Myocardial infarction and heart failure increase risk for ventricular arrhythmias and sudden cardiac death. Autonomic dysregulation and sympathetic hyperactivity accompany these diseases and trigger lethal arrhythmias. Interventions that target the central nervous system to inhibit sympathetic outflow have not been effective in patients, but interventions that target the peripheral sympathetic nervous system decrease arrhythmias and prolong life. We hypothesize that central nervous system activity is amplified by post- ganglionic neurons in cardiovascular disease to enhance norepinephrine and neuropeptide Y release at the heart, which contributes to pathology. We have discovered excitatory collaterals between sympathetic post- ganglionic neurons that foster synchronous amplification of preganglionic signals. We hypothesize that disease-induced changes in the heart trigger morphological and electrical transformation of sympathetic postganglionic neurons that results in sympathetic hyperactivity. To identify the mechanisms responsible for hyper-sympathetic changes, we exploit transgenic mouse models coupled with neurochemistry, single cell RNAseq, patch clamp electrophysiology, retrograde tracing and 3D reconstruction of labeled neurons to link structure with function. We will connect neural function to norepinephrine and neuropeptide Y release in the heart. The combined power of single cell synaptic measures with mouse genetics and retrograde tracing offers unique opportunities to resolve mechanisms responsible for augmented transmission specific to cardiac projecting neurons. We will test the hypotheses that myocardial infarction and heart failure drive increased cardiac sympathetic transmission: through expanding dendritic arbors and their synaptic inputs (Aim 1); through enhancing neuronal activity (Aim 2); and through altering neuronal calcium handling (Aim 3). We have assembled a unique team of accomplished experts, key animal models, and powerful genetic tools to accomplish these studies. We expect that novel insights and targets for therapeutic intervention will come from the studies described here, and that this work with have implications for treatment of the many diseases characterized by high sympathetic activation.
Patients with myocardial infarction and heart failure have a high risk for cardiac arrhythmia and sudden cardiac death. Both conditions are characterized by increased cardiac sympathetic transmission, and sympathetic hyperactivity can trigger lethal arrhythmias. The goal of our research is to elucidate the mechanisms that underlie enhanced peripheral sympathetic transmission to the heart in cardiovascular disease. This will lay the groundwork for new therapeutic options that target the nervous system to decrease arrhythmia risk and prevent sudden cardiac death.
