Mechanically-Induced Cardiac Excitation: Mechanisms and Modifiers

• Applicant: Dr. Callum Michael Zgierski-Johnston
• Subject Area: Cardiology, Angiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423056183

Mechanoelectric coupling is an integral part of cardiac autoregulation, allowing the heart to respond to changes in circulatory demand. This intrinsic regulatory process is present even in the transplanted (i.e. denervated) heart. Mechanoelectric coupling can be utilised to externally trigger competent cardiac contractions (for example by a precordial thump [PT]) which are significantly more productive than passive chest compressions (cardiac output is 77 % of baseline for mechanically-induced excitation, compared to 38 % even with optimally performed chest compressions). For many decades, PT was thought to be a potentially useful means of terminating tachy-arrhythmias, but more recent studies have shown this to be an ill-founded expectation, based on the positive publication bias of case reports and non-prospective study designs. Still, according to the latest International Consensus Statement on cardio-pulmonary resuscitation science, “There is insufficient evidence to recommend for or against the use of the precordial thump for witnessed onset of asystole caused by atrioventricular conduction disturbance”. So the use of PT for mechanical pacing in severe bradycardia is an area with an internationally acknowledged need for research, such as proposed here.The clinical applicability of mechanical pacing is also uncertain due to a lack of sustainability, where hearts respond to a limited number of stimuli before loss of 1:1 capture. When mechanical pacing is initiated, the heart undergoes a competent contraction in response to every stimulus. However, after a number of beats the heart will stop responding, even though it remains electrically excitable. This is not a permanent cessation of mechanical capture: After a period of time without mechanical interventions, recovery of 1:1 capture occurs, with hearts returning to the same level of sustainability as before (no tissue injury). The underlying mechanisms of mechanical induction of contractions, and the reasons for the temporary loss of capture, are not known. Both preclude assessment of the clinical utility of mechanical pacing.The overall goals of my project are (i) to understand mechanisms of mechanically-induced excitation, (ii) to explain loss and recovery of capture, and (iii) to identify mechanical, electrical, and pharmacological modulators of these phenomena, to potentially enable sustainable mechanical pacing of the heart. To address these goals I will perform rabbit whole-heart optical mapping of both membrane voltage and local shortening. I will examine maximal mechanical pacing rates in the acutely asystolic heart and assess potential modulators of sustainability, to provide a thorough scientific foundation for the assessment of the utility of serial PT in the emergency setting of primary asystole. These experiments will be done in conjunction with the development of computational models to integrate data, steer wet-lab research, and project towards potential clinical relevance.

• DFG Programme: Research Grants
• International Connection: Canada, New Zealand
• Cooperation Partners: Amir HajiRassouliha, Ph.D.; Professor T Alexander Quinn, Ph.D.