TY - JOUR
AU - Pressman, Gregg
AB - Abstract Risk prediction of future atherothrombotic cardiovascular events is currently based on conventional risk factor assessment and the use of validated algorithms, such as the Framingham Risk Score, the Pooled Cohort Equations, and the European SCORE Risk Charts. However, the identification of subclinical organ damage has emerged as a potentially more accurate predictor of individual risk. Several imaging modalities have been proposed for identification of preclinical atherosclerosis. Coronary artery calcification scanning performed using cardiac computed tomography and calculation of the Agatston score is the most commonly used technique in clinical practice for detection of subclinical disease, prognostic stratification of asymptomatic individuals and implementation of preventive strategies. Furthermore, conventional echocardiographic examination may offer an assessment of cardiac calcifications at different sites, such as the mitral apparatus (including annulus, leaflets and papillary muscles), aortic valve and ascending aorta, that are associated with the clinical manifestation of atherosclerotic disease and are predictive of future cardiovascular events. The aim of this paper is to summarize available evidence on the clinical use of cardiac calcification, review the pathogenetic mechanisms involved, including similarities with atherosclerosis, and evaluate its potential for risk stratification and prevention of clinical events in the primary prevention setting. Subclinical atherosclerosis, risk prediction, aortic valve sclerosis, mitral annulus, valve calcification, calcium score Introduction Over the last few decades, significant declines in cardiovascular disease (CVD) mortality, particularly due to coronary artery disease (CAD), have been reported in Western countries. Such trends have been attributed to improved patient management during hospital admission for acute coronary syndrome, and to increased attention to primary prevention and risk factor control.1,2 However, CVD remains the main cause of death in the United States, where approximately every 40 s an American suffers an acute myocardial infarction.3 Cardiovascular risk prediction, currently based on conventional risk factor assessment,4 is consequently deemed fundamental in clinical care, though the assessment of subclinical organ damage has emerged as a potentially more accurate picture of individual risk.5,6 Several imaging modalities have been evaluated and proposed for identification of preclinical atherosclerosis and phenotypic evidence of disease.7 Coronary artery calcification (CAC) scoring, via computed tomography (CT) and calculation of the Agatston score, is the most commonly used technique for detection of subclinical disease, prognostic stratification of asymptomatic individuals and implementation of preventive strategies.8–13 However, its use is somewhat limited by its cost, limited availability and the associated risk of radiation exposure.14 On the other hand, ultrasound imaging is a radiation free investigation which is potentially valuable for assessing atherosclerotic disease, as it may provide non-invasive information at low cost during routine examination. Several studies have demonstrated an association between different ultrasound indexes obtained from the vascular tree (such as carotid intima-media thickness and pulse wave velocity, carotid or femoral artery plaque, left anterior descending coronary flow velocity) and CAD.15 These parameters, particularly CAC score on CT and carotid or femoral plaque on vascular ultrasound examination, offer a validated approach for risk stratification.6 Of interest, conventional echocardiographic examination may offer a semi-quantitative assessment of cardiac calcifications at different sites: the mitral apparatus (annulus, leaflets and papillary muscles), aortic valve and ascending aorta16 (Figures 1 and 2). Calcification of intracardiac structures on echocardiography corresponds to valve calcium detected by CT, and is also related to CAC (Figure 3). An Agatston score > 40017 is associated with cardiac calcification and clinical manifestation of atherosclerotic disease and is clearly predictive of high risk for future cardiovascular events.8,18 Figure 1. Open in new tabDownload slide Calcifications imaged by two-dimensional echocardiogram. On the left: aortic sinus and mitral posterior annulus calcifications are evident on a parasternal long-axis view; on the right, mitral annulus and papillary muscle calcification and aortic valve calcification are visible on an apical two-chamber view (arrows indicate calcifications). Figure 2. Open in new tabDownload slide Two-dimensional echocardiogram, parasternal short axis view: calcific tricuspid aortic valve calcification (left) and normal tricuspid aortic valve (right) for comparison (arrows indicate calcifications). Figure 3. Open in new tabDownload slide Cardiac calcifications imaged by non-contrast computed tomography (CT) and two-dimensional echocardiography (right). Arrows indicate calcifications. Panels (a,b) illustrate aortic calcification by non-contrast CT and panel (c) by echocardiography-parasternal long axis-view; panels (d,e) illustrate mitral valve calcification by non-contrast CT and panel (f) by echocardiography; panels (g) and (h) illustrate ascending aorta calcification by non-contrast CT (g) and panel (h) by echocardiography, respectively. Modified from Gaibazzi et al.11 The aim of this paper is to review the available evidence on pathogenetic mechanisms of cardiac calcification, examine its similarities with atherosclerosis, explore