Despite significant improvements in revascularization strategies and medical management, ischemic heart disease (IHD) remains the top cause of mortality and disability worldwide. The myocardium lacks regenerative capacity and consequently, recovery depends on re-establishing microvascular integrity and sustaining angiogenesis to preserve viable myocardium. Emerging and novel bioengineering approaches, such as stem cells, extracellular vesicles (EVs), and matrix-based strategies, seek to address this unmet need by promoting neovascularization and structural restoration. However, clinical translation remains limited by poor engraftment, product variability, and arrhythmogenic risk. Large animal models provide a clinically relevant platform to thoroughly investigate these interventions and ideally enhance their translational potential. This review discusses cellular approaches leveraging stem and progenitor cells and acellular modalities using extracellular vesicles, growth factors, or extracellular matrix-based scaffolds with an emphasis on large animal translational models and clinical trials.

BACKGROUND: Ischemic heart disease is the leading cause of mortality and human suffering globally. It often leaves patients with residual symptomatic burden despite current optimized procedural and medical options. Sotagliflozin, a dual SGLT1/2 (sodium-glucose cotransporter 1 and 2) inhibitor, has emerged for its clinically evident ischemic cardiovascular benefits. We hypothesize that sotagliflozin treatment exerts direct myocardial benefits in ischemic heart disease, independent of comorbid conditions. METHODS: Yorkshire swine (n=22) underwent placement of an ameroid constrictor around the left circumflex coronary artery. Following a 2-week period in which the ameroid gradually closes, swine (n=18) were randomized to receive either 400 mg daily sotagliflozin (n=8) or no drug (n=10) for 5 weeks. Afterwards, swine underwent terminal harvest to acquire cardiac functional data with pressure-volume loops, myocardial perfusion by microsphere injection, and ventricular sectioning. To investigate the cellular and tissue-level impact of therapy, histology, immunoblotting, and high-throughput techniques were performed. RESULTS: Sotagliflozin swine had improved ejection fraction, cardiac output, and stroke work compared with no drug ( P <0.05) and a reduction in tau ( P =0.04). Absolute blood flow to the ischemic myocardium was increased in the sotagliflozin group ( P =0.03). Sotagliflozin swine had a reduction in 3-nitrotyrosine and trichrome staining, representing decreased reactive nitrogen species and myocardial fibrosis ( P =0.03 for both). Molecularly, sotagliflozin swine demonstrated increased expression of endothelial nitric oxide synthase and superoxide dismutase 3 ( P =0.02, P =0.04; respectively), with upregulated arginine metabolism, protein kinase A/cyclic adenosine monophosphate signaling, as well as glycolysis, fatty acid oxidation, and citric acid cycle. CONCLUSIONS: Sotagliflozin treatment improved left ventricular function, myocardial perfusion, and diastolic relaxation, likely through reduced nitrosative stress and myocardial fibrosis, improved nitric oxide coupling, enhanced insulin signaling, and favorable metabolic shifts. This study suggests a potential role for sotagliflozin as a cardioprotective therapy in patients with ischemic heart disease beyond current treatment strategies.

Cyanotic congenital heart disease (CCHD) remains a major contributor to infant morbidity and mortality in the United States, yet the influence of maternal social determinants of health on risk is not fully understood. This study examined associations of maternal age, education, and race/ethnicity with the live birth prevalence of CCHD using recent national birth data from the Centers for Disease Control and Prevention (CDC) National Vital Statistics System (2022–2023). CCHD was identified from birth certificate records and analyzed as a binary outcome. Regression analyses were performed to evaluate relationships between maternal characteristics and CCHD occurrence. Overall, CCHD was a rare outcome with a modest decline in prevalence between the two years examined. Increasing maternal age was associated with higher odds of CCHD, while Latina ethnicity was associated with lower odds compared to the reference group. Other racial/ethnic categories and maternal education level were not significantly associated with CCHD risk in adjusted analyses. These findings suggest that certain maternal factors, particularly age and ethnicity, are associated with variation in the live birth prevalence of CCHD and underscore the need for further research into underlying environmental and structural contributors not captured in standard birth records.