Intracoronary Wharton’s Jelly Mesenchymal Stem Cells After STEMI Reduce Incident Heart Failure: Phase 3 PREVENT-TAHA8 Results

Highlights

– PREVENT-TAHA8, a phase 3 randomized trial, tested intracoronary infusion of allogeneic Wharton’s jelly mesenchymal stem cells (WJ‑MSCs) given 3–7 days after first ST-elevation myocardial infarction (STEMI) in patients with LVEF <40%.

– WJ-MSCs significantly reduced incidence of heart failure (HR 0.43; 95% CI 0.21–0.89; P=0.024) and readmission for heart failure (HR 0.22; 95% CI 0.06–0.74; P=0.015), and improved 6-month LVEF (mean adjusted difference ≈5.9%).

– No statistically significant differences were observed for all-cause mortality, cardiovascular mortality, or readmission for recurrent myocardial infarction.

Background and unmet need

Acute myocardial infarction (AMI) remains a major cause of mortality and is a leading antecedent of chronic heart failure (HF). Despite major advances in reperfusion and secondary prevention, a substantial proportion of patients with large infarcts develop adverse left ventricular (LV) remodeling and progressive HF. Therapies that reduce infarct expansion, preserve myocardial viability, or favorably modify post-infarction remodeling have the potential to reduce incident HF and related morbidity.

Cell-based therapies—particularly mesenchymal stem/stromal cells (MSCs)—have attracted interest because of pleiotropic effects such as paracrine signaling, immunomodulation, angiogenic stimulation, and potential anti-fibrotic actions. Prior trials of cell therapy in acute and chronic ischemic heart disease reported heterogeneous results, with many early phase studies showing modest improvements in surrogate measures (LVEF, infarct size), and larger trials producing mixed or neutral clinical outcomes. PREVENT-TAHA8 investigated whether intracoronary infusion of an off-the-shelf allogeneic MSC product derived from Wharton’s jelly of the umbilical cord could prevent progression to clinical heart failure after a large first STEMI.

Study design

PREVENT-TAHA8 is reported as a phase 3 randomized clinical trial conducted at three tertiary hospitals in Shiraz, Iran. Key design features include:

• Population: Adults with a first ST-elevation acute myocardial infarction and left ventricular ejection fraction (LVEF) <40%.
• Randomization: 1:2 allocation to standard care (control) or intracoronary WJ‑MSC infusion plus standard care.
• Intervention: Intracoronary infusion of allogeneic Wharton’s jelly-derived MSCs administered 3–7 days after the index AMI.
• Primary endpoint: Incidence of heart failure during follow-up.
• Secondary endpoints: Readmission for heart failure, all-cause mortality, cardiovascular mortality, readmission for myocardial infarction, and change in LVEF at six months.
• Follow-up: Median 33.2 months; final analysis included 396 patients (136 intervention, 260 control).

Key findings

Primary outcome:

During follow-up, the incidence of new heart failure events was lower in the WJ-MSC group versus control: 2.77 vs 6.48 events per 100 person‑years. The hazard ratio (HR) was 0.43 (95% CI 0.21–0.89; P=0.024), indicating an approximately 57% relative reduction in the risk of incident HF associated with intracoronary WJ-MSC therapy.

Secondary clinical endpoints:

• Readmission for heart failure: 0.92 vs 4.20 events per 100 person‑years; HR 0.22 (95% CI 0.06–0.74; P=0.015). This represents a marked reduction in HF‑related rehospitalization.
• Composite cardiovascular endpoint (cardiovascular mortality or readmission for myocardial infarction or heart failure): 2.80 vs 7.16 events per 100 person‑years; HR 0.39 (95% CI 0.19–0.82; P=0.012).
• Readmission for myocardial infarction: numerically lower in WJ‑MSC group (1.23 vs 3.06 events per 100 person‑years) but not statistically significant (HR 0.40; 95% CI 0.14–1.19; P=0.10).
• All-cause mortality: 1.81 vs 1.66 events per 100 person‑years; HR 1.10 (95% CI 0.40–3.02; P=0.86), showing no evidence of increased mortality but also no mortality benefit in this trial.
• Cardiovascular mortality: 0.91 vs 1.33 events per 100 person‑years; HR 0.68 (95% CI 0.18–2.57; P=0.57).

Left ventricular function:

At six months, patients who received WJ-MSCs experienced a significantly greater improvement in LVEF compared with controls. The adjusted difference (β) was 5.88 percentage points (95% CI 4.00–7.76; P<0.001). This magnitude of improvement is clinically meaningful and consistent with the observed reductions in HF incidence and HF readmissions.

