Retrograde Coronary Venous Infusion as a Delivery Strategy in Regenerative Cardiac Therapy: an Overview of Preclinical and Clinical Data

Retrograde Coronary Venous Infusion as a Delivery Strategy in Regenerative Cardiac Therapy: an... An important aspect of cell therapy in the field of cardiac disease is safe and effective delivery of cells. Commonly used delivery strategies such as intramyocardial injection and intracoronary infusion both present with advantages and disadvantages. Therefore, alternative delivery routes are explored, such as retrograde coronary venous infusion (RCVI). Our aim is to evaluate safety and efficiency of RCVI by providing a complete overview of preclinical and clinical studies applying RCVI in a broad range of disease types and experimental models. Available data on technical and safety aspects of RCVI are incomplete and insufficient. Improvement of cardiac function is seen after cell delivery via RCVI. However, cell retention in the heart after RCVI appears inferior compared to intracoronary infusion and intramyocardial injection. Adequately powered confirmatory studies on retention rates and safety are needed to proceed with RCVI in the future. . . Keywords Cell therapy Myocardial infarction Heart IC Intracoronary failure Retrograde coronary venous infusion IM Intramyocardial LVEF Left ventricular ejection fraction MVO Microvascular obstruction RC Retrograde cardioplegia RCVI Retrograde coronary venous infusion Abbreviations AMI Acute myocardial infarction CCS Canadian Cardiovascular Society scale CHF Congestive heart failure Introduction CMI Chronic myocardial infarction CRA Chronic refractory angina Cell therapy has proven to be safe and feasible for treat- CS Coronary sinus ment of cardiac disease. Yet, the clinical relevance of cell therapy is uncertain. Recent meta-analyses show a mar- ginal (2–5%) increase of cardiac function measured by Associate Editor Adrian Chester oversaw the review of this article left ventricular ejectionfraction(LVEF)[1, 2]. Taking into account the dynamic nature and the high perfusion Electronic supplementary material The online version of this article characteristics of the cardiac tissue [3], an important as- (https://doi.org/10.1007/s12265-018-9785-1) contains supplementary material, which is available to authorized users. pect of cell therapy is the location and mode of delivery. Two commonly used administration techniques are * Steven A. J. Chamuleau intramyocardial (IM) injection and intracoronary (IC) in- S.A.J.Chamuleau@umcutrecht.nl fusion [1, 2]. IM injection has the benefit of targeted de- 1 livery of cells in a target region, e.g., the border zone of Department of Cardiology, Division Heart and Lungs, University the infarct [4], but this procedure is time-consuming, suf- Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands fers from rapid wash-out of cells via venous drainage after injection [3], and needs specific systems in the catheteri- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands zation laboratory. IC infusion is quick and easy to perform 174 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 but the coronary system is often diseased in the target population, leading to inaccessibility of coronary arteries. Manipulation inside the coronary artery can potentially induce embolisms leading to decreased coronary blood flow [5–7]. Therefore, alternative delivery routes are ex- plored. The coronary venous system is easily accessible and typically free of atherosclerotic disease. Retrograde coronary venous infusion (RCVI) is considered to be a good alternative to IM and IC administration. RCVI is performed by placing a balloon-catheter in the coronary sinus (CS) or into one of the coronary veins. In order to maximize the therapeutic potential, the balloon is kept inflated temporarily to prevent the loss of infused cells due to antegrade venous flow and to allow the cells to Fig. 1 Flowchart of the systematic search disseminate in the heart. For optimal effect, this occlusion is often prolonged for a certain period after cell infusion. Our aim is to provide a complete overview of preclinical articles included in this review is 27 (Fig. 1). All articles and clinical studies applying RCVI as a cell delivery strat- were published between 2003 and 2016. egy and focus on safety aspects and efficiency measures. Preclinical and Clinical Experience Retrograde coronary venous infusion has been performed in a Methods number of different studies. In total, 21 preclinical studies are included in this review; 8 rat studies [10–17], 3 dog studies Search Strategy and Eligibility [18–20] and 10 pig studies [9, 21–29]. Patients were treated in 6studies [30–35]. The full search strategy is available as Online Resource 1. In brief, we have performed a search using the PubMed Preclinical Experience Treatment was given in acute (acute and Embase databases on May 15, 2017. Trials were eli- myocardial infarction (AMI)) [9, 13–15, 19, 20, 22–25, 29] gible for inclusion if they met the following criteria: (1) and chronic setting (chronic myocardial infarction (CMI)) original (preclinical or clinical) study, (2) full text avail- [10–12, 17, 21, 26–29] and in chronic heart failure (CHF) able in English, (3) covering cell therapy, (4) investigating [18]. One study treated healthy subjects (n =1) [16]. Cell safety or efficacy of retrograde CS/venous administration. products administered included skeletal myoblasts (n =6) An additional cross-reference screening was performed of [10, 12, 15, 16, 21, 26], bone marrow mononuclear cells included articles. The flowchart of the search is presented (n =2) [11, 29], peripheral blood mononuclear cells (n =2) in Fig. 1. [22, 24], adipose-derived stem cells (n =3) [18, 23, 24], mes- enchymal stem cells (n =6) [13, 14, 19, 20, 25, 27], embry- onic endothelial progenitor cell (n =1) [9], autologous Results unfractionated bone marrow (n =1) [28], and cardiac explant-derived c-Kit+ cells (n =1) [17]. One study adminis- Search Results tered both adipose-derived stem cells and peripheral blood mononuclear cells [24]. The entire search yielded a total of 4333 (3451 Medline and 882 Embase) hits, of which 110 reports were removed Clinical Experience In the clinical setting, treatment was given after duplicate screening. Another 4155 reports were ex- in AMI [31], CHF [30, 32], and chronic refractory angina cluded after title/abstract screening because they did not (CRA) [33–35]. Infused cell products included bone marrow fulfill the inclusion criteria. The remaining 68 articles mononuclear cells (n =3) [30, 31, 33], umbilical cord were screened on the availability of full text, leading to subepithelial cells (n =1) [32], and autologous unfractionated another 42 exclusions. One article was excluded due to a bone marrow (n =2) [34, 35]. shared dataset [8]. The cross-reference screening led to Table 1 shows study characteristics on disease model, re- one additional inclusion that did not come up in the orig- cipients, and used cell type and number. In summary, there is inal search due to the absence of one part of the search broad experience with RCVI across species, disease models, string in the title and abstract [9]. The total number of and used cells. J. of Cardiovasc. Trans. Res. (2018) 11:173–181 175 Table 1 Practical aspects of RCVI regarding disease type, location of infusion, and infused cell type and number Study Species Number of Model Administration Cell type Number of cells subjects Small animals Di Lascio [10] Rat 66 CMI RCV SMB 2 × 10^6 /100 g Fukushima [11] Rat 35 CMI RCV BMMNC 10^7 Fukushima [12] Rat 85 CMI RCV SMB 5 × 10^6 Huang [13] Rat 90 AMI RCV MSC 10^6 Huang [14] Rat 38 AMI RCV MSC 10^6 Suzuki [15] Rat 62 AMI RCV SMB 10^6 Suzuki [16] Rat 20 NP RCV SMB 10^6 Zakharova [17] Rat 32 CMI RCV CEDC 10^6 Large animals Pogue [18] Dog 15 CHF RCV ASC 10^7 Sun [19] Dog 28 AMI RCV MSC 10^7 Wang [20] Dog 18 AMI RCV MSC 10^8 Formigli [21] Pig 15 CMI RCV SMB 8 × 10^7 Hagikura [22] Pig 15 AMI RCV PBMNC 5 × 10^6 Hong [23] Pig 7 AMI RCV ASC 10^7 Hou [24] Pig 5 AMI RCV PBMNC/ASC 10^7 Kupatt [9] Pig ns AMI RCV EEPC 5 × 10^6 Lu [25] Pig 36 AMI RCV MSC 10^8 Prifti [26] Pig 15 CMI RCV SMB Ns Sato [27] Pig 13 CMI RCV MSC 10^7 Vicario [28] Pig 16 CMI RCS AUBM Ns Yokoyama [29] Pig 21 AMI & CMI RCV BMMNC 3.2 ± 1.2 × 10^9 Clinical trials Patel [30] Human 46 CHF RCS BMMNC 3.7 × 10^9 Silva [31] Human 9 AMI RCV BMMNC 10^8 Tuma [33] Human 14 CRA RCS BMMNC 8.2 × 10^8 Tuma [32] Human 18 CHF RCS UCSEC 1×, 2×, 4 × 10^8 Vicario [34] Human 14 CRA RCS AUBM 0,04 or 0,08 × 10^8/kg Vicario [35] Human 15 CRA RCS AUBM >0,04 × 10^8/kg CMI chronic myocardial infarction (administration of cells > 1 week post MI), AMI acute myocardial infarction (administration of cells up to 7 days post MI), CHF chronic heart failure, NP no pathology, CRA chronic refractory angina, MI myocardial infarction, SMB skeletal myoblasts, BMMNC bone marrow mononuclear cells, PBMNC peripheral blood mononuclear cells, ASC adipose-derived stem cells, MSC mesenchymal stem cells, EEPC embryonic endothelial progenitor cells, UCSEC umbilical cord subepithelial cells, AUBM autologous unfractionated bone marrow, CEDC cardiac explant-derived c-Kit+ cells, RCV retrograde coronary venous infusion, RCS retrograde coronary sinus infusion, ns not specified Practical Aspects of RCVI occluded differed both within and between animal species (Tables 1 and 2). There is a high degree of heterogeneity in the way that RCVI is performed. Important differences between models are (1) the infusion duration, (2) the volume of infused cell suspension, Clinical Experience (3) the time that the CS or coronary vein is occluded to prevent cells from draining directly into the right atrium, (4) the number In clinical trials, cells were mainly infused via the CS. The of cells infused, and (5) the location of infusion (Tables 1 and 2). amount of cells infused was generally higher, ranging from approximately 1 × 10^8 to 4 × 10^9 cells. Notable differences Preclinical Experience between preclinical and clinical trials are that infused cell vol- umes were many times greater in clinical trials compared to Cells are predominantly infused via the coronary veins in preclinical trials and that the CS or coronary vein was occlud- preclinical trials. The infused cell number ranged from ap- ed longer in clinical trials (Tables 1 and 2). proximately 1 × 10^6 to 3 × 10^9. Infusion duration, infused We found a striking reporting difference regarding practical cell volume, and the time that the CS or coronary vein was aspects of RCVI, with roughly 20% of studies not adequately 176 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 Table 2 Heterogeneity regarding Study type Infusion duration (min) Infused volume (ml) Occlusion time (min) practical aspects of RCI both within and between species Rat studies (n =8) 1.0 [0.5–1.0] (n =3) 1.0 [0.5–1.0] (n = 8) 5.0 [1.0–5.0] (n =8) Dog studies (n =3) No data (n =0) 10.0 [10.0–20.0] (n = 3) Insufficient data (n =2) Pig studies (n = 10) 10.0 [0.25–40.0] (n =9) 15.0 [10.0–25.0] (n = 10) 10.0 [5.0–20.0] (n =7) Human studies (n =6) 5.0 [4.0–6.0] (n =6) 60.0 [40.25–120.0] (n =6) 15.0 [11.0–17.0] (n =5) Overall (n = 27) 5.0 [0.88–11.25 (n = 18) 10 ml [1.0–40.0] (n = 27) 10.0 [5.0–12.75] (n =22) Data are presented as median with interquartile ranges calculated using IBM SPSS statistics 21 min minute(s), ml milliliter(s), n number of studies that statistics are based on describing procedural characteristics. This hampers the possi- was also reported in some patients in another clinical trial [31]. bility to repeat certain experiments if desired. In a population of patients with heart failure, a transient in- crease in Troponin-I levels was seen in all patients that re- solved within 24 h after catheterization. No arrhythmias were Safety Issues seen in this patient population and there was no evidence of damage to the CS after infusion [32]. No occurrence of ar- Here, safety is described as occurrence of arrhythmias related rhythmias, no rise in cardiac enzymes, and no pericardial ef- to RCVI, elevation of heart enzymes, cardiac tamponade, fusion after retrograde delivery of cells was seen in patients presence of pericardial fluid, microvascular obstruction with chronic refractory angina [33]. (MVO), damage to the CS, and mortality. It should be noted that some studies did not report safety aspects due to the pur- pose and setup of these studies. Mortality Safety Aspects Other than Mortality Preclinical Experience Mortality rates were reported in 16 ar- ticles, with no RCVI-related deaths occurring in 11 of these 16 Preclinical Experience Thirteen preclinical studies reported studies. The available mortality data are difficult to interpret safety aspects of RCVI. One study only described that RCVI because it is likely that other factors besides RCVI, such as is safe without providing data on safety [29]. Seven studies surgical procedure, have had influence on mortality rates. only reported absence of arrhythmias without providing in- Loss of subjects that could possibly be attributed to RCVI depth data [10, 14–16, 22, 26, 28]. Five articles provided more was seen in 5 studies, described below. in-depth data on safety aspects of RCVI [11, 12, 18, 20, 23]. A loss of 11/66 rats (16.7%) after RCVI was seen in one These five studies will be discussed in more detail below. study. This loss could be attributed to the fact that a thoracot- In two studies, IM injection was associated with an in- omy was performed to access the coronary vein and might not creased chance of both spontaneous ventricular tachycardias be related to the RCVI procedure itself. Since all animals and ventricular premature contractions after cell administra- received cells through RCVI, there is no control group for tion compared to RCVI, suggesting that RCVI is safer in these mortality [10]. A comparison was made between mortality experimental models [11, 12]. Another study closely moni- rates after IM injection and RCVI in two rat studies. tored dogs for occurrence of arrhythmias and reported tran- Mortality rates were comparable between IM injection and sient atrial fibrillation during CS catheterization in 6 out of 15 RCVI with the first study showing mortality rates of 2/34 rats dogs and a pre-existent ventricular arrhythmia in one dog [18]. (5.9%) after IM injection and 2/35 rats (5.7%) after RCVI In another dog study, no occurrence of arrhythmias or cardiac [11]. Similar results were seen in the second study with a tamponade associated with RCVI was seen [20]. RCVI did mortality of 4/48 rats (8.3%) in the IM injection group com- not lead to MVO after cell administration in one pig study pared to 4/49 rats (8.2%) in the RCVI group [12]. Surgical [23]. stress and bleeding were suggested to be the cause of mortal- ity. A common complication with RCVI in small animals is Clinical Experience All six clinical studies reported safety as- sustained bleeding from the catheter insertion site because the pects of RCVI. Two studies only reported absence of arrhyth- catheter has to be inserted into the fragile left cardiac vein via mias without providing in-depth data [34, 35]. The other four the left superior vena cava or CS. A comparison was made studies provided more in-depth information on safety. In one between conventional RCVI and a modified method of RCVI clinical trial, absence of arrhythmias associated with RCVI to see if bleeding could be limited in small animals. was reported, but a rise