Myocardial infarction (MI) produces ischemic cardiomyocyte injury followed by inflammation, scar formation, ventricular remodeling, and variable loss of contractile function. MSC and extracellular-vesicle research has investigated paracrine cytoprotection, immunomodulation, angiogenic signaling, and remodeling rather than reliable replacement of large numbers of lost cardiomyocytes. Clinical studies of cell therapy after MI have used heterogeneous cell populations, timing, routes, doses, imaging methods, and endpoints, producing inconsistent estimates of benefit. Any investigational cell or EV strategy must remain distinct from established acute MI care, including rapid reperfusion, antithrombotic therapy, secondary prevention, and guideline-directed management.
Figure 1 placeholder — Myocardial infarction
Ischemic cardiomyopathy
Ischemic cardiomyopathy is chronic ventricular dysfunction caused by coronary artery disease and prior ischemic injury. Potential cell-based mechanisms include effects on perfusion, inflammation, fibrosis, viable but dysfunctional myocardium, and ventricular remodeling. Trials of MSCs and related cell products have reported variable signals in symptoms, functional capacity, ventricular volumes, scar, or ejection fraction, but product and study heterogeneity prevents a class-wide efficacy conclusion. Demonstrating improved perfusion or a small imaging change does not establish myocardial regeneration, durable reverse remodeling, reduced hospitalization, or improved survival.
Figure 2 placeholder — Ischemic cardiomyopathy
Heart failure
Heart failure is a clinical syndrome with multiple phenotypes, including reduced, mildly reduced, and preserved ejection fraction, and with diverse ischemic and nonischemic causes. MSC or EV mechanisms cannot be assumed to operate similarly across these phenotypes. Investigational studies have emphasized immunomodulation, vascular effects, antifibrotic signaling, and myocardial support. Clinical interpretation requires background guideline-directed medical therapy, device therapy when indicated, phenotype, congestion status, renal function, functional capacity, hospitalization, quality of life, and mortality. A biomarker or ejection-fraction change is not a substitute for patient-important outcomes.
Figure 3 placeholder — Heart failure
Peripheral arterial disease
Peripheral arterial disease (PAD) is atherosclerotic obstruction of arteries supplying the limbs and is associated with cardiovascular and limb risk. MSC and other cell-therapy studies have explored therapeutic angiogenesis, collateral-vessel development, endothelial signaling, and tissue repair, particularly in patients with severe ischemia who have limited revascularization options. Human studies vary in cell source, route, dose, disease severity, and endpoints such as walking distance, perfusion, ulcer healing, amputation, and survival. Investigational biological therapy must not replace smoking cessation, antithrombotic and lipid-lowering therapy, exercise, foot care, diabetes management, and revascularization when appropriate.
Figure 4 placeholder — Peripheral arterial disease
Critical limb ischemia
Critical limb ischemia—now commonly termed chronic limb-threatening ischemia (CLTI)—is the severe end of PAD, characterized by ischemic rest pain, nonhealing wounds, or gangrene attributable to arterial insufficiency. Because amputation and mortality risks are high, clinically meaningful trials should prioritize wound healing, limb salvage, amputation-free survival, pain, function, and survival rather than perfusion biomarkers alone. Cell-based therapeutic-angiogenesis studies have reported heterogeneous results and have not established a universal MSC standard of care. Revascularization assessment, infection control, wound care, pressure off-loading when relevant, and multidisciplinary vascular management remain central.
Figure 5 placeholder — Critical limb ischemia
Endothelial dysfunction
Endothelial dysfunction describes impaired vascular endothelial regulation of vasomotor tone, thrombosis, inflammation, permeability, and vessel homeostasis. It is a mechanistic feature across atherosclerosis, diabetes, hypertension, heart failure, and other cardiovascular disorders rather than a single disease. MSC and EV research has examined nitric-oxide signaling, oxidative stress, inflammatory pathways, endothelial-cell survival, and angiogenic communication. Improvement in an endothelial assay or flow-mediated dilation can support a mechanistic hypothesis but does not by itself establish fewer myocardial infarctions, improved limb outcomes, or better survival. Pathological angiogenesis and prothrombotic interactions remain important countervailing considerations.
Figure 6 placeholder — Endothelial dysfunction
Clinical takeaway
Cardiovascular MSC/EV research is indication-specific. Signals in perfusion, inflammation, fibrosis, or ventricular function do not establish class-wide myocardial regeneration, therapeutic angiogenesis, or improved survival.
Biological rationale
Proposed actions include cytoprotection, immunomodulation, angiogenic signaling, endothelial support, antifibrotic effects, extracellular-matrix remodeling, and modulation of host repair.
Product identity
Bone-marrow-, adipose-, umbilical-, and other tissue-derived stromal products; autologous and allogeneic cells; selected precursor populations; and EV preparations are not interchangeable.
Preclinical evidence
Animal models support vascular, anti-inflammatory, and remodeling hypotheses, but experimental timing, infarct size, limb-ischemia models, dose, and background treatment often differ from human disease.
Human clinical evidence
Human trials have produced mixed signals across MI, ischemic cardiomyopathy, heart failure, PAD, and CLTI. Heterogeneous products, small samples, variable controls, and surrogate endpoints limit generalization.
Trial design
Cardiovascular trials should prespecify clinically meaningful endpoints and account for revascularization, contemporary medical therapy, device therapy, rehabilitation, wound care, and competing cardiovascular risk.
Dose and administration
Intracoronary, transendocardial, intramyocardial, intravenous, intra-arterial, and intramuscular delivery create different retention, distribution, procedural, and safety profiles.
Safety
Potential concerns include vascular occlusion, arrhythmia, inflammatory or immune reactions, thrombo-inflammatory effects, procedure-related myocardial or vascular injury, infection, and theoretical pathological angiogenesis.
Regulatory status
Regulatory status is specific to the exact product, indication, route, jurisdiction, and date. Trial participation or facility registration is not equivalent to marketing authorization.
Standard care
Reperfusion after acute MI, guideline-directed heart-failure therapy, aggressive atherosclerotic-risk reduction, supervised exercise, wound care, and surgical or endovascular revascularization remain central where indicated.
Knowledge gaps
Major gaps include validated potency assays, optimal route and dose, treatment timing, responder phenotypes, durable clinical endpoints, comparative effectiveness, and long-term safety.
Bottom-line evidence statement
Cardiovascular MSC and EV approaches remain investigational and must be evaluated against contemporary standard care using patient-important cardiovascular and limb outcomes.
Additional controlled terminology
A cardiomyocyte is a contractile heart-muscle cell injured by myocardial ischemia. Reperfusion restores blood flow but can be followed by ventricular remodeling; ejection fraction and myocardial scar are important but incomplete measures of outcome. Therapeutic angiogenesis seeks new or improved vascular supply, potentially involving collateral circulation and the endothelial cell. Nitric oxide and oxidative stress influence vascular function, while atherosclerosis drives much PAD. Chronic limb-threatening ischemia can present with ischemic rest pain, wounds, or gangrene; limb salvage and amputation-free survival are clinically meaningful endpoints. Flow-mediated dilation is a vascular-function measure. Guideline-directed medical therapy should remain background care. Intracoronary delivery, transendocardial delivery, and intramyocardial delivery are distinct cardiac routes. Revascularization remains a core treatment for appropriate coronary and limb ischemia, and pathological angiogenesis is a potential mechanistic risk.