the relative advantages of different detection methodologies and define its usefulness for cardiovascular risk stratification and prevention. Definition and prevalence Cardiac calcifications are frequently encountered on routine echocardiographic examination or CT scanning. They are generally asymptomatic and their prevalence varies according to the site evaluated, age and presence of cardiovascular risk factors (e.g. chronic kidney disease19 or diabetes18). The most often affected sites are the aortic valve (prevalence about 24% in a general population referred for preventive medicine services) and the mitral annulus (prevalence 8% in the same population, and up to 15% with increasing age and number of risk factors or presence of chronic kidney disease).19–21 A major issue in evaluating cardiac calcification prevalence and incidence is the lack of a clear and shared definition.22 Almost two decades ago, Otto and colleagues published data from the Cardiovascular Health Study,23 in which the presence of aortic valve sclerosis (AVS; echocardiographically defined as thickening of the cusps with a maximum velocity of 2.5 m/s on aortic valve continuous wave Doppler) was observed in 29% of subjects over 65 years of age who were free of clinical CVD. Of interest, the presence of AVS was associated with near double the risk of all-cause mortality and cardiovascular death, as well as an increased number of atherosclerotic events including myocardial infarction (MI), angina pectoris, stroke and heart failure over a follow-up period of 5 years. The increased risk of all-cause mortality and cardiovascular death remained, after adjustment for age, gender and baseline factors, associated with AVS (hypertension, current smoking, raised LDL cholesterol levels and diabetes). On the other hand, among subjects with documented CAD (defined as history of MI, angina, coronary angioplasty or bypass graft surgery) events rates were higher in patients with AVS, but for each separate outcome there were only small increases in relative risks when compared with patients without AVS. It seems therefore that AVS may not be a benign incidental finding but rather an independent marker of increased cardiovascular risk, especially in subjects without evidence of CAD. Furthermore, the presence of AVS, in patients admitted for chest pain (with normal cardiac enzymes), was a strong predictor of obstructive CAD, independent of other CAD risk factors.24 Other reports demonstrated a strong association between mitral annulus calcification (MAC) and CAD,25–27 aortic atheroma28 and carotid plaque.29 Fox et al., in the Framingham Heart Study, described an association between MAC, assessed by echocardiography, and an increased incidence of fatal and non-fatal events.30 After multivariable adjustment for conventional cardiovascular risk factors, MAC remained associated with an increased risk of incident CVD (hazard ratio: 1.5; 95% confidence interval (CI): 1.1 to 2.0), cardiovascular death (hazard ratio: 1.6; 95% CI: 1.1 to 2.3) and all-cause mortality (hazard ratio: 1.3; 95% CI: 1.04 to 1.6). Another study in a multiethnic population confirmed the association between MAC and risk of MI and vascular death. When MAC was severe (calcification thickness > 4 mm) a borderline significant association with ischaemic stroke was found.31 The prognostic role of cardiac calcification was also confirmed in a high-risk population of type 2 diabetics. Rossi et al. evaluated more then 900 subjects and observed that approximately 45% of them had AVS, MAC or both. In this ‘real-world’ study, calcifications involving the aortic valve and/or on mitral apparatus predicted an increased risk of CVD and all-cause mortality; these associations were independent of traditional risk factors, diabetes-related variables, kidney function and echocardiographic variables (left ventricular mass, left ventricular ejection fraction, wall motion score index and left atrial diameter).32 An interesting analysis was conducted on hypertensive patients with left ventricular hypertrophy (defined by conventional electrocardiographic criteria) in the LIFE (Losartan Intervention For Endpoint-reduction) study population: AVS was associated with a 50% higher risk of the composite outcome (cardiovascular death, non-fatal stroke and non-fatal MI) after adjustment for multiple risk factors and urine albumin/creatinine ratio (UACR).33 Thus, AVS and high UACR may represent two different aspects of the atherosclerotic process, possibly in the large and small arteries, respectively. Poggianti et al. evaluated a population with known or suspected CAD and found an independent association between AVS and endothelial dysfunction (assessed by flow-mediated vasodilation), an early stage lesion in atherosclerosis.34 Like atherosclerosis, cardiac calcifications progress over time; Elmariah et al. described an increase in the extent of MAC during follow-up and its relationship with conventional cardiovascular risk factors,35 which can lead to clinically relevant mitral regurgitation36 or non-rheumatic mitral stenosis, particularly in the elderly.37 Worsening of AVS over time has also been reported, with approximately one-third of those affected developing some degree of calcific aortic stenosis during mid–long-term follow-up.38 Thus, according to the available evidence cardiac calcification progression over time is associated with coronary and extracoronary atherosclerosis, in both the preclinical phase and the symptomatic phase of disease. A recent report in a primary prevention setting suggests that the risk-stratification capability of cardiac