Background-In horses, cardiac abnormalities are often classified as either structural or electrical, despite clear interdependence between these processes. Specifically, the interaction between the mitral valve and ventricular myocardium and their role in ventricular remodeling and arrhythmia formation remains incompletely understood. This dissertation aimed to investigate myocardial dysfunction and autonomic regulation during endotoxemia, define the structural and electrical interface between valvular disease and myocardium, and characterize cellular mechanisms of equine valvular dysfunction.

Methods-A combination of experimental, observational, and in vitro approaches were utilized. Experimentally induced endotoxemia was used to evaluate myocardial function via echocardiography, including tissue Doppler imaging (TDI) and two-dimensional speckle tracking (2DST), and autonomic regulation via 24-hour Holter electrocardiography and heart rate variability (HRV) analysis. Cardiac phenotyping, postmortem morphologic and histologic assessment, and three-dimensional electro anatomical mapping (3DM) were performed to investigate relationships between mitral valve prolapse (MVP), myocardial fibrosis, and arrhythmogenic substrate. Equine valvular endothelial (VEC) and interstitial (VIC) cell culture was developed and utilized to evaluate serotonin receptor 2B (5HTR2B) expression and response to serotonin stimulation.

Results-Endotoxemia resulted in systolic and diastolic myocardial dysfunction, characterized by decreased ejection fraction, prolonged index of myocardial performance, and reduced longitudinal strain, despite no increase in cardiac troponin. HRV analysis demonstrated decreased parasympathetic tone and increased sympathetic activity, consistent with autonomic imbalance, without a change in arrhythmia burden. Structural studies identified correlations between MVP, mitral regurgitation and posterior papillary muscle fibrosis. Use of 3DM demonstrated increased left ventricular late potentials in horses with subjective MVP, supporting the presence of arrhythmogenic substrate. At the cellular level, equine VEC and VIC culture was feasible, and differential 5HTR2B protein expression was identified following serotonin stimulation, particularly increased fluorescence in VICs and decreasing fluorescence in VECs from horses with mitral regurgitation without corresponding gene expression changes.

Conclusions-These findings demonstrate that myocardial dysfunction, autonomic dysregulation, valvular abnormalities, and cellular signaling pathways are interconnected contributors to equine cardiac disease. Integration of structural, electrical, and molecular findings supports a model of ventricular remodeling and arrhythmia formation and highlights the importance of comprehensive investigation in understanding and managing equine cardiovascular disease.