic–mitral valvular curtain. connective tissue layer [29-34]. Elastic and collagen fibers as Its structure is mainly fibrous tissue, which is similar to the well asneuronal structures are present in the annulus. mitral valve cusp structure. The triangle formed by the non- coronary and the right-coronary aortic sinus is merged in the Commissures membranous portion of the septum and is made up of fibrous The apex of annulus in the region where the lannula of two tissue. However, the triangle formed by the right-coronary cusps are connected to the aortic wall. This occurs at the height and left-coronary sinus in the region of the subpulmonary of the sinotubular junction and is known as a commissure. In infundibulum is different. This triangle is mainly reinforced by this region, two cusps are attached to the aortic wall in paral- lel for a short distance, which makes three commissures. The first one is formed by the right- and left-coronary cusps and is oriented anteriorly. Itis relatively opposite to the equiva- lent commissure of the pulmonary valve. The second one is formed by the right and non-coronary cusps and is on the right anterior. Finally, the third one is formed by the left- and non-coronary cusps, typically on the right posterior aspect of the aortic root. The commissures are made up of fibres and structurally support the valve cusps. They arepositioned above three triangular regions known as the interleaflet triangles [35]. The pressure load on the leaflets is transferred to the an- nulus, mostly by a network of collagen fibers in the closing phase. The majority of these fibers appear to originate at the commissure level. The collagen fibers of the middle layer are positioned inthe radial direction in the region close to the commissures. At one end, these fibers penetrate to the in- Figure 6. Schematic diagram of the aortic root (cut and open tima layer of the aortic root and atthe other end, they blend longitudinally) [41]. to the media layer in which they are fixed. This particular 6 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 muscular tissue except for its apex, which is a fibrous structure. tubular junction. The transition from the aortic root to the The interleaflet triangles may contain a variety of contractile ascending aorta takes place in this region. The sinotubular and cytoskeletal proteins such as desmin, vimentin, and junction passes through the upper part of each individual smooth muscle α-actin, signifying that these structures may commissure and subsequently indicates the upper end of the play a major role in the regulation of aortic root function [40-44]. connection of each valve cusp. It should be noted that dilation of the aortic root at this level canlead to aortic insufficiency Aortic Sinuses [48-50]. The sinotubular junction has similar microstructure In the aortic root right after the valve, there are three nearly to the sinuses and the ascending aorta. The sinus wall is symmetrical lumpsor bulges,which are also known as aortic significantly thinner than the wall thatrepresents the fold as sinuses. They are located between the attachments of the the higher portion of the aortic root. valve cusps and the sinotubular junction. At the base of the aortic root, it is partly made up of ventricular musculature Leaflets but the sinus wall is mainly made up of the aortic wall and The native aortic valve has three semi-lunar soft-tissue leaflets is thinner than the healthy aorta. Two of the sinuses make or cusps: the left coronary leaflet, the right coronary leaflet and connections to the coronary arteries at very specific spots the non-coronary leaflet, following the names of the sinuses and have a significant impact on coronary flow. Generally, they correspond to. The basal attachment region of the leaflets the sinuses are named according to their connection to the forms the annular ring of the aortic valve, which is located coronary arteries (coronary ostia) resulting in the right, left, between the left ventricle and the ascending aorta. In the fully and non-coronary sinus. The non-coronary sinus is the largest closed position, the three leaflets come into contact on their one in healthy conditions, which has no connection to any free edge to a nodulus known as the coaptation zone. Each arteries. The location of coronary ostia is not the same for all leaflet includes outer endothelial layers and interstitial cells cases,as the left coronary ostium is located inside the sinus scattered in the matrix, known as the interstitium [41,49]. The in 70% of cases, slightly above the sinotubular junction in matrix is located between the endothelial layers. Interstitial almost 22% of cases, and at the level of the junction in 9% cells are spindle shaped and are composed of a variety of of cases. The right coronary ostium is located in 78% of cases fibroblasts, smooth muscle cells and myofibroblasts. Further- inside the sinus, 13% slightly above the junction and 10% at more, endothelial cells have a cobblestone-like structure. The the level of the junction. Also, there is an additional segment fibrosa, suggested to be the major structural layer, is located to the right coronary ostium in 75% of cases [42-45]. on the aortic side and has considerable surface rippling due The attachment of arteries tothe heart is through a fibrous to the presence of collagen in the form of thick and long tissue known as arterial fibre-rings. The structure of this tissue is bundles and fibers. These collagen bundles and fibers are similar to connective tissue (such as tendons), which have non- embedded within an elastin matrix. The orientation of these distinct boundaries in the region of structural and anatomical fibers and bundles are in thecircumferential direction, which attachment of the heart and the aorta. The sinuses hold very results in a soft structure. It is noticeably stiffer and stronger dissimilar constituents, but the largest portion of them and in the circumferential direction when compared to the radial the three corresponding layers of the aortic wall (known as direction. The ventricularis, which is located on the ventricular tunica intima, tunica media and tunica externa (also known side, is smooth and mainly made up of elastin and collagen. as adventitia)) have similar structures. The internal layer of the However, it is moderately flabby and soft due to the absence of intima is made up of endothelial cells thatare oriented in the structural organization, unlike fibrosa. Spongiosa is the central longitudinal direction of the vessel [46]. The subendothelial layer andis mainly made of water similar to hydrogels. This connective tissue is positioned inthe same direction as the layer also contains glycosaminoglycans and a small amount endothelial cells. This layer is separated from the intima by of elastin and collagen fibres [50-53]. the membrana elastica interna. The media is made up of The leaflet layers are highly heterogenous and there is con- ring-shape structures such as elastic fibres, smooth muscle siderable blending of these layers with each other and with cells, collagen fibres (mostly type II and III) and proteoglycans the extracellular matrix. The fibrosa covers the whole leaflet (PGs). The adventitia is the outer layer, which is detached from and consists of almost 50% collagen (90% Type I collagen) by the intima by the membrana elastica externa. The elements dry weight and 10% elastin. The ventricularis covers all but the of the externa are similar to theintima, which are oriented coaptation region where two adjacent leaflets contact and longitudinally and are made up of collagen fibres (mostly consists of almost 50% collagen (90% Type I collagen), 20% type I). The wall of the sinuses has the same microstructure elastin. The fibrosa’s structure is oriented in the circumferential whose wall thickness is considerably thinner than that of the direction shown in Figure 7 [54]. ascending aorta [47]. Available thickness data for aortic valve leaflets shows con- siderable inconsistency between various studies. The mean Sinotubular Junctions thickness has been reported to range from 0.57 mm at the The easily identifiable fold at the top of the sinus is the sino- leaflet edge to 1.20 mm at the leaflet base in healthy human 7 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ventricular side (i.e., ventricularis) and multiple rims on the arterial side, (i.e., fibrosa). The endothelial cells on the cusps and the entirety of the vascular systems are connected to each other in a similar fashion. The only difference is that the endothelial cells on the leaflets are aligned in the direction of flow. This is unlike the endothelial lining pattern in the other locations of the vascular system wherethe cells are aligned perpendicular to the direction of flow. This particu- Figure 7. The leaflet anatomy. lar arrangement of the endothelial cells is due to a biaxial pressure load on the leaflet tissue and wall shear stresses in all blood vessels. Between the ventricularis and fibrosa (i.e., tissues. The thickness was found usingdifferent techniques ventricular and aortic surfaces), five layers of connective such as scanning acoustic microscopy, X-ray attenuation tissue are identifiable: lamina radialis, lamina ventricularis, technique, etc. When using the X-ray attenuation technique lamina fibrosa, lamina spongiosa, and lamina arterialis. The on the porcine valve, mean thickness has been reported to lamina ventricularis is considered as a supplementary layer be nearly 0.8 mm at the base and 0.4 mm in the rest of the that is found between the ventricular endothelium and the leaflet. Also, there is a correlation between the leaflet thickness lamina radialis [63]. Generally, three discrete layers, the lamina and the hydration level of the tissue sothat the mass of the radialis, lamina spongiosa and the lamina fibrosa are easily leaflet highly depends on the time during which the tissue identifiable. The connective tissuesare mechanically attached is exposed to. An example of this would be dextran solutions to each other and forma well-defined sponge-like structure. with varying concentrations. In this case, immersionof the It has been suggested that this special microstructure is ef- tissue in high-concentration dextran solutions decreases fective inreorganizingcollagen’sintial construction after the the mass of the tissue, whereasimmersion of the tissue in external pressure load is removed. The arterial layer holdsgrainy low-concentration solutions increases the tissue mass. This bundles of collagen fibres thatare oriented circumferentially. indicatesthat the aortic valve leaflet tissue willingly obtains or These construct the macroscopical folds analogous to the loses fluid volume by osmosis. The change in fluid volume in free edge of the cusps. This optimal arrangement of fibresis fibrosa and ventricularis is not as much as that of in spongiosa. is highlyeffective in transferring the externalload of the cusps In fact, significant amount of this change in fluid volume to the base and eventually to the wall of the aortic root. The occurs in spongiosa. It is suggested that the source of this main cells in the leaflet tissue are known as interstitial cells, osmotic pressure gradient is because of the high concentra- which are located in the extracellular matrix. These cells are tion of glycosaminoglycans, known as GAGs. GAG fibers are originallyconsidered as smooth muscle cells and exhibitfeatures hydrophilic polysaccharides placed in the ECM of spongiosa. of both fibroblasts and smooth muscle cells (myofibroblasts). The GAG content of bioprosthetic aortic valve leaflets, such It should be noted that they have similar mechanical proper- as porcine valves, is decreased during implant preparation. ties to fibroblasts or smooth muscle cells. As well, they are However, lack of GAG fibers may result in failure of prosthetic significantly effective in the regular function of the aortic valve leaflets. The estimation of glycosaminoglycan content valve and undertakedimensionalchanges during the closing during bioprosthetic valve preparation can be attained by and opening phases [64-69]. measuring osmotic swelling using a high-frequency ultra- sound, which is non-destructive [55-61]. Dynamics of Cardiac Aortic Valve In ultrasound-basedtechniques, the main source of ambigu- The aortic heart valve is a unidirectional valve thathas two ity in the leaflet tissue thickness evaluation is the unknown primary functions. The first is that it allows a pressure dif- speed of sound in the tissue. Using scanning acoustic micros- ferential to form between the left ventricle and the aorta copy, it has been foundthat the speed of sound is nearly 1620, when it is closed. When ventricular systole takes place, the −1 1550 and 1590 ms for fibrosa, spongiosa and ventricularis, pressure in the left ventricle is increased due to contraction respectively, in a normal, formalin fixed human aortic valve of the myocardium in the left ventricle. The increase of the leaflet tissue. It should be noted that fresh leaflet tissues ventricular pressure continuesto the point whereit exceeds are better hydrated than fixed tissues, and the speed of the pressure in the aorta. In this stage, the high ventricular −1 sound in 20°C water is 1480 ms . If the leaflet is considered pressure causes the aortic valve to open, which normally takes as a monolayer and homogenous structure, the pulse–echo between 20 to 30 ms. The second is that in the opening phase, measurement method can be implemented to assess the the valve controls the direction of blood flow to be in only average sound speed in the tissue. However, the sound speed one direction. It also controls the passive transport due to can vary in different layers by a factor of 5% [62]. the pressure differential, which allows the oxygenated blood The aortic valve cusps are covered by a continuous layer to enter the aorta and the systemic circulation of the body. of endothelial cells which provide a smooth surface on the The closing phase starts at the beginning of diastole when 8 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 the left ventricle dilates and fills from the left atrium. These valve leaflet tissue repair and therefore helps determine the opening and closing phases of the native aortic valve are vital structural integrity and/or durability of the aortic heart valve for theproper dynamic transport of oxygenated blood [70]. leaflet tissue. It has been suggested that heart valve interstitial Due to the pulsatile nature of the blood flowing through cells preserve valve tissue homeostasis through a controlled the valve, the blood reaches its maximum velocity after the extracellular matrix, mostly by collagen biosynthesis. It is leaflets have fully opened in the first half of the systolic phase. importantto understandthe relation between the oxygen During the second half, the flow rate decreases quickly. The tension in the valve tissue and the leaflet cells biosynthetic small pressure gradient that is developed affects the low activity. The existence of a blood supply and capillary network momentum fluid near the wall of the aortic root more than within aortic valve leaflet tissue suggests that oxygen deliv- that at the centerline. This causes a reverse flow in the sinus ered to the tissue by diffusion is not enough. More oxygen is region, which has an irregular concaved-like morphology. This delivered to the cusps by microcirculation [70-73]. reverse flow increases during the closing phase and impacts It is known that aortic valves possess significant mechani- the valve at the start of diastole, as shown in Figure 8 [71]. cal properties in order to function.A large cellular population, including mostlyfibroblasts and myofibroblasts, are present in the leaflet tissue. This implies that oxygen factors, such as consumption (VO ) or diffusion (DO ), of the valve leaflet 2 2 tissue need to be taken into consideration. Unfortunately, for different vascular structures, these values are not available as they have not been measured. For example these values for the dog femoral artery at body temperature (37°C) is –4  –1  –1  VO  =1.8×10 mL O ×mL O · mL tissue · s and the for dog 2 2 2  –6  2  –1 aorta adventitia DO =11.4×10 cm · s . Also, as an