There is a significant body of literature to suggest that coronary artery disease (CAD) is a highly sex-specific disease. The study of sex-specific therapeutics and sex-specific responses to treatment for CAD remains underreported in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are of growing interest in the treatment of ischemic heart disease and heart failure; however, the sex-specific response to SGLT2 inhibitors is unknown. We studied an SGLT2 inhibitor, canagliflozin, in a swine model of metabolic syndrome (MS) and chronic myocardial ischemia with emphasis on the sex-specific outcomes. Yorkshire swine (n = 21) were obtained at 6 weeks of age and fed a high-fat diet to induce MS. Left thoracotomy was performed on all swine at 11 weeks of age for the placement of an ameroid constrictor to model chronic myocardial ischemia. Swine recovered for two weeks, then were assigned to either the drug group, CAN 300 mg daily group (M = 5, F = 5), or the control group (CON, M = 5, F = 6). Both groups received 5 weeks of therapy. After completion of therapy, swine underwent functional assessment and terminal harvest. The male animals treated with CAN (CAN-M) had significant increases in stroke volume and cardiac output (p = 0.047, p < 0.001) compared to control males (CON-M), which were not seen in females treated with CAN (CAN-F) compared to control females (CON-F). Effective arterial elastance was decreased in CAN-M compared to CON-M. The CAN-F group had a significant increase in ischemic myocardial capillary density compared to CON-F (p = 0.04). There was no difference in capillary density between the CAN-M and CON-M groups. CAN treatment resulted in sex-specific changes in angiogenesis and myocardial function. The CAN-M group had significant improvements in cardiac function based on afterload reduction, stroke volume, and increased cardiac output not seen in the CAN-F group. The CAN-F group had increased ischemic myocardial capillary density. These findings provide a foundation for further investigation of the sex-specific effects of SGLT-2 inhibitors in humans.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide, underscoring the urgent need for innovative therapeutic strategies. The cardiac extracellular matrix (ECM) undergoes extreme transformations during IHD, adversely influencing the heart’s structure, mechanics, and cellular signaling. Researchers investigating the regenerative capacity of the diseased heart have turned their attention to exploring the modulation of ECM to improve therapeutic outcomes. In this review, we thoroughly examine the current state of knowledge regarding the cardiac ECM and its therapeutic potential in the ischemic myocardium. We begin by providing an overview of the fundamentals of cardiac ECM, focusing on the structural, functional, and regulatory mechanisms that drive its modulation. Subsequently, we examine the ECM’s interactions within both chronically ischemic and acutely infarcted myocardium, emphasizing key ECM components and their roles in modulating angiogenesis. Finally, we discuss recent ECM-based approaches in biomedical engineering, focusing on different types of scaffolds as delivery tools and their compositions, and conclude with future directions for therapeutic research. By harnessing the potential of these emerging ECM-based therapies, we aim to contribute to the development of novel therapeutic modalities for IHD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the viral spike proteins, which are key structural components that mediate host cell binding and entry and alter downstream signaling through multiple interactions with endothelial surface receptors. Endothelial dysfunction is a central consequence of COVID-19, contributing to vascular inflammation, barrier disruption, thrombosis, and multi-organ injury affecting the pulmonary, cardiovascular, cerebral, and renal systems. Emerging evidence demonstrates that spike protein-mediated effects, independent of productive viral infection, disrupt endothelial homeostasis through angiotensin-converting enzyme 2 (ACE2) dysregulation, integrin engagement, altered calcium signaling, junctional protein remodeling, oxidative stress, and pro-inflammatory and pro-apoptotic pathways. This review is intentionally focused on spike (S) protein-driven mechanisms of endothelial dysfunction; pathogenic vascular effects attributed to other SARS-CoV-2 structural proteins, including the nucleocapsid (N) protein, are beyond the scope of this discussion. In this review, we synthesize current experimental and translational data detailing the molecular mechanisms by which the SARS-CoV-2 spike protein drives endothelial dysfunction across multiple organ systems and discuss potential therapeutic strategies aimed at preserving endothelial integrity in acute COVID-19 and its long-term vascular sequela.

Background: Cardiovascular disease (CVD), including myocardial ischemia, remains the leading cause of mortality. Current therapies for ischemic myocardium rely largely on invasive revascularization strategies, highlighting the need for improved non-invasive diagnostic and therapeutic approaches. Recent studies suggest that extracellular vesicles (EVs) play a critical role in cardiovascular pathophysiology and may offer novel clinical applications. Methods: This review synthesizes current preclinical and clinical literature on EV biology, including their classification, isolation, and characterization methods, and mechanisms of Intercellular communication. Published studies evaluating EVs as biomarkers and non-surgical therapeutics across major cardiovascular conditions were critically analyzed. Results: EVs facilitate intercellular communication by transferring bioactive molecules that influence disease progression and cardiac repair. Accumulating evidence supports their potential utility as biomarkers for disease prediction and severity assessment, as well as cell-free therapeutics in myocardial infarction, cardiomyopathies, atrial fibrillation, and heart failure. However, significant gaps remain, including the lack of validated EV-based biomarkers, inconsistent isolation and characterization methodologies, limited in vivo tracking data, and barriers to clinical translation. Conclusions: EVs represent a promising frontier in non-invasive cardiovascular diagnostics and therapeutics. Addressing current methodological and translational challenges, alongside advances in EV bioengineering, will be essential to realize their full clinical potential in CVD management.

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.