Neuro-cardiac Mechanisms of Sudden Unexpected Death in Epilepsy

About This Grant

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. SUDEP mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and cardiac arrhythmias. Genes encoding voltage-gated sodium channel subunits are high SUDEP risk genes. Loss- of-function variants in SCN1A are linked to the Developmental and Epileptic Encephalopathy (DEE) Dravet syndrome (DS). Importantly, SCN1A is expressed in both heart and brain. Thus, we proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in channelopathy-linked genetic epilepsies. We have shown evidence for altered cardiac myocyte sodium current density, calcium handling, and action potentials (APs), as well as cardiac arrhythmias in mouse models of DEE. We also showed that induced pluripotent stem cell (iPSC)- derived cardiac myocytes derived from DS patients have substrates for arrhythmias. DS patients also often display disordered breathing, suggesting dysfunctional neural control of respiration may underly SUDEP risk. Importantly, no mouse or iPSC model can completely replicate the human DS phenotype. Because mouse cardiac APs are very different from humans, we used human iPSC-cardiac myocyte models to investigate cell autonomous effects of SCN1A haploinsufficiency, however, cells in 2-dimensional culture cannot replicate complex cardiac tissues, cardiovascular changes, or cardiac autonomic innervation. From the control of breathing standpoint, mouse metabolic adaptability makes them more resistant to hypoxia and prolonged apneas than humans. Thus, we developed a transgenic rabbit Scn1a DS model because rabbits more closely replicate human cardiac and respiratory physiology than mice and, unlike iPSCs, provide a complete organism to translate to the clinical setting. The goal of this proposal is to use DS rabbits to test the hypothesis that Scn1a haploinsufficiency results in altered cardiac and brainstem excitability in addition to generalized seizures, leading to cardiac arrhythmia, altered heart rate variability (HRV), and impaired respiratory pattern generation in the brainstem. We will test our hypothesis by addressing three Aims: 1. To determine whether DS rabbits have cardiac arrhythmias and altered HRV in addition to seizures and to determine whether acutely isolated ventricular and atrial cardiac myocytes have altered excitability. 2. To determine whether DS rabbits have altered regulation of respiration, including changes in the pattern of respiratory motor output, altered patterns of dorsolateral pontine respiratory-related neuronal activity in an intact pontomedullary respiratory circuit, and altered excitability of and GABAergic synaptic transmission onto brainstem dorsolateral pontine neurons. 3. To determine whether intracerebroventricular administration of a TANGO antisense oligonucleotide targeting Scn1a haploinsufficiency can alter brainstem respiratory-related neuronal activity, HRV, or cardiac arrhythmias secondary to autonomic dysfunction in DS rabbits.