Stem Cell Therapy in Ischemic Heart Disease and Heart Failure: An Integrated Systematic Review of Recent Meta-Analyses and Randomized Clinical Evidence

Abstract

Background: Heart failure (HF), particularly heart failure with reduced ejection fraction (HFrEF), remains one of the leading causes of cardiovascular morbidity and mortality worldwide despite substantial advances in pharmacological therapy, device implantation, and revascularization strategies [4,5]. Progressive ventricular remodeling, irreversible cardiomyocyte loss, chronic inflammation, impaired angiogenesis, and myocardial fibrosis continue to limit myocardial recovery in many patients. Consequently, regenerative therapies, particularly mesenchymal stem cell (MSC)-based interventions, have emerged as promising strategies to restore myocardial function through immunomodulation, angiogenesis, anti-fibrotic activity, mitochondrial transfer, and paracrine signaling [6,13]. Nevertheless, the clinical efficacy of stem cell therapy remains controversial because published randomized trials have reported inconsistent findings [7–12].
Objective: This systematic review integrates findings from three recent high-quality systematic reviews and meta-analyses to evaluate the current evidence regarding stem cell therapy in ischemic heart disease and ischemic heart failure, focusing on efficacy, safety, cardiac remodeling, and clinical outcomes [1–3].
Methods: Three recent systematic reviews/meta-analyses published in 2025–2026 were analyzed. Collectively, these reviews synthesized evidence from more than one hundred randomized clinical trials evaluating intracoronary, transendocardial, intramyocardial, and other catheter- based stem cell delivery techniques in patients with acute myocardial infarction (AMI), chronic ischemic heart disease (CIHD), and ischemic heart failure (IHF). Primary outcomes included left ventricular ejection fraction (LVEF), while secondary outcomes included ventricular remodeling indices, NYHA functional class, myocardial perfusion, exercise capacity, quality of life, major adverse cardiovascular events (MACE), hospitalization, and mortality [1–3].
Results: The largest meta-analysis included 82 randomized controlled trials comprising 5,781 patients and demonstrated a statistically significant overall improvement in LVEF, with greater benefits observed among patients with chronic ischemic heart disease and ischemic heart failure than in acute myocardial infarction [3]. In contrast, a recent meta-analysis restricted to contemporary HFrEF trials found no statistically significant improvement in LVEF but demonstrated significant enhancement in patients’ quality of life without increased major adverse cardiovascular events [1]. A third meta-analysis focusing exclusively on transendocardial delivery revealed significant reductions in LV end-systolic volume, improved myocardial perfusion, and functional status while confirming an acceptable safety profile despite neutral effects on LVEF [2].
Conclusions: Current evidence suggests that stem cell therapy is safe and capable of improving several markers of cardiac remodeling and functional recovery. Nevertheless, improvement in global systolic function, particularly LVEF, remains inconsistent across contemporary studies. Future investigations should prioritize standardized cell manufacturing protocols, optimized delivery techniques, appropriate patient selection, and mechanistic biomarkers to better define the role of regenerative therapy in ischemic heart failure [1–6].