Research

Cardiology

Stem cells have been shown to have the ability to self-replicate, differentiate into heart muscle cells, prevent fibrosis, reduce inflammation, and induce growth of new blood vessels among other biological effects. These effects have been shown to improve cardiac function and clinical indices, alleviate structural changes in the heart, improve survival and quality of life and reduce occurrence of re-hospitalization.

Based on the early human clinical trials there appears to be a strong argument for the safe and effective use of intravenous stem cell therapy in the treatment of cardiovascular disease and heart attack. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.

Below we highlight and summarize selected studies demonstrating the safety and efficacy of intravenous stem cell therapy in cardiovascular conditions and heart attack. All of the selected studies used intravenous administration but used different cell types and tissue types. We also include systematic reviews/meta-analysis for additional evidence.

SELECTED SYSTEMATIC REVIEWS AND META-ANALYSES:

Efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy: a systematic appraisal and meta-analysis (Rong et al)

In 2019 Rong et al performed a systematic appraisal and meta-analysis to assess the efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy. They included eight randomized controlled trials involving 531 patients which met study inclusion criteria. Stem cell derived tissue used and route of delivery was not uniform among studies. Analysis of results showed that stem cell therapy had a positive impact in patients with dilated cardiomyopathy. Stem cell therapy significantly improved left ventricular ejection fraction (LVEF) and significantly reduced both left ventricular end systolic volume (LVESV) and left ventricular end-diastolic chamber (LVEDV) size. However, stem cell therapy did not have an effect on mortality and 6 minute walk test (6MWT). Rong et al concluded “This meta-analysis suggests that stem cell therapy improves left ventricular ejection fraction and reduces left ventricular end-systolic volume and left ventricular end-diastolic chamber size in patients with dilated cardiomyopathy. However, future well-designed large studies might be necessary to clarify the effect of stem cell therapy in patients with dilated cardiomyopathy.”

Efficacy and Safety of Stem Cell Therapy in Advanced Heart Failure Patients: A Systematic Review with a Meta-analysis of Recent Trials Between 2017 and 2019 (Jayaraj et al)

In 2019 Jayaraj et al conducted a systematic review with meta-analysis of six randomized, controlled trials involving 526 patients with advanced heart failure to assess safety and efficacy of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. Their data showed statistically significant improvement among included studies in left ventricular ejection fraction (LVEF) and left ventricular end systolic volume (LVESV), two common clinical indices of cardiovascular disease. Regarding safety Jayaraji et al found no difference in risk for all-cause mortality between treatment and control groups, and most trials reported no or did not report treatment related complications such as arrhythmia, stroke or heart attack. Jayaraji et al concluded that the “Results suggest that stem cell therapy was associated with a moderate improvement in LVEF, and the safety analysis indicates no increased risk of mortality in patients with advanced heart failure.”

Efficacy of mesenchymal stem cell therapy in systolic heart failure: A systematic review and meta-analysis (Fan et al)

In 2019 Fan et al conducted a systematic review of nine studies involving 612 patients with systolic heart failure treated with stem cell therapy using mixed cell types and routes of administration. Stem cell treatment showed benefits in multiple end points including mortality, incidence of remission, 6 minute walking test (6MWT), NYHA class and left ventricular ejection fraction (LVEF). In those who received stem cell therapy, the overall death rate was reduced by 36% and hospital readmission was reduced by 34%. Compared to placebo group, 6MWT increased by 40.44 m, NYHA class was reduced and LVEF was increased by 5.25%. Fan et al concluded that “Our results suggested that MSC treatment is an effective therapy for HF by improving the prognosis and exercise capacity”. The purpose of this systematic review was to provide efficacy data and thus provided limited detail on safety.