in cardiac enzymes was seen in some Conventional RCVI was described as delivery of cells by patients after RCVI [30]. Rise in cardiac enzymes after RCVI direct insertion of a catheter in the left cardiac vein via the J. of Cardiovasc. Trans. Res. (2018) 11:173–181 177 CS. Modified RCVI was described as cardiac vein catheteri- In conclusion, there seems to be no relation between the zation via the left internal jugular vein. A mortality of 3/7 rats way RCVI is performed and the occurrence of adverse events, (42.9%) was seen in the group that received cells via conven- arrhythmias, and mortality. Especially large animal studies tional RCVI versus 0/20 rats (0%) in the group with modified and clinical trials do not report mortality or arrhythmias relat- RCVI [14]. One small animal study reported a loss of 18/62 ed to RCVI. Although RCVI is reported to be safe in the rats (29%) within 24 h after RCVI, which the authors linked to majority of studies presented here, safety data on RCVI are development of acute heart failure rather than the RCVI [15]. underreported with the majority of studies providing no or insufficient safety data to conclude that RCVI is a safe method Clinical Experience In all six clinical trials, mortality rates were for cell delivery in the heart. Safety and mortality data are reported but mortality related to RCVI did not occur. provided in Table 3. Table 3 Safety and mortality data Study Species Reported safety aspects Mortality related to retrograde infusion procedure Small animals Di Lascio [10] Rat No arrhythmias, described as safe 16,7% (11/66) probably related to thoracotomy) Fukushima [11] Rat More VPC and VT in IM group vs RCVI group, RCVI: 5.7% (2/35) vs IM: 5.9% (2/34) described as safe Fukushima [12] Rat More VPC and VT in IM group vs RCVI group, RCVI: 8.2% (4/49) vs IM: 8.3% (4/48) described as safe Huang [13] Rat ns ns Huang [14] Rat No arrhythmias conventional technique: 42.9% (3/7) modified technique: 0 Suzuki [15] Rat No arrhythmias, described as safe 29% (18/62) within 24 h, probably due to acute heart failure Suzuki [16] Rat No arrhythmias 0% Zakharova [17] Rat ns 0% Large animals Pogue [18] Dog Transient AF during procedure in 6/15 dogs, 0% described as safe Sun [19] Dog ns 0% Wang [20] Dog No arrhythmias, no cardiac tamponade, described 0% as safe Formigli [21] Pig ns 0% Hagikura [22] Pig No arrhythmias, described as safe 0% Hong [23] Pig No MVO, described as safe 0% Hou [24] Pig ns 0% Kupatt [9] Pig ns ns Lu [25] Pig ns ns Prifti [26] Pig No arrhythmias, described as safe 0% Sato [27] Pig ns 0% Vicario [28] Pig No arrhythmias ns Yokoyama [29] Pig Described as safe ns Clinical trials Patel [30] Human Rise in cardiac enzymes in some patients, no 0% arrhythmias associated with RCVI, described as safe Silva [31] Human Rise in cardiac enzymes in some patients 0% Tuma [33] Human No rise in cardiac enzymes, no arrhythmias, no 0% pericardial effusion, described as safe Tuma [32] Human No arrhythmias, rise in cardiac enzymes in all 0% patients, no evidence of CS leak or damage, described as safe Vicario [34] Human No arrhythmias, described as safe 0% Vicario [35] Human No arrhythmias, described as safe 0% VPC ventricular premature contraction, VT ventricular tachycardia, IM intramyocardial injection, RCVI retrograde coronary venous infusion, ns not specified, AF atrial fibrillation, MVO microvascular obstruction, CS coronary sinus 178 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 Efficiency Measures be noted that the three large animal experiments [9, 23, 24] consist of very small sample sizes. RCVI appeared to be either Retention Rate inferior to [23, 24] or equal to [11, 12] IM injection or IC infusion regarding cell retention. Retention rates in Table 4 Preclinical Experience The therapeutic benefit of cell therapy are presented as the percentage of total administered cells that is in part based on the retention of cells in the heart. In total, is retained in the heart. In one study [23], retention of cells in eight preclinical studies provide data on the percentage of the heart was reported as a percentage of cells retained in five administered cells that retain in the heart after RCVI major thoracoabdominal organs. We converted the data to a (Table 4). Different methods are used to determine cardiac percentage of total administered cells that are retained in the retention of cells. One method is the use of real-time polymer- heart in order to achieve comparability between studies. If ase chain reaction for the Y-chromosome-specific Sry gene to retention of cells was measured at multiple time points, we detect the amount of transplanted male cells in female sub- reported retention at the first time point, because retention jects. Other methods include administration of β- decreased in time in the majority of these studies. A decrease galactosidase-expressing cells, or to label cells radioactively was not seen in three studies [15, 16, 23]. This can be ex- 111 99m with Indium or Tc -hexamethylpropylenamineoxime for plained by the fact that two of these studies used expression quantitative analysis using scintigraphy. The retention rates of β-galactosidase as a measure of cardiac cell retention [15, show a high degree of heterogeneity that can partially be ex- 16]. Increased expression of β-galactosidase over time was plained by differences in animal model, disease model, cell attributed to proliferation of administered cells. The third arti- type, infusion time point, follow-up time point, and quantifi- cle [23] presented the retention of cells in the heart as a per- cation technique. Most studies report a retention ≤ 10% and centage of the total retention in five major organs. A possible two studies report a remarkably higher retention of respective- explanation for the increase in retention at a later time point ly 31.4 ± 4.8 and 29.8 ± 6.9% [15, 16]. The latter studies ap- could be that the decrease in the number of cells in the heart plied an indirect measurement of retention by using β- was relatively less than the decrease in the number of cells in galactosidase-expressing cells, and comparing the level of β- the five major organs, making this decrease in the heart look galactosidase activity to the standard curve. One study used a like an increase [23]. method to optimize retention (magnetic targeting) that result- ed in an increase of retention from approximately 2% after Clinical Experience Retention of cells in the heart was deter- routine RCVI to 8.5% with magnetic targeting [13]. It should mined in one clinical trial, showing inferiority of RCVI versus Table 4 Retention of cells in the heart Study Species # Retention Retention Application method method time point RCVI retention IC retention IM retention Peripheral IV Sign retention comparison Small animals Fukushima [11] Rat 35 Sry 3 days 1.84 ± 0.27% – 1.45 ± 0.27% – ns Fukushima [12] Rat 85 Sry 3 days 10 ± 5% – 14 ± 5% – ns a d Huang [13] Rat 90 Sry 24 h 2%/8.5% –– – P <0.001 Suzuki [16]Rat 20 β-galactosidase 10 min 31.4 ± 4.8% –– – na Suzuki [15]Rat 62 β-galactosidase 10 min 29.8 ± 6.9% –– – na c c Large animals Hong [23] Pig 7 Radiolabel 1 h ±8% ±25% –– P =0.037 Hou [24] Pig 5 Radiolabel 1 h 3.2 ± 1% 2.6 ± 0.3% 11.3 ± 3% – Not sign Kupatt [9] Pig 6 Radiolabel 1 h 2.7% –– 0.5% ns Clinical trials Silva [31] Human 9 Radiolabel 4 h 4.62% 16.14% –– P =0.01 In case retention was not measured as % of total administered dose (e.g., as a % of uptake in major organs), we calculated the retention % of total administered dose. This was the case in one study [23] Sry polymerase chain reaction for the Y-chromosome-specific Sry gene, β-galactosidase presence of β-galactosidase-expressing cells, radiolabel retention measured by scintigraphy after