impor- tant oxygen parameter in the leaflet tissue, the solubility of oxygen within the tissue needs to be taken into account.The solubility of blood in plasma at body temperature (37°C) is –5  –1 –1 2.82×10 mL O · mL tissue · mm Hg . In addition, water con- 2  tent of the valve leaflet tissue is 90%, sosolubility of oxygen in the valve leaflet is then calculated to be 90% of that for –5  –1  –1 plasma, k=2.54×10 mL O · mL tissue · mm Hg . On the basis 2  of these oxygen transport factors and assuming that PaO is 2  100 mm Hg, the assessed maximum distance that oxygen Figure 8. Typical flow curve for the aortic valve showing can be supplied from the leaflet surface into the tissue is various events during diastole [71]. nearly 0.2 mm. The significant amount of oxygen delivered through the vascular supply of the aortic valve is located- During systole, vortices and secondary circulation zones de- mainly at the valve base. This is because tissue thickness is velop in all three sinuses right behind the leaflets of the aortic high,ranging from 0.692 to 0.860 mm. It is assumedthat the valve, which significantly assists in a quick and efficient valve oxygen transport properties,such as diffusivity and solubility closure. The backflow volume (or the regurgitation flow during of oxygen within the tissue,and the metabolic requirements closure) has been shown to be less than 5% of the forward flow of the valve are closeto those of other vascular structures. in native valves, more for prosthetic valves. This period of re- By assuming this,is clear that an oxygen supply route, such verse flow can be measured using experimental means, such as as microcirculation,in addition to that of diffusion from the Doppler ultrasound techniques or computational methods [72]. leaflet surfaces is required for places where the leaflet tissue In each cycle atthe end of the closing phase, there is a massive thickness is higher than a certain value [73]. impact, known as hammer pressure, which is applied on the Given that the thickness of the leaflet tissue is highly aortic side of the valve, i.e., fibrosa. This pressure is a typical variable, the largest part of the leaflet receives the necessary force experienced by a valve in the aortic position and is similar oxygen by diffusion from the blood stream surrounding the to the water hammer effect. This load is a pressure induced valves. However,if the thickness is higher than a given value, force caused by the kinetic energy of moving blood when it the leaflet tissue may need an additional oxygen supply route. is forcedto stop or change direction rapidly. For native aortic This route would be through the microcirculation and micro cardiac valves, this closing phase takes about 35 ms and the arteries in the tissue. This is due to the collagen content in the impact lasts foralmost 5.8 ms. leaflet, which changes the thickness of the leaflet locally. The area of the leaflet is comprised of large amount of collagen Heart Valve Tissue Oxygenation fibers in the form of bundles that reach an average thickness The partial pressure of oxygen has a controlling effect on the of 0.2 mm. The corrugated surface of the leaflets due thepres- 9 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ence of collagen bundles also provides a larger surface, which pulmonary valve. Since the pulmonary valve leaflets are thin- can increase the available surface for oxygen to be delivered ner, that they can function well within the high-pressure and to the tissue via diffusion. Also, when a leaflet is loaded or oxygen-rich environment of the left ventricle and the aortic unloaded due to systolic and diastolic pressures, it will affect root, in spite of the loss of blood supply. This is because of the tissue thickness. The change in thickness is not prevalent the pulmonary valve’s capability to receive enough oxygen in the base regions, but can be up to 40% in the other regions through diffusion only from its surfaces in the new position. of the leaflet tissue. This relatively high thickness change in Also, the new environment has a higher partial pressure of the areas far from the base region explains why oxygen is oxygen compared to the previous i.e., native PO environ- 2  supplied only by diffusion there and that microcirculationand ment in the pulmonary circulation is 40 mm Hg whereas the presence of micro arteries is not required. Another point to pressure in the aortic root is 100 mm Hg. Valve leaflets are take into consideration is when two adjacent leaflets come to complicated structures with a precise balance of components, contact at the end of systole, one side of the leaflets becomes soa slight change in geometry and composition can lead to passive and would no longer be able to receive oxygen from significant functional effects. Due to this,tissue characteristics, both sides of the tissue via diffusion [74]. cellular density,oxygen consumption and diffusion properties The microcirculation components and micro arteries thatare must be well understood. This is essential for the application present close to the base are mostly capillaries and areknown of tissue engineering of the heart valve leaflet tissue [77]. as the capillary bed.However, the presence of arterioles and venules has been also reported. This bed is located mostly Mechanical Characterization of Aortic Valves in the spongiosa layer, which is almost in the middle of the The aortic valve is a unidirectional and almost passive check- leaflet. The presence of the microcirculation at any location valve that controls the direction of blood flow from the left in the leaflet indicates that the partial pressure of oxygen due ventricle to the rest of the body through the systemic circula- to diffusion is considerably low. As such, micro arteries are tion. Mechanical stresses such as tensile, shear and bending required to supply additional oxygen to the tissue. In addition, stresses are high and time-dependent as they change very the density of the micro arteries may vary from location to quickly during the opening and closing phases. Each heart location in the leaflet tissue,enough that almost 30% of the beat, known as a cardiac cycle, causes one time opening and base region and nearly 3% of other leaflet areas are vascular- one time closing on the aortic valve. This takes almost 0.83 ized. It has been shown that the density of the micro vessels seconds. This cycle repeats approximately 100,000 times a day 3, in the base of the left coronary leaflet is 4.9 vessels/mm and almost 3.72 billion times in an average lifetime. A cascade whereas in the other layers, such as the noncoronary and right of biochemical and biomechanical events at the molecular coronary leaflets,it is almost the same at5.1 vessels/mm In and cellular leveloccurin order for the aortic valve to maintain the regions relatively far from the base, the density of micro its function. In fact, any types of valve abnormality (which vessels decreases to approximately0.66 vessels/mm [70-75]. could be congenital or due to disease or trauma) affect its Given that the major factor in oxygen supply and demand function in a substantial way.The extracellular matrix (ECM), is the thickness of the leaflet tissue, it should be noted that the main portion of the leaflet tissue, is the extracellular part the metabolic rate within the tissue is just as important. The of multicellular structure that provides structural, biochemical metabolic rate of the tissue depends on the state of the and biomechanical support to the tissue cells. Asmulticellu- tissue,as damage and repair may significantly affect the larity evolved independently in different multicellular roots, metabolic rate. Therefore, metabolic rate plays a major role the composition of the ECM differs between multicellular in the oxygen supply to the tissue and the tissue composi- structures; however, cell-to-cell communication, cell adhesion tion, including the formation of microcirculation and micro and differentiation are common functions of the ECM. The vessels [76]. ECM within the heart valve leaflet tissue mainly consists of These factors are extremely important in tissue engineering collagen, elastin, proteoglycans (PGs), and glycosaminoglycans of heart valve leaflet tissue. Given the porous structure of a (GAGs). The ECM plays a major role in the unique mechanical scaffold and cells sitting sporadically within the scaffold, a full properties of the valve tissue and the overall valve function. understanding of leaflet function, anatomy, state, and oxygen Within the ECM, there is another protein known as pericellular demand and supply for cells is necessary. In general conditions metrics (PCM). PCM bonds with and immediately surrounds with a normal metabolic rate, an overall thickness of nearly the cells. The role of PCM is to serve as a source of ligands 0.4 mm is enough for a leaflet to obtain its essential oxygen for cells receptors. When the leaflet tissue is under external via diffusion. A good example is the comparison between loads, PCM transfers these mechanical forces to the cells and the aortic valve and the pulmonary valve in the Ross Proce- develops intracellular signaling pathways. There are multiple dure. The Ross Procedure is a particular aortic valve surgery types of ECM with different distinctive mechanical proper- in which the patient’s diseased aortic valve is replaced with ties so that a variety of micromechanical environments are his or her own pulmonary valve. The pulmonary valve is then available for the tissue cells. This is significant because there replaced with a xenograft valve or a cryopreserved cadaveric is strong hypothesis that the tissue cells react to mechanical 10 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 signals and consequently adapt gene expression and protein production. Also, ECM can easily link with soluble molecules in the ECM, e.g., growth factors, so it can host variety of bioactive factors which are influential on cell behavior. Any changes in the composition of the ECM are significant because it may lead to heart valve disease and/or majorly affect the valve functions [78]. The valve leaflet is soft and flexible andhas a layered, com- plex and heterogeneous architecture. Three distinct layers Figure 9. (a) Mechanical behavior of collagen and elastin fibers during the cardiac cycle and (b) the morphology of the aortic are identifiable, two of which are known as structural layers: leaflet during the opening and closing phases, i.e., systole and fibrosa and ventricularis. The third layer is a non-structural diastole [81]. layer which is located in between fibrosa and ventricularis, known as spongiosa. Like other tissues, the leaflet tissue has an extremely specialized, functionally adapted extracellular bundles in the fibrosa layer, and in addition forms a three- matrix. The mechanical properties of the valve tissue have dimensional interconnected network in the spongiosa layer. direct impact with the composition of the matrix, including When the tissue is unloaded, these networks cause the col- collagen, elastin and PGs. It is important for the heart valve lagen fibers to return to their wavy and crimped shape in the leaflet tissue to be soft and flexible when unloaded, but nearly three layers of the valve tissue. The particular roll of each layer inextensible, strong and stiff when fully loaded. The design is varying. Fibrosa is thought to be load bearing due to the features of the leaflet tissue include a rippling surface, which presence of collagen fibers. The role of spongiosa is conferring is like an array of collagen fibers and bundles in fibrosa elon- flexibility, dampening vibrations from closing, and resisting gated from one commissure to the other commissure. Elastin delamination due to the presence of glycosaminoglycans and collagen are the main proteins that provide mechanical and proteoglycans. The role of ventricularis is restoration of characteristics of aortic heart valves. Elastin is a protein which the wavy and crimped state of collagen fibers in ventricularis is structurally available in sheets, tubes or fibers. It is highly due to its high amount of elastin [82]. extensible and elastic, having a stiffness of almost 2100 times Aortic heart valve leaflet tissues are highly nonlinear, less than collagen fibers. Given that elastin has a relatively low anisotropic and heterogeneous. These properties have been mechanical stiffness, its energy loss in cyclic loading conditions developed according to the physiological conditions of the is extremely low. It is so low that that it is considered to be the valve and are consistent with the mechanical environment in purest natural elastic material. The maximum load and force which the valve functions. The two main directions in which on the leaflets is when the valve is fully closed, which happens the mechanical properties of the valve leaflet tissue are fo- in the diastolic phase. In the very early stages where load is cusedare the commissure-to-commissure direction (known small, the tissue offers a very small resistance to elongation. as the circumferential direction) and the radial direction In this stage, only elastin fibers provide mechanical strength (perpendicular to circumferential). During diastole, when the and force transmission. In this stage, elongation of the tissue load applied on the tissue is maximum, collagen fibers and is relatively high and collagen fibers are coil-like structures. bundles in the fibrosa layer are the layer responsible fortoler- Upon load increase, the collagen fibers start to uncoil and ating nearly 80 mmHg pressure. In order for the leaflet tissue gradually stretch. As the strength and stiffness of the tissue to withstand such a high tensile load, collagen fibers bond increases, the amount of force on the tissue also increases, and together. They formparallel collagen bundles that are aligned accordingly more collagen fibersuncoil. In this stage, elastin in the circumferential direction. Although the collagen fibers fibers do not contribute to the mechanical characteristics of have nearly 1-2% yield strain, the crimping and waviness of the the tissue.In addition, elongation of the tissue is consistently fibers allows the fibrosa to tolerate approximately 40% strain low and the main elements providing mechanical strength in when fully loaded. Flattening of wavy fibers provides nearly are collagen fibers. In excessive loading conditions, when the 17% strain capacity, whereas the waviness allows additional force would further increase,the tissue cannot tolerate it and nearly 23% strain capacity. During the opening phase, leaflets eventually ruptures. When the tissue tears apart, the corruga- are relaxed and elastin maintains the mechanical strength of tions completely flatten and the crimps of the collagen fibers the leaflet tissue. In this phase, collagen fibers return back to become oriented in the radial direction. In a complete cardiac their original wavy and crimped shape and the surface area cycle, the leaflet dimensions changes between the systolic of the tissue isdecreased. Spongiosa, which mainly consists anddiastolic phases, but there is no change in dimensions of GAG fibers, enables the rearrangement of the collagen and during systole or diastole (Figure 9) [70-80]. elastic fibers, diminishes vibration, dissipates energy from The attachments of the three layers are made ofelastin closing, provides a smooth contact between the leaflets, and fibers that are distributed in the entire leaflet tissue. Elastin prevents delamination between layers [80]. also provides intrafibrillar binds between collagen fibers and In case of diseased aortic valves, for example; the calcific 11 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 aortic valve, collagen fibers and bundles as well aselastin fibers est on the endothelium layer in the noncoronary sinus of the in the fibrosa layer are disrupted and disordered. Due to this root. This is due to drag force being less due to hemodynamic proteoglycan deposition is increased. ECM remodeling occurs conditions around the coronary outlets, which justifies why because of matrix metalloproteinases and the potent elastase the noncoronary leaflet is affected more intensely than the cathepsin S, which are composed