Myocardial infarction (MI) accounts for over 800 000 acute care hospitalizations annually in the USA, with nearly a third of patients suffering from ST-elevation myocardial infarction (STEMI) 1. Enormous improvements in patient care, including rapid reperfusion by percutaneous coronary intervention (PCI) and evidenced-based pharmacotherapy such as antithrombotics, inhibitors of the renin–angiotensin–aldosterone system, and β-blockers, have led to a significant decrease in acute coronary syndrome (ACS)/MI mortality over the past decade 1–3. However, epidemiologic studies show that improvements in survival are counterbalanced by increased morbidity in ACS/MI patients driven by the development of heart failure (HF) occurring in about a quarter of ACS/MI patients 4–6. The occurrence of HF, either at index ACS/MI or after discharge (late-onset), has prognostic importance 7,8. A recently published retrospective cohort study investigated first-time ACS/MI patients with no previous HF (9406 STEMI, 11 008 non-STEMI, and 4910 unstable angina) and found a cumulative HF rate of 23.4% in STEMI, 25.4% in non-STEMI, and 16% in patients with unstable angina at 1 year 8. In this study, HF was associated with an over four times higher 1-year mortality rate in both index HF (13.9%) and postdischarge HF (10.6%) compared with that in patients with no HF (2.4%) 8. Moreover, during the course of the disease, HF patients often require hospital re-admission for symptom control and suffer from loss in quality of life and productivity, placing high demands on resources.
Therefore, the concept of myocardial regeneration, limiting myocardial necrosis and thus left-ventricular systolic dysfunction following ischemia, through stem cell therapy is appealing (for review, see 9,10). Conclusive judgment on its success in clinical trials is limited because of their heterogeneity, including differences in observation periods, inclusion criteria, cell type (e.g. embryonic, inducible pluripotent, or adult progenitor cells) and number infused, as well as route of administration (e.g. transvenous, transarterial, or epicardial) and technical methods of examination (e.g. ultrasound, single-photon emission computed tomography) 9–12. Some years ago, the stem cell concept was challenged by experimental findings showing that circulating progenitor cells can contribute toward atherosclerotic lesion development in mice and by case studies reporting luminal loss of the infarct-related artery (IRA) after intracoronary delivery of stem cells in MI patients 13–17. The issue of promoting atherosclerosis has been addressed in only a few studies so far. Assmus et al.18 reported a retrospective quantitative coronary angiography (QCA) study comparing the IRA of 83 MI patients treated with bare-metal stents and 83 patients additionally treated with progenitor cells. No difference was found for late lumen loss or restenosis between the groups 18. Arnold et al.19 investigated the distal nonstented segment of the IRA and the contralateral artery (CLA) in 37 STEMI patients who underwent bone-marrow stem cell therapy by QCA at baseline and at the 9-month follow-up and compared the results with those of matched controls. In addition, intravascular ultrasound (IVUS) was performed in 15 of the stem cell-treated patients 19. Again, no difference was found between the patients with stem cell treatment and controls in the IRA and CLA, and IVUS did not show any changes over the time course investigated 19.
In this issue of Coronary Artery Disease, Qiu and colleagues now report the effects of an intracoronary CD133+-enriched hematopoietic bone-marrow stem cell injection on atherosclerosis in a substudy of the ongoing COMPARE-AMI trial 20,21. The authors performed QCA and IVUS of the IRA and CLA at baseline and at the 4-month follow-up after PCI in 17 stem cell-treated patients and 20 placebo-treated patients. No differences in IRA analysis with respect to the median percent of in-stent neointima hyperplasia or reduction of minimum lumen area were found between those treated and placebo controls. Similarly, no differences in changes in proximal and distal nonstented segment lumen area and plaque burden of the IRA were detected. Furthermore, in the CLA, no differences were found for any of the parameters investigated. The only significant difference found was in the attenuated plaque (representing hypoechoic/mixed atheroma with ultrasound attenuation, but without calcification) behind the stent. Here, compared with baseline, a significant decrease in the maximum arc of attenuated plaque was found in the placebo, but not in the stem cell group 21. Interestingly, in STEMI, attenuated plaque is more often found in association with a high inflammatory state and complex coronary lesions and has been linked to microvascular obstruction or no-reflow following successful PCI 22,23. However, the number of patients investigated in the study by Qiu et al.21 is relatively small and the follow-up period is short; thus the impact of this difference remains to be elucidated and the overall conclusion (no promotion of atherosclerosis by stem cell therapy in the long run) remains tentative. Still, this is an excellent study, applying state-of-the-art techniques and using a well-matched placebo control group, and is thus certainly reassuring.
