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We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (G\u03b1s) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of G\u03b1s in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity.<\/jats:p>","DOI":"10.1093\/function\/zqac055","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T12:18:10Z","timestamp":1667305090000},"source":"Crossref","is-referenced-by-count":1,"title":["Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy"],"prefix":"10.1152","volume":"4","author":[{"given":"Sonia","family":"Sebastian","sequence":"first","affiliation":[{"name":"William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , Charterhouse Square , London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee S","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases\/National Institutes of Health , Building 10, Room 8C101 , 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