ofmacrophages. Also, in other two leaflets. Also, if two of the leaflets fuse together, calcific fibrosa, osteocalcin and osteonectin, which are bone the calcification process is accordingly affected. Patients with proteins, are found in the tissue. These proteins accelerate bicuspid valves are subjected to higher shear and normal mineralization and cause the osteoblastic differentiation of stresses, which lowers the calcification process considerably. valvular interstitial cells [81]. However, almost all patients with bicuspid valves develop significant hemodynamic complications over time leading Calcification of the Heart Valve Tissue to aortic stenosis, which is not the case for patientswith a Aortic valve calcification is a condition where calcium depos- trileaflet valve (Figure 10) [80-82]. its accumulateon the aortic valve. These deposits can cause (1) weakening of the structure of the leaflet tissue, and (2) narrowing at the opening of the aortic valve. This narrowing can become significant enough that it may reduce blood flow through the aortic valve, a condition called aortic valve stenosis.Aortic valve calcification may be an early sign for a heart disease, even if the patient does not have any other heart disease symptoms. Generally, calcification and stenosis affect patients who are 65+ in age. However, when it occurs in younger patients, the reason might be acongenital heart diseaseor kidney failure. Calcification is one of the significant issues leading to the mechanical failure of tissue heart valve replacements. After treating tissue valves with glutaraldehyde, calcification originates primarily within remainingcells that Figure 10. Histology of a calcified leaflet tissue in the early have been devitalized. In this process, the tissue is covered and late lesions. Early lesion determines accumulation of with calcium phosphate mineraldeposits through a reac- cells, extracellular lipid, and matrix in the sub-endothelial region on fibrosa, which is characterized by movement of tion of calcium-rich extracellular fluid with phosphorusin normal sub-endothelial elastic lamina. In the late lesion the tissue. Calcification of the heart valve leaflet tissue and however, accumulation of lipid, cells, and extracellular matrix mineralization of bone are precisely the same concept. There is more significant. Elastic lamina is considerably moved and have been many studies as to how to prevent calcification discontinued. (Adopted from Verhoeff-van Gieson stain, original magnification ×100) [83]. in the heart valve leaflet tissue, which are summarized into 4 categories: (1) Making a stable link between calcification- inhibitors and glutaraldehyde fixed tissue, (2) Removing ormodifying calcifiable agents, (3) Modifying glutaraldehyde In the early stages, extracellular lipid accumulation is ob- fixation, and (4) Usinganother tissue cross-linker other than served in several minor regionsunder the endothelial layer, glutaraldehyde [80-82]. also known as sub-endothelial level. In this stage, the elastic Calcification ofthe aortic valve is a slow process. Itwas lamina is displaced and extended into the nearby layer, i.e., initially thought to be a deteriorating mechanism because fibrosa. There is histological evidence indicating that plasma of the vigorous wearandtear of the leaflet structures. In this lipoproteins are the source of these lipids. The formation of mechanism, calcium is passively deposited on the leaflets. foam cells takes place whenadapted low density lipoprotein Based oncomprehensive histopathological and clinical data,it (LDLs), which are related to proinflammatory and growth- is known that calcification process in aortic valves is an active stimulatory properties, are taken up by macrophages. disease similar to atherosclerosis with chronic inflammation, In the early stages, inflammatory cells includingT lympho- lipoprotein deposition, and active leaflet calcification. In the cytes and macrophagesplay a major role in the calcification early stages, variation of mechanical forces, such as shear stress, process. Macrophages are differentiated from monocytes, may form a notch on the aortic valve leaflets as a result of which have been penetrated to the endothelial layer by adhe- endothelial disruption. The state of normal and shear stresses sion molecules. T lymphocytes are activated within the sub- is influential on the calcification initiation and progression endothelium and fibrosa and then release cytokines. Cytokines on the tissue. Normal stresses are highest on fibrosa near include transforming growth factor-β1and interleukin-1β, the attachment of the leaflets and the root at the beginning which is a proinflammatory cytokine related to matrix metal- of the systolic phase, simply because the leaflets act like a loproteins. All of these proteins contribute to the formation of cantilever beam. Among the three sinuses, shear stress is low- extracellular matrix, remodeling, and focal calcification [72]. 12 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 Angiotensin-converting enzyme (ACE)is also identifiable in may be congenital or due to other causes later in life. the calcification process. It can be formed locally or extracel- lularly and colocalized with apolipoprotein B. The colocalized Congenital Valve Disease  ACE with apolipoprotein B is a module of taken LDL particles, This type of valve disease most often affects the aortic or which implies that the ACE could be carried into the lesion via pulmonary valve due to geometrical issues. These include LDL cholesterol particles. Moreover, angiotensin II, which is an abnormal size of the valve, the issues with the leaflet the promoted version of monocyte infiltration and the uptake geometry or the way they are attached [75-77]. of modified LDL within atherosclerotic lesions, is observed In the aortic valve, two of the leaflets may fuse together in the early stages of the calcification process. This suggests and play the role of one, which is known as bicuspid aortic that ACE is active enzymatically. Also, a fraction of fibroblasts valve disease. In this case, instead of the normal three leaf- within the fibrosa is transformed into myofibroblasts, which lets or cusps, the aortic valve has only two leaflets. This can are similar to smooth muscle cells with expression of α-actin, reduce the compliance of the valve and leaflets, which in desmin, and vimentin. In advanced stages, angiotensin type-1 turn negatively affects the dynamics of the valve in the clos- receptors form on a fraction of the myofibroblasts that ex- ing and opening phases. One of the issues of bicuspid aortic press α-actin, further reinforcing that ACE detected is active valve diseases is the leakage due to the non-parallel contact enzymatically [72-75]. between the two leaflets [75-77]. In the early stages of the calcification progression, the pro- cess is active and quick,which essentially leads to the leaflet Acquired Valve Disease hardening and severe stenosis. In areas where lipoprotein is A range of diseases and infections, such as endocarditis or built-up and inflammatory cells are infiltrated, microscopic rheumatic fever, may affect the structure and composition of regions of calcification are observed. Matrix vesicles (the loca- normal valves which is also known as acquired valve disease tion of calcification) are released when valvular fibroblasts are (Figure 11). stimulated by oxidized LDL. A protein which participates in bone formation, osteopontin, is expressed by macrophagesin A B which the level of mRAN expression is proportional to the level and location of calcification. A portion of myofibroblasts consists of osteoblast phenotypes,which participate inthe de- velopment of calcific nodules. The formation of these nodules is increased once the myofibroblasts are exposed to oxidized LDL and transforming growth factor-β1.During the calcification progression, deposition of calcium on the leaflet continues in a rapid way,which is the same as bone formation. For sig- Figure 11. Diseased aortic valve: (A) Rheumatic Fever, and nificant number of patients (~85%) ,the type of calcification (B) Endocarditis [84]. is dystrophic.For the remaining 15% of patients, it is lamellar or endochondral bone tissue where hematopoietic marrow and remodeling are evidenced. Bone tissues on the leaflets An untreated bacterial infection, which is usually strep throat, lead to expression of factors promoting osteogenesis. In pa- might be the reason for rheumatic fever. The initial infection tients with increased bone demineralization or osteoporosis, typically happens in children and is the origin of inflammation the occurrence of calcification is higher. This is thought to be of the heart valves. However, symptoms associated with the related to ectopic calcification or an increased body mineral inflammation may become apparent 20-40 years later. Also, turnover. The calcification progression may be controlled by the presence of bacteria in the bloodstream for whatever factors such asconnective tissue growth factor, polymorphisms reason may cause endocarditis. This may cause growths and of interleukin-10, and chemokine receptor-5 [76]. holes in the valves and scarring, which in turn causes leakage Calcification is also an issue with bioprosthetic valves. in the closing phase [78]. However, the occurrence of calcification innative valve failure Some of the geometrical or structural issues associated with appears to increase with age, which is in contrast to tissue the diseased valves are: (1) the chordae tendinae or papillary native valves. This inconsistencyproposes that the calcification muscles may stretch or tear, (2) the annulus of the valve can process of bioprosthetic valves is unlike the process perceived dilate and become wide due to structural deficiencies, and in native valves [77]. (3) the valve leaflets can become stiff, fibrotic and calcific [85]. Mitral valve prolapse (MVP) is a geometrical and con- Aortic Valve Disease structional deficiency of the mitral valve which affects 1% Valvular heart disease is any disease involving one or more to 2% of the population. While the mitral valve cannot hold heart valves (the aortic and mitral valves on the left and the its structural integrity, the leaflets flop back into the left pulmonary and tricuspid valves on the right). Valve problems atrium during diastole (the heart’s contraction).In turn, the 13 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 back flow rate and static leakage significantly increases. MVP motion affects around 25% of the population above the age also causes the tissues of the valve to become abnormal and of 65. Calcific aortic stenosis, however, affects roughly 2% to stretchy, which specifically occurs in the anterior-posterior 3% of the population above the age of 75. Congenital bicuspid direction, perpendicular to the transverse direction of the aortic valve stenosis is known to be the main source of aortic valve (Figure 12). stenosis; the estimated overall occurrence of an anatomic bicuspid aortic valve is around 1% to 2% of the population. Of these, about 50% are prone to develop aortic stenosis and up to 30% will develop aortic regurgitation. Aortic stenosis due to a congenital bicuspid aortic valve is more frequent in men compared to women, but later life calcific disease of the aortic valve affects both genders similarly. Congenital aortic stenosis is typically caused by failure of the valve commis- sures that causes aortic stenosis, mostly in young adults or children [72-76]. Aortic valve disease such as calcific disease, calcification of the congenital bicuspid valve, and congenital aortic stenosis can be mostly diagnosed clinically by the evaluation of echo- cardiography data. Calcific aortic stenosis, which is known as degenerative or senile form, involves patients with other risk Figure 12. Mitral valve prolapse: side view of the factors for atherosclerotic disease. The progression of aortic normal valve on left and the diseased valve on right valve disease is a dynamic process, with inflammation, lipid [86]. deposition, and calcification. This type of aortic stenosis pro- Treatment may be with medication but often (depending on gresses gradually for the patients between the ages of 70 and the severity) involves valve repair or replacement. The aortic 90. Echocardiography is usually effective in finding varying valve is the heart valve that is the most susceptible to diseases degrees of nodular thickening and calcification of the leaflets as it sustains the largest pressure difference between the left with limited systolic motion. Adult patients with congenital ventricle and the main aorta. This is neccessary to ensure the bicuspid valves (also known as heart murmur) are mainly oxygenated blood is distributed effectively throughout the men and and is most commonly found in patients between arterial system [71]. the ages of 40 and 60. In bicuspid valves, two of the leaflets There are two major diseases that can affect the aortic are typically merged together. This can be diagnosed using valve: (1) aortic stenosis, in which the valve fails to open fully, electrocardiography by the presence of a raphe, eccentric thereby obstructing blood flow out from the heart, and (2) closure, leaflet doming, and fish mouth orifice during sys- aortic insufficiency (also known as aortic regurgitation) in tole. Congenital aortic stenosis in which the valve is either which the aortic valve is incompetent and blood flows pas- unicuspid or bicuspid typically occurs in children and infants sively back to the heart in the wrong direction. These two and can be diagnosed using echocardiography data. Minor conditions frequently co-exist. Whatever the cause of valvular causes of aortic stenosis includerheumatic disease, radiation disease, it burdens the heart with an increased work rate to heart disease, and homozygous hypercholesterolemia [76]. maintain stroke volume. This could lead to: (1) heart muscle Aortic stenosis may cause chronic left ventricular hyper dysfunction (including left ventricular hypertrophy), and (2) pressure. In all ages, the natural history of aortic stenosis potential congestive heart failure [72]. and the functional integrity of the mitral valve are related to one another. As long as sufficient mitral valve function Aortic Stenosis is preserved, the pulmonary bed will not be affected by the Aortic stenosis is mainly due to obstruction of blood flow systolic hyper pressure caused by aortic stenosis. Contrary at the aortic valve and does not includethe subvalvular and to mitral valve disease, in which the pulmonary circulation is supravalvular types of this disease. Aortic valve stenosis is typi- directly influenced, compensatory concentric left ventricular cally characterized by restricted systolic opening of the valve hypertrophy permits the hyper-pressurized ventricle to sustain leaflets, in which the mean transvalvular pressure gradient stroke volume with slight growths in diastolic pressure. In some is at least 10 mm Hg. The reason of the stenosis can be also cases, patients may stay asymptomatic for several years [76]. characterized by the anatomy and disease process affecting Ultimately, however, left ventricular hypertrophy leads to the valve tissue [72-75]. either diastolic dysfunction with the initiation of congestive Two of the major aortic stenosis cases are calcific aortic and symptoms or myocardial oxygen requirements exceeding congenital bicuspid aortic stenoses. Minor cases include rheu- supply, causing the initiation of angina. In some patients, matic aortic and congenital aortic stenoses. Minor thickening exertional syncope can occur, possibly reflecting the incapa- and/or calcification of the aortic valve without limited leaflet bility to increase cardiac output and sustain blood pressure 14 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 as a reaction to vasodilation [76]. Aortic Regurgitation or Aortic Insufficiency Aortic regurgitation is characterized by the ineffectiveness of the aortic valve, causing a portion of the left ventricular forward stroke volume to returnto the left ventricle during diastole. The reason of the regurgitation, as for aortic stenosis, can be further characterized due to the anatomy of the valve, aortic root, and