radiolabeled cell infusion, RCVI retrograde coronary sinus/venous infusion, IC intracoronary infusion, IM intramyocardial injection, IV intravenous, ns not specified, na not applicable, # number of subjects 2% in case of normal delivery, 8.5% in case of magnetic targeting Comparison between RCVI infusion and IM retention Corrected for total injected dose Normal delivery versus magnetic targeting J. of Cardiovasc. Trans. Res. (2018) 11:173–181 179 99 m IC infusion [31]. Cells labeled with Tc - 33% only report absence of arrhythmias without mentioning hexamethylpropylenamineoxime were used to assess reten- other safety parameters. Only a limited number of studies tion in the heart. Just like the three pig studies, sample size provide more in-depth safety information regarding RCVI. was small and retention rates were comparable [9, 23, 24]. The six clinical trials included in this overview report cardiac enzyme rise as the only safety issue associated with RCVI and Functional Outcomes show no arrhythmias associated with RCVI, no development of pericardial fluid, and no sustained damage to the CS after The goal of cardiac reparative therapy is improvement of car- RCVI. It is understandable that the first priority of research diac function or decrease of disease characteristics such as focused on cell therapy lies with validating the effectiveness angina complaints in order to improve quality of life and de- of cell therapy in itself. From this perspective, it is logical that crease mortality. Here, we focused on the effect of cell admin- some studies do not report on safety of delivery because this istration on (1) LVEF (AMI, CMI, CHF), (2) improvement on was not the purpose of the study. Nevertheless, due to the poor the Canadian Cardiovascular Society scale (CSS) (CRA), and reporting of safety aspects, we cannot make an accurate as- (3) myocardial perfusion (CRA). sessment of the safety profile of RCVI. However, retrograde accessing of the coronary venous Preclinical Experience Most of the preclinical studies that re- system hasbeenperformedfor alongtimeinthefieldof ported changes in LVEF (12/15) showed a significant increase cardiac surgery in a great number of patients. With retro- in LVEF versus baseline and/or controls. Three studies only grade cardioplegia (RC), the myocardium is retrogradely showed improvement of LVEF when cells were combined perfused during cardiac surgery to induce cardiac arrest with growth factors [22] or no effects on LVEF at all [18, 19]. and protect the myocardium. With RC, a balloon-catheter is used to occlude the opening of the CS, in a way com- Clinical Experience Three out of four clinical studies reported parable to RCVI. RC is reported to be safe, with injury to significant improvement of LVEF. The study that did not theCSoccurringin0.06to0.6%ofpatients[36, 37], show improvement of LVEF after RCVI compared IC infu- resulting in formation of hematoma on the atrioventricular sion with RCVI and reported that patients receiving cells groove, perforation of the CS wall, pericardial effusion, or through IC infusion did show improvement in LVEF [31]. laceration of the right ventricle or CS [37–40]. These data The difference in cell retention between IC infusion and would suggest that the technical part of RCVI, namely the RCVI in these patients might be the explanation for this dif- insertion of a balloon-tipped catheter in the CS followed ference in functional outcome. Two other studies show com- by infusion of fluid, should be safe. parable retention rates between IM injection and RCVI and Cells delivered through RCVI are able to improve cardiac function and alleviate angina symptoms. However, in terms of both groups show comparable functional gains [11, 12]. In case of CRA, changes in CCS scale and improvement in myo- cell retention, the data suggest that RCVI is a limitedly effec- cardial perfusion were reported [33–35]. tive delivery strategy for cell therapy. In fact, IC infusion and In the majority of cases, cells administered with RCVI are IM injection show either higher or equal retention rates. It is able to effectuate improvement of cardiac function in a range likely that inferior retention rates decrease the efficacy of of different experimental models. An overview of functional RCVI. outcomes is presented in Online Resource 2. Due to the limited number of studies included in this re- view, we cannot conclude that RCVI is favorable in certain disease types or that certain cell types performed better than Discussion others in the included studies. In conclusion, the available data on technical and safe- Cell delivery strategies should meet two important demands. ty aspects of RCVI are insufficient and incomplete. First and foremost, the technique should be safe. Second, it Furthermore, retention data show inferior results com- should be effective in delivering cells to the heart. In this pared to IC infusion and IM injection. We conclude that paper, we provided an overview of RCVI. at present, there are not enough arguments to proceed There is a high degree of heterogeneity regarding technical with this technique in the clinical arena. Well-designed aspects of RCVI both between and within species. confirmatory studies on retention rates and safety data Furthermore, roughly 20% of studies do not adequately de- are required to proceed with RCVI in the future. scribe procedural characteristics, which hampers the possibil- ity to repeat these experiments technically. Funding This research is part of Cardiovasculair Onderzoek Nederland The main finding is that relevant data regarding technique (grant number: CVON2011-2012), an initiative of the Dutch Heart and safety are poorly reported. For instance, 30% of included Foundation, Netherlands FederationofUniversityMedical Centers (NFU), Royal Netherlands Academy of Arts and Science (KNAW), and studies do not report on safety aspects of RCVI at all, while 180 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 Nederlandse Organisatie voor Wetenschappelijk Onderzoek/Nederlandse of phosphatidylinositol 3-kinase/AKT kinase. Circulation, 112(9 Organisatie voor Gezondheidsonderzoek en Zorginnovatie (NWO/ Suppl), I117–I122. https://doi.org/10.1161/circulationaha.104. ZonMW). 524801. 10. Di Lascio, G., Harmelin, G., Targetti, M., Nanni, C., Bianchi, G., Gasbarri, T., et al. (2012). Cellular retrograde cardiomyoplasty and Compliance with Ethical Standards relaxin therapy for postischemic myocardial repair in a rat model. Texas Heart Institute Journal, 39(4), 488–499. Conflict of Interest The authors declare that they have no conflict of 11. Fukushima, S., Varela-Carver, A., Coppen, S. R., Yamahara, K., interest. Felkin, L. E., Lee, J., et al. (2007). Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular Ethical Approval This article does not contain any studies with human arrhythmias in a rat chronic ischemic heart failure model. participants or animals performed by any of the authors. Circulation, 115(17), 2254–2261. https://doi.org/10.1161/ circulationaha.106.662577. 12. Fukushima, S., Coppen, S. R., Lee, J., Yamahara, K., Felkin, L. E., Open Access This article is distributed under the terms of the Creative Terracciano, C. M., et al. (2008). Choice of cell-delivery route for Commons Attribution 4.0 International License (http:// skeletal myoblast transplantation for treating post-infarction chronic creativecommons.org/licenses/by/4.0/), which permits unrestricted use, heart failure in rat. 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Stem Cells Translational 10.1016/j.athoracsur.2005.11.037. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Cardiovascular Translational Research Springer Journals

