Abstract
BACKGROUND: Ventricular arrhythmias (VAs) are a leading cause of death and arise from a combination of cardiac muscle injury and dysfunction of the intramyocardial sympathetic nerves that control cardiac electrophysiology. The adrenergic mechanisms by which intramyocardial nerves contribute to arrhythmogenesis are poorly understood. Semaphorin-plexin signaling pathways are responsible for developmental guidance of sympathetic nerves onto the heart and have previously been associated with VAs in humans. OBJECTIVES: This study sought to investigate adrenergic control of arrhythmogenesis, and explored the cardiac electrophysiology of a Plexin-A3/-A4 double knockout mouse model with loss of cardiac adrenergic nerves. METHODS: Cardiac structure and function were studied by using tissue clearing, immunohistochemistry, and echocardiography. Electrocardiogram and optical mapping of action potentials were used to evaluate electrophysiological responses to pharmacologic β-adrenergic stimulation and blockade. Circulating catecholamines were measured and β-adrenergic receptor density quantified in cardiac membranes. Finally, a phenome-wide association study was performed by using data from the UK Biobank to search for associations between PLXNA4 and human arrhythmias. RESULTS: Mice with loss of plexin-dependent cardiac innervation had structurally normal hearts but displayed spontaneous VAs driven by adrenergic hypersensitivity, as well as increased cardiac β-adrenergic receptor density. Several human PLXNA4 variants were associated with arrhythmia phenotypes. CONCLUSIONS: These data establish a model of VAs driven by enhanced adrenergic receptor signaling, in the absence of structural heart disease. This model can be used to investigate adrenergic mechanisms of arrhythmogenesis and to identify novel antiarrhythmic targets.