the disease process influencing the valve [77]. Aortic regurgitation is mainly a product of leaflet pathol- ogy or aortic root disease,but alsocould also be caused by a congenital unicuspid or bicuspid aortic valve often due to leaflet prolapse. Infective endocarditis affecting the aortic valve may lead to aortic regurgitation because of lack of coaptation, Figure 13. Heart valve disease and available options. perforation, or leaflet retraction. In fact, aortic root dilation and loss of leaflet coaptation due to any pathological process can lead to aortic regurgitation. As to the related diseases of ally worldwide. The age range of the majority of patients with the aortic root leading to aortic regurgitation, the following aortic valve pathology in need of replacement is between 60 diseases can be outlined: annuloaortic ectasia, familial aortic and 80. Among the two main aortic valve diseases, replacement aneurysmal disease, long standing hypertension, hereditable for aortic insufficiency, aortic stenosis of ~15% is performed diseases of connective tissue (e.g., Marfan syndrome), and much less frequently than for aortic stenosis of~85% [1]. As ventricular septal defects as observed in tetralogy of Fallot. of the related diseases to aortic stenosis, there are several of Minor conditions includeEhlers-Danlos syndrome, radiation note, including congestive heart failure, syncope,angina, or a heart disease, inflammatory aortitis, aortic valvulitis developed combination of these. If left untreated, the life expectancy of by giant cell aortitis, syphilitic aortitis, ankylosing spondylitis, patients reduces significantly. For instance, it would be a 50% reactive arthritis, and rheumatoid arthritis. Chronic aortic re- reduction over a period of 5 years for angina, over a period of gurgitation leads to volume overloading of the left ventricle 3 years for syncope, and over a period of 2 years for conges- and, unlike mitral regurgitation, also leads to an increase of tive heart failure. Also, these diseases in a small percentage of pressure in the left ventricle. The volume overload could be patients may cause sudden death. Aortic insufficiency has a insignificantand thereforecause no important symptoms slower progress rate than the aortic stenosis as it can normally for possibly decades [77]. The consequence of aortic regur- be diagnosed by fatigue symptoms. In some cases, it can be gitation is an intense diastolic leak, left ventricular dilation diagnosed by the slow development of congestive heart failure, and hypertrophy, where the left ventricle becomes a more and in these patients typically angina pectoris and syncope spherical shape. The ejection fraction generally is conserved don’t occur often. In order to diagnose these diseases, normally untilthe final stages of the disease. Since patients may resist echocardiography is implemented to assess ventricular func- against severe aortic regurgitation with minimal symptoms, tion, the severity of stenosis, and insufficiency. Also, cardiac constant careful monitoring of left ventricular dimensions and catheterization is performed to evaluate cardiac output and systolic function should occur. This is because the aortic root estimate aortic valve area. An image-based method can be and proximal ascending aortic dilation can happen together. implemented in the coronary arteries to check for any major Aortic valve replacement is in order if a patient is sympto- lesions. To predict postoperative prosthetic valve infection, a matic from either aortic insufficiency or aortic regurgitation, precise dental or oral examination is usually performed [1-5]. or if the heart begins to expand as tested by echocardiogram. There are a number of options for repairing or replacing Other types of valve disease consist of: (1) coronary artery the diseased valves. Although surgery is a common solution, disease, (2) myocardial infarction, (3) cardiomyopathy (heart there are novel non-surgical procedures under developed muscle disease), (4) syphilis, (5) hypertension, (6) aortic aneu- nowadays. Some available surgical techniques include [2-7]: rysms, and (7) connective tissue diseases. Rare cases include • A commissurotomy surgery is applied to diseased valves tumors, some types of drugs, and radiation. There are two with thickened and fused leaflets. This surgery, known main options available to remedy the diseased valve: (1) heart as valvuloplasty or valvular reconstructing procedure, is valve repair, which leads to tissue engineering and regenera- done by cutting the spots in which the cusps are stuck tive medicine, and (2) heart valve replacement, which leads together. to medical devices (Figure 13). • In some other cases, if the issue is with the annulus, the required surgery is called annuloplasty. In this surgery, Prosthetic Heart Valves sutures are sewn around a circle so that the opening There are nearly 350,000 valve replacement procedures annu- becomes smaller. In more severe cases, a well-designed 15 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 ring (known as an annuloplasty ring) holds the original ge- mitral valves. In general, there are two types of valves that ometry of the healthy annulus. It is applied to reconstruct are considered for valve replacement: the annulus back to its original shape. The annuloplasty (1) Mechanical valves must be made up of durable bio- ring provides more mechanical support to the valve so it materials such as metals, carbon, ceramics and polymers. A can function more effectively. A surgeon may reconstruct sewing ring wrapped with a biomaterial is used to attach a valve by removing some abnormal segments (such as the valve to the tissues in the patient’s heart. The major ad- fatty bulges or calcified nodules) off the diseased cusps vantage is durability. However, anticoagulant therapy (blood and sewing it back together. diluter) must be taken the rest of the patient’s life to prevent • If the issue is with the deposition of calcium on the valve thromboembolism (blood clots). tissue, decalcification surgery is applied and calcium (2) Biological or tissue valves (known as xenograph) which buildups from the leaflets are removed.  are made up of animal tissue such as pig (known as porcine • The Mitral and tricuspid valves are supported by cords, valves) valve or a pericardial tissue of cow (known as bovine known as chordae tendineae, and papillary muscles. If valves). the issue with the diseased valve has to do with the cords, (3) Human tissues donated from a cadaver (known as al- i.e., stretched or weakened cords, which may lead to the lograft or homograft) are also an option. valve ineffectiveness, the surgery required would replace (4) The replacement can be harvested from patient’s own or shorten the cords.   tissues (known as autograft), which is through a surgery • If there are holes or tears in the cusps, a tissue patch known as the Ross procedure (also called switch procedure). may be applied. In this surgery, the valve is taken from the patient’s normally There are fairly new techniques (to be discussed later) where functioning pulmonary valve and is replaces the diseased the surgical process is done but with much less damage on aortic valve. The pulmonary valve is then replaced with a patients. These approaches are collectively known as minimally prosthetic valve, such as homograft or porcine valve. Biologi- invasive surgery (MIS). In MIS, surgeons monitor the heart cal valves are not mechanically efficient and have durability using an appropriate imaging technique and operate using issues, unlike mechanical valves, and need to be replaced a new class of surgical tools inserted through small incisions. every 10 to 15 years. Also, anticoagulant therapy may be Minimally invasive valve repair is a developing technique that needed for these patients for a short duration. Bioprosthetic is also known as endoscopic or robotic heart surgery [18]. valves are mostly recommended for young patients, while Furthermore, there areother techniques under development mechanical valves are recommended for the elderly. This is highly regarded asreplacements to conventional surgeries, mainly because older patients may not be able to afford a known as non-surgical therapy. These techniques are called new open heart surgery [45-51]. percutaneous or catheter-based surgeries thatdo not require any chest incisions and patients do not need the heart-lung Indication for replacement surgery machine during the procedure. A thin elastic tube (known as Heart valve replacement was first initiated in the early 1960s a catheter) is inserted into the body through a blood vessel and is now a normal surgical procedure. It employs devices and is then directed tothe intended destination in the heart. made of nonliving, nonresorbable biomaterials for used to Percutaneous or balloon valvuloplasty is applied in patients substitute the valvular mechanical functions. Replacement with calcifies or stenosed valves, which is more common for of heart valves offers a large improvement in the quality of the mitral valve than the aortic valve. An inflatable balloon life for thousands of patients and can be considered one of tip on the end of the catheter is situated in the stenosed valve the major accomplishments of biomedical engineering. It is and inflated to expand the opening,completely crushing the estimated that more than 280,000 replacement heart valves calcified tissue.  are implanted annually worldwide, makingthe social and For the mitral valve, multiple methods of percutaneous economic impact of heart valveresearch and development valve repair are in the development phase. If the gap between considerable [1-5]. the anterior and the posterior leaflets is large, it can be re- There is no assurance that a surgical procedure or medical paired using a technique known as edge-to-edge repair. In treatment canprevent or defer valve disease. Procedures such this surgery, a delivery catheter equipped with a clip is sent as balloon valvotomy could be applied as a bridge to surgery, through the femoral vein from the groin into the left part of with a temporary relief of symptoms beingprovided. Patients the heart. The clip is situated beyond the diseased valve in with symptomatic severe aortic stenosis, who may also have an open location and then pulled back so that it hooks the undergoneother cardiac procedures like coronary artery by- leaflets. Once closed, the leaflets are held together and the pass graft surgery, have a poor prognosis and are considered valve leakage is fixed [27-33]. for aortic valve replacement. The severity of aortic stenosis If repair is not sufficient for the patient, then replacement is assessed by diagnostic physical measurements,where could be an option. Replacement is more generally applied the effective orifice area (EOA), the hemodynamic features for the treatment of aortic valves or extensively damaged such as jet velocity, turbulence, the ejection fraction and the 16 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 transvalvular pressure drop are evaluated. EOA is generally Advent of caged ball valves was a major innovation in the measured by the Gorlin formula as follows: Orifice Area = CO/ treatment of patients with valvular heart disease. The place (HR.SEP. 44.3C. SQR(deltaP) where CO is the cardiac output, of caged ball valves in history remains undisturbed, as they HR is the heart rate, and SEP is systolic ejection period. 44.3C continue to serve as a benchmark against which the newer is a constant thatis assumed to be 0.1 for the aortic valve. In tilting disc and bileaflet designs are evaluated. It is also clear this formula,the unit of time is min, the unit of length is cm, from information in literature that these mechanical valves delta P is the pressure drop across the valve with the unit of comewith a number of complications, the majority of which are mmHg [21-32]. related to higher pressure drops and poor hemodynamics [87]. Mechanical heart valves are used to replace diseased hu- In 1952, Dr. Charles Hufnagel, implanted the first ever man heart valves in approximately 50% of cases. Bioprosthetic ball and cage valve,which was named after himself as the heart valves are used in the other 45% of cases. Pulmonary Hufnagel’s valve (Figure 14). This valve was a unique design autograft valves and human cryopreserved homograft valves of a ball entrapped in a transparent glassy type cage. The represent the remainder of implanted valves. Autografts and ball was made of methacrylate covered by silicon rubber homografts exhibit excellent durability after implantation, and the cage made of methacrylate. This material was the but are not readily available for all patients. first implanted in an animal model to test a tube made of methacrylate for arterial replacement in late 1940’s. The mate- Mechanical Heart Valves rial for the ball was immediately modified; instead, a hollow Mechanical heart valves (MHV ) are artificial valves made of nylon ball covered by silicon rubber was implemented. It was synthetic biomaterials that are developed to replace diseased thought that a smaller ball with smaller momentum could valves.They are designed to provide the same function as the reduce noise and enhance dynamic behaviour of the valve, natural valves of the human heart. This is applicable to the four such as the regurgitation flow and the impact force between human cardiac valves: tricuspid, pulmonic, mitral, and aortic the case and the ball. More than 200 of Hufnagel’s valves were valves, as discussed in the previous chapter. The main function implanted for patients with aortic insufficiency [87]. of the prosthetic valves is to preserve unidirectional forward In the early designs of caged ball valves, the issue was flow, which in turn regulates the flow of the oxygenated and with the contact that the ball could make with the aortic wall deoxygenated blood through the systemic and pulmonary during the systolic phase, which could lead to hemodynamic systems. These systems are connected to the heart by the vena complications in those regions. In order to address this issue, cava veins, pulmonary artery, pulmonary vein, and the aorta. the idea was to improve the cage by giving the floating ball Numerous cardiac valve disease processes, (explained briefly in a larger, yet controlled space. In this design, a second outer the previous chapter) of both acquired and congenital causes, concentric cagethat slightly penetrates the left ventricle may lead to one of the four heart valves diseases. They are in chamber was added to the valve. This model was implanted the form of stenosis, known as obstructed forward flow, and/ or increased backward flow, known as regurgitation/dynamic backflow. Each of the mentioned conditions would burden the heart with extra work andwould lead to serious complica- tions in the patients, such as heart failure [1]. In general, the durability of mechanical heart valves is long enough that the patient would not need another open heart and/or valve replacement surgeries. The issue with mechanical valves is that the patient would need to take anticoagulation therapy for the rest of their life. The main types of mechanical heart valves are considered as follows: (1) The ball and cage valves, (2) Disc and cage valves, (3) Tilt- ing disc valves, (4) Bileaflet valves, (5) Polymeric valves and (6) Percutaneous valves. Ball and Cage or Caged Ball Valves The first open heart surgery to repair a stenotic aortic valve took place in 1912. In this procedure, the aortic root wall was invaginated with a finger and the aorta was pushed through the valve. The next registered open heart surgery took place in 1914, which was about the dilation of a calcified aortic valve. This was achieved with apparatuses passed from the Figure 14. Hufnagel’s caged ball valve [88]. innominate artery or another arterial source [87]. 