Retrograde Coronary Venous Infusion as a Delivery Strategy in Regenerative Cardiac Therapy: an Overview of Preclinical and Clinical Data

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Medicine & Public Health; Cardiology; Human Genetics; Biomedical Engineering; Biomedicine, general; Medicine/Public Health, general
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Abstract

An important aspect of cell therapy in the field of cardiac disease is safe and effective delivery of cells. Commonly used delivery strategies such as intramyocardial injection and intracoronary infusion both present with advantages and disadvantages. Therefore, alternative delivery routes are explored, such as retrograde coronary venous infusion (RCVI). Our aim is to evaluate safety and efficiency of RCVI by providing a complete overview of preclinical and clinical studies applying RCVI in a broad range of disease types and experimental models. Available data on technical and safety aspects of RCVI are incomplete and insufficient. Improvement of cardiac function is seen after cell delivery via RCVI. However, cell retention in the heart after RCVI appears inferior compared to intracoronary infusion and intramyocardial injection. Adequately powered confirmatory studies on retention rates and safety are needed to proceed with RCVI in the future. . . Keywords Cell therapy Myocardial infarction Heart IC Intracoronary failure Retrograde coronary venous infusion IM Intramyocardial LVEF Left ventricular ejection fraction MVO Microvascular obstruction RC Retrograde cardioplegia RCVI Retrograde coronary venous infusion Abbreviations AMI Acute myocardial infarction CCS Canadian Cardiovascular Society scale CHF Congestive heart failure Introduction CMI Chronic myocardial infarction CRA Chronic refractory angina Cell therapy has proven to be safe and feasible for treat- CS Coronary sinus ment of cardiac disease. Yet, the clinical relevance of cell therapy is uncertain. Recent meta-analyses show a mar- ginal (2–5%) increase of cardiac function measured by Associate Editor Adrian Chester oversaw the review of this article left ventricular ejectionfraction(LVEF)[1, 2]. Taking into account the dynamic nature and the high perfusion Electronic supplementary material The online version of this article characteristics of the cardiac tissue [3], an important as- (https://doi.org/10.1007/s12265-018-9785-1) contains supplementary material, which is available to authorized users. pect of cell therapy is the location and mode of delivery. Two commonly used administration techniques are * Steven A. J. Chamuleau intramyocardial (IM) injection and intracoronary (IC) in- S.A.J.Chamuleau@umcutrecht.nl fusion [1, 2]. IM injection has the benefit of targeted de- 1 livery of cells in a target region, e.g., the border zone of Department of Cardiology, Division Heart and Lungs, University the infarct [4], but this procedure is time-consuming, suf- Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands fers from rapid wash-out of cells via venous drainage after injection [3], and needs specific systems in the catheteri- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands zation laboratory. IC infusion is quick and easy to perform 174 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 but the coronary system is often diseased in the target population, leading to inaccessibility of coronary arteries. Manipulation inside the coronary artery can potentially induce embolisms leading to decreased coronary blood flow [5–7]. Therefore, alternative delivery routes are ex- plored. The coronary venous system is easily accessible and typically free of atherosclerotic disease. Retrograde coronary venous infusion (RCVI) is considered to be a good alternative to IM and IC administration. RCVI is performed by placing a balloon-catheter in the coronary sinus (CS) or into one of the coronary veins. In order to maximize the therapeutic potential, the balloon is kept inflated temporarily to prevent the loss of infused cells due to antegrade venous flow and to allow the cells to Fig. 1 Flowchart of the systematic search disseminate in the heart. For optimal effect, this occlusion is often prolonged for a certain period after cell infusion. Our aim is to provide a complete overview of preclinical articles included in this review is 27 (Fig. 1). All articles and clinical studies applying RCVI as a cell delivery strat- were published between 2003 and 2016. egy and focus on safety aspects and efficiency measures. Preclinical and Clinical Experience Retrograde coronary venous infusion has been performed in a Methods number of different studies. In total, 21 preclinical studies are included in this review; 8 rat studies [10–17], 3 dog studies Search Strategy and Eligibility [18–20] and 10 pig studies [9, 21–29]. Patients were treated in 6studies [30–35]. The full search strategy is available as Online Resource 1. In brief, we have performed a search using the PubMed Preclinical Experience Treatment was given in acute (acute and Embase databases on May 15, 2017. Trials were eli- myocardial infarction (AMI)) [9, 13–15, 19, 20, 22–25, 29] gible for inclusion if they met the following criteria: (1) and chronic setting (chronic myocardial infarction (CMI)) original (preclinical or clinical) study, (2) full text avail- [10–12, 17, 21, 26–29] and in chronic heart failure (CHF) able in English, (3) covering cell therapy, (4) investigating [18]. One study treated healthy subjects (n =1) [16]. Cell safety or efficacy of retrograde CS/venous administration. products administered included skeletal myoblasts (n =6) An additional cross-reference screening was performed of [10, 12, 15, 16, 21, 26], bone marrow mononuclear cells included articles. The flowchart of the search is presented (n =2) [11, 29], peripheral blood mononuclear cells (n =2) in Fig. 1. [22, 24], adipose-derived stem cells (n =3) [18, 23, 24], mes- enchymal stem cells (n =6) [13, 14, 19, 20, 25, 27], embry- onic endothelial progenitor cell (n =1) [9], autologous Results unfractionated bone marrow (n =1) [28], and cardiac explant-derived c-Kit+ cells (n =1) [17]. One study adminis- Search Results tered both adipose-derived stem cells and peripheral blood mononuclear cells [24]. The entire search yielded a total of 4333 (3451 Medline and 882 Embase) hits, of which 110 reports were removed Clinical Experience In the clinical setting, treatment was given after duplicate screening. Another 4155 reports were ex- in AMI [31], CHF [30, 32], and chronic refractory angina cluded after title/abstract screening because they did not (CRA) [33–35]. Infused cell products included bone marrow fulfill the inclusion criteria. The remaining 68 articles mononuclear cells (n =3) [30, 31, 33], umbilical cord were screened on the availability of full text, leading to subepithelial cells (n =1) [32], and autologous unfractionated another 42 exclusions. One article was excluded due to a bone marrow (n =2) [34, 35]. shared dataset [8]. The cross-reference screening led to Table 1 shows study characteristics on disease model, re- one additional inclusion that did not come up in the orig- cipients, and used cell type and number. In summary, there is inal search due to the absence of one part of the search broad experience with RCVI across species, disease models, string in the title and abstract [9]. The total number of and used cells. J. of Cardiovasc. Trans. Res. (2018) 11:173–181 175 Table 1 Practical aspects of RCVI regarding disease type, location of infusion, and infused cell type and number Study Species Number of Model Administration Cell type Number of cells subjects Small animals Di Lascio [10] Rat 66 CMI RCV SMB 2 × 10^6 /100 g Fukushima [11] Rat 35 CMI RCV BMMNC 10^7 Fukushima [12] Rat 85 CMI RCV SMB 5 × 10^6 Huang [13] Rat 90 AMI RCV