calcification is lost in patients with atrial fibrillation, possibly due to the considerably higher baseline risk of these patient.39 In conclusion, not only the presence and grade of CAC, but also MAC, AVC and extracardiac calcium, in the thoracic or abdominal aorta, are predictive of future major coronary events, major cardiovascular events and mortality in asymptomatic subjects, and this has been confirmed again in the population of the Framingham study.10 Based on the available studies, meta-analyses have also been published in the last years. Pradelli et al., in a meta-analysis including some 44,000 patients evaluated by conventional echocardiography,40 confirmed the prognostic role of aortic valve calcification (AVC) and MAC in predicting fatal and non-fatal cardiovascular events. According to their pooled analyses of published studies, risks for all-cause mortality, cardiovascular mortality and CAD were 14%, 53% and 150% higher among subjects with AVS/AVC than in those without. Likewise, subjects with MAC/mitral valve sclerosis had increased risk for all-cause mortality, cardiovascular mortality, stroke and MI of 53%, 65%, 42% and 40% respectively, versus those without. Similar findings were obtained in a separate meta-analysis of AVS subjects by Coffey et al.41 Another recent meta-analysis including more then 35,500 subjects assessed by echocardiography (∼10,500 AVS patients and ∼25,000 controls) confirmed the associations between AVS and CAD, stroke and cardiovascular mortality42 (Table 1). There are also special groups of patients in whom detection of cardiac calcification represents a strong indicator of coronary or extra-coronary atherosclerosis and is a predictor of markedly poor outcome. In particular, among patients with varying degrees of chronic renal failure,43 diabetes mellitus32 or rheumatologic disease (such as rheumatoid arthritis44), the presence of cardiac calcification has important value in identifying those at increased risk of future cardiovascular events. Table 1. Impact of aortic and mitral valve sclerosis and calcification on cardiovascular events and mortality from meta-analysis by Pradelli et al., Di Minno et al. and Coffey et al. See the text for details. . Risk ratio [95% CI] . Aortic valve lesion (AVC/AVS) . Mitral valve lesions (MAC/MVC) . Pradelli et al.33 . Di Minno et al.35 . Coffey et al.34 . Pradelli et al.33 . All cause mortality 1.14 [1.01–1.30] N/A 1.36 [1.17–1.59] 1.53 [1.24–1.89] Cardiovascular mortality 1.53 [1.19–1.98] 1,41 [1.16–1.71] 1.69 [1.32–2.15] 1.65 [1.36–2.00] Stroke 1.16 [0.91–1.48] 2,70 [1.45–5.01] 1.27 [1.01–1.60] 1.42 [1.15–1.75] Myocardial infarction 1.24 [0.98–1.57] NA NA 1.40 [1.14–1.72] . Risk ratio [95% CI] . Aortic valve lesion (AVC/AVS) . Mitral valve lesions (MAC/MVC) . Pradelli et al.33 . Di Minno et al.35 . Coffey et al.34 . Pradelli et al.33 . All cause mortality 1.14 [1.01–1.30] N/A 1.36 [1.17–1.59] 1.53 [1.24–1.89] Cardiovascular mortality 1.53 [1.19–1.98] 1,41 [1.16–1.71] 1.69 [1.32–2.15] 1.65 [1.36–2.00] Stroke 1.16 [0.91–1.48] 2,70 [1.45–5.01] 1.27 [1.01–1.60] 1.42 [1.15–1.75] Myocardial infarction 1.24 [0.98–1.57] NA NA 1.40 [1.14–1.72] AVC: aortic valve calcification; AVS: aortic valve sclerosis; CI: confidence interval; MAC: mitral annulus calcification; MVC: mitral valve calcification. NA: not available Open in new tab Table 1. Impact of aortic and mitral valve sclerosis and calcification on cardiovascular events and mortality from meta-analysis by Pradelli et al., Di Minno et al. and Coffey et al. See the text for details. . Risk ratio [95% CI] . Aortic valve lesion (AVC/AVS) . Mitral valve lesions (MAC/MVC) . Pradelli et al.33 . Di Minno et al.35 . Coffey et al.34 . Pradelli et al.33 . All cause mortality 1.14 [1.01–1.30] N/A 1.36 [1.17–1.59] 1.53 [1.24–1.89] Cardiovascular mortality 1.53 [1.19–1.98] 1,41 [1.16–1.71] 1.69 [1.32–2.15] 1.65 [1.36–2.00] Stroke 1.16 [0.91–1.48] 2,70 [1.45–5.01] 1.27 [1.01–1.60] 1.42 [1.15–1.75] Myocardial infarction 1.24 [0.98–1.57] NA NA 1.40 [1.14–1.72] . Risk ratio [95% CI] . Aortic valve lesion (AVC/AVS) . Mitral valve lesions (MAC/MVC) . Pradelli et al.33 . Di Minno et al.35 . Coffey et al.34 . Pradelli et al.33 . All cause mortality 1.14 [1.01–1.30] N/A 1.36 [1.17–1.59] 1.53 [1.24–1.89] Cardiovascular mortality 1.53 [1.19–1.98] 1,41 [1.16–1.71] 1.69 [1.32–2.15] 1.65 [1.36–2.00] Stroke 1.16 [0.91–1.48] 2,70 [1.45–5.01] 1.27 [1.01–1.60] 1.42 [1.15–1.75] Myocardial infarction 1.24 [0.98–1.57] NA NA 1.40 [1.14–1.72] AVC: aortic valve calcification; AVS: aortic valve sclerosis; CI: confidence interval; MAC: mitral annulus calcification; MVC: mitral valve calcification. NA: not available Open in new tab Pathogenesis of cardiac calcification The mechanisms contributing to the formation of cardiac calcification are not fully understood. It was previously believed that cardiac calcification is a passive phenomenon, caused by tissue degeneration, but subsequent advanced cellular and molecular biology techniques revealed ectopic calcification to be an active biological process. Valve/vascular calcification is divided into two main forms, one involving the intimal layer of the endothelium, and the other the medial layer. The process of intimal calcification is better understood, being derived from atheroma formation and calcium deposition. Calcification of the media (Mönckeberg sclerosis) is not driven by inflammation but rather a breakdown of extracellular matrix and vascular smooth muscle cell phenotypic changes45 which occur preferentially along the elastic lamina, and the calcium and phosphate building blocks necessary for mineralization.46 