17 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 in 7 patients, two of which survived. The patients that survived damaged by the stellite ball. Model 2400, also known as the needed following valve replacements, one for a perivalvular track valve, was developed for the aortic position in 1972 leak after 3 years and one for bacterial endocarditis after 22 and the covering fabric of the stent was eliminated. There years. In these models, the ball (which was made of silicon) were other Edwards-Starr Models thatwere developed for showed excellent structural integrity as it had not deteriorated the aortic position, such as model 1260, and for the mitral after 22 years implantation [89]. position,such as models 6000 and 6120. In these models, the The next model of the the ball and cage valve was designed cage was fabric free and made of stellite and the ball made by M. Lowell Edwards, a retired engineer, and Dr. Albert Starr, of silastic rubber. These models were implanted more than a young cardiac surgeon, in the early 1960’s. The valve was 300,000 times worldwide with almostno issues with the ball commercially branded as the Edwards-Starr ball and cage due tothe postmold silicone rubber heat cure process. The valve. It was a bulky valve (Figure 15) where the ball was made last models of Edwards-Starr valves contained the stent or of elastomer rubber and the cage was made of methacrylate. strut with no cloth and the ball made of heat-cured silicon These were also known as Lucite (methacrylate) valves. This elastomer, which lasted until early 2000 [89]. valve was implanted in a 50 years old patient who was diag- nosed with calcific mitral stenosis and the patient survived Magovern-Cromie Ball and Cage Valve for several years. There was animmediate improvement on Other ball and cage models were developed as well in the the Lucite valves byswitching from methacrylate to stellite 1960’s. Dr. Magovern, a cardiothoracic surgeon, and Harry metal for the cage [89]. Cromie, an engineer,designed a ball and cage valve for the aortic position. It possessed a unique feature for fixation without suturing. Following their names, it was branded as the Magovern-Cromie ball and cage valve. In this model, the ball was made of heat-cured silicon rubber and the cage was made of titanium. For implantation, a rotating tool was de- signed in order to insert the valve into position and engage it with several vertical pins in the aortic annulus. This model had significant advantage over other available models at the time simply because the implantation process was quick. Thisremovedthe need for the cardiopulmonary bypass,which was not as safe and reliable as it is today. This valve was im- planted in aortic position in ~7300 patients and in the mitral position in ~200 patient till 1988. The issue with this valve was structural defect of the ball after some time, which was reported in 2%of patients. This was also the main issue with the Edwards-Starr valves, which was addressed properly later with the post-mold heat cure process of the ball (Figure 16-1). Figure 15. Edwards-Starr caged ball valve, ball is made of plastic and metal and stent (cage) made of sterile cases [90]. In the Edwards’ laboratory,several ball and cage models were developed for both the aortic and mitral positions over almost 10 years. A number of models of Edwards-Starr valves were commercialized and named as the Edwards-Starr 1000, 1200, Figure 16. (1) McGovern-Cromie caged ball valve designed 1250, 2300, 2400, etc. Model 1000 was developed for the aortic in ~1965, (2) Smeloff-Cutter caged ball valve designed in ~1966, (3) Debakey-Surgitool caged ball valve designed in position in the early 1960’s. In the1200 model, the cage was 1969, and (4) Braunwald-Cutter caged ball valve designed in made of heavy stellite, the annulus covered by Teflon fabric, 1968 [90]. and the ball a hollow stellite ball. The silicon rubber ball was no longerused because lipids could be absorbed, leading to fast deterioration. In the model 1250, the ball was made of Smeloff-Cutter ball and cage valve hollow stellite, and was little different from model 1200. The The next idea for a caged ball valve was to provide a full-flow issue with models 1200 and 1250 was that they were noisy. orifice model, which was commercialized as the Smeloff-Cutter Model 2300 was developed in 1967 where whole stent was ball and cage valve in 1966. This valve followed the name of covered by cloth. This could control the noise issue to some Dr. Edward Smeloff, a cardiac surgeon, and the Cutter labo- extent; however, the new issue was that the fabric could be ratory at the University of California, Berkeley. In this model, 18 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 two titanium cages were addedon each side of the valve and valve in 1965. This design was for the mitral position with the ball was made of heat-cured silastic. The effective design the cage made of stellite and the ball made of silastic. The of the cage allowed the silicon ball to sit on the smaller cage wear was still a major issue with the disc in this model,and in the closing phase. This valve was implanted in ~72,000 shortly after in 1975 the material used for disc was modified patients in both aortic and mitral positions (Figure 16-2) [89]. to Derlin. This model was implanted in 12,000 patients until 1980 when the manufacturing of these valves was stopped. Debakey-Surgitool ball and cage valve The Kay-Shiley disc and cage valve was probably one of the Dr. DeBakey and Harry Cromie of Surgitool proposed a new most widely used mitral valve prostheses from 1965 to 1980. design for a ball and cage valve, commercialized as Debakey- Later on, Dr. Kay improved the design of his valve by adding Surgitool caged ball valve in 1967. In this design, the cage was a muscle-guard in order to prevent disc impingement. This made of titanium and the ball was made of high molecular model was never marketed and was never used by any other weight polyethylene instead of heat-cured silicon rubber. surgeons other than himself [89]. However, the material for the ball was soon changed to a hollow pyrolytic carbon ball. This was the first ever valve in Beall-Surgitool Disc and Cage Valve which a new carbon-based material was implemented. The In 1971, Dr. Arthur Beall, a cardiologist, and Mr. Howard Cro- idea was to improve the quality of the ball to be more resist- mie of Surgitool designed a disc and cage valve where the ant against any structural defects. However, to some degree disc was fairly flat and made of Teflonwiththe cage made of hard the ball and soft titanium cage caused structural defects Titanium. A few design modifications were implemented on and rapid wear rate in the cage.Strut and cage fracture was this model such as: (1)a velour fabric was used to cover the reported in multiple occasions (Figure 16-3). [89]. annular apron, (2) the Teflon disc was replaced by Pyrolyte, etc. This model was implanted in nearly 5,000 patients in Braunwald-Cutter ball and cage valve the aortic position until 1985. The production of this model Drs. Braunwald and Morrow proposed a new model of ball was stopped mainly due tofabric wear on the annular apron. and cage valve wherethe cage was made of titanium and the ball was made of silicon rubber. In this model, the cage and Cooley-Cutter biconical disc and cage valve annulus werecovered by a flexible polyurethane-Dacron fabric. Similar to a biconical ball and cage valve, a biconical disc and This valve was used in the mitral position with attached Teflon- cage was proposed by Dr. Denton Cooley, a cardiac surgeon, ropefor chordae tendoneae. Later on, it was observed that the and his engineering colleagues at the Cutter laboratory in fabricwas penetrated by fibrous connective tissue,leading to late 1960’s, In this model, the disc was made of Titanium and the idea that covering the titanium cage with the ball and cage the cage was biconical and made of Pyrolyte. This model was valve fabric might decrease thrombus formation (Figure 16-4). conceptually very similar to the Smeloff-Cutter valvewherefull- The development of the cloth for covering the cage was flow orificewas achievable due to a double strut cage. This continued. In a new design, the cagewas covered with knit valve was implanted in nearly 3000 patients in both the mitral Dacron tubes and the inflow ring with an ultrathin polypropyl- and the aortic positions. ene mesh fabric, which led to low incidences of valve-related The major advantage of the caged ball and cageddisk problems. However, the main issue with this model was with valves over others isthat theymaintain a very simple design. the fabric. As itwas not mechanically stable, fabric wear and In fact, in these models,the onlymoving part is a ball or a disc silicon ball structural defect were reported frequently. in the most simplistic way. The major drawback of these valves, however, is that they have a poor hemodynamic performance. Disc and Cage Valves As theblood must flow around the ball, this lead to a higher From an engineering standpoint, it makes sense if the ball pressure drop across the valve and caused the heart to per- in the traditional ball and cage valve was replaced by a disc. form extra work. The disc cage valve is much worse than the For a heart valve, a lighter and more agile disc could be more ball and cage valves, which makes these valve have a higher effective (e.g., quicker dynamic response) than a heavy ball. rate of thromboembolism (Figure 17). This is because dynamic stresses on the occluder (disc or ball) and the cage could be reduced, the regurgitation flow could Tilting Disc Valves be lessened, and the overall dimensions of the valve could be From an engineering standpoint, if the motion of the disc in much smaller with a disc. The main question; however, was a disc and cage valve could be controlled by a mechanism, if disc and cage valves could offer a better hemodynamic it follows that the hemodynamics of the valve may improve performancethan ball and cage valves. significantly. One of the obvious disadvantages of the design of the disc and cage valve is the high pressure-drop across Kay-Shiley Disc and Cage Valve the disc. Also, the blood flow is easily disturbed due to the Dr. James Kay a professor of cardiac surgery, and Donald Shiley, geometry of the disc,which may lead to turbulent flow down- an engineer, proposed the first ever design of a disc and cage stream of the valve. This disadvantage can be addressed to 19 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 Figure 17. (1) Kay-Shileycaged disk valve designed in 1966, (2) Beall-Surgitool caged disk valve designed in 1974, and (3) Cooley-Cuttercaged disk valve designed in 1974 [90,91]. Figure 18. (1) Bjork-Shiley flat disk valve designed in 1960, (2) Bjork-Shiley convexo-concave tilting disc valve some point by improving the design of the cage and disc designed in 1975 [90,91]. valve by replacingthe floating disc with a tilting disc. Bjork-Shiley Flat Disc Valve disc was made of Pyrolyte and the strut was made of Titanium. in 1960, Dr. Viking Bjork, a cardiac surgeon, and Donald Shiley, The major feature of this model was the design of the strut an engineer,proposed the first tilting disc valve. In this model, wherethe motion of the flat disc of valve wasregulated by the disc was made of Derlin polymer, and instead of a cage, two protuberant side-prongs. This model was successful to they designed a strut. The strut was made of stellite, which some extent and was implanted in almost 55,000 patients in was intended to control the motion of the disc in both the both the aortic and the mitral positions. The fabrication of this opening and closing phases. This model was considered for valve was stopped in 1976 simply because it was replaced by both the aortic and the mitral positions and was implanted the consecutive models, the Omniscience tilting disc valves. in almost 300,000 patients until 1986. Derlin polymer was not an appropriate biomaterial for this application because Omniscience Tilting Disc Valve it absorbs water, which can cause defects in the structure of This model was a modification to the Lillehei-Kaster tilting disc the disc. In the later models of this valve, the material for the valve by Robert Kaster where the profile of the protuberant disc was changed to Pyrolyte in order to address this issue. prongs on the annulus was improved. Also, the disc of the Lillehei-Kaster valve was no longer flat. A slight curvilinear Bjork-Shiley Convexo-Concave Tilting Disc Valve profile in the Omniscience valve was incorporated to the In 1975, the geometry of the strut and the disc in the flat disk disc. In this model, the strut was made of Titanium and the Bjork-Shiley valve was significantly improved in order to pro- disc was made of Pyrolyte. This model has been implanted vide a better hemodynamic performance. In this model, the in almost 75,000 patients in the aortic position and in nearly two struts (inlet strut and outlet strut) were made of stellite 25,000 patients in the mitral position. The major feature of and the disc was made of Pyrolyte. The struts were welded this model compared to other available tilting disc valves to the annulus. The idea was to design a 3D structure for was its curvilinear disc. the strut to allow the disc to slide forward and downward by approximately 2 mm more, compared to the standard Omnicarbon Tilting Disc Valve Bjork-Shiley model. Also, the disc was no longer flat as it was The Omnicarbon and Omniscience valves were designed and replaced by a convexo-concavedisc. This model improved manufactured around the same time. The major advantage of the hemodynamics of the Bjork-Shiley valve significantly and the Omnicarbon over Omniscience was the material used for was implanted in almost 85,000 patients in both the aortic the strut, which was Pyrolyte rather than Titanium. The other and mitral positions. The main issue with this valve was the design features were basically identical. These two models fracture of the struts,and in particular, the outlet strut. This were very successful, possessing outstanding durability and malfunction was reported in almost 2% of the patients. Due structural integrity properties. to this issue, the manufacturing of this model stopped in 1986. It should be noted that a mono-strut tilting disc Bjork-Shiley Hall-Kaster and Medtronic-Hall Tilting Disc Valves valve,whereonly one strut is attached to the annulus without In 1977, Robert Kaster and Dr. Karl Victor Hall, a cardiac surgeon, welding, was implanted in more than 100,000 patients with designed a new tilting valve which was named first as the no structural failure reports (Figure 18). Hall-Kaster and later as the Medtronic-Hall tilting disc valves. In this model, the strut plays the role of thedisc’s guide. In the Lillehei-Kaster Tilting Disc Valve centre of the disc, there is a hole through which the guide is In 1970, Dr. C. Walton Lillehei, a cardiac surgeon, and Ms. passed. The strut is made of Titanium and the disc is made of Robert Kaster, an engineer, designed a new tilting disc valve Pyrolyte. This model was implanted in almost 190,000 patients named the Lillehei-Kaster tilting disc valve. In this model, the in the aortic position and in nearly 125,000 patients in the 20 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 mitral position with no structural failure reports. There are still was that a well-polished Pyrolyte surface and heparin will some hospitals in the world where this model is implanted not bind. Nowadays, it is well established that the Bokros in patients (Figure 19). material was the most blood compatible material (thrombo resistant, nonheparinized material) that had been developed until that point. This material was applied to the ball in the DeBakey-Surgitoolball and valve model.This was the model he was focused on previously. This model was implanted in almost 300 patients in the aortic position and in 200 patients in the mitral position with fairly good clinical results. This model, however, had a major drawback.There was rather stagnant blood flow in the region of the super-strut imple- mented to capture the flexible leaflets. This region was often Figure 19. (1) Lillehei-Kaster tilting disk designed in 1970, (2) Omniscience tilting disk, and (3) Hall-Kaster the location of thrombus; however, no clinical episodes of and Medtronic-Hall tilting disk designed in 1977 [90,91]. thromboembolism were observed. From an engineering perspective, if the disc in a disc and cage Kalke-Lillehei Bileaflet Valve valve is broken down into two pieces, each engaged within In 1964, Drs. Bhagabant Kalke and C. Walton Lillehei proposed the ring