MSC 10^6 Huang [14] Rat 38 AMI RCV MSC 10^6 Suzuki [15] Rat 62 AMI RCV SMB 10^6 Suzuki [16] Rat 20 NP RCV SMB 10^6 Zakharova [17] Rat 32 CMI RCV CEDC 10^6 Large animals Pogue [18] Dog 15 CHF RCV ASC 10^7 Sun [19] Dog 28 AMI RCV MSC 10^7 Wang [20] Dog 18 AMI RCV MSC 10^8 Formigli [21] Pig 15 CMI RCV SMB 8 × 10^7 Hagikura [22] Pig 15 AMI RCV PBMNC 5 × 10^6 Hong [23] Pig 7 AMI RCV ASC 10^7 Hou [24] Pig 5 AMI RCV PBMNC/ASC 10^7 Kupatt [9] Pig ns AMI RCV EEPC 5 × 10^6 Lu [25] Pig 36 AMI RCV MSC 10^8 Prifti [26] Pig 15 CMI RCV SMB Ns Sato [27] Pig 13 CMI RCV MSC 10^7 Vicario [28] Pig 16 CMI RCS AUBM Ns Yokoyama [29] Pig 21 AMI & CMI RCV BMMNC 3.2 ± 1.2 × 10^9 Clinical trials Patel [30] Human 46 CHF RCS BMMNC 3.7 × 10^9 Silva [31] Human 9 AMI RCV BMMNC 10^8 Tuma [33] Human 14 CRA RCS BMMNC 8.2 × 10^8 Tuma [32] Human 18 CHF RCS UCSEC 1×, 2×, 4 × 10^8 Vicario [34] Human 14 CRA RCS AUBM 0,04 or 0,08 × 10^8/kg Vicario [35] Human 15 CRA RCS AUBM >0,04 × 10^8/kg CMI chronic myocardial infarction (administration of cells > 1 week post MI), AMI acute myocardial infarction (administration of cells up to 7 days post MI), CHF chronic heart failure, NP no pathology, CRA chronic refractory angina, MI myocardial infarction, SMB skeletal myoblasts, BMMNC bone marrow mononuclear cells, PBMNC peripheral blood mononuclear cells, ASC adipose-derived stem cells, MSC mesenchymal stem cells, EEPC embryonic endothelial progenitor cells, UCSEC umbilical cord subepithelial cells, AUBM autologous unfractionated bone marrow, CEDC cardiac explant-derived c-Kit+ cells, RCV retrograde coronary venous infusion, RCS retrograde coronary sinus infusion, ns not specified Practical Aspects of RCVI occluded differed both within and between animal species (Tables 1 and 2). There is a high degree of heterogeneity in the way that RCVI is performed. Important differences between models are (1) the infusion duration, (2) the volume of infused cell suspension, Clinical Experience (3) the time that the CS or coronary vein is occluded to prevent cells from draining directly into the right atrium, (4) the number In clinical trials, cells were mainly infused via the CS. The of cells infused, and (5) the location of infusion (Tables 1 and 2). amount of cells infused was generally higher, ranging from approximately 1 × 10^8 to 4 × 10^9 cells. Notable differences Preclinical Experience between preclinical and clinical trials are that infused cell vol- umes were many times greater in clinical trials compared to Cells are predominantly infused via the coronary veins in preclinical trials and that the CS or coronary vein was occlud- preclinical trials. The infused cell number ranged from ap- ed longer in clinical trials (Tables 1 and 2). proximately 1 × 10^6 to 3 × 10^9. Infusion duration, infused We found a striking reporting difference regarding practical cell volume, and the time that the CS or coronary vein was aspects of RCVI, with roughly 20% of studies not adequately 176 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 Table 2 Heterogeneity regarding Study type Infusion duration (min) Infused volume (ml) Occlusion time (min) practical aspects of RCI both within and between species Rat studies (n =8) 1.0 [0.5–1.0] (n =3) 1.0 [0.5–1.0] (n = 8) 5.0 [1.0–5.0] (n =8) Dog studies (n =3) No data (n =0) 10.0 [10.0–20.0] (n = 3) Insufficient data (n =2) Pig studies (n = 10) 10.0 [0.25–40.0] (n =9) 15.0 [10.0–25.0] (n = 10) 10.0 [5.0–20.0] (n =7) Human studies (n =6) 5.0 [4.0–6.0] (n =6) 60.0 [40.25–120.0] (n =6) 15.0 [11.0–17.0] (n =5) Overall (n = 27) 5.0 [0.88–11.25 (n = 18) 10 ml [1.0–40.0] (n = 27) 10.0 [5.0–12.75] (n =22) Data are presented as median with interquartile ranges calculated using IBM SPSS statistics 21 min minute(s), ml milliliter(s), n number of studies that statistics are based on describing procedural characteristics. This hampers the possi- was also reported in some patients in another clinical trial [31]. bility to repeat certain experiments if desired. In a population of patients with heart failure, a transient in- crease in Troponin-I levels was seen in all patients that re- solved within 24 h after catheterization. No arrhythmias were Safety Issues seen in this patient population and there was no evidence of damage to the CS after infusion [32]. No occurrence of ar- Here, safety is described as occurrence of arrhythmias related rhythmias, no rise in cardiac enzymes, and no pericardial ef- to RCVI, elevation of heart enzymes, cardiac tamponade, fusion after retrograde delivery of cells was seen in patients presence of pericardial fluid, microvascular obstruction with chronic refractory angina [33]. (MVO), damage to the CS, and mortality. It should be noted that some studies did not report safety aspects due to the pur- pose and setup of these studies. Mortality Safety Aspects Other than Mortality Preclinical Experience Mortality rates were reported in 16 ar- ticles, with no RCVI-related deaths occurring in 11 of these 16 Preclinical Experience Thirteen preclinical studies reported studies. The available mortality data are difficult to interpret safety aspects of RCVI. One study only described that RCVI because it is likely that other factors besides RCVI, such as is safe without providing data on safety [29]. Seven studies surgical procedure, have had influence on mortality rates. only reported absence of arrhythmias without providing in- Loss of subjects that could possibly be attributed to RCVI depth data [10, 14–16, 22, 26, 28]. Five articles provided more was seen in 5 studies, described below. in-depth data on safety aspects of RCVI [11, 12, 18, 20, 23]. A loss of 11/66 rats (16.7%) after RCVI was seen in one These five studies will be discussed in more detail below. study. This loss could be attributed to the fact that a thoracot- In two studies, IM injection was associated with an in- omy was performed to access the coronary vein and might not creased chance of both spontaneous ventricular tachycardias be related to the RCVI procedure itself. Since all animals and ventricular premature contractions after cell administra- received cells through RCVI, there is no control group for tion compared to RCVI, suggesting that RCVI is safer in these mortality [10]. A comparison was made between mortality experimental models [11, 12]. Another study closely moni- rates after IM injection and RCVI in two rat studies. tored dogs for occurrence of arrhythmias and reported tran- Mortality rates were comparable between IM injection and sient atrial fibrillation during CS catheterization in 6 out of 15 RCVI with the first study showing mortality rates of 2/34 rats dogs and a pre-existent ventricular arrhythmia in one dog [18]. (5.9%) after IM injection and 2/35 rats (5.7%) after RCVI In another dog study, no occurrence of arrhythmias or cardiac [11]. Similar results were seen in the second study with a tamponade associated with RCVI was seen [20]. RCVI did mortality of 4/48 rats (8.3%) in the IM injection group com- not lead to MVO after cell administration in one pig study pared to 4/49 rats (8.2%) in the RCVI group [12]. Surgical [23]. stress and bleeding were suggested to be the cause of mortal- ity. A common complication with RCVI in small animals is Clinical Experience All six clinical studies reported safety as- sustained bleeding from the catheter insertion site because the pects of RCVI. Two studies only reported absence of arrhyth- catheter has to be inserted into the fragile left cardiac vein via mias without providing in-depth data [34, 35]. The other four the left superior vena cava or CS. A comparison was made studies provided more in-depth information on safety. In one between conventional RCVI and a modified method of RCVI clinical trial, absence of arrhythmias associated