Microphysiological Model of Human Cardiac Sympathetic Innervation

Johns Hopkins University, Baltimore MD

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Abstract

PROJECT SUMMARY An inherited heart condition known as arrhythmogenic cardiomyopathy (ACM) is characterized by abnormal mechanical coupling of cardiomyocytes, increasing fibrosis, fat deposition, and severe arrhythmias that can lead to rapid cardiac death. Denervation of the cardiac sympathetic nerves is still a treatment option for ACM, which suggests that the functional modification of cardiac sympathetic neurons may be detrimental in the setting of this disease. However, there is a lack of understanding about both the development of sympathetic maladaptation and its unique contribution to ACM disease. To address this, this supplemental project focuses on determining how and when remodeling of cardiac sympathetic neurons happens, as well as how they contribute to the etiology of the disease. To do this, we will use genetically manipulated ACM animal models and investigate the role of postganglionic sympathetic neurons in ACM development. The Specific Aims of this supplemental project are (1) to identify key transcriptional programs and how they interact spatiotemporally to drive pathologic remodeling of postganglionic cardiac sympathetic neurons in ACM pathogenesis and (2) to define the functional role of pathogenic remodeling of postganglionic cardiac sympathetic neurons in ACM pathology. This information is expected to shed light on how interplay between altered neurons and cardiomyocytes contributes to the pathophysiology of ACM.