by hinges,this could provide a central blood stream a new design for mechanical heart valves. They came up through the valve. In fact, the hemodynamics in bileaflet valves with the first ever design of bileaflet mechanical valves with must be better compared to previous models, as listed: ball a pivot mechanism. They designed a bileaflet mechanical and cage valves, disc and cage valves, and tilting disc valves. valve in which the pivot sites for the two solid leaflets were This is simply because the central area of the valve, where located at the equator of the housing or annulus. In their initial the velocity of blood could be maximum, is wide open to the model, they used an overriding semicircular strut/brace to blood flow. The bileaflet concept, a hinge mechanism, and a avoid leaflet escapement. Later on, after Dr. Kalke joined Dr. low profile are some of the basic design features of bileaflet Lillehei’s laboratory, together they proposed a design wherea heart valve prosthesis. They have two semicircular leaflets pivot mechanism for the two leaflets was considered (first engaged within the ring by hinges. The leaflet hinge is located ever design of the pivot mechanism) so that the overriding at the center of the valve annulus, and leaflets open and close strut/bracewas no longer necessary. Only a few of these Kalke- similar to a butterfly’s wings. The relation between the leaflet Lillehei valves were fabricated and only one was implanted in motion and the flow through the valve is: (1) Leaflets open a patient who died after 48 hours in 1968. The cause of death rapidly when the forward flow starts, (2) around peak flow, was advanced rheumatic mitral disease, so the fabrication of the leaflets remain stable at the maximumopening position, the Kalke-Lillehei valves wasstopped mainly because of the and (3) leaflets maintain the opening position while the flow lack of an appropriate biomaterial for this model. rate decreases slowly after the peak flow. Leaflets are still in the open position as the flow rate drops to almost zero. Finally, St. Jude Medical Bileaflet Valves the leaflets start to close when backflow happens. Bileaflet The design of the St. Jude Medical bileaflet valve was concep- valves are the most protected as the leaflets hardly protrude tually similar to the design of the Kalke-Lillehei valve and was from the valve ring, even during maximum opening. first introduced in 1977. In the design of the St. Jude valve, however, the focus was more on the improvement of the Gott-Daggett Bileaflet Valve pivot hinge. In this model, both the leaflets and the housing In 1969, the application of a hollow ball made of Pyrolyte (also were made of Pyrolyte, which made the St. Jude valve the first known as pyrolytic carbon) in a ball and cage valve (used in ever valve made entirely of carbon. Xinon Posis, an engineer, the DeBakey-Surgitool valve) was a further evolution in the proposed the first design of a St. Jude valve in 1976 wherethe design of mechanical valves. Drs. Vincent L Gott and Ronald pivots werenear the periphery, providing a central opening. Daggett, a professor of polymer engineering, designed the Xinon Posis,with Dr. Demetre Nicoloff, a cardiac surgeon, and Gott-Daggett bileaflet valve in 1963. In this model, the housing Donald Hunson, an engineer, redesigned the St. Jude Medical (annulus) was made of carbon coated Lexanand the leaflets valve multiple times.The focus was mostly on a modification were made of silicon coated Teflon fabric. In fact, the valve of the hinge design. Posis, Jack Bokros, the initiator of the idea was flexible, and was branded as the Gott-Daggett bileaflet of using carbon in valve construction, and Hanson improved valve. The housing also had a graphite-benzalkonium-heparin the design of the hinge and introduced the new concept of a coating,making this the first ever prosthetic valve with car- leaflet-tab spinning in a butterfly-recessinsideof the housing bon coating. Dr. Bokros, who was the initiator of this idea, wall. The design of this model was a success and soon became suggested that binding of heparin andPyrolyte could offer a major alternative for the replacement of the diseased valves. excellent blood compatibility properties.However, the issue This valve has been implanted millions of times in patients in 21 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 both the aortic and the mitral positions. ATS Bileaflet Valves The ATS bileaflet valve, similar to the St. Jude medical valve, Carbomedics bileaflet valves was a new design of bileaflet heart valve that was made of In 1986, Dr Bokros designed a similar valve to the St. Jude Pyrolyte in 1994. This model was branded as the ATS Open where was made of Pyrolyte both the leaflets and the hous- Pivot valve prosthesis. The main feature of the ATS prosthesis ing were made of Pyrolyte. In this model, the main feature was the design of the hinge,where a ball hinge was propo- was the housing that could rotate with respect to the sewing sedinstead of a cavity hinge. Since this model’s pivot areas ring. This valve was marketed as the Carbomedics bileaflet are fully exposed to the blood stream, the hinge area can valve and was implanted in more than 350,000 patients in the be washed out effectively. The sewing cuff is attachedto a aortic position and in 250,000 patients in the mitral position. titanium ring in a way a rotation during implantation. Radi- opacity is also provided, which is helpful for visualization by On-X bileaflet valves roentgenography. The radiopacity is possible in this model Dr. Bokros introduced a new design for bileaflet mechanical because of the presence of 20% tungsten in the leaflet con- heart valves in 1996. This model was an overall improvement struction. The ATS bileaflet valve is thought to provide a better on St. Jude medical bileaflet valves and was branded as the hemodynamics and less noise compared to other bileaflet On-X valve. The surfaces of the leaflets and the housing were valves. The ATS bileaflet valve has been implanted in nearly coated with pure carbon and extremely polished to provide 1200 patients in both the aortic and the mitral positions from high quality surface properties. In the On-X valves, silicon 1994 to 2000 (Figure 20). had been completely removed from its structure, unlike conventional models. This is because silicone embedded carbon may lead to a low surface quality, which in turn increases chance of blood damage near the surfaces of the leaflets and housing. That was the case in the regions close to the hinges. The most significant design feature of this model was that itaddressed insufficient hemodynamics in small aortas. Periodic incidents ofhemolytic anemia, extreme pannus overgrowth or tissue interference, and thrombogenic complications are the issues associated with hemodynamics of bileaflet mechanical valves, especially in small sizes. Low profile valves (low length to diameter ratio) are prone to tissue ingrowth (pannus). The profile (length to diameter ratio) of the On-X valve is designed to be similar to that of thenative Figure 20. (1) Gott-Daggett bileaflet valve designed in aortic valve,therefore providing unique protection from tissue 1969, (2) Kalke-Lillehei bileaflet valve designed in 1964, (3) damages on both the inflow and outflow sides. An inlet flare, St. Jude Medical valves designed in 1977, (4) Carbomedics valves designed in 1986, (5), On-X valve designed in 1994, full annulus support, and leaflet guards are allcomponents in and (6) ATS valve designed in 1994 [90,91]. the design. The opening angle is considered to be 90º (> 80º in SJM), which is thought to improve the hemodynamics of the valve significantly. The design of the pivot hinge is also Sorin Bileaflet Valves improved, which may in turn lead to more stability of the The idea behind the Sorin bileaflet valves was to design and hinges and less thromboembolic complications. Pivots are fabricate an advanced version of the original bileaflet model, high potential sites of clot formation,due to the possibility of which would overcome some of its inherent deficiencies and flow stagnation (stasis). In the On-X design, the location and surpass its performance. In order to improve the bileaflet the geometry of the hinges were designed so they are being valves available at the end of the penultimate decade of the constantly washed out in every cardiac cycle more efficiently last century, Sorin Biomedica (Saluggia, Italy) focused on three compared to conventional valves. This is done to eliminate main points: hemocompatibility (minimal damage to blood possible flow stagnant regions around the hinges. The backflow components and prevention of thrombotic deposits); hemo- channels are sensibly designed in order toavoid hemolysis dynamics (low resistance flow pattern similar to that in natural by allowing blood flow to penetrate tthe pivot areas. The im- valves); and durability. Experience with the Sorin tilting disc proved hemodynamics provided in the On-X valve is thought valve clearly indicated that the most biocompatible material to decreasethe anticoagulation therapy in low-riskpatients. for blood contacting surfaces is pyrolytic carbon, whether it This valve has been implanted in so many patients so far in is solid or used as a coating. Maximal hemodynamic perfor- both the aortic and the mitral positions and together with mance was achievedwith the design of the curved leaflets St. Jude Medical valve are the most widespread prosthetic and the aerofoil inner housing profile. Structural stability and valves alternative considered by cardiac surgeons globally. excellent mechanics resulted from the choice of a titanium 22 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 alloy for the housing when combined with the decreased the leaflets are made of pericardium, which will be attached thrombogenicity of the pyrolitic carbon coating. The hinge later on to a synthetic stent. In terms of the design procedure, design was based on the principle of rolling without sliding. porcine valves are one step ahead of bovines, simply because Consequently, uninterrupted washing of the hinge surfaces porcine valves are already a valve, whereas bovine valves is achieved at each point of the cardiac cycle with controlled should be designed and fabricated in a form of a valve. Al- blood leakage. The housing is rotatable within the sewing ring. lografts are those harvested from cadaver. They are excellent Short-term results were reported by Casselman and Goldsmith, alternatives for bioprosthetic valves, but are not readily avail- andintermediate results were subsequently presented in a able at the right size and time when needed. Autogratfs are large cohort of 1350 patients. harvested from a patient’s own body, in which the patient’s pulmonary valve is moved to the aortic position through the Elliptic St. Jude Medical Valves Ross Procedure. The Ross procedure, also known as a pulmo- In 2014, the Heart Valve Performance laboratory at the Univer- nary autograft, is a cardiac surgery in which a diseased aortic sity of British Columbia (the authors) published a manuscript valve is substituted with the patient’s own pulmonary valve. in the Journal of Biomechanics. They suggested a new design A pulmonary allograft or any other prosthetic valve is then for the stent (housing) of SJM valves in which 15% ovality was used as the patient’s pulmonary valve. This operation is applied to the stent whileits perimeter remains constant. In a more often recommended in infants and children, but is not pilot study, the hemodynamic performance of the proposed uncommon in adults as well. design was analyzed in the closing phase and then compared The arrival of tissue valves is associated with the introduc- to that of conventional SJM models. Results showed that while tion of glutaraldehyde for the fixation of biological tissue by Dr. the elliptic SJM model offers a shorter closing phase (9.7% Carpentier in 1969. The tissue treatment with glutaraldehyde shorter), the regurgitation flow remains almost unchanged. is essential for the design and fabrication of bioprosthetic In other words, even though the dynamic response of the valves, including porcine and bovine pericardium valves, valve improved, the regurgitation flow did not decrease. Thus, which are made of animal tissues. The main issue with the a more efficient and effective orifice area (EOA) was provided animal tissues used in the structure of prosthetic valves is by the proposed model. The elliptic concept can be applied the potential of thrombogenic complications. In 1970, the to the On-X valve as well and improved hemodynamics are Hancock standard porcine BHV was implanted in the aortic expected in the elliptic On-X valve compared to the conven- position. After a while, the Hancock modified orifice (MO) BHV tional On-X models (Figure 21). was introduced in order to addressthe high post-implantation gradients associated with small-size valves in the aortic posi- tion. The issue was due to the bulky muscle under the right coronary leaflet. In this model, a composite valve is designed where the right coronary leaflet is replaced with a leaflet from another valve,with the muscle bar already removed. After this model, the Carpentier-Edwards standard porcine BHV was in- troduced in 1975.The consecutive generationsof BHVsconsist of the Carpentier-Edwards supraannular (SAV ) porcine model, which was introduced in 1981; the Hancock II porcine model, Figure 21. (1) Sorin bileaflet valves [90,91], and (2) the elliptic St. Jude Medical valve designed in 2014. which has been available since 1982; and the Medtronic intact porcine model, which was introduced in 1985. These BHV Tissue Valves or Bioprosthetic Heart Valves (BHVs) models are known to offer improved zero-pressure fixation Bioprosthetic heart valves, which are also known as tissue that maintainsdelicate but significant histologic features of valves, are the prostheses made entirely of animal or human the valve leaflets, along with anti-mineralization treatments tissues. BHVs are divided into 3 groups: xenograft, allograft to decreasecalcification-oriented deterioration of the valve and autograft. Xenograts are those made of animal tissues. tissue. The idea is to provide the new designs with a more Two candidate animals, pigs and cows, are commonly used for flexible, lower-profile stent and smaller sewing rings,which bioprosthetic aortic valves. Xenograft valves harvested from can essentially lead to a larger orifice area. pigs are known as porcine, and those harvested from cows The first bovine BHV model was the Ionescu-Shiley valve are known as bovine valves. Porcine valves are basically the introduced in 1971. 