A New Pacing Approach for Cardiac Conditioning and Enhanced Cardioprotection - Significant advances in prevention and mitigation of cardiovascular disease have been made, but related morbidity and mortality remain high. Cardiac conditioning is a therapeutic approach to induce endogenous protective adaptive responses in the heart for counteracting myocardial loss. Identification of new, widely applicable, practical, and effective strategies to induce cardiac conditioning continue to be a priority. Exercise is one of the most powerful modifiers of cardiovascular risk, with proven benefits for both healthy and diseased hearts. One key component of exercise is episodic heart rate (HR) acceleration interspersed with periods of rest. The degree and pattern of HR acceleration informs the benefit of physical activity, with a HR increase to 75-85% maximum predicted by age, for 75-150 min/wk, divided over 3-5 d/wk, being a typical recommendation for promoting cardiovascular conditioning. Conversely, an impaired HR response to exercise is associated with adverse clinical outcomes in healthy adults and those with heart disease. Furthermore, our recently published findings indicate that an episodic exercise-similar envelope of HR acceleration can serve as a trigger for myocardial conditioning and ischemic stress resistance. Specifically, in mice sham intervention was compared to exercise-similar episodic HR acceleration, delivered by an atrial pacing protocol with preserved atrioventricular and interventricular synchrony. The episodic exercise-similar pacing envelope improved myocardial ischemic stress tolerance with an effect size similar to that afforded by treadmill exercise or ischemic preconditioning. Hearts from paced mice displayed changes in Ca2+ handling, coupled with changes in transcriptional and posttranslational remodeling associated with a cardioprotective paradigm. In human subjects with already-implanted pacing devices for treatment cardiomyopathies with chronic, medically refractory systolic heart failure, and left ventricular ejection fraction (EF) <=35%, the exercise-similar pacing pattern, delivered through manual programming, was hemodynamically and symptomatically well- tolerated. Furthermore, preliminary results in subjects who underwent pacing intervention 3 days/week over 4 weeks indicate increased 6-min walk distance, as well as trend towards improved EF, vs. sham intervention. Building on these data, the proposed project will further delineate the mechanisms for myocardial conditioning promoted by the exercise HR envelope using two synergistic but independent approaches: 1) Study of wildtype and genetic mouse models to probe, dissect and validate molecular mechanisms underlying cardioprotection driven by an exercise HR pattern, and 2) Leveraging the compatibility of the proposed intervention with existing clinical pacing platforms to establish a mechanistic link between exercise’s HR pattern and cardiac conditioning in human subjects with cardiomyopathies. If successful, the results will lay the groundwork for expanded use of existing pacing hardware as a novel treatment to improve functional status and quality of life, reduce the risk of cardiovascular events, and promote engagement in physical activities.
