AI-Driven Assessment of The Efficacy And Safety of Gene and Cell-Based Therapies for Ischemic Heart Disease: A Systematic Review of Clinical Trials

Abstract

Background: Ischemic heart disease (IHD) is the most common cause of morbidity and mortality in the world. In spite of the new technology in revascularization and pharmacotherapy, a significant number of patients still report refractory angina, dysfunction of perfusion and chronic ventricular dysfunction. Gene and cell-based regenerative therapies are some of the biological interventions that have been identified as promising because of their ability to promote angiogenesis, reduce ischemic injury, and augment myocardial repair. The results of clinical trials have however been inconsistent and the overall effectiveness, safety, and quality of such therapies have not been adequately synthesized.

Objective: To carry out a systematic review and assessment of the effectiveness, safety, and methodological quality of clinical trials on gene-based and cell-based therapies of IHD, and also to compare therapeutic outcomes among the various types of vectors, various cell populations, different routes of delivery, and types of imaging.

Methods: A methodical search of PubMed/MEDLINE, EMBASE, Web of Science, Scopus, Cochrane Library, ClinicalTrials.gov and IEEE Xplore and Google Scholar was done to find studies published between 2000 and January 2024. They consisted of randomized controlled trials, controlled cohorts, and phase I-III human clinical trials on gene or cell therapies to treat IHD. Screening, data extraction, and quality assessment were conducted by two independent reviewers based on Cochrane RoB 2 and ROBINS-I software. Random-effects meta-analysis was used to pool the outcomes of LVEF, perfusion indices, angina frequency, 6-minute walk distance and major adverse cardiovascular events (MACE). Correlation analysis was used to measure relationships among dose, sample size, delivery route, imaging modalities and therapeutic results.

Results: Out of the 5,820 records identified, 42 trials comprising of 4980 treated patients and 3450 controls had passed the inclusion criteria. Combined results showed an improvement of +4.2% (95% CI 3.152) in mean LVEF and 9.1% in mean perfusion defect in treatment groups, with the most functional improvements of +56) and VEGF/HGF gene therapies having the greatest perfusion improvements. Symptomatic improvement entailed a decrease of 3.8 angina episodes/week and increment of 46 meters in 6-minute walk distance. The results of safety outcomes were positive as there were no significant differences between the controls and mortality, arrhythmias, and MACE. Correlations found therapeutic response positively correlated with increased cell count or higher dose of vectors (r = 0.62), intramyocardial delivery (r = 0.71), and AI-assisted quantification of imaging (r = 0.58). The methodological heterogeneity was still high particularly in the type of delivery methods, types of vectors, cell processing, and follow-up period.

Conclusions: Both gene-based and cell-based therapy has shown promising efficacies along with satisfactory safety profiles in the enhancement of myocardial perfusion, ventricular functioning, and symptom burden of IHD. Angiogenic gene vectors, MSCs, and CPCs seem to be the most efficient. Nevertheless, variability in the protocols, small sample size, and short follow up periods are a limitation to clinical translation. To advance in the future, it is necessary to conduct large and multicentric trials using standardized means of delivery, using standardized imaging criteria, using AI-enhanced outcome measurement, and conducting long-term safety follow-up. Regenerative therapies with proper standardization and validation can become a permanent part of the precision cardiology of patients with severe ischemic disease.