10 years later, the first improvement aortic valve harvested from pigs and have similar structure to on that model was made, and a low-profile model was de- nd that of humans. This is simply because several components of signed where the rate of failure was much higher. On the 2 the cardiovascular system in pigs, such as the heart structure, attempt on that model, a final model III was developed and systemic pressure, aortic heart valve, mitral valve, and aortic implemented clinically. This was before the Shiley model was root is similar to those of humans. Bovine valves are made withdrawn off the market, and the production of pericardial of the precordium tissue harvested from cows. In fact, only valves was officially terminated in 1977. The Mitroflow pericar- 23 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 dial valve was introduced and first was implanted clinically in 1982. The most commonly used pericardial BHV presently is theCarpentier-Edwards pericardial valve, which was designed and clinically implanted in 1980. There are modified versions of this valve available on the market, which are known as the Perimount RSR37 and Magna series (Figure 22). Figure 23. (1) Hancock porcine valve and (2) Carpentier- Edwards pericardium bioprosthetic heart valve (Edwards LifeSciences Ltd.) [92]. Following the same concept as natural valves, the function of BHVs is pressure-driven. Ifthere is a pressure gradient across the valve (or the blood pressure before the valve Figure 22. (1) Ionescu-Shiley BHV designed and fabricated becomeslarger than the pressure after), the cusps are forced in 1971, (2) The Mitroflow pericardial valve designed and fabricated in 1982, and (3) Toronto SPV valve designed and towards the outside by reversing their curvature. This causes fabricated in 1991 [90,91]. the valve to open. When the blood pressure after the valve becomeslarger than the pressure before, the valve closes by The first clinically approvedBHV stentless model for the aortic pushing the cusps toward the center. As the total surface area position was the Toronto stentless porcine valve,also known of the cuspsis more than that of the orifice, the two adjacent as the SPV valve, which wasdesigned and fabricated in 1991. cusps overlap in the center.This is known as the coaptation In this design, the available orifice area was significant, which area,which plays a major role in complete closure of the valve originated in the concept of stentless BHV models. To reach without leakage or dynamic backflow (regurgitation flow). such a remarkable effective orifice area, the sewing ring The main issue with the BHVs is thatcross-species implanta- was minimized and the supporting struts were eliminated. tion of animal tissues causes an immune rejection and therefore In the design of the SPV valve, a native porcine valve that quick tissue deterioration. For this reason, bovine or porcine was reinforced by a small quantity of fabric was considered. valves are treated with glutaraldehyde. Glutaraldehyde is The fabric wasthen sewn to the patient’s annulus in a planar regularly implemented in biomaterialsas an amine-reactive fashion. Then a small amount of porcine aorta around the homo-dual-functional cross-linker.For instance, it is used to valve commissures was implanted straight into the patient’s determine theoligomeric state of proteins. Glutaraldehyde is native aorta. to for other conventional stentless BHV models, also implemented in polyacrylamide gel electrophoresis(SDS- the Edwards Prima Plus porcine BHV model, the 3F Therapeu- PAGE) to fix peptides and proteins before staining. In fact, the tics stentless equine BHV model, and the Medtronic Freestyle objective of SDS-PAGE is to distinguish certainproteins based porcine BHV model are quality considerations. on their size only. Usually, a gel is treated with a 5% solution for The first experimental animal studies that includedauto- nearly 30 minutes. It is then completely washed to eliminate graftof the aortic tissue were performed in 1952. In this study, the yellow stain caused by reacting with free hydroxylmethy an allograft aortic valve was implanted into the descending laminomethane. In general, a cross-link is a bond between two aorta of a dog. A few years later, an allograft aortic valve polymeric chains, including long molecules, etc. This bond was implanted into the human descending aorta in 1955. may be ionic or covalent, and these polymeric chains may The method for subcoronary implantation of allografttissue be synthetic, such as rubber, like materials, or natural,such via the single-suture technique was initiated and applied in as proteins. The concept of ”cross-linking” for proteins typically 1962 in patients with a freeze-dried aortic valve, a feat imple- refers to the use of cross-links to improve the targeted protein’s mented shortly afterward byBarrett-Boyes. There have been physical properties. In biomaterials, crosslinkingrefers to the multiple revolutionary techniques which were used for the use of a concept or method to link proteins together,which is sterilization of homograft valves, such as (a) formaldehyde, implemented for protein–protein interactions studies. (b) chlorhexidine, (c) propiolactone, (d) methylene oxide, (e) Glutaraldehyde is a water-soluble cross-linker, which com- gamma radiation, and (f ) storage using a carbon dioxide pletely decreases tissue antigenicity. Furthermore, glutar- freezer at -70ºC. Presently, most homograft valves are (g) aldehyde devitalizes tissues and destroys all existing cells, cryopreserved with low-dose antibiotics. therefore preventing degradation by host enzymes, and steri- Porcine aortic valves or bovine pericardial sheets can be lizes the tissue for implantation. BHVs are less thrombogenic mounted on supports to make a valve with stent,which is to than mechanical heart valves and do not need long-term mimic the valvular architecture, or they can be left un-mounted anticoagulation. to make a stentless valve (Figure 23). In general, BHVs’performancein both hemodynamics and 24 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 structure is excellent for many years after implantation, but valve decomposition. Also, the absence of an intact layer of their long-term durability is an issue. Clinical reportsshow that endothelial cells may let free influx of blood components more than 50% of patients with a BHV replacement develop and could also contribute to valve-related thrombogenicity. complications within 10 years, which suggests that the ma- Finally, the majority of conventional BHVs, except for newer jority of implanted BHV valves need to be explanted after 20 stentless models, do not uphold their cardiac skeleton-valve years. It is known that a second open-heart surgery to recover continuity and thus may increasingly influence heart func- and replace the defective valve is prone to high clinical risks, tion negatively. and therefore is not recommended. The absence of long- BHVs gained extensive use during the mid-1970s. The term valve durability is particularly significant in the case of major advantage of bioprosthetic valves compared to me- pediatric patients, where additional surgical procedures are chanical valves is that bioprosthetic valves are less prone to needed to accommodate the natural growth of the patients. thromboembolic complications. Consequently, most patients The choice between BHVs and MHVs depends highly on receiving bioprosthetic valves do not need to take anticoagu- individualpatient features. MHVs are more durable but need lation therapy. The main disadvantage ofbioprosthetic valves, life-long anticoagulant therapy, whereasBHVs are prone to particularly in small valve sizes, is large pressure drops (albeit deterioration more quickly but do not need anticoagulation their excellent hemodynamics) compared to some mechanical therapy. The major reasons for BHV failure are (1) structural valvesof the same size. Complications, such as jet-like flow destruction and (2) calcification of the tissue constituent. through the existing gaps between the valve leaflets, ma- Analysis of failed BHVs naturally discloses the coexistence of terial fatigue and/or wear, and calcification of value cusps, structural deteriorationand calcification. Structural failuremay particularly in children and young adults are of the issues not be associated with calcification, so it can be a purely associated with BHVs. Valve deterioration, however, typically stress-induced disruption of fiber architecture, or induced by takes place gradually in these valves. The main advantage enzymatic deterioration. Mechanical stresses/deformationsof of the conventional mechanical valves is their long-term the tissue were thought to effectivelyaccelerate calcification durability. Conventional mechanical valves are manufac- and vice versa, calcium deposits intensely affect mechanical tured from a variety of biomaterials, includingPyrolyte and properties. These progressions may be synergistic, but based Titanium. Structural failure of mechanical valves is not usual, on comprehensive studies on the subject, is it thought that butwhen it happens, it is catastrophic. One main disadvan- each may happen independently. It is also suggested that the tage of the use of mechanical valves is the need for life-long geometrical design factors of the prosthetic valves are highly anticoagulation therapy to lessenthe risk of thrombosis and influential in the mechanical deterioration rate of the valve. thromboembolic complications. Since the anticoagulation It should be noted that the calcification process in native therapy may result in bleeding complications, careful control aortic valves and bioprosthetic tissue valves follow dissimilar of anticoagulation medication is necessaryfor the patient’s concepts. In general, the calcification process of BHVs is as- well-being and quality of life. sociated with a cascade of bioelectrochemical and bioelectro- The choice of an appropriate BHV for the patient is deter- mechanical events are yet to be understood. However, tissue mined by the patient’s age, since BHVs have a relatively short composition and the glutaraldehyde tissue treatment seem to lifespan. There are significant differences between BHVs be two important factors. In most studiesreportedsofar, the and MHVs. MHVs are extremely durable, but require lifelong mineral phase consists of bone-like hydroxyapatite linked anticoagulation therapy. They are often recommended for with collagen and elastin, which then chemically devitalizes younger patients in order to avoid the need for a second cells. One of the suggested methods to prevent calcification open heart surgery or valve replacement procedure. Their in BHVs is to remove, devitalize or extract inhabitant cells, use also appears to be reasonable when the patient already modify the structure of collagen and elastin fibers, and add must take anticoagulation therapy for other medical reasons. natural inhibitors. In some cases, MHVs are preferred if the patient has a very It is well known that mechanical and biological factors narrow aortic basebecause their effective opening area is contribute considerably to failure of BHVs. Even though BHVs’ larger than BHVs with the same size. The risk of prosthesis performance in hemodynamics and structure is excellent, they endocarditis is similarly significant in the two types of pros- do not havesatisfactory biological factors thatare necessaryfor theses.The conventionalBHVsexhibit acceptable long-term true biomimetic valves. Their absence of biologic properties results in the aortic and mitral positions. For older patients may justify their insufficient durability after implantation. As (65+), the degeneration rate of BHVsat 15 years is reported BHVs lack living cells, unlike native valves,they are incapable to be between 10% and 35%. If a consecutive valve replace- of maintaining and adapting with the valvular matrix com- ment procedure is required, the operative mortality is almost position or maintaining an adequate calcium homeostasis. In 5%. The degeneration rate of BHVs is inversely proportional fact, degenerative processes pushedby mechanical fatigue, to the age of the patient at the time of implantation, so BH- proteolytic enzymes, and calcium deposition gradually dete- Vsare normally recommended for patients who are the age riorate the structural components and result in progressive of 65+. If a concurrent surgical procedure is necssary, such as 25 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 correcting a cardiac arrhythmia by surgery during the valve valve, causing stented BHVsto bemore desirable than stent- replacement, this may influence the choice of BHVs for the less. It should be noted thatstented BHVs’ also have better patient. In contrast, if the patient is already taking anticoagula- long-term resultsand their implantation is associated with tion therapy because of, for instance, chronic atrial fibrillation, consistently lower risk. However, stentless valves hold certain an MHV should not necessarily be selected for the patient. clinical advantages, such as their excellent hemodynamic properties. The preliminary reports of 10-year studies show The choice of a prosthetic valve in the aortic position that stentless valves have similar deterioration, rateswhich The implantation of BHVs in the aortic position is desirable if is ~20%, compared to conventional stented valves. Patients the lifespan of the prosthetic is not an issue. Recent report- with a narrow aortic base and a high risk of inconsistency sindicate that the new generation of BHVsare more durable between the size of the valve and aortic base may benefit than earlier models. In addition, since the age limit is taken from stentless valves. Also, autograft valves hold the same into consideration, re-operation rates have decreased signifi- degeneration rates as xenografts, which has been extensively cantly. There are the reasons that the implantation of BHVs is reported in long-term follow-up studies. recommended for more elderly patients nowadays. BHVs are known for their risk of degeneration and their The choice of a prosthetic valve for the mitral position need for re-operation 10-20 years after implantation; however, and ablative surgery in atrial fibrillation they are still recommended for the patients under the age of Prosthetic valves for the mitral position are chosen based on 60. Also, in young patients who are taking oral anticoagula- similar same criteria as the aortic position. The rate of deterio- tion therapy, BHVs are a considerable alternative. The risks ration of the BHVs, however, is higher in the mitral position. involved in the second valve replacement surgery havebeen It is normally recommended that BHVs not be implanted in considerably reduced, which is mostly due to the advances patients less than 65 years oldin the mitral position unless it in cardioprotection. Consequently, BHVs are recommended is absolutely necessary.The following conditions are consid- for younger patients; however,a second valve replacement ered for the choice of prosthetic valves in the mitral position: surgery with an acceptable degree of risk may be required • BHVs for patients of any age who are taking oral antico- after 10+ years after implantation. Also, patients who have agulation therapy and for whom oral anticoagulation is a lower life expectancy due to chronic health issues, such unconditionally prescribed as coronary heart disease, are considered for BHVs and not • MHVs for patients who are under the age of 65 with MHVs. The following conditions are considered for the choice longstanding atrial fibrillation of prosthetic valves in the aortic position: • BHVs for patients over the age of 65 • MHVs for patients who already have an MHV in their • BHVs for patients under the age of 65 due to a personal mitral or tricuspid positions decision - after enough discussion with the patients about • BHVs for patients of any age who are taking oral antico- the risks of anticoagulation therapy and the need for a agulation therapy and for whom oral anticoagulation is second valve replacement surgery unconditionally prescribed If the patient also suffers from atrial fibrillation along with a • MHVs for patients under the age of 65 for whom oral valvular heart disease, the approach is to perform both abla- anticoagulation is not prescribed tive methods to attain sinus rhythm and valvular replacement • BHVs for patients under the age of 65 due to a personal during the same procedure. If the valve can be repaired or decision - after enough discussion with the patients about a BHV is implanted, then oral anticoagulation therapy may the risks of the anticoagulation therapy and the need for be stopped. It is reasonable to implant MHVs in those pa- a second valve replacement surgery tients since they would require the anticoagulation therapy • BHVs for patientsover the age of 65 if the risk of throm- postoperatively regardless. Nearly 75% to 90% of patients boembolism is consistently low undergoing the rhythm surgery and mitral valve replacement • A secondary valve replacement surgery with a autograft surgery concurrently may still be in sinus rhythm for up to six is recommended for patients with active prosthesis months after. The success rate of ablative surgery is known to endocarditis be higher if the patient has atrial fibrillation for less than one • BHVs for young female patientsif the patient is consider- year. Also, ablative surgery may decrease the incidence of a ing having childrenin future. heart stroke. BHVs are considered an appropriate choice for There are some regulations and platforms available from those patients who cannot be permanently converted to sinus clinical trials for surgeons to choose the right prosthetic rhythm, and consequently still need the oral anticoagulation valve and replacement