NRF2 and MAO-Ai therapy to improve cardiac health and prevent arrhythmias in Friedreich’s ataxia

The mechanisms leading to cardiomyopathy and arrhythmias (irregular heart rhythm) in FA patients are poorly understood. Calcium (Ca2+) flow is thought to be disrupted, leading to the decline in function and the appearance of arrhythmias. The autonomic nervous system (ANS) is the automatic communication between the brain and heart that controls bodily functions like breathing or heartbeats. Despite increasing evidence of ANS dysfunction in FA, its involvement in disrupted cardiac function has yet to be entirely investigated. A dysfunction of the ANS could produce cardiac catecholaminergic “storms” when degradation of catecholamines (neurotransmitters important for stress responses, e. g. adrenaline) is not matched with their supply. The monoamine oxidase-A (MAO-A) is an enzyme that degrades catecholamines. Emerging studies indicate that cardiac MAO-A inhibition protects against catecholamine-induced arrhythmias by controlling Ca2+ levels. With this grant, UC Davis graduate student Francisco Figueroa and his supervisor Dr. Elena Dedkova DVM, PhD will investigate the role of the ANS in an FA mouse and will test the effect of Clorgyline, a known MAO-A inhibitor alone or in combination with OMAV on cardiac contractile function, arrhythmias and survival of the mouse.