Hence, medial calcification produces increases in arterial stiffness and has been associated with hypertension, diabetes, chronic kidney disease and osteoporosis.47 Intimal calcification also involves the endocardium of the valve leaflets. Although most cellular and histopathological studies were performed on aortic valve samples, the mechanism seems to be the same for the other sites, because all four cardiac valves have a similar layered architectural but are subjected to different shear stress.48 Valvular calcification can be divided into two phases:49 an early initiation phase dominated by injury, lipid deposition and inflammation, with many similarities to atherosclerosis, and a later propagation phase, where pro-calcific and pro-osteogenic factors drive disease progression (Figure 4). Histopathological studies of the early stages of MAC50 and AVS51 show focal subendocardial plaque-like lesions that extend to the adjacent fibrosa layer. These lesions generally contain ‘atherogenic’ lipoproteins, including low-density lipoprotein (LDL), lipoprotein(a) and evidence of LDL oxidation, inflammatory cell infiltrate and microscopic calcification.52–54 Mendelian randomization studies have highlighted a strong association of lipoprotein(a) (Lp(a)) with calcific aortic valve disease.55 Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin transforms lysophosphatidylcholine into lysophosphatidic acid. Autotaxin is transported into the aortic valve by Lp(a) and is also secreted by valve interstitial cells. Autotaxin-lysophosphatidic acid then promotes inflammation and mineralization of the aortic valve.56 Figure 4. Open in new tabDownload slide Pathogenesis of cardiac calcifications. See text for details. ACE: angiotensin converting enzyme; Ca2+: calcium ion; IL-1β: interleukin 1 beta; LDL: low-density lipoprotein; MMP: matrix metalloproteinases; TGFβ: transforming growth factor beta; TNFα: tumour necrosis factor alpha. Modified illustration from Servier Medical Art: www.servier.fr/servier-medical-art Early valvular lesions are likely to be initiated by endocardial disruption due to increased mechanical or decreased shear stress, similar to that seen in early atherosclerotic lesions.57 The endothelium/endocardium, in these impact areas, responds by increasing the production of adhesion molecules such as ICAM and VCAM, which promote the adhesion and infiltration of monocytes and lymphocytes to participate in tissue repair and induce expression of genes responsible for inflammatory cells infiltration and lipid deposition.58 Extracellular lipid accumulation is usually seen in a small area in the endocardial region, with displacement of the elastic lamina and extension into the adjacent fibrosa. Micro-calcification co-localizes with sites of lipid deposition. The formation of these microcalcifications may be mediated by cell death and release of apoptotic bodies in these areas.59 Such apoptotic bodies are similar to the matrix vesicles found in bone, which contain the prerequisite components for calcium crystal deposition (including calcium and inorganic phosphate ions) and facilitate the formation of needle-like crystals of hydroxyapatite. When the homeostasis of valve tissue is disturbed, immune cells (such as macrophages and T cells) infiltrate the damaged area and secrete various pro-inflammatory cytokines: tumour necrosis factor (TNF), transforming growth factor (TGF)-1, interleukin (IL)-1β and matrix metalloproteinase, thus perpetuating a cycle of calcium formation and valvular injury. Furthermore, the fibrotic process within the valve may be mediated by reduced nitric oxide expression following endothelial injury.60 The renin–angiotensin system is also believed to play a role through angiotensin 1 profibrotic effects.61,62 Ultimately, valve calcification depends upon the presence of osteoblast-like cells that develop an osteogenic phenotype.63 Pro-inflammatory cytokines released by macrophages (IL-1β, IL-6, IL-8, TNF-α, insulin-like growth factor-1 and TGF-β)64,65 activate various calcific pathways (Wnt3-Lrp5-catenin signalling pathway,66 the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL) pathway67 and Runx-2/NOTCH-1 signalling68), causing valvular interstitial cells (VICs) to undergo osteogenic differentiation. These osteoblast-like cells then lay down a collagen matrix and other bone-related proteins, causing valvular thickening and stiffening before producing calcium. Additionally, apoptotic remnants of some VICs and inflammatory cells create a nidus for apoptosis-mediated calcification. Calcification of the valve induces compliance mismatch, resulting in increased mechanical stress and injury. This results in further calcification via osteogenic differentiation and apoptosis. A self-perpetuating cycle of calcification, valve injury, apoptosis and osteogenic activation is established and drives the propagation phase of the disease. Biomarkers of calcification Identifying individuals at risk for arterial and/or valve calcification would allow for early detection of disease and application of preventive measures. Evidence suggests that some biomarkers may help in this process. Circulating proteins like fetuin-A, matrix Gla protein (MGP), OPG, Klotho, fibroblast growth factor 23, nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) may play a role in the pathophysiology of cardiac calcification and can be measured in plasma samples. Fetuin-A (a2-Heremans-Schmid glycoprotein)69 is a serum multifunctional protein produced in the liver that acts as a potent inhibitor of ectopic calcification. It has a high affinity for bone mineral and prevents the