surgery. However,currently personal therapy. This is because if a BHV was implanted (as oppose to experience and individual assessment play a vital role in these an MHV ), a lower target INR would be required. decisions. This is often the case if the patient suffers from difficult anatomy and/or substantial comorbidity. Other Cases Ease of surgery is also important in the choice of the right MHVs were recommended for patients associated with 26 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 dialysis-dependent renal failure. In this situation, if BHVs were valve tissue, and easily permits contraction and expansion. used, their abnormal metabolic situation couldincrease the This is consistent with the aortic root’s movement during degeneration rate. Recently, long-life studies suggest that cardiac cycle; hence, it provides natural hemodynamics. Also, BHVs can also be implanted for those patients as their life it is also likely that polymeric biomaterials can be treated to expectancy is already reduced.The degeneration rate due to enhanceblood-compatibility. Research on prosthetic heart BHVs implantation is oftenlonger than their remaining lifetime. valves made of flexible polymers is not recent, as it has been Since oral anticoagulation therapy is more problematic in ongoing for more than 45 years. Biomaterials tested include: dialysis patients than in others, MHVs are not recommended silicone rubber, poly-carbonateurethane,Silastic, poly-olefin for these patients even though MHVs have longer durabil- (PO), poly-tetrafluoroethylene (PTFE), SR-impregnated Dacron, ity. Recently, prosthetic valves were not recommended for and poly-urethane (PU). PU is known to have good consistency patients with end-stage renal failure because of the risks of with blood, life-long durability, and thrombogenic resistance. systemic anticoagulation. However, calcification is a major issue with PU. Mechanical In the case of patients that are young women desiring to properties of the polymeric material are a significant concern have children, there is no appropriate type of prosthetic valves in the effective formation of a polymer based prosthetic valve. that can be recommended yet. In general, pregnant women In the past two decades, growing insight has been obtained with prosthetic valves are prone to heart failure, arrhythmia, into the significance of optimal hemodynamic performance or maternal endocarditis with high degree of propensity. of elastomeric valves for their durability. Presently, some PVs Pregnancy decreases the life-span of BHVs significantly,and have shown their efficacy in assist devices for short-term use it is strongly recommended that the female patients manage [93-98]. their pregnancy period to be within the first five years after the The advent of the PVs was perhaps in the late 1950’s. A implantation. It should be noted that pregnant women with trileaflet PV made of silicone rubber (SR) was designed and MHVs hold the highest rate of maternal and fetal complica- fabricated, and then was implanted in several patients in the tions. In patients under treatment with phenprocoumone, the aortic position in 1960 and 1962. The main issue with all of miscarriage rate is ~70%, which can be improved to ~20% if these valves was thromboembolic complications. Certainly, oral anticoagulation is replaced by heparin. The rate of chronic the choice of material is a major factor in the development cardiac complications in pregnant female patients with MHVs of PVs. Acceptable characteristics with regard to blood- is ~20%, which is almost twice as high as the rate with BHVs. compatibility, anti-thrombogenicity, resistance to calcification Age is a dominant factor for the choice of the best prosthetic and degradation,as well as excellent mechanical and material valve. For patients over the age of 65, it is understandable that properties are significant factors for the chosen polymers to a BHV be recommended. This is because these patients’ life be considered for a prosthetic valve. expectancy is decreased by comorbidity. For patients under Silicone has great mechanical properties and is considered the age of 65, MHVs are highly recommended, specifically as a blood-compatible biomaterial. It was first used in 1960 for for the mitral position. If a patient in this age group shows prosthetic valves. The issue with silicone is the formation of chronic issues to anticoagulation, then BHVs are recommended. thrombosis and stiffening of valve leaflets,which was found Patients with chronic atrial fibrillation cannot be perma- in long-term clinical studies. This was enough evidence for nently converted to a sinus rhythm by an ablative procedure. silicone not to be considered as a blood-compatible bioma- For patientswith mild arterial fibrillation, permanent oral terial for PVs in 1966. Also, mechanical properties of silicone, anticoagulation therapy can be stopped by implantation of such as low stiffness and strength, failure and short durabil- a BHValong with ablative surgery. For patients with a narrow ity were other reasons against its use. Short life-span and aortic base, a stentless BHV is recommended, even though durability was reported for silicone and poly-olefin rubbers the implantation surgery is more difficult and more time- in vivo in 1980. PVs made of PTFE or Teflon showed excellent consuming. For patients with endocarditis, mainly BHVs are hemodynamics properties at first. However, its low resistance proposed. For patients with prosthesis endocarditis, mainly to thromboembolism, calcification and leaflet thickening were stented or stentless MHVs are recommended. the major issues with these materials, preventing them from further application in 1990. Polymeric Valves (PVs) Segmented Poly-Urethane (SPU) was introduced for PVs as Polymeric valves (PVs)are those made of flexible and synthetic an excellent biocompatible material in 1982. Medical grade biomaterials. PVs may have geometry similar to that of the SPU has been used effectively in numerous cardiovascular native aortic heart valve. This design is a response to the un- devices, including artificial hearts, ventricle assist devices similar geometry of the MHVs, which are made of stiff materials ( VAD) and blood pumps and cannulas. The trileaflet PV made (Pyrolyte) with leaflets protruding in front of the blood flow. of SPU, which was designed similar to the native aortic valve, The capacity of polymeric materials to preserve or closely showed excellent hemodynamic characteristics. It reduced simulate normal hemodynamics is because they hold a soft turbulence and blood trauma,showedgreat flexure durabil- texture. This structure mimics the stiffness of native heart ity, high strength and intrinsic non-thrombogenic features. 27 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 PU has numerous applications in medical devicesfor a variety mechanical properties, superior surface quality and refusal of purposes. Ithas multiple constructive properties due to its to platelet adhesion. The mechanical properties of POSSPCU two-phased microstructure,which includes hard crystalline are comparable to that of commercially available products, segments and soft elastomeric segments. The hard segment e.g., Estane, Elasteon, and Chronoflex C. It was suggested to makes forthe structural strength, whereas the soft segment reinforce POSSPCU by adding POSS nano-particles into the provides the flexibility and complianceto the material. PU polymer matrix in order to improve its tensile strength and elastomers are copolymers encompassing polyethers that hardness. The hydrophobic properties of the nanocomposite are connected together by a urethane group or blocks of low polymer reduce its tendency to adsorption of blood proteins, molecular weight polyesters. There are 3 monomers forming which is essential in avoiding thrombosis and calcification on these elastomers, namely an isocyanate source, which is ei- the polymer surfaces. ther aromatic or aliphatic, a chain extender or curative,and a In 2014, the author and his colleagues developed and dem- macroglycol. One application of aromatic isocyanate, which onstrated a novel one-piece, tricuspid valve made completely is very reactive, is methylene diphenyl diisocyanate (MDI). of polyvinyl alcohol cryogel reinforced by bacterial cellulose If a diamine chain extender is applied, typically it does not natural nanofibers (PVA-BC). The mechanical properties of need a catalyst for synthesis. Oneapplication of an aliphatic the valve were effectively improved with decrease in flexural isocyanate is the cyclo-aliphatic diisocyanate H12MDI, which stresses of the leaflets. The stress concentrations at the com- contains polymers that change color to yellow if exposed to missural areas where the leaflets are connected to the stent ultraviolet radiation and some aromatic PUs. Aromatic PUs were also avoided. However, further studies are neededto are the polymerswhich are made of methylene dianiline evaluate the potential of the PVA-BC valve as an effective (MDA),are known carcinogens and display instant cell toxicity. alternative to the conventional PVs (Figure 24). The hard segments are formed by the reaction of a diisocyn- ate with a short chain diamine or diol, which are known as chain extenders. Normal extenders for medical application are 1,4 butane diol or ethylene diamine. The soft segments are formed by the reaction of the diisocynate with higher molecular weight polyols, e.g., polyesther or polycarbonate. In recent years, notable progress has been made in poly- mer synthesis,which has resulted in a more bio-stable PU. A broader range of SPUs for PV leaflets is available now, such as polyester urethane, polycarbonate urethane (PCU), and polyether urethane (PEU). The issue with PEU is that it is unsuit- able for long-term implants,mainly because of the hydrolytic degradation. In fact, inin vivo conditions, it is susceptible to Figure 24. A one-piece, tricuspid valve made completely of polyvinyl alcohol cryogel reinforced oxidative degradation. Also, PCU holds a higher oxidative by bacterial cellulose natural nanob fi ers (PVA-BC). stability, and its biodegradation rate compared to PEU is considerably lower and is restricted to a thinner surface layer. If PU is chain extended with ethylene diamine (PEUE), its A polymeric MHV suitable for long-term implantation is yet to biostability is improved and can be used in the leaflets of be found due to a combination of valve design and material PVs. This is because of its good rubbery characteristics, which problems. This is currently an active area in the heart valve improves the durability of the valve. PU can also be promoted performance laboratory at the University of British Columbia. to PCU and polyhedral oligomeric silsesquioxanes(POSS), which improves the thromboresistance property of the new Percutaneous Valves nanocomposite PU polymers. In 2007, POSSPCU was shown This type of valve is currently under development for older to have decreased inflammation and capsular development adults. It is also known as a transcatheter aortic valve,which is in a sheep model, and no degradation was reported within 3 applied for patients with severe symptomatic aortic stenosis. years after implantation. The high fibrinogen adsorption on Moreimportantly, it is for those who are high-risk operable POSSPCU and significant contact-angle hysteresis indicated candidates and are not considered suitable for traditional that adsorbing and inactivating fibrinogen on its surface al- open heart surgery. This technology is performed on a beat- lows POSSPCU to prevent inflammation. This new composite ing heart and does not needa heart-lung machine.Percuta- polymer offered a better blood-compatibility and a superior neous heart valve replacement or transcatheter devices are biological stability than other conventional silicone based a relatively innovative technology involving the insertion of biomaterials. an artificial heart valve (or a device) using a catheter, rather The POSSPCU nanocomposite polymer has great poten- than through the conventional open heart surgery. The por- tial for cardiovascular applications because of its excellent tal of entry could be either via the femoral artery or vein, or 28 Mohammadi et al. Cardiovascular System 2017, http://www.hoajonline.com/journals/pdf/2052-4358-5-2.pdf doi: 10.7243/2052-4358-5-2 directly through the myocardium tissue around the apical Conclusion section of the heart. An expandable (or self-expandable) In order to expand the patients’ options for the implantation prosthetic heart valve is delivered and positioned at the site of BHVs, which are believed to have better performance than of the diseased native valve, which is already crushed back by MHVs, the durability of stented BHVs should be improved. This an inflatable transcatheter balloon. Similar to angioplasty, a lies in in methods of BHVs’ construction and preservation. The catheter is positioned in the femoral artery and then is guided main issue with stentless BHVs is the complications associ- into the left ventricle. Alternatively, it can be sent through ated with the implantation process, which are not desirable the left ventricle through the apex of the heart. An inflatable by surgeons. There is a clear link between the conventional balloon is then sent in place to crush the diseased valve, and BHVs and the next generation of prosthetic valves. Also, other then a percutaneous valve (which is compressed in a tiny options such astranscatheter technologies (percutaneous tube) is placed on the balloon catheter and is guided directly valves), minimally invasive techniques, and the construction inside the crushed valve. The valve’s frame is inflated (or the of prosthetic valves using tissue engineering seem to be frame opens itself if self-expandable) to secure the valve in promising options for the future. place. This surgery is executed with general anaesthesia in a hybrid suite in which both catheterization and surgical capa- Competing interests The authors declare that they have no competing interests. bilities are available. To proceed with this procedure, a team of cardiologists and imaging specialists, heart surgeons and Authors’ contributions cardiac anaesthesiologists are needed to simultaneously utilize Authors’ contributions HM GF echocardiography and fluoroscopy. The percutaneous heart Research concept and design ✓ ✓ valve replacement procedure is considered a quick surgery Collection and/or assembly of data ✓ -- and is significantly less invasive than the conventional open Data analysis and interpretation ✓ ✓ heart surgery. Potential benefits of percutaneous valves Writing the article ✓ -- are reduced recovery time and lower surgical risk. Potential Critical revision of the article ✓ ✓ drawbacks are valve migration simply because the valve is Final approval of article ✓ ✓ not sewn into place, issuesrelated to catheter-based delivery, Statistical analysis ✓ ✓ and valve durability. Acknowledgement In available percutaneous valves, such as Edwards SAPIEN NSERC DG Program and the University of British Columbia for XT, the frame (inflatable) is made of cobalt chromium and the financial support. leaflets are made of animal tissues, such as bovine pericardium. The frame could be self-expandable and made of Nitinol, such Publication history Senior Editor: Juan Jose Badimon, Mount Sinai School of Medicine, USA. as in Medtronic CoreValve. Potential advantages of percutane- Received: 01-May-2017 Final Revised: 14-Aug-2017 ous valves include decreased recovery time and lower surgical Accepted: 06-Sep-2017 Published: 21-Sep-2017 risk. Potential disadvantages include a greater risk for valve migration (since the valve is not sewn into place), complications associated with catheter-based delivery, and uncertain valve References durability. Also, similar to bioprosthetic valves, these valves 1. Mohammadi H and Mequanint K. Prosthetic aortic heart valves: modeling and design. Med Eng Phys. 2011; 33:131-47. | Article | are highly associated with thrombogenic complications and PubMed calcification (Figure 25). 2. Taber, Clarence Wilbur and Venes, Donald. Taber’s cyclopedic medical dictionary. F a Davis Co . 2009; 1018-23. 3. Keith L. Moore, Arthur F. 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