Effect of stem cell transplantation on patients with ischemic heart failure: A systematic review and meta-analysis of randomized controlled trials (Wang et al)

In 2019 Wang et al performed a large scale meta-analysis of clinical trials to investigate the efficacy and safety of stem cell therapy in patients with ischemic heart failure. Fourteen randomized controlled trials involving 669 patients met inclusion criteria. Stem cell derived tissue used and route of delivery was not uniform among studies. Wang et al found that when compared to the control group, stem cell therapy significantly lowered the NYHA class and Canadian Cardiovascular Society (CCS) angina grade indicating reduction in symptoms. Patients treated with stem cell therapy also had lower left ventricular end systolic volume (LVESV) and increased left ventricular ejection fraction (LVEF). No differences in left ventricular end diastolic volume (LVEDV) or mortality was observed. Wang et al concluded that “this meta-analysis suggests that stem cell transplantation is a safe and effective treatment option for patients with IHF since SCT resulted in a reduction in the NYHA class, CCS grade, and LVESV, as well as an increase in LVEF, but did not affect mortality.”

Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis (Lalu et al)

In 2018 Lalu et al conducted a systematic review of twenty-three studies involving 1,148 patients with acute heart attack or ischemic heart failure to assess the safety and efficacy of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. The data revealed that patients treated with stem cells had an increase of left ventricular ejection fraction (LVEF) compared to controls and significant improvement in the 6 minute walking test (6MWT). Impact on quality of life and NYHA class, a common assessment used in cardiovascular disease, was mixed. Regarding safety, Lalu et al observed no association between stem cells and acute adverse events (AEs) in all 23 studies and no difference in risk of mortalities between treatment and control groups. Lalu et al concluded that “There was a significant improvement in overall LVEF in patients who received MSCs” and “Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe.”

Bone marrow-derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy—A meta-analysis (Wen et al)

In 2018 Wen et al performed a meta-analysis to assess the effects bone marrow mononuclear cells (BMMNCs) on left ventricular ejection fraction (LVEF) in patients with non-ischemic dilated cardiomyopathy. Seven randomized controlled trials involving 463 patients met inclusion criteria. Their results show that treatment with BMMNCs significantly improved LVEF by 3.79%. Effects on LVEF were sustained as demonstrated by a more significant improvement in patients with longer follow up of 15 months to 5 years. They also found that BMMNCs had no impact on the risk of all cause death. Wen et al concluded that “Bone marrow-derived mononuclear cells transplantation is associated with a moderate, but significant, improvement in LVEF in patients with nonischaemic DCM.”

Adult stem cell therapy and heart failure, 2000 to 2016: A systematic review (Nguyen et al)

In 2016 Nguyen et al conducted a systematic review of twenty-nine randomized, controlled trials involving 2817 patients with heart failure and ischemic heart disease. Stem cell derived tissue used and route of delivery was not uniform among studies. Their data showed mixed results on the impact of stem cell therapy on left ventricular ejection fraction (LVEF), but observed overall modest benefit in patients who received stem cell therapy. No serious adverse events were reported after intracoronary or IV stem cell treatments. Two studies using skeletal myoblast cells reported acute arrhythmias. Nguyen et al concluded that “Safe delivery of cells has been demonstrated in both preclinical and clinical trials” and “Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies.”

Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. (Fischer et al)

A 2016 systematic review by Fisher et al of thirty-eight studies involving 1907 patients with ischemic heart disease and congestive heart failure demonstrated safety of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. Their data showed low quality evidence that bone marrow derived stem cells reduce mortality, improve left ventricular ejection fraction (LVEF) and NYHA class, and may reduce the incidence of non-fatal heart attack. Serious adverse events (SAEs) during mapping or injection procedure were infrequent, early postoperative SAEs were rare and adverse events (AEs) associated with bone marrow aspiration were rare. Fisher et al concluded that “This systematic review and meta-analysis found low-quality evidence that treatment with bone marrow-derived stem/progenitor cells reduces mortality and improves left ventricular ejection fraction over short- and long-term follow-up and may reduce the incidence of non-fatal myocardial infarction and improve New York Heart Association (NYHA) Functional Classification in people with chronic ischaemic heart disease and congestive heart failure.”

