Effects of recapitulating respiratory sinus arrhythmia by dynamic pacing with phasically varying cycle length on susceptibility to cardiac arrhythmia

The normal heartbeat is an electrical event that triggers contraction of heart muscle through a process involving calcium ions. Although regular, the heartbeat is not constant like a metronome. Rather, in health, the heart rate waxes and wanes in time with breathing. The healthy heart speeds up slightly with inhalation and slows down slightly with exhalation. Although the functional advantage of the cyclic variation in heart rate with breathing rhythm is unclear, it has been suggested that it may occur to promote heart pumping efficiency and may have a stabilising effect on the heart rhythm. The effect is present at birth, is common in athletes and its loss strongly predicts the risk of cardiac arrest and death. However, it is not known whether the loss of variation of heart rate makes cardiac arrest more likely. Cardiac arrest is thought to be caused by a major disturbance to the usual regular heartbeat, often a period of very rapid, erratic beating called fibrillation. The mechanisms of fibrillation are not fully understood but involve abnormal recovery of the heartbeat in preparation for the next heartbeat. This project will examine the hypothesis that imposing regular variation in the heart rate prevents the processes that initiate fibrillation. The research uses techniques and expertise established at the University of Bristol, involving a team of scientists, surgeons and arrhythmia doctors and will involve recordings of electrical activity and of changes in calcium ions in single isolated heart muscle cells. Experiments will also be conducted to make electrical recordings from isolated, perfused-hearts to establish whether the effects of varying heart rate in single cells also reduce risk of fibrillation in intact, whole hearts. If the hypothesis is correct, the information from this study is likely to be highly valuable to the development of artificial pacemaker devices that restore regular variation in heart rate to reduce risk of death in patients. A significant proportion of patients with heart failure undergo pacemaker implantation. These improvements in understanding could potentially, with subtle changes to pacemaker programming, improve quality of life and reduce sudden death for patients living with heart failure, a major health burden. In addition we hope to improve our understanding of these dangerous heart rhythms and potentially open up other novel treatment strategies.

Respiratory sinus arrhythmia (RSA) is a naturally occurring periodic oscillation in heart rate in phase with the respiratory cycle that is prominent in athletes and neonates and is lost with age and cardiovascular disease. RSA represents the respiratory frequency component of heart rate variability, and its loss is a strong prognostic indicator of cardiovascular mortality, including sudden cardiac death, in patients. However, it is not known whether the loss of RSA increases propensity to arrhythmia. Oscillating bidirectional interaction between membrane potential and intracellular [Ca2+] has been causally linked with cardiac alternans, beat-to-beat variability of repolarisation (BVR) and the genesis of arrhythmias. It is well established that the action potential (AP) and Ca2+ transient (CaT) depend critically on cycle length (the reciprocal of heart rate) and that changes in pacing protocol alter responses of the AP and CaT to step changes in cycle length, known as short-term cardiac memory. Computer simulations indicate that imposing variation in pacing cycle length reduces the propensity to alternans, BVR and arrhythmia. This project examines the hypothesis that mimicking RSA through dynamic pacing with phasic variation of cycle length modifies coupling between the AP and CaT, producing short-term cardiac memory, and is protective against arrhythmia. The proposed research involves recordings of APs, membrane currents, CaT, SR Ca content and sarcomere shortening from isolated single cells using whole-cell patch clamp and fluorescence recording techniques. The effects of dynamic pacing on the electrophysiology and susceptibility to arrhythmia of Langendorff-perfused whole hearts will also be examined.

The immediate potential beneficiaries from this research are the applicant and academic peers (basic and clinical scientists). In addition to establishing whether dynamic pacing with phasically varying cycle length has the potential to reduce risk of arrhythmia, the key objective of the proposed programme of research is for the named fellow to acquire research skills and obtain a PhD. The development and training of the applicant as a clinical academic will thereby have impact on UK clinical research in the long term, particularly in his own specialty of cardiology. Moreover, the applicant will contribute to the development of cardiac electrophysiology and patient care as he practises within cardiology throughout his future career.
The University of Bristol, the Bristol Heart Institute and the School of Physiology, Pharmacology & Neuroscience contribute to improving the public's awareness of the benefits of basic science and clinical research. If the research is relevant and appropriate, it will be disseminated to the public through outreach activities, including in local schools. The applicant will contribute to the teaching of undergraduate students at the University of Bristol and so the skills, research data, and personal attributes acquired through this fellowship will benefit this activity.
In addition to the fellow, this research is expected to benefit basic and clinical scientists in the University of Bristol working in the field of cardiac electrophysiology and arrhythmias. Since the supervisors and their teams have national and international links, there will be interaction and benefits to all teams. The proposed project forms part of a larger body of work being undertaken by basic scientists (Julian Paton, Jules Hancox, Andrew James) and clinicians (Ed Duncan, Angus Nightingale, Eva Sammut, Raimondo Ascione) at the University of Bristol examining the potential therapeutic benefit of the re-establishment of respiratory sinus arrhythmia-like phasic variation in cycle length. Thus, the data obtained from this work will provide important information for the development of novel pacing paradigms for use with implantable pacemaker devices. Future steps will involve translationally relevant models of heart disease and arrhythmia (e.g. pigs). In this respect, the large animal research facility in Bristol known as The GLP Translational Biomedical Research Centre (TBRC), co-funded by the MRC (MR/L012723/1), the BHF (IG/14/2/30991) and the University of Bristol, will represent a suitable venue for such work.
In the long term, we expect this research to benefit cardiologists, cardiac surgeons, and basic scientists with interests in cardiac electrophysiology and the development of therapies for the treatment of heart failure and arrhythmic risk who would gain from a better understanding of cardiovascular medicine and the underlying fundamental biology. Ultimately, we hope that this research will be of direct relevance and significant benefit to patients who are recipients of implanted pacemaker devices and at risk of potentially lethal ventricular tachyarrhythmias. Improved understanding of the role of heart rate variability and sudden death may enhance development of prediction algorithms to identify those most at risk of sudden cardiac death to target therapies and reduce preventable death. The ultimate clinical outcome would be an improvement in cardiac function and risk of arrhythmia, and reduction in morbidity, mortality, and the need for on-going cardiovascular support. This could potentially offer a ground-breaking paradigm shift for heart failure device therapy in a patient group who continue to suffer with a very poor prognostic outlook.