The authors thank A. Gale for editing the manuscript.
Conflicts of interest
There are no conflicts of interest.
1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al.. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015; 131:e29–e322.
2. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, et al.. AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130:2354–2394.
3. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al.. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:529–555.
4. Velagaleti RS, Pencina MJ, Murabito JM, Wang TJ, Parikh NI, D’Agostino RB, et al.. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation 2008; 118:2057–2062.
5. Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, McAlister FA. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol 2009; 53:13–20.
6. McManus DD, Chinali M, Saczynski JS, Gore JM, Yarzebski J, Spencer FA, et al.. 30-year trends in heart failure in patients hospitalized with acute myocardial infarction. Am J Cardiol 2011; 107:353–359.
7. Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A, Aumont MC, Lopez-Sendon J, et al.. Global Registry of Acute Coronary Events I: determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004; 109:494–499.
8. Kaul P, Ezekowitz JA, Armstrong PW, Leung BK, Savu A, Welsh RC, et al.. Incidence of heart failure and mortality after acute coronary syndromes. Am Heart J 2013; 165:379–385 e372.
9. Garbern JC, Lee RT. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell 2013; 12:689–698.
10. Ptaszek LM, Mansour M, Ruskin JN, Chien KR. Towards regenerative therapy for cardiac disease. Lancet 2012; 379:933–942.
11. Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur A, Watt S, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2012; 2:CD006536.
12. Tian T, Chen B, Xiao Y, Yang K, Zhou X. Intramyocardial autologous bone marrow cell transplantation for ischemic heart disease: a systematic review and meta-analysis of randomized controlled trials. Atherosclerosis 2014; 233:485–492.
13. Mansour S, Vanderheyden M, De Bruyne B, Vandekerckhove B, Delrue L, Van Haute I, et al.. Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction. J Am Coll Cardiol 2006; 47:1727–1730.
14. Vanderheyden M, Mansour S, Bartunek J. Accelerated atherosclerosis following intracoronary haematopoietic stem cell administration. Heart 2005; 91:448.
15. Silvestre JS, Gojova A, Brun V, Potteaux S, Esposito B, Duriez M, et al.. Transplantation of bone marrow-derived mononuclear cells in ischemic apolipoprotein E-knockout mice accelerates atherosclerosis without altering plaque composition. Circulation 2003; 108:2839–2842.
16. George J, Afek A, Abashidze A, Shmilovich H, Deutsch V, Kopolovich J, et al.. Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 2005; 25:2636–2641.
17. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, et al.. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002; 8:403–409.
18. Assmus B, Walter DH, Lehmann R, Honold J, Martin H, Dimmeler S, et al.. Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction. Eur Heart J 2006; 27:2989–2995.
19. Arnold R, Villa A, Gutierrez H, Sanchez PL, Gimeno F, Fernandez ME, et al.. Absence of accelerated atherosclerotic disease progression after intracoronary infusion of bone marrow derived mononuclear cells in patients with acute myocardial infarction – angiographic and intravascular ultrasound – results from the TErapia Celular Aplicada al Miocardio Pilot study. Am Heart J 2010; 159:e1151–e1158.
20. Mansour S, Roy DC, Bouchard V, Nguyen BK, Stevens LM, Gobeil F, et al.. Compare-AMI trial: Comparison of intracoronary injection of CD133+ bone marrow stem cells to placebo in patients after acute myocardial infarction and left ventricular dysfunction: study rationale and design. J Cardiovasc Transl Res 2010; 3:153–159.
21. Qui F, Maehara A, El Khoury R, Généreux P, LaSalle L, Mintz GS, et al.. Impact of intracoronary injection of CD133+
bone marrow stem cells on coronary atherosclerosis progression in patients with STEMI: a COMPARE-AMI IVUS Substudy. Coron Artery Dis 2015; 27:5–12.
22. Shiono Y, Kubo T, Tanaka A, Tanimoto T, Ota S, Ino Y, et al.. Impact of attenuated plaque as detected by intravascular ultrasound on the occurrence of microvascular obstruction after percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2013; 6:847–853.
23. Lee SY, Mintz GS, Kim SY, Hong YJ, Kim SW, Okabe T, et al.. Attenuated plaque detected by intravascular ultrasound: clinical, angiographic, and morphologic features and post-percutaneous coronary intervention complications in patients with acute coronary syndromes. JACC Cardiovasc Interv 2009; 2:65–72.