with RCVI to see if bleeding could be limited in small animals. was reported, but a rise in cardiac enzymes was seen in some Conventional RCVI was described as delivery of cells by patients after RCVI [30]. Rise in cardiac enzymes after RCVI direct insertion of a catheter in the left cardiac vein via the J. of Cardiovasc. Trans. Res. (2018) 11:173–181 177 CS. Modified RCVI was described as cardiac vein catheteri- In conclusion, there seems to be no relation between the zation via the left internal jugular vein. A mortality of 3/7 rats way RCVI is performed and the occurrence of adverse events, (42.9%) was seen in the group that received cells via conven- arrhythmias, and mortality. Especially large animal studies tional RCVI versus 0/20 rats (0%) in the group with modified and clinical trials do not report mortality or arrhythmias relat- RCVI [14]. One small animal study reported a loss of 18/62 ed to RCVI. Although RCVI is reported to be safe in the rats (29%) within 24 h after RCVI, which the authors linked to majority of studies presented here, safety data on RCVI are development of acute heart failure rather than the RCVI [15]. underreported with the majority of studies providing no or insufficient safety data to conclude that RCVI is a safe method Clinical Experience In all six clinical trials, mortality rates were for cell delivery in the heart. Safety and mortality data are reported but mortality related to RCVI did not occur. provided in Table 3. Table 3 Safety and mortality data Study Species Reported safety aspects Mortality related to retrograde infusion procedure Small animals Di Lascio [10] Rat No arrhythmias, described as safe 16,7% (11/66) probably related to thoracotomy) Fukushima [11] Rat More VPC and VT in IM group vs RCVI group, RCVI: 5.7% (2/35) vs IM: 5.9% (2/34) described as safe Fukushima [12] Rat More VPC and VT in IM group vs RCVI group, RCVI: 8.2% (4/49) vs IM: 8.3% (4/48) described as safe Huang [13] Rat ns ns Huang [14] Rat No arrhythmias conventional technique: 42.9% (3/7) modified technique: 0 Suzuki [15] Rat No arrhythmias, described as safe 29% (18/62) within 24 h, probably due to acute heart failure Suzuki [16] Rat No arrhythmias 0% Zakharova [17] Rat ns 0% Large animals Pogue [18] Dog Transient AF during procedure in 6/15 dogs, 0% described as safe Sun [19] Dog ns 0% Wang [20] Dog No arrhythmias, no cardiac tamponade, described 0% as safe Formigli [21] Pig ns 0% Hagikura [22] Pig No arrhythmias, described as safe 0% Hong [23] Pig No MVO, described as safe 0% Hou [24] Pig ns 0% Kupatt [9] Pig ns ns Lu [25] Pig ns ns Prifti [26] Pig No arrhythmias, described as safe 0% Sato [27] Pig ns 0% Vicario [28] Pig No arrhythmias ns Yokoyama [29] Pig Described as safe ns Clinical trials Patel [30] Human Rise in cardiac enzymes in some patients, no 0% arrhythmias associated with RCVI, described as safe Silva [31] Human Rise in cardiac enzymes in some patients 0% Tuma [33] Human No rise in cardiac enzymes, no arrhythmias, no 0% pericardial effusion, described as safe Tuma [32] Human No arrhythmias, rise in cardiac enzymes in all 0% patients, no evidence of CS leak or damage, described as safe Vicario [34] Human No arrhythmias, described as safe 0% Vicario [35] Human No arrhythmias, described as safe 0% VPC ventricular premature contraction, VT ventricular tachycardia, IM intramyocardial injection, RCVI retrograde coronary venous infusion, ns not specified, AF atrial fibrillation, MVO microvascular obstruction, CS coronary sinus 178 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 Efficiency Measures be noted that the three large animal experiments [9, 23, 24] consist of very small sample sizes. RCVI appeared to be either Retention Rate inferior to [23, 24] or equal to [11, 12] IM injection or IC infusion regarding cell retention. Retention rates in Table 4 Preclinical Experience The therapeutic benefit of cell therapy are presented as the percentage of total administered cells that is in part based on the retention of cells in the heart. In total, is retained in the heart. In one study [23], retention of cells in eight preclinical studies provide data on the percentage of the heart was reported as a percentage of cells retained in five administered cells that retain in the heart after RCVI major thoracoabdominal organs. We converted the data to a (Table 4). Different methods are used to determine cardiac percentage of total administered cells that are retained in the retention of cells. One method is the use of real-time polymer- heart in order to achieve comparability between studies. If ase chain reaction for the Y-chromosome-specific Sry gene to retention of cells was measured at multiple time points, we detect the amount of transplanted male cells in female sub- reported retention at the first time point, because retention jects. Other methods include administration of β- decreased in time in the majority of these studies. A decrease galactosidase-expressing cells, or to label cells radioactively was not seen in three studies [15, 16, 23]. This can be ex- 111 99m with Indium or Tc -hexamethylpropylenamineoxime for plained by the fact that two of these studies used expression quantitative analysis using scintigraphy. The retention rates of β-galactosidase as a measure of cardiac cell retention [15, show a high degree of heterogeneity that can partially be ex- 16]. Increased expression of β-galactosidase over time was plained by differences in animal model, disease model, cell attributed to proliferation of administered cells. The third arti- type, infusion time point, follow-up time point, and quantifi- cle [23] presented the retention of cells in the heart as a per- cation technique. Most studies report a retention ≤ 10% and centage of the total retention in five major organs. A possible two studies report a remarkably higher retention of respective- explanation for the increase in retention at a later time point ly 31.4 ± 4.8 and 29.8 ± 6.9% [15, 16]. The latter studies ap- could be that the decrease in the number of cells in the heart plied an indirect measurement of retention by using β- was relatively less than the decrease in the number of cells in galactosidase-expressing cells, and comparing the level of β- the five major organs, making this decrease in the heart look galactosidase activity to the standard curve. One study used a like an increase [23]. method to optimize retention (magnetic targeting) that result- ed in an increase of retention from approximately 2% after Clinical Experience Retention of cells in the heart was deter- routine RCVI to 8.5% with magnetic targeting [13]. It should mined in one clinical trial, showing inferiority of RCVI versus Table 4 Retention of cells in the heart Study Species # Retention Retention Application method method time point RCVI retention IC retention IM retention Peripheral IV Sign retention comparison Small animals Fukushima [11] Rat 35 Sry 3 days 1.84 ± 0.27% – 1.45 ± 0.27% – ns Fukushima [12] Rat 85 Sry 3 days 10 ± 5% – 14 ± 5% – ns a d Huang [13] Rat 90 Sry 24 h 2%/8.5% –– – P <0.001 Suzuki [16]Rat 20 β-galactosidase 10 min 31.4 ± 4.8% –– – na Suzuki [15]Rat 62 β-galactosidase 10 min 29.8 ± 6.9% –– – na c c Large animals Hong [23] Pig 7 Radiolabel 1 h ±8% ±25% –– P =0.037 Hou [24] Pig 5 Radiolabel 1 h 3.2 ± 1% 2.6 ± 0.3% 11.3 ± 3% – Not sign Kupatt [9] Pig 6 Radiolabel 1 h 2.7% –– 0.5% ns Clinical trials Silva [31] Human 9 Radiolabel 4 h 4.62% 16.14% –– P =0.01 In case retention was not measured as % of total administered dose (e.g., as a % of uptake in major organs), we calculated the retention % of total administered dose. This was the case in one study [23] Sry polymerase chain reaction for the Y-chromosome-specific Sry gene, β-galactosidase presence of