Can exercise training prevent or reduce myocardial infarction induced arrhythmias?

Cardiovascular disease (CVD) is the largest cause of death worldwide. Commonly, CVD is a consequence of myocardial infarction (MI) associated heart failure (HF). Post-MI, many patients die of cardiac arrhythmias. MI increases the risk of arrhythmias in the myocardium as well as arrhythmias caused by dysfunction of the cardiac conduction system (CCS). Despite advancement in our understanding of how electrophysiological changes in MI-induced HF predispose to arrhythmias, the precise link between mechanical dysfunction and arrhythmias needs further investigation. Effective treatment and prevention strategies depend on a better understanding of cellular and molecular mechanisms responsible for cardiac arrhythmias. Exercise training has shown great promise in improving the prognosis and quality of life for HF patients. Our group has shown that exercise training can reverse detrimental effects of MI in the working myocardium. Whether the beneficial effects of exercise extends to MI induced arrhythmogenic electrical remodelling remains unclear. Here we propose to investigate the mechanisms via which exercise training reverses arrhythmogenic remodelling of myocardium and the CCS following MI-induced HF. We will use a model of exercise training in rats with MI-induced HF, various electrophysiological and molecular biology methods. We expect that the study will reveal translationally relevant molecular targets and further opportunities to fully understand the effects of exercise training in preventing or reducing lethal arrhythmias in HF patients with MI. We have studied arrhythmogenic response to electrical stimulation in vivo and in isolated heart in both trained and untrained MI hearts. In addition we have studied the incidence of ventricular fibrillation in both groups (compared to control). Results show that MI sedentary rats were significantly more prone to arrhythmias compared to sham and MI exercise trained. The exercise intervention partly restored the electrical status of the MI group. Gene sequencing on healthy animals and trained animals with and without a MI shows that some genes are differently expressed when comparing groups. The findings will be linked to electrophysiological findings. Calcium leak from ryanodine receptor in heart cells is a major cause of arrhythmias in HF. Moore laboratory at University of British Colombia are interested in the mechanisms that regulate the ryanodine receptors? open probability and in their pathological changes leading to diastolic calcium leak. As a visiting post doc at UBC (2017-2018)I have investigated, using super-resolution microscopy, how ryanodine receptors move in response to stimuli such as phosphorylation. We hypothesise that movement of ryanodine receptor may provide a mechanism of changing the open probabilities. An abstract of preliminary data have been presented in biophysical journal 2020, https://doi.org/10.1016/j.bpj.2019.11.697.

- Økt kompetanse om gunstige effekteter av trening etter hjerteinfarkt - Bidrag til å avklaring om høyintensistetstrening kan redusere risiko for arytmier etter hjerteinfarkt - det er første gang man har kunnet gjøre programmert electrisk stimulering først in vivo hvor eksperimenter utføres under fysiologiske forhold, for så å utføre samme protokoll på isolert hjerte (langendorf-perfusjon) under kontrollerte forhold, ex vivo - Et bidrag til å avklaring om høyintensistetstrening kan redusere insidens av arytmier etter hjerteinfark - Videreutviklet gode samarbeid med ulike fagmiljø. - Resultater er relevant for pågående klinisk studie på fysisk aktivitet og arytmi - Resultater vil være viktig for å utarbeide nye hypoteser og starte nye prosjekter innefor trening og rytmeforstyrrelser

Cardiovascular disease (CVD), which is the single largest cause of death worldwide, is commonly associated with myocardial infarction (MI). ~10-15% of the survivors die within one year of the MI as a result of a cardiac arrhythmia. It is well known that exercise training can improve the prognosis and quality of life for heart failure patients, however if or how exercise training prevent or reduce myocardial infarction induced arrhythmias are not well explored. Much research has focused on understanding the electrophysiology and molecular mechanisms behind arrhythmias in cardiac disease, however if exercise training reverses the arrhythmogenic remodelling in the heart is currently not well explored. Using a MI rat model of exercise training we will through various electrophysiological methods, qPCR, Western blot, immunohistochemistry and next generation sequencing investigate the upstream determinants of training-induced remodelling and identify novel pathways that could prevent or reduce MI infarction induced arrhythmias. We will study exercise induced remodelling in both working myocardium as well as remodelling in the cardiac conduction system of MI hearts.