A systematic review of randomised controlled trials examining the therapeutic effects of adult bone marrow-derived stem cells for non-ischaemic dilated cardiomyopathy (Lu et al)

In 2016 Lu et al performed a systematic review including randomized controlled trials assessing the effects of bone marrow derived stem cells in patients with non-ischemic dilated cardiomyopathy. Seven trials which included 482 patients satisfied the inclusion criteria. The injection routes were intracoronary for all trials except for one that used an intra-myocardial route. Bone marrow derived mononuclear cells (BM-MNCs) or CD34+ cells were the major cell types involved in these trials. Cell dose ranged from 35 million to 295 million cells. The co-primary endpoints were changes in mortality rate and left ventricular ejection fraction (LVEF). Secondary endpoints were changes in 6 minute walk test (6MWT) and left ventricular chamber size. Results show patients who received stem cell therapy had a significant reduction in mortality rates, began to have improvements in LVEF within 6 months and had significantly improved LVEF between 6-12 months. Stem cell therapy also reduced left ventricular end systolic volume (LVESV) between 6-12 months but did not change left ventricular end- diastolic chamber size. There were no significant changes in 6MWT. Lu et al concluded that “Bone marrow-derived stem cell therapy might have improved prognoses and appeared to provide moderate benefits in cardiac systolic function at mid-term follow-up.”

Effects of stem cell therapy on dilated cardiomyopathy (Jiao et al)

In 2014 Jiao et al performed a meta-analysis of clinical trials investigating the effect of stem cell therapy in patients with dilated cardiomyopathy. Seven trials involving 599 patients met inclusion criteria. Results show that when compared to control groups, patients who received stem cell therapy experienced benefit in numerous parameters including improved left ventricular ejection fraction (LVEF) and 6 minute walking test (6MWT), reduced mortality and reduced rate of heart transplantation. Jiao et al concluded that their results “demonstrated that stem cell therapy improves cardiac function and reduces mortality in dilated cardiomyopathy patients, which suggested that stem cell therapy may represent a new therapy option for dilated cardiomyopathy.”

SELECTED CLINICAL TRIALS:

Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: A phase 1/2 randomized controlled trial (RIMECARD trial [Randomized clinical trial of intravenous infusion umbilical cord mesenchymal (Bartolucci et al)

In 2017 Bartolucci et al conducted a double blind, randomized, placebo-controlled trial to evaluate safety and efficacy of intravenous (IV) umbilical cord derived stem cells in thirty patients with chronic heart failure with reduced ejection fraction. Patients were randomized to receive intravenous stem cells at a dose of 1 million cells/kg of body weight or placebo. Each group had 15 patients. Primary endpoints were safety and change in left ventricular ejection fraction (LVEF) by transthoracic echocardiogram and cardiac MRI. Secondary endpoints included change in left ventricular end-systolic volume (LVESV), end-diastolic volume (LVEDV), NHYA class and Minnesota Living with Heart Failure Questionnaire (MLHFQ; a commonly used questionnaire in heart failure), peak oxygen consumption (pVO2), ventilatory efficiency (VE/CO2), and laboratory markers. Their data showed patients treated with IV stem cells had improvement in multiple primary and secondary end points throughout follow up period but no impact on pVO2. Patients in the placebo group did not improve in LVEF or NYHA class. Compared to baseline patients treated with stem cells exhibited statistically significant improvements in LVEF at 3, 6 and 12 months. No acute treatment related adverse events (AEs), no significant differences in adverse events (AEs) between placebo and treatment group, and no significant abnormalities in laboratory tests were observed during the 12 month follow up. Secondary endpoints including VE/VCO2, brain natriuretic peptide levels (BNP; a blood marker associated with heart failure), NYHA class and MLHFQ also improved in the treatment group. They observed no noteworthy reductions in LVESV or LVEDV. Bartolucci et al condcluded that “Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs.”

