Research program : Neuro-cardiac coupling

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Neuro-cardiac coupling

Cardiac arrhythmias are the leading cause of undeserved and sudden death. They represent electrical abnormalities that disturb the sinusal electrophysiological excitation, electrical conduction and finally impede efficient cardiac contraction. Arrhythmias are mainly related to an impairment of ionic homeostasis through ionic channel inherited mutation or acquired dysfunction. In parallel, the cardiac function is tightly regulated by the autonomous nervous system (ANS) composed of the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS).

Many observations including ours highlighted the importance of the ANS in the initiation and maintenance of electrical disturbances. While the PNS slow down the heart rate by acetylcholine at the level of the atria, the SNS innervation of the sino-atrial node and ventricles increases heart rate, conduction velocity, and force through norepinephrine (NE) secretion. Thus, any pathophysiological changes in the ANS balance directly affects myocardial excitability and function. A number of human pathologies (i.e., myocardial infarction, diabetes) are associated with both structural and functional remodeling in ANS, leading to a heterogeneity in NE release within the heart and predisposing to an electrical instability both at atrial and ventricular levels. Besides changes in the neurons-cardiomyocytes coupling, any remodeling of the sympathetic innervation may impact the sympatho-vagal control of heart rhythm and electrical stability and then compromise efficiency. Furthermore, neurons and cardiomyocytes are excitable cells that share numerous functional ionic channels involved in both depolarization and repolarization of action potential.

As a consequence, ionic channel dysfunction may affect both neurons and cardiomyocytes excitability and many patients undergoing cardiac arrhythmia also present neural disorders such as epileptic seizure or autism. In this context, a better understanding of the neuro-cardiac dynamic coupling and the sympatho-vagal (im)balance in inherited cardiac channelopathies and acquired cardiopathies is crucial to optimize the prevention and the prediction of arrhythmic events. To decipher the neuro-cardiomyocytes, we are developing original approaches using human cell co-cultures and patients specific hiPSC derived cardiomyocytes and hiPSC derived neurons. On the other hand, we are optimizing technologies for vital signs monitoring (SmartVista UE project and micromagnetometry) in order to acutely analyze and predict arrhythmic events.

These innovative approaches serve to establish and understand the role of the myocardial innervation and the SNA in the genesis of fatal arrhythmia as well as to predict the Torsadogenic potential of iatrogen compounds, both in animal models and in patients. A better characterization of the Brain-Heart axis in the development of arrhythmic disorders and sudden cardiac death will also permit to identify novel therapeutics strategies in metabolic pathologies and inflammatory-related cardiomyopathies (Axis1, Axis3). In particular, we characterize the anti-arrhythmic potential of drug candidates such as non-enzymatic metabolites of omega-3 polyunsaturated fatty acids (NEO-PUFAs).