UCLA

The autonomic nervous system (ANS) has a profound influence on cardiac function. Alterations in ANS balance has tremendous impact on the initiation and progression of cardiac pathology. Current standards of care (pharmacology, surgery, devices) have proven efficacy, but well-known limitations as well. Bioelectronic therapy has the potential to provide a reversible, on demand, scalable approach to cardiac control. The hypothesis of this thesis is that imbalances in information processing between different levels of the cardiac neuraxis is a primary determinant in mediating electrical instability of the heart and progression into heart failure. As a corollary, mitigating imposed neural imbalances within the hierarchy for cardiac control is cardioprotective.

To investigate bioelectronic modulation of the parasympathetic control of cardiac pathology, vagal nerve stimulation (VNS) was employed in a guinea pig pressure overload (PO) model of heart failure with preserved ejection fraction (HFpEF). Guinea pigs were subjected to aortic constriction, in the presence or absence of VNS. The effects on disease were assessed in the whole animal (echocardiography) and at the neural (intracellular current clamp recordings of intrinsic cardiac (IC) neurons) and myocyte (protein expression) levels.

To investigate bioelectronic modulation of sympathetic drive to the heart, proof of concept studies involving kilohertz frequency alternating current (KHFAC) and charge-balanced direct current carousel (CBDCC) were employed in an anesthetized porcine model. CBDCC was also used to determine impact on arrhythmia potential in a porcine myocardial infarction (MI) model.

With VNS therapy, PO-induced hemodynamic responses (increased cardiac output, systolic/diastolic left ventricular volumes) were prevented. Enhancements in synaptic efficacy muscarinic sensitivity were also mitigated. Myocyte hypertrophy was prevented using right-sided VNS. PO-induced hypertrophic myocardium also abnormal energetics, which was modulated with VNS application.

For sympathetic control, KHFAC and CBDCC demonstrated reversible, current-dependent impact on cardiac indices (activation recovery intervals (ARI), heart rate, and contractility). In the MI model, extrasystolic (S1-S2) stimulations induced ventricular arrhythmias in all animals (n=7), whereas right-sided CBDCC application reduced inducibility by 83%. The ventricular effective refractory period (VERP) was prolonged with CBDCC (323�26 ms) compared to baseline (271�32 ms).

In conclusion, the data within this thesis provides validation for a mechanism-based approach to cardiac therapy that combines the potential of bioelectronic therapy with a detailed knowledge of cardiac neuraxis structure/function, addressing a significant unmet need in managing both arrhythmia burden and the progression of heart failure.