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial (Butler et al)

In 2017 Butler at el conducted a single blind, placebo controlled, crossover, randomized phase IIa trial to assess the safety and preliminary efficacy of intravenously administered bone marrow derived ischemia-tolerant mesenchymal stem cells (itMSCs) in twenty-two patients with non-ischemic cardiomyopathy. itMSCs are mesenchymal stem cells grown under hypoxic conditions and were donated from healthy volunteers. Patients were randomized to receive intravenous stem cells at 1.5 million cells/kg or placebo. At 90 days, patients in each group crossed-over and received the alternative therapy. Primary study endpoints include all-cause mortality, all cause hospitalization and adverse events assessed at multiple time points up to 450 days post treatment. Butler et al observed no major differences in death, hospitalization or serious adverse events between groups. There was one treatment related adverse event related to bruising at intravenous infusion site. Multiple secondary efficacy ends points were specified. They include change in left ventricular ejection fraction (LVEF), wall motion summary score, and left ventricular end diastolic volume (LVEDV) at 90 days post infusion. 6 minute walking distance (6MWD), NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) as well as various serum biomarkers were also assessed at 30 day and 90 day after treatment. After the crossover was complete, results were analyzed. Compared to baseline, NYHA class was significantly improved in patients receiving stem cell therapy. Statistically significant improvements were observed in health status and functional capacity as measured by changes in KCCQ and in 6MWD at 90 days. Although there were no differences in LVEF, LVEDV, and LVESV between itMSC and placebo groups there were significant changes when compared to baseline. The LVEDV and LVESV were significantly decreased and the LVEF was improved within the itMSC group when compared to baseline. Compared to baseline the itMSC group showed significant changes in immumodulatory markers. Other biomarkers including N-terminal pro-B-type natriuretic peptide (proBNP) and troponin were not significant during the itMSC phase. Butler et al concluded that “This study shows that despite low myocardial engraftment, intravenously administered MSCs improve clinical end points, effects possibly caused, in part, by systemic anti-inflammatory effects.” “Overall, this study found a single dose of intravenous itMSCs to be safe, to be well-tolerated, and to provide clinically relevant signals for efficacy.”

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial (Fang et al)

In a small 2016 study to assess safety and efficacy of IV umbilical cord derived mesenchymal stem cells in three patients with systolic heart failure, Fang et al observed improvement in left ventricular ejection fraction (LVEF), six minute walk test (6MWT) and NYHA class. No complications, adverse events (AEs) or serious adverse events (SAEs) were observed during the 12 month follow up and no cases of distal coronary artery occlusion, acute cardiac dysfunction and ventricular arrhythmia occurred. Fang et al concluded that “[stem cell] therapy is a reasonable salvage treatment in HF” and due to their small study population “future large scale randomized clinical trials are likely to be designed to elucidate the efficacy.”

Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction.

In 2015 Chullikana et al assessed the safety and efficacy of an investigational new drug named Stempeucel (bone marrow-derived mesenchymal stromal cells) in patients with acute heart attack. Patients were randomly assigned to receive Stempeucel or placebo two days after percutaneous coronary intervention. Adverse events were similar between stem cell and placebo group. There were no treatment related adverse events and no serious adverse events occurred in patients who received stem cell therapy. Left ventricular ejection fraction (LVEF) using echocardiography was improved by almost 5% at 6 months. Perfusion score and size of infarct was not significantly different between the two groups. Chullikana et al concluded that “This study showed that Stempeucel was safe and well tolerated when administered intravenously in AMI patients 2 days after percutaneous coronary intervention.”

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction (Hare et al)

In 2009 Hare et al conducted a double blind, placebo controlled trial to assess the safety intravenous bone marrow derived mesenchymal stem cells (BM-MSCs) in 53 patients with heart attack who had reperfusion treatment. Primary endpoint was incidence of treatment related adverse events within 6 months. Left ventricular ejection fraction (LVEF) by echocardiography and magnetic resonance imaging and left ventricular volumes were exploratory efficacy ends points. Patients received intravenous stem cells at 0.5, 1.6 and 5 million cells/kg of body weight or placebo. Rates of adverse events between treatment and placebo group were similar and no differences in laboratory values for kidney and liver function were observed. Global symptom score in all patients and the LVEF in a subset of patients with anterior heart attack were both significantly better in treatment group compared to placebo. Treatment with stem cells increased LVEF and reversed remodeling of left ventricle as measured by cardiac MRI. Patients treated with stem cells also had reduced episodes of ventricular tachycardia and improved pulmonary function tests. Despite demonstrating improvements in LVEF and other parameters, this trial was designed to assess safety. Hare et al concluded that “Intravenous allogeneic hMSCs are safe in patients after acute MI.”