Safety:

The trial report indicates that WJ-MSC infusion was not associated with a statistically significant excess in all-cause or cardiovascular mortality. Detailed procedural and safety endpoints (for example, peri-procedural MI, arrhythmia, coronary complications, immunological reactions) should be reviewed in the full publication for a comprehensive safety assessment. The absence of a mortality signal in this cohort is reassuring but longer-term and larger studies are required for definitive safety characterization.

Interpretation and mechanistic plausibility

The reductions in incident HF and HF readmissions, together with the improvement in LVEF at six months, support the biological plausibility that intracoronary WJ-MSCs can favorably modify post-infarction remodeling. Potential mechanisms include anti-inflammatory and immunomodulatory effects that reduce infarct expansion; paracrine stimulation of angiogenesis improving perfusion in the border zone; attenuation of fibrosis; and support for myocardial salvage of stunned or hibernating myocardium.

Allogeneic Wharton’s jelly MSCs are an attractive therapeutic product because they are readily available off the shelf, have low immunogenicity, and possess robust paracrine activity in preclinical models. Intracoronary delivery targets cells to the infarct-related artery and microvascular bed at a time when recruitment and retention may be optimized.

Strengths of the study

• Phase 3 randomized design with a clinically relevant primary endpoint (incident heart failure).
• Relatively large sample size for a cell-therapy trial and extended median follow-up of ~33 months for clinical events.
• Objective echocardiographic endpoint (LVEF) with a clinically meaningful magnitude of improvement.
• Use of an allogeneic, off-the-shelf MSC product that could be standardized and scaled if efficacy and safety are confirmed.

Limitations and considerations

• Control group received standard care rather than a sham intracoronary infusion; absence of a procedural placebo control can permit performance and ascertainment biases, particularly for subjective outcomes. However, hard endpoints such as HF hospitalizations are less susceptible to bias than subjective measures.
• The trial was conducted in three centers in Shiraz, Iran. Generalizability to other healthcare settings, ethnic groups, and regulatory contexts requires confirmation in broader international cohorts.
• Detailed safety data, immunologic monitoring, and longer-term follow-up beyond the median 33 months will be important to exclude late adverse effects, including arrhythmogenesis, immunologic sensitization, or tumorigenicity—though the latter has not been a major signal in MSC clinical research to date.
• Optimization questions remain: ideal cell dose, timing of infusion (early vs later), route (intracoronary vs intramyocardial), and whether benefits are additive to contemporary guideline-directed medical therapy and device strategies.
• Prior cell therapy trials have produced heterogeneous results. Comparisons are complicated by differences in cell type (bone marrow mononuclear cells, bone marrow MSCs, adipose-derived cells, WJ-MSCs), autologous versus allogeneic source, timing, and endpoints. PREVENT-TAHA8’s positive results with WJ‑MSCs are encouraging but require independent replication.

Implications for clinical practice and research

PREVENT-TAHA8 provides the most direct randomized evidence to date that an allogeneic MSC product delivered intracoronarily soon after a large STEMI can reduce the subsequent incidence of heart failure. If these results are corroborated in independent multicenter trials that include diverse populations and sham-control designs, WJ-MSC therapy could become an adjunctive strategy in a high‑risk subset of post-STEMI patients (for example, first large infarct with LVEF <40%) to prevent progression to chronic HF.

Key next steps should include: international multicenter confirmatory trials; standardized manufacturing and quality-control processes; cost-effectiveness and delivery pathway analyses; studies clarifying optimal timing, dosing, and patient selection; and mechanistic biomarker studies to identify responders and refine therapy.

Conclusion

PREVENT-TAHA8 reports that intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells given early after a first STEMI with LVEF <40% reduced incident heart failure and HF readmissions and improved six‑month LVEF compared with standard care. These findings are promising and support further confirmatory trials and mechanistic work before widespread clinical adoption. For clinicians, this study highlights a potential new avenue for preventing the transition from large infarction to chronic heart failure, addressing an important unmet need in post-MI care.

Funding and trial registration

Trial registration: ClinicalTrials.gov NCT05043610. Funding sources and detailed disclosures are provided in the primary publication (Attar A, Mirhosseini SA, Mathur A, et al. BMJ. 2025;391:e083382).

References

1. Attar A, Mirhosseini SA, Mathur A, Dowlut S, Monabati A, Kasaei M, Abtahi F, Kiwan Y, Vosough M, Azarpira N. Prevention of acute myocardial infarction induced heart failure by intracoronary infusion of mesenchymal stem cells: phase 3 randomised clinical trial (PREVENT-TAHA8). BMJ. 2025 Oct 29;391:e083382. doi: 10.1136/bmj-2024-083382. PMID: 41224473; PMCID: PMC12570275.

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