Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction

心肌脂肪变性所致左心室性别差异的机制及调控 功能障碍 肥胖症已经在世界范围内达到流行的程度，并导致2型肥胖症的患病率同步上升。 糖尿病(T2D)，以及相关的心血管疾病和死亡风险。心脏的风险 肥胖的失败超过了传统的危险因素，如高血压和 冠状动脉疾病。底物代谢的改变被认为是导致心脏功能障碍的重要原因。 肥胖和糖尿病心脏；然而，导致功能障碍的确切机制仍不完全 明白了。一种越来越流行的理论涉及脂肪过度储存(称为脂肪变性)和脂毒性损伤 心肌细胞。然而，这些数据几乎完全是使用临床前啮齿动物模型得出的， 翻译人类研究远远落后于此。将这项工作翻译成人类受试者的尝试已经 仅限于与各种潜在共病的患者组之间的相关性。要解决这一重大问题 我们提出了一种新的、创新的食物限制模型，该模型可重现地引起瞬时的、 年轻健康个体心肌甘油三酯含量的生理性增加。这项实验 方法将提供最受控制的环境来测试心肌脂肪变性是否与心脏 功能障碍--与潜在的共病无关。我们的初步数据表明，当暴露在 急性脂类过度储存，男性--而不是绝经前的女性--会发展成左室舒张功能障碍。在此基础上 观察我们将：1)检验心脏脂肪变性导致左心功能不全与性有关的假设 通过比较年龄匹配的男性和绝经前女性在急性禁食前后的情况，发现这是一种二相性 干预。2)测试雌激素对心脏脂肪变性引起的功能障碍具有保护作用的假设，通过 用促性腺激素释放激素拮抗剂抑制卵巢性激素并重复禁食研究 补充雌激素。3)测试血浆和心肌脂肪酸组成是否具有性别二型性，通过 进行全面的血浆和心肌脂质组学评估。结果将提供新的和 心肌脂肪变性的独立作用及其对心脏的影响的重要机制见解 在其他健康的年轻人类受试者中发挥作用。结果还承诺解决国家卫生研究院的任务 关注性别对疾病风险的影响。总而言之，这些新颖和创新的研究将促进 改变诊断和治疗模式的方法，以减轻肥胖和心脏病的负担 糖尿病。

Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction Obesity has reached epidemic proportions world-wide, and has led to a parallel rise in the prevalence of type 2 diabetes mellitus (T2D), together with an associated risk of cardiovascular disease and death. The risk for heart failure in obesity is greater than can be accounted for by traditional risk factors such as hypertension and coronary artery disease. Altered substrate metabolism is thought to contribute importantly to dysfunction of the obese and diabetic heart; however, the exact mechanism leading to dysfunction remains incompletely understood. One increasingly popular theory involves lipid overstorage (termed steatosis) and lipotoxic injury to cardiomyocytes. These data have been derived almost entirely using pre-clinical rodent models however, with translational human research being far less developed. Attempts to translate this work to human subjects have been limited to correlations in patient groups with various underlying co-morbidities. To address this major limitation, we propose a novel and innovative food restriction model, which reproducibly causes a transient, physiological increase in myocardial triglyceride content in young healthy individuals. This experimental approach will provide the most controlled environment to test if myocardial steatosis is directly related to cardiac dysfunction—independent of underlying co-morbidities. Our preliminary data suggest that when exposed to acute lipid overstorage, men—but not premenopausal women— develop LV diastolic dysfunction. Based on this observation we will: 1) Test the hypothesis that cardiac steatosis induced left ventricular dysfunction is sexually dimorphic, by comparing age-matched men and premenopausal women before and after an acute fasting intervention. 2) Test the hypothesis that estrogen is protective against cardiac steatosis-induced dysfunction, by suppressing ovarian sex hormones with a GnRH antagonist and repeating the fasting studies with and without estrogen add-back. 3) Test whether plasma and myocardial fatty acid composition is sexually dimorphic, by performing comprehensive plasma and myocardial lipidomics assessment. The results will provide new and important mechanistic insight into the independent role of myocardial steatosis and its influence on cardiac function in otherwise healthy young human subjects. The results also promise to address the NIH mandate focusing on the influence of sex on disease risk. Taken together, these novel and innovative studies will facilitate paradigm-changing diagnosis and treatment approaches to reduce the burden of heart disease in obesity and diabetes.