LANDMARK TRIALS OF STEM CELL THERAPY IN ACUTE HEART ATTACK AND HEART FAILURE:

Terashvili et al presented 20 landmark clinical trials that used mostly bone marrow derived stem cells to treat acute heart attack and heart failure. They include Janssens etl al, BOOST, ASTAMI, REGENT, REPAIR-AMI, MAGIC, FOCUS-CCTRN, POSEIDON, SCIPIO, CADUCEUS, TOPCARE-AMI, TAC-HFT, MSC-HF, MESAMI, SWISS-AMI, REGENERATE-AMI, PreSERVE-AMI, MiHeart-AMI, TIME and RIMECARD. Of these 20 trials only six (REPAIR-AMI, SCIPIO, TOPCARE-AMI, MSC-HF, MESAMI and RIMECARD) showed statistically significant improvement in left ventricular ejection fraction (LVEF), a common clinical measurement used in cardiovascular disease.

Of these six, the RIMECARD trial is the only trial that used intravenous application and the only trial to use umbilical derived stem cells. The promising results of this study confirm that umbilical cord derived stem cells are safe and effective, and suggest that intravenous delivery of stem cells is an effective method of application in cardiovascular conditions.

SOURCES OF SYSTEMATIC REVIEWS/META-ANALYSES:

• Rong, S.-L., Wang, Z.-K., Zhou, X.-D., Wang, X.-L., Yang, Z.-M., & Li, B. (2019). Efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy: a systematic appraisal and meta-analysis. Journal of Translational Medicine, 17(1). https://doi.org/10.1186/s12967-019-1966-4
• Jayaraj, J. S., Janapala, R. N., Qaseem, A., Usman, N., Fathima, N., Kashif, T., … Bakshi, S. (2019). Efficacy and Safety of Stem Cell Therapy in Advanced Heart Failure Patients: A Systematic Review with a Meta-analysis of Recent Trials Between 2017 and 2019. Cureus. https://doi.org/10.7759/cureus.5585
• Fan, M., Huang, Y., Chen, Z., Xia, Y., Chen, A., Lu, D., … Ge, J. (2019). Efficacy of mesenchymal stem cell therapy in systolic heart failure: A systematic review and meta-analysis. Stem Cell Research and Therapy, 10(1). https://doi.org/10.1186/s13287-019-1258-1
• Wang, Y., Xu, F., Ma, J., Shi, J., Chen, S., Liu, Z., & Liu, J. (2019). Effect of stem cell transplantation on patients with ischemic heart failure: A systematic review and meta-analysis of randomized controlled trials. Stem Cell Research and Therapy, Vol. 10. https://doi.org/10.1186/s13287-019-1214-0
• Lalu, M. M., Mazzarello, S., Zlepnig, J., Dong, Y. Y. (Ryan), Montroy, J., McIntyre, L., … Fergusson, D. A. (2018). Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Translational Medicine, Vol. 7, pp. 857–866. https://doi.org/10.1002/sctm.18-0120
• Wen, Y., Ding, J., Zhang, B., & Gao, Q. (2018). Bone marrow-derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy—A meta-analysis. European Journal of Clinical Investigation, 48(4). https://doi.org/10.1111/eci.12894
• Nguyen, P. K., Rhee, J. W., & Wu, J. C. (2016). Adult stem cell therapy and heart failure, 2000 to 2016: A systematic review. JAMA Cardiology, Vol. 1, pp. 831–841. https://doi.org/10.1001/jamacardio.2016.2225
• Fisher, S. A., Doree, C., Mathur, A., Taggart, D. P., & Martin-Rendon, E. (2016). Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. The Cochrane Database of Systematic Reviews, 12, CD007888. https://doi.org/10.1002/14651858.CD007888.pub3
• Lu, Y., Wang, Y., Lin, M., Zhou, J., Wang, Z., Jiang, M., & He, B. (2016). A systematic review of randomised controlled trials examining the therapeutic effects of adult bone marrow-derived stem cells for non-ischaemic dilated cardiomyopathy. Stem Cell Research & Therapy, 7(1), 186. https://doi.org/10.1186/s13287-016-0441-x
• Jiao, R., Liu, Y., Yang, W.-J., Zhu, X.-Y., Li, J., & Tang, Q.-Z. (2014). Effects of stem cell therapy on dilated cardiomyopathy. Saudi Medical Journal, 35(12), 1463–1468. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25491210