β-galactosidase-expressing cells, radiolabel retention measured by scintigraphy after radiolabeled cell infusion, RCVI retrograde coronary sinus/venous infusion, IC intracoronary infusion, IM intramyocardial injection, IV intravenous, ns not specified, na not applicable, # number of subjects 2% in case of normal delivery, 8.5% in case of magnetic targeting Comparison between RCVI infusion and IM retention Corrected for total injected dose Normal delivery versus magnetic targeting J. of Cardiovasc. Trans. Res. (2018) 11:173–181 179 99 m IC infusion [31]. Cells labeled with Tc - 33% only report absence of arrhythmias without mentioning hexamethylpropylenamineoxime were used to assess reten- other safety parameters. Only a limited number of studies tion in the heart. Just like the three pig studies, sample size provide more in-depth safety information regarding RCVI. was small and retention rates were comparable [9, 23, 24]. The six clinical trials included in this overview report cardiac enzyme rise as the only safety issue associated with RCVI and Functional Outcomes show no arrhythmias associated with RCVI, no development of pericardial fluid, and no sustained damage to the CS after The goal of cardiac reparative therapy is improvement of car- RCVI. It is understandable that the first priority of research diac function or decrease of disease characteristics such as focused on cell therapy lies with validating the effectiveness angina complaints in order to improve quality of life and de- of cell therapy in itself. From this perspective, it is logical that crease mortality. Here, we focused on the effect of cell admin- some studies do not report on safety of delivery because this istration on (1) LVEF (AMI, CMI, CHF), (2) improvement on was not the purpose of the study. Nevertheless, due to the poor the Canadian Cardiovascular Society scale (CSS) (CRA), and reporting of safety aspects, we cannot make an accurate as- (3) myocardial perfusion (CRA). sessment of the safety profile of RCVI. However, retrograde accessing of the coronary venous Preclinical Experience Most of the preclinical studies that re- system hasbeenperformedfor alongtimeinthefieldof ported changes in LVEF (12/15) showed a significant increase cardiac surgery in a great number of patients. With retro- in LVEF versus baseline and/or controls. Three studies only grade cardioplegia (RC), the myocardium is retrogradely showed improvement of LVEF when cells were combined perfused during cardiac surgery to induce cardiac arrest with growth factors [22] or no effects on LVEF at all [18, 19]. and protect the myocardium. With RC, a balloon-catheter is used to occlude the opening of the CS, in a way com- Clinical Experience Three out of four clinical studies reported parable to RCVI. RC is reported to be safe, with injury to significant improvement of LVEF. The study that did not theCSoccurringin0.06to0.6%ofpatients[36, 37], show improvement of LVEF after RCVI compared IC infu- resulting in formation of hematoma on the atrioventricular sion with RCVI and reported that patients receiving cells groove, perforation of the CS wall, pericardial effusion, or through IC infusion did show improvement in LVEF [31]. laceration of the right ventricle or CS [37–40]. These data The difference in cell retention between IC infusion and would suggest that the technical part of RCVI, namely the RCVI in these patients might be the explanation for this dif- insertion of a balloon-tipped catheter in the CS followed ference in functional outcome. Two other studies show com- by infusion of fluid, should be safe. parable retention rates between IM injection and RCVI and Cells delivered through RCVI are able to improve cardiac function and alleviate angina symptoms. However, in terms of both groups show comparable functional gains [11, 12]. In case of CRA, changes in CCS scale and improvement in myo- cell retention, the data suggest that RCVI is a limitedly effec- cardial perfusion were reported [33–35]. tive delivery strategy for cell therapy. In fact, IC infusion and In the majority of cases, cells administered with RCVI are IM injection show either higher or equal retention rates. It is able to effectuate improvement of cardiac function in a range likely that inferior retention rates decrease the efficacy of of different experimental models. An overview of functional RCVI. outcomes is presented in Online Resource 2. Due to the limited number of studies included in this re- view, we cannot conclude that RCVI is favorable in certain disease types or that certain cell types performed better than Discussion others in the included studies. In conclusion, the available data on technical and safe- Cell delivery strategies should meet two important demands. ty aspects of RCVI are insufficient and incomplete. First and foremost, the technique should be safe. Second, it Furthermore, retention data show inferior results com- should be effective in delivering cells to the heart. In this pared to IC infusion and IM injection. We conclude that paper, we provided an overview of RCVI. at present, there are not enough arguments to proceed There is a high degree of heterogeneity regarding technical with this technique in the clinical arena. Well-designed aspects of RCVI both between and within species. confirmatory studies on retention rates and safety data Furthermore, roughly 20% of studies do not adequately de- are required to proceed with RCVI in the future. scribe procedural characteristics, which hampers the possibil- ity to repeat these experiments technically. Funding This research is part of Cardiovasculair Onderzoek Nederland The main finding is that relevant data regarding technique (grant number: CVON2011-2012), an initiative of the Dutch Heart and safety are poorly reported. For instance, 30% of included Foundation, Netherlands FederationofUniversityMedical Centers (NFU), Royal Netherlands Academy of Arts and Science (KNAW), and studies do not report on safety aspects of RCVI at all, while 180 J. of Cardiovasc. Trans. Res. (2018) 11:173–181 Nederlandse Organisatie voor Wetenschappelijk Onderzoek/Nederlandse of phosphatidylinositol 3-kinase/AKT kinase. Circulation, 112(9 Organisatie voor Gezondheidsonderzoek en Zorginnovatie (NWO/ Suppl), I117–I122. https://doi.org/10.1161/circulationaha.104. ZonMW). 524801. 10. Di Lascio, G., Harmelin, G., Targetti, M., Nanni, C., Bianchi, G., Gasbarri, T., et al. (2012). Cellular retrograde cardiomyoplasty and Compliance with Ethical Standards relaxin therapy for postischemic myocardial repair in a rat model. Texas Heart Institute Journal, 39(4), 488–499. Conflict of Interest The authors declare that they have no conflict of 11. Fukushima, S., Varela-Carver, A., Coppen, S. R., Yamahara, K., interest. Felkin, L. E., Lee, J., et al. (2007). Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular Ethical Approval This article does not contain any studies with human arrhythmias in a rat chronic ischemic heart failure model. participants or animals performed by any of the authors. Circulation, 115(17), 2254–2261. https://doi.org/10.1161/ circulationaha.106.662577. 12. Fukushima, S., Coppen, S. R., Lee, J., Yamahara, K., Felkin, L. E., Open Access This article is distributed under the terms of the Creative Terracciano, C. M., et al. (2008). Choice of cell-delivery route for Commons Attribution 4.0 International License (http:// skeletal myoblast transplantation for treating post-infarction chronic creativecommons.org/licenses/by/4.0/), which permits unrestricted use, heart failure in rat. 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Journal of Cardiovascular Translational ResearchSpringer Journals

Published: Feb 1, 2018

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