Predictive Value of Circulating Progenitor Cells in Acute Coronary Syndrome: Implications for Treatment

Acute coronary syndromes (ACS), and notably acute myocardial infarction (AMI), continue to be one of the leading causes of cardiovascular morbidity and mortality. Although significant progress has been achieved in the prevention, diagnosis, and management of patients with ACS, the burden of recurrent events, progression to heart failure, and sudden cardiac death remains high. The research and development of biomarkers that predict which patients are at high risk for events and therapies that prevent and/or improve the outcome of patients with ACS is therefore imperative.

After initial treatment and stabilization of patients with AMI, subsequent care is focused on restoring daily activities and preventing long-term complications with current standard of care medical therapy. However, it remains unclear which patients need more intensive medications, procedures, and follow-up assessments, ultimately at imminent risk for adverse outcomes and death. Is there a clinical test we can develop to identify these patients and tailor treatment towards?

Previous studies have demonstrated that various circulating progenitor cell (CPC) types play pivotal roles in recovery and remodeling post ischemic events. Specifically, CD133+ and CD34+ progenitor cells have been shown to mobilize to areas of ischemia post injury, participating in angiogenesis and vasculogenesis¹. In addition to having specific functional roles, CD133+ and CD34+ cells have exhibited promising prognostic value for stratifying patient risks and therefore tailoring patient treatment. Werner et al. demonstrated that CD34+ CPCs were predictive of future cardiovascular events in patients with coronary artery disease (CAD), specifically identifying patients at increased risk for AMI and death². Cogle et al. found that patients with chronic ischemic heart disease or AMI who had elevated levels of CD34+ cells at baseline had a significant improvement in left ventricular ejection fraction (LVEF) after receiving intracoronary bone marrow mononuclear cell (BMMNC) therapy compared to those with diminished CD34+ cells at baseline, supporting the notion that CPCs can predict response to therapy³. In peripheral artery disease, there have been numerous studies investigating the prognostic value of CPCs⁴. However, there is a paucity of studies identifying the correlation between CPCs as biomarkers in ACS.

In this issue of Circulation Research, Tahhan et al. investigated the hypothesis that CPC counts are significantly elevated in patients with AMI compared to those with stable CAD and that low CPC counts are associated with mortality⁵. In 2028 patients with unstable angina, AMI, or stable CAD, circulating CD34+ cells, CD34+/CD133+ cells, CD34+/CXCR4+ cells, and CD34+/VEGF2R+ were assessed and numbers were correlated with mortality during a 1 to 2 year follow up. The authors had three important conclusions: (1) endothelial-enriched as well as hematopoietic CPC counts were higher in patients after AMI compared to those with unstable angina or stable CAD, (2) the higher CPC counts correlated with corresponding higher bone marrow progenitor cell numbers, and (3) the higher hematopoietic, but not the endothelial-enriched, CPC counts were associated with lower total and cardiovascular mortality in patients with ACS. Ultimately, this study identifies a novel predictive role for CD34+ CPCs as a biomarker of future cardiovascular morbidity and mortality in ACS, but it leaves us with the intriguing question of the therapeutic implications.

Importantly, how can we treat patients who have low CD34+ CPCs and are thus deemed at increased risk for mortality? Stem cell therapy has shown promise in improving various cardiovascular endpoints in patients with ischemic and non-ischemic heart disease. Losordo et al. found that intramyocardial CD34+ cells significantly reduced angina frequency and improved exercise tolerance in patients with refractory angina⁶. In the REPAIR-AMI trial, intracoronary delivery of BMMNCs into patients with AMI improved left ventricular contractility and resulted in a reduction in trial end points including death, recurrence of AMI, and revascularization procedures⁷. Similar findings were reported in patients with chronic ischemic heart disease in which intracoronary delivery of BMMNCs produced moderate improvement in LVEF⁸. However, there have been a number of studies showing a lack of efficacy of BMMNCs on cardiac parameters in patients with AMI as well as chronic ischemic cardiomyopathy, such as the TIME and LateTIME⁹, Trial of Hematopoietic Stem Cells in Acute Myocardial Infarction (TECAM)¹⁰, and FOCUS-CCTRN¹¹, respectively, highlighting the need to elucidate what makes therapy effective and how to maximize responsiveness. Notably, despite some evidence that CPC counts predict response to therapy³, the TECAM trial failed to show efficacy of intracoronary BMMNCs with or without G-CSF mobilization therapy, even though the absolute numbers of CD34+ progenitor cells injected were higher in those that received G-CSF prior to BMMNC infusion.

It is well established that multiple comorbidities such as diabetes mellitus, metabolic syndrome, aging, and smoking diminish CD34+ counts. Vrtovec et al. found that patients with diabetes mellitus and dilated cardiomyopathy did not respond to CD34+ cell therapy, whereas patients with either insulin resistance or normal glucose tolerance and dilated cardiomyopathy had improvements in LVEF¹².

Our group demonstrated in the TAC-HFT trial that bone marrow-derived mesenchymal stem cells (MSCs) improve cardiac function and structure in patients with chronic ischemic cardiomyopathy as compared to BMMNCs and placebo¹³. Furthermore, we showed that allogeneic MSCs improve endothelial function [assessed by flow-mediated vasodilatation (FMD) and endothelial progenitor cell-colony forming units (EPC-CFU) bioactivity assay] as well as LVEF and other cardiac functional and structural parameters in patients with ischemic or dilated cardiomyopathy¹⁴. EPCs are a specific population of CPCs characterized by the surface expression of VEGFR2, CD133, and CD34. After a few weeks in culture, expression of endothelial markers including von Willebrand Factor and VE-cadherin is evident¹⁵. EPCs home to sites of endothelial injury and participate in angiogenesis. An underlying mechanism of MSC therapy is the stimulation of endogenous precursor cells, including EPCs¹⁴. Accordingly, the benefits of MSC therapy may include the activation of neoangiogenic pathways through stimulation of EPCs.

Based on these promising findings in patients with heart failure, ongoing clinical trials by our group are investigating whether intravenous MSC therapy improves endothelial function (assessed by EPC-CFU bioactivity and FMD) in patients with type 2 diabetes mellitus (ACESO; NCT02886884), metabolic syndrome (CERES; NCT03059355), or aging frailty (CRATUS; NCT02065245).

In conclusion, Tahhan et al. made an important contribution to the field by identifying a predictive biomarker of mortality in patients with ACS. However, while low CPC counts may identify those at high risk, how to best treat these patients remains undefined. While G-CSF mobilization therapy to increase bone marrow CD34+ progenitors has failed to provide a therapeutic benefit in patients with ischemic heart disease, MSC therapy has produced improvements in endothelial function as well cardiac function and structure. Whether these effects will translate into better long-term outcomes, including reduced mortality, remains to be determined.