SOURCES OF SELECTED TRIALS:

• Bartolucci, J., Verdugo, F. J., González, P. L., Larrea, R. E., Abarzua, E., Goset, C., … Khoury, M. (2017). Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: A phase 1/2 randomized controlled trial (RIMECARD trial [Randomized clinical trial of intravenous infusion umbilical cord mesenchymal. Circulation Research, 121(10), 1192–1204. https://doi.org/10.1161/CIRCRESAHA.117.310712
• Butler, J., Epstein, S. E., Greene, S. J., Quyyumi, A. A., Sikora, S., Kim, R. J., … Gheorghiade, M. (2017). Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial. Circulation Research, 120(2), 332–340. https://doi.org/10.1161/CIRCRESAHA.116.309717
• Fang, Z., Yin, X., Wang, J., Tian, N., Ao, Q., Gu, Y., & Liu, Y. (2016). Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial Experimental and Therapeutic Medicine, 12(5), 3328–3332. https://doi.org/10.3892/etm.2016.3748
• Chullikana, A., Majumdar, A. Sen, Gottipamula, S., Krishnamurthy, S., Kumar, A. S., Prakash, V. S., & Gupta, P. K. (2015). Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy, 17(3), 250–261. https://doi.org/10.1016/j.jcyt.2014.10.009
• Hare, J. M., Traverse, J. H., Henry, T. D., Dib, N., Strumpf, R. K., Schulman, S. P., … Sherman, W. (2009). A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2009.06.055

SOURCES OF LANDMARK STUDIES ON ACUTE HEART ATTACK AND HEART FAILURE:

• Janssens: https://www.sciencedirect.com/science/article/pii/S0140673605678610
• BOOST: https://academic.oup.com/eurheartj/article/30/24/2978/634984
• ASTAMI: https://www.nejm.org/doi/full/10.1056/NEJMoa055706
• REGENT: https://academic.oup.com/eurheartj/article/30/11/1313/640625
• REPAIR-AMI: https://www.ncbi.nlm.nih.gov/pubmed/19996415
• MAGIC: https://www.ncbi.nlm.nih.gov/pubmed/18285565
• FOCUS-CCTRN: http://refhub.elsevier.com/S1053-0770(18)30281-7/sbref77
• POSEIDON: https://www.ncbi.nlm.nih.gov/pubmed/23117550
• SCIPIO: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448934/
• CADUCEUS: https://www.sciencedirect.com/science/article/pii/S0735109713041223
• TOPCARE-AMI: https://link.springer.com/article/10.1007%2Fs00392-011-0327-y
• TAC-HFT: https://jamanetwork.com/journals/jama/fullarticle/1780025
• MSC-HF: https://academic.oup.com/eurheartj/article/36/27/1744/2398107
• MESAMI: https://www.sciencedirect.com/science/article/abs/pii/S0167527316302285
• SWISS-AMI: https://www.ncbi.nlm.nih.gov/pubmed/23596006
• REGENERATE-AMI: https://academic.oup.com/eurheartj/article/37/3/256/2467155
• PreSERVE-AMI: https://www.ncbi.nlm.nih.gov/pubmed/27821724
• MiHeart-AMI: https://www.ncbi.nlm.nih.gov/pubmed/29569254
• TIME: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.311466
• RIMECARD: https://www.ncbi.nlm.nih.gov/pubmed/28974553