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.

Serotonin (5-hydroxytryptamine, 5-HT) is a vasoactive amine and important regulator of vascular tone. Aberrant serotonergic activity contributes to vascular pathology in multiple cardiovascular disease states, including hypertension, diabetes, metabolic syndrome and chronic myocardial ischemia. Serotonin also plays a vital role in postoperative vascular dysfunction after cardioplegic arrest with cardiopulmonary bypass (CP/CPB). Perioperative microvascular dysfunction following CP/CPB manifests as an increased propensity for vasospasm or vasoplegia, with different effects in different tissue beds (coronary, skeletal muscle, pulmonary and systemic microcirculations). Given the importance of serotonin as a modulator of vasogenic responses, we present a selected narrative survey of the current literature concerning the effects of altered serotonergic activity on vascular dysfunction in the context of CP/CPB and other cardiometabolic diseases. This review begins with a discussion of normal serotonin biology and signaling pathways, then moves into disease-specific discussions covering five major areas of focus: metabolic syndrome, diabetes, hypertension, myocardial ischemia and CP/CPB.