Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy.
Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy.
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DOI：
10.1093/function/zqac055
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发表时间：
2023
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我们旨在确定心率（HR）减慢对心功能的病理生理影响。我们最近开发了一种小鼠模型，在该模型中，使用cre-loxP技术在加入他莫昔芬后，可以有条件地删除窦房结（SA）中的刺激性异源三聚体G蛋白（Gαs）。添加他莫昔芬导致心动过缓。我们使用这种方法来检查HR减慢的生理和病理生理效应。我们首先通过让老鼠在跑步机上跑步来观察对运动表现的影响。在添加他莫昔芬后，SA结中Gαs条件性缺失的小鼠以较慢的速度跑了较短的距离。同窝对照组在他莫昔芬后保持了运动能力。多巴酚丁胺超声心动图负荷试验也得到了与突变体心脏容量受损一致的结果。然后，我们使用两种模型检查HR降低是否影响病理性心脏肥大：心肌梗死的左前降支冠状动脉结扎和高血压性心脏病的腹主动脉缩窄。在同窝对照组中，两种程序均导致心脏肥大。然而，在手术干预前诱导HR降低显著改善了肥大。为了评估潜在的蛋白激酶途径，可能会被激活的左心室相对心动过缓，我们使用了磷酸抗体阵列，这表明选择性激活磷酸肌醇-3激酶。总之，HR降低可防止病理性心脏肥大，但限制了生理性运动能力。
We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gαs) 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 Gαs 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.
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