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

心肌脂肪变性所致左心室功能障碍的性别差异机制及调节

• 批准号: 10092208
• 负责人: Michael Douglas Nelson
• 金额: $ 67.31万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092208
• 关键词: Acute; Address; Age; Anti-Inflammatory Agents; Back; Cardiac; Cardiac Myocytes; Cardiovascular system; Cessation of life; Clinical; Controlled Environment; Coronary Arteriosclerosis; Cross-Sectional Studies; Data; Dehydration; Diabetes Mellitus; Diagnosis; Epidemic; Equipment; Estrogens; Evaluation; Exercise; Experimental Models; Exposure to; Familial generalized lipodystrophy; Fasting