UCLA

Autonomic dysregulation in cardiovascular disease plays a major role in the pathogenesis of arrhythmias. Cardiac neural control relies on complex feedback loops consisting of efferent and afferent limbs, which carry sympathetic and parasympathetic signals from the brain to the heart and sensory signals from the heart to the brain. Cardiac disease leads to neural remodeling and sympathovagal imbalances with arrhythmogenic effects. Preclinical studies of modulation at central and peripheral levels of the cardiac autonomic nervous system have yielded promising results, leading to early-stage clinical studies of these techniques in atrial fibrillation and refractory ventricular arrhythmias, particularly in patients with inherited primary arrhythmia syndromes and structural heart disease. However, significant knowledge gaps in basic cardiac neurophysiology limit the success of these neuromodulatory therapies. At the level of the myocardium, remodeling of injured sympathetic nerves on the heart after myocardial infarction (MI) contributes to adverse outcomes such as sudden arrhythmic death, yet the underlying structural mechanisms are poorly understood. We sought to examine microstructural changes on the post-MI heart and to directly link these changes with electrical dysfunction. We developed a high-resolution pipeline for anatomically precise alignment of electrical maps with structural myofiber and nerve-fiber maps created by customized computer vision algorithms. Using this integrative approach in a mouse model, we identified distinct structure-function correlates to objectively delineate the infarct border zone, a known source of post-MI arrhythmias. During tyramine-induced sympathetic nerve activation, we demonstrated regional patterns of altered electrical conduction aligned directly with altered neuroeffector junction distribution, pointing to potential neural substrates for cardiac arrhythmia. The pathophysiological alterations in sympathetic function of border zone nerve sprouts led us to initiate further mechanistic studies of how altered neural patterning fundamentally affects cardiac electrophysiology. Overall, this dissertation establishes a synergistic framework for examining structure-function relationships after MI with microscopic precision, which has potential to advance understanding of arrhythmogenic mechanisms.