(9) Closed-loop Control of Norepinephrine to Attenuate Sympathetic Response to Cardiac Stressors

Introduction: Chronic elevated sympathetic stress has been implicated in the pathogenesis of several cardiovascular disorders including arrhythmias and heart failure. Sympathetic control of cardiac function occurs through postganglionic innervation from stellate ganglia. Norepinephrine (NE) is the primary neurotransmitter released from sympathetic efferent nerves and causes increased cardiac output. Downregulation of sympathetic tone can be achieved via catheter ablation or surgical resection of the paravertebral chain; however, these techniques are irreversible. Alternatively, electrical sympathetic nerve block is a treatment that can be applied instantly, is rapidly reversible, and can be titrated to customizable dosages.

Methods: NE levels were measured in real-time using fast scanning cyclic voltammetry (FSCV) via platinum sensor electrodes placed in the myocardium of the left ventricle in both healthy and myocardial infarction (MI) porcine models. The infarcted model was created by injecting polystyrene microspheres to embolize the distal portion of the left anterior descending coronary artery 8 weeks prior to testing. NE release was induced via 5 minutes of decremental programmed pacing of the right ventricle.
A closed-loop controller was used to detect changes in NE levels measured with FSCV and respond with graded electrical nerve block of the right-side paravertebral chain (T1-T2 level). Direct current (DC) electrical nerve block was provided using a carbon separated interface nerve electrode (CSINE), controlled by a fuzzy logic controller (FLC) to titrate the level of nerve block to maintain the NE release at a pre-defined setpoint.
NE levels in response to the 5-minute programmed pacing protocol were first measured with no nerve block. Setpoints of 66% and 33% of this maximum level were chosen, and the controller modulated the DC nerve block amplitude to limit NE release to these values. Programmed pacing was repeated with the controller set to one of these setpoints and the resultant NE release and controller output were recorded.

Results: The controller was able to effectively modulate the release of NE in the myocardium. The figure shows the measured normalized increase in current measured by FSCV as a result of the programmed pacing in both the healthy and infarcted animal.

Conclusion: Electrical nerve block of the sympathetic inputs to the heart can reduce the release of NE induced by cardiac stressors. Reduction in NE reduces the likelihood of arrhythmia occurring after an infarction event. Closed-loop control allows for the therapy to only be applied when needed, and to adapt to individual patient needs in real-time.