precipitation of basic calcium phosphates from supersaturated solution. Mice with fetuin-A deficiency develop extensive polidistrectual soft tissue calcifications.70,71 In haemodialysis patients, systemic fetuin-A levels are significantly lower than in healthy controls, and are associated both with a propensity for calcification and with an increase in mortality.51 Furthermore, among subjects with CAD but without severe chronic kidney disease, an inverse association between fetuin-A plasma levels and prevalence of valvular calcification has been observed. Fetuin-A concentrations are inversely associated with MAC and AVS, but only among subjects without diabetes mellitus; this relationship persisted after adjustment for age, gender, race/ethnicity, LDL cholesterol, triglycerides and albumin.72 Recently, a meta-analysis confirmed a relationship between patients with AVS, in subjects without chronic kidney disease, and significant lower circulating levels of fetuin-A compared with control subjects.73 MGP is a vitamin K-dependent low molecular weight protein found in bone and cartilage which is highly expressed in kidney, cardiac valves and the medial layer of arteries. It binds with bone morphogenic protein-2 and plays an important role in preventing soft tissue calcification. MGP has also been detected in atherosclerotic plaques where it is a powerful inhibitor of calcium precipitation. In experimental models, MGP knockout mice develop accelerated calcification of the aorta and coronary arteries and die within two months.74 However, in humans, MGP has been associated with risk factors for atherosclerosis but not with coronary calcifications per se.75 Of note, the ability of warfarin to induce calciphylaxis is due to its inhibitory effects on vitamin K, which is required for MGP action. OPG is a cytokine of the TNF receptor superfamily and is expressed widely in many tissues besides osteoblasts, including spleen, bone marrow, heart, liver and kidney. It regulates osteoclastogenesis by acting as a decoy receptor to competitively inhibit RANKL interaction with its receptor RANK. Evidence exists showing a relationship between the progression of atherosclerosis and CAC, and level of serum OPG in haemodialysis patients.76 It is also predictive of all-cause mortality in this patient subset.77 Thus, OPG may be a good candidate biomarker of cardiovascular calcification and atherosclerosis in patients with end stage renal disease. Klotho and FGF23 are multifunctional proteins involved in the regulation of calcium-phosphate metabolism. A defect in klotho gene expression in a mouse model leads to a premature aging disorder including arteriosclerosis, osteoporosis, skin atrophy and ectopic calcification;78 FGF23–/– mice display high serum phosphate levels and increased renal phosphate reabsorption.79 NPP1 is an enzyme which hydrolyses adenosine triphosphate to generate inorganic pyrophosphate (PPi), a potent physiological hydroxyapatite crystal deposition inhibitor. In healthy populations it is constitutively expressed in vascular smooth muscle cells. NPP1–/– mice develop cartilaginous metaplasia and medial calcification of the aorta that can be inhibited by exogenous PPi.80 MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression; several studies have demonstrated their clinical utility in the diagnosis and prognosis of cardiovascular conditions. A recent small experimental study showed the possible relevance of miRNA-8059 as a biomarker for CAC. miRNA-8059 was downregulated in the blood of patients with CAC score > 100.81 Although these biomarkers show promise as a possible means to identify subjects with cardiac calcification (and atherosclerosis) it is too soon to predict if they will be useful in clinical practice. Methods and approaches used to detect cardiac calcification The presence of cardiac calcification, and/or a CAC score > 0, is an indicator of systemic atherosclerosis21 and a predictor of a poor cardiovascular outcome. Thus, the recognition of even small calcium deposits on valves and other cardiac structures is clinically relevant. Incidental findings of calcified cardiac valves or aortic wall, as seen on chest X-ray or CT, can alert physicians to the presence of atherosclerotic disease. The extent of cardiac calcification on CT can be expressed quantitatively by applying the same Agatston score used for assessing CAC.82 However, echocardiography represents a more suitable approach to detect the presence of intracardiac calcium because it is non-invasive, patient friendly and much more economical. It should be recognized that, at this time, the ultrasound approach is not exact but semiquantitative; by summing the numbers of calcified sites and the estimated size of each calcification it is possible to gauge overall extent of calcification.83–90 Previous studies have found a good relationship between a semiquantitative echocardiographic global cardiac calcium score and cardiac calcification score measured on CT.15,87 Despite the lack of a clear definition, most studies have shown a good inter- and intra-observer concordance in the evaluation of cardiac calcification.87–90 Cardiac calcification is generally defined as a nodular brightness (of variable size), or diffuse brightness, exceeding that of normal valve tissue. At times it can be difficult on echocardiographic images to distinguish calcification from sclerotic lesions. Thus, commonly used cardiac calcification scores usually include some sclerotic lesions. However, if we consider that sclerosis is the precursor lesion of calcification and that sclerotic nodules often contain areas of focal calcification, this is not necessarily a drawback. In searching for cardiac calcification, echocardiographers should also be aware that the use of tissue harmonic imaging, although it allows a better visualization of valves, can make valves appear thicker or even give the appearance of sclerosis.91 Despite these limitations there is robust evidence that assessment of cardiac calcification during routine echocardiography is reproducible and reasonably accurate. Grading cardiac calcifications Currently, there is no validated method using ultrasound to quantitatively assess the extent of cardiac calcification, that is, a calcium score similar to the Agatston coronary calcium score obtained on CT. Some studies have simply marked the presence or absence of MAC and AVC. Others assessed the presence of calcification in different areas and factored in the size of calcium deposits. Similar to the Agatston score for CAC, in which greater amounts of calcium deposition predict worse outcome, it is probable that an echo cardiac calcification score can predict events in a graded fashion. Proposed scores have generally examined the number and extent of calcifications in four sites: aortic valve, mitral annulus, ascending aorta and papillary muscle15,86–90 (Tables 2 and 3). The higher the score, the greater the overall burden of calcification. By using an echocardiographic approach which comprehensively assesses calcification of aortic and mitral valves, papillary muscle and ascending aorta, predictions can be made about: 1) coronary and total cardiac calcium burden as assessed by CT;15 2) presence of CAD by angiography,86,92,93 and 3) cardiovascular outcomes.18,22,23,30–33,39,40,89,90,94–99 Table 2. Semiquantitative score of cardiac calcification on the echocardiographic examination. Grade . Papillary muscle calcium . Mitral annulus calcium . Aortic valve sclerosis/ calcification . Ascending aorta wall calcium . 0 Absent Absent Absent Absent 1 Present Mild (<5 mm) Mild Present 2 Moderate (5–10 mm) Moderate 3 Severe (>10 mm) Severe Grade . Papillary muscle calcium . Mitral annulus calcium . Aortic valve sclerosis/ calcification . Ascending aorta wall calcium . 0 Absent Absent Absent Absent 1 Present Mild (<5 mm) Mild Present 2 Moderate (5–10 mm) Moderate 3 Severe (>10 mm) Severe Papillary muscle calcium, if present, is assigned a score of 1. The same value is applied for the presence of ascending aorta calcification. At the aortic valve level, each leaflet is graded on a scale from 0 (normal) to 3 (severe) according to its thickening and calcific deposition; the highest score for a given cusp is assigned as the overall degree of aortic valve sclerosis. Aortic valve sclerosis/calcification is graded as follows: absent = normal thickness (<2 mm), and normal reflectivity; mild = thickness > 2 mm and/or increased reflectivity; moderate = thickness > 4 mm and/or diffuse or focal cusp hyper-reflectivity; severe = thickness > 6 mm and/or marked echo reflectivity. Calcified nodules indicate severe calcification. Mitral annular calcification is also graded on a scale from 0 (normal) to 3 (severe), based on the dimension of calcified nodules or plates. Open in new tab Table 2. Semiquantitative score of cardiac calcification on the echocardiographic examination. Grade . Papillary muscle calcium . Mitral annulus calcium . Aortic valve sclerosis/ calcification . Ascending aorta wall calcium . 0 Absent Absent Absent Absent 1 Present Mild (<5 mm) Mild Present 2 Moderate (5–10 mm) Moderate 3 Severe (>10 mm) Severe Grade . Papillary muscle calcium . Mitral annulus calcium . Aortic valve sclerosis/ calcification . Ascending aorta wall calcium . 0 Absent Absent Absent Absent 1 Present Mild (<5 mm) Mild Present 2 Moderate (5–10 mm) Moderate 3 Severe (>10 mm) Severe Papillary muscle calcium, if present, is assigned a score of 1. The same value is applied for the presence of ascending aorta calcification. At the aortic valve level, each leaflet is graded on a scale from 0 (normal) to 3 (severe) according to its thickening and calcific deposition; the highest score for a given cusp is assigned as the overall degree of aortic valve sclerosis. Aortic valve sclerosis/calcification is graded as follows: absent = normal thickness (<2 mm), and normal reflectivity; mild = thickness > 2 mm and/or increased reflectivity; moderate = thickness > 4 mm and/or diffuse or focal cusp hyper-reflectivity; severe = thickness > 6 mm and/or marked echo reflectivity. Calcified nodules indicate severe calcification. Mitral annular calcification is also graded on a scale from 0 (normal) to 3 (severe), based on the dimension of calcified nodules or plates. Open in new tab Table 3. Comparison between two semiquantitative scores of cardiac calcification on the echocardiographic examination. See the text and references for details. . Global cardiac calcium score (Pressman et al.87) . Semiquantitative score (Gaibazzi et al.89) . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Posterior annulus . PML restriction . Anterior annulus . AML restriction . MV calcification . Subvalvular apparatus calcification . AV calcification . Aortic root calcification . Mitral annulus calcium . Papillary muscle calcium . AV sclerosis/calcification . Ascending aorta wall calcium . Grade/ score 0–3 0–1 0–1 0 = absent 1 = valve opening on LAX ≤ 10 mm 0 = absent 1 = mild 2 = > mild 0–1 0 = absent 1 = nodule(s) in < 3 leaflets 2 = nodules in three leaflets but non-restrictive 3 = restrictive 0–1 0 = absent 1 = mild (<5 mm) 2 = moderate (5–10 mm) 3 = severe (>10 mm) 0–1 0 = absent/normal thickness (<2 mm) 1 = mild (thickness  > 2 mm and/or increased reflectivity) 2 = moderate (thickness > 4 mm and/or diffuse or focal cusp hyper-reflectivity) 3 = severe (thickness > 6 mm and/or marked echo reflectivity) 0–1 . Global cardiac calcium score (Pressman et al.87) . Semiquantitative score (Gaibazzi et al.89) . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Posterior annulus . PML restriction . Anterior annulus . AML restriction . MV calcification . Subvalvular apparatus calcification . AV calcification . Aortic root calcification . Mitral annulus calcium . Papillary muscle calcium . AV sclerosis/calcification . Ascending aorta wall calcium . Grade/ score 0–3 0–1 0–1 0 = absent 1 = valve opening on LAX ≤ 10 mm 0 = absent 1 = mild 2 = > mild 0–1 0 = absent 1 = nodule(s) in < 3 leaflets 2 = nodules in three leaflets but non-restrictive 3 = restrictive 0–1 0 = absent 1 = mild (<5 mm) 2 = moderate (5–10 mm) 3 = severe (>10 mm) 0–1 0 = absent/normal thickness (<2 mm) 1 = mild (thickness  > 2 mm and/or increased reflectivity) 2 = moderate (thickness > 4 mm and/or diffuse or focal cusp hyper-reflectivity) 3 = severe (thickness > 6 mm and/or marked echo reflectivity) 0–1 PML: posterior mitral leaflet; AML: anterior mitral leaflet; LAX: long axis view; MV: mitral valve; AV: aortic valve Open in new tab Table 3. Comparison between two semiquantitative scores of cardiac calcification on the echocardiographic examination. See the text and references for details. . Global cardiac calcium score (Pressman et al.87) . Semiquantitative score (Gaibazzi et al.89) . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Posterior annulus . PML restriction . Anterior annulus . AML restriction . MV calcification . Subvalvular apparatus calcification . AV calcification . Aortic root calcification . Mitral annulus calcium . Papillary muscle calcium . AV sclerosis/calcification . Ascending aorta wall calcium . Grade/ score 0–3 0–1 0–1 0 = absent 1 = valve opening on LAX ≤ 10 mm 0 = absent 1 = mild 2 = > mild 0–1 0 = absent 1 = nodule(s) in < 3 leaflets 2 = nodules in three leaflets but non-restrictive 3 = restrictive 0–1 0 = absent 1 = mild (<5 mm) 2 = moderate (5–10 mm) 3 = severe (>10 mm) 0–1 0 = absent/normal thickness (<2 mm) 1 = mild (thickness  > 2 mm and/or increased reflectivity) 2 = moderate (thickness > 4 mm and/or diffuse or focal cusp hyper-reflectivity) 3 = severe (thickness > 6 mm and/or marked echo reflectivity) 0–1 . Global cardiac calcium score (Pressman et al.87) . Semiquantitative score (Gaibazzi et al.89) . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Mitral valve . Subvalvular apparatus . Aortic valve . Ascending aorta . Posterior annulus . PML restriction . Anterior annulus . AML restriction . MV calcification . Subvalvular apparatus calcification . AV calcification . Aortic root calcification . Mitral annulus calcium . Papillary muscle calcium . AV sclerosis/calcification . Ascending aorta wall calcium . Grade/ score 0–3 0–1 0–1 0 = absent 1 = valve opening on LAX ≤ 10 mm 0 = absent 1 = mild 2 = > mild 0–1 0 = absent 1 = nodule(s) in < 3 leaflets 2 = nodules in three leaflets but non-restrictive 3 = restrictive 0–1 0 = absent 1 = mild (<5 mm) 2 = moderate (5–10 mm) 3 = severe (>10 mm) 0–1 0 = absent/normal thickness (<2 mm) 1 = mild (thickness  > 2 mm and/or increased reflectivity) 2 = moderate (thickness > 4 mm and/or diffuse or focal cusp hyper-reflectivity) 3 = severe (thickness > 6 mm and/or marked echo reflectivity) 0–1 PML: posterior mitral leaflet; AML: anterior mitral leaflet; LAX: long axis view; MV: mitral valve; AV: aortic valve Open in new tab Echocardiographic quantification of intracardiac calcification In order to standardize the definition and characterization of cardiac calcification, there is increasing interest in quantitative approaches. A new echocardiographic technique which allows differentiation of normal myocardium from fibrotic tissue was recently tested by comparison with cardiac magnetic resonance imaging and late gadolinium enhancement.100 This method is based on an ultrasound pulse scheme originally devised for contrast-echocardiography which operates through cancellation of ‘linear’ signals returning from normal myocardium (Figure 5). By slightly altering the standard echocardiograph setting used for ventricular opacification the investigators were able to reveal enhanced signals from abnormal fibrotic tissue which demonstrated a ‘non-linear’ response. Significant for this discussion, signals from calcified tissues were especially prominent. Because of the high signal amplitude ratio between calcified and non-calcified cardiac tissue (even higher than between fibrotic tissue and normal myocardium) this ‘eSCAR’ setting may prove useful for quantification of calcium deposits in the heart. More data are needed to validate this approach and confirm its utility in clinical practice. Figure 5. Open in new tabDownload slide The eSCAR or ‘calcium’ setting. Any commercially available echocardiography machine equipped with a standard phased array 2D transthoracic probe can be used for this purpose. A simple process for optimum eSCAR setting requires increasing the mechanical index and setting appropriate general gain, starting from the left ventricle opacification (LVO) setting. From the 2D standard setting the built-in 2D LVO setting, originally devised for left ventricle contrast-opacification, is activated, exploiting power-modulation/pulse inversion harmonic imaging (transmit 1.6 MHz/receive 3.2 MHz). The LVO setting was tuned to an intermediate mechanical index, between 0.40 and 0.47, and general gain between 70% and 77%, depending on individual patient echogenicity. This eSCAR setting exponentially enhances contrast between scar or calcified tissue and normal myocardium. Scar area quantification: echocardiographic calcium can be quantified using free software designed for digital image processing and measurement of video intensity in manually traced regions of interest. First, image contrast, already increased by the eSCAR setting (which nulls normal myocardium), was further enhanced by use of a binary filter (‘default’ thresholding method), producing only black or white pixels. Regions of interest were then positioned onto each area demonstrating white pixels, taking care not to include the pericardium, possible scarred myocardium or other non-cardiac structures, which may also be characterized by strong signals when using the eSCAR setting. eSCAR area was then quantified by the area measurement function of the software, after the proper scale was set. Clinical implications Risk stratification of asymptomatic subjects The currently recommended approach for identifying asymptomatic subjects at risk of future cardiovascular events is based on the use of validated algorithms such as the Framingham Risk Score,101 the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equations4 and the European SCORE Risk Charts.102,103 Each of these uses the presence or absence of conventional risk factors (e.g. age, male gender, hypertension, diabetes, active smoking, hypercholesterolaemia) to estimate risk of future cardiovascular events. The Pooled Cohort atherosclerotic cardiovascular risk calculator was designed to improve risk assessment compared with the previously devised Framingham risk score, particularly in Blacks. However these scores have well recognized limitations, especially in women and younger individuals. A complementary approach, the non-invasive detection of atherosclerosis before development of clinical symptoms, could allow reclassification of subjects into higher or lower risk categories. This would allow more appropriate application of preventive treatments (initiation of lipid lowering therapy, for example) and more appropriate use of diagnostic tests for identifying significant coronary or extracoronary artery stenosis. The body of evidence on the predictive and risk-reclassification role of CAC on CT is large and founded on several well-designed prospective studies. New algorithms using CAC on top of conventional risk estimates have been derived and validated,12,104–106 which have led the European Guidelines on CV Prevention103 and the 2018 ACC/AHA guideline on the management of cholesterol104 to include the presence and grade of CAC at CT in cardiovascular risk estimation. The impact of a low socio-economic status, as expression of an increased burden of cardiovascular risk factors, on the extent of CAC, has been recently emphasized.107 Furthermore, the combination of CAC and carotid atherosclerosis, such as increased intima-medial thickness, has allowed to refine risk calculation for cerebrovascular events and prioritize the need for statin therapy.108 Ultrasound cardiac calcification also has a wealth of studies supporting its use for risk-stratification. No appropriately designed and powered prospective study has yet investigated its use on top of conventional risk factors in a primary prevention setting, although it appears this should be the next step in the investigation of this promising subclinical marker of atherosclerosis. It has been suggested by many investigators that non-invasive imaging for detection of calcification of valves and other cardiac structures can allow better risk stratification of asymptomatic subjects, particularly those at intermediate risk.106 Its use is now recognized and encouraged, especially in subjects undergoing routine echocardiographic examination for other indications (i.e. left ventricular hypertrophy, cardiac murmurs, atypical symptoms). Limitations Although the prevalence of intracardiac calcification is very high in older people and appears strongly related to age, the incidental finding of calcifications on echocardiographic examination should not be considered simply a natural manifestation of aging. Rather, it is a clear marker of atherosclerosis and a predictor of future cardiovascular events, even in asymptomatic individuals. Furthermore, valve calcifications usually increase over time, similarly to the well known phenomenon of coronary artery calcium progression, and the possibility of cardiac calcification regression has not been described; thus, the assessment of valve calcification is not useful for assessment of therapeutic interventions. Conclusion Early recognition of the clinical importance of these calcifications can allow better stratification of individuals into higher risk categories for poor outcomes. Such an approach should result in earlier and more optimal prevention strategies in these vulnerable patients. Author contribution PF, MH and GP contributed to the conception and design of the work. NG and AR contributed to the analysis and interpretation of literature. PF and ND drafted the manuscript. All co-authors critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. 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TI - Cardiac calcification as a marker of subclinical atherosclerosis and predictor of cardiovascular events: A review of the evidence
JF - European Journal of Preventive Cardiology
DO - 10.1177/2047487319830485
DA - 2019-07-01
UR - https://www.deepdyve.com/lp/oxford-university-press/cardiac-calcification-as-a-marker-of-subclinical-atherosclerosis-and-KcqlurTOpv
SP - 1191
EP - 1204
VL - 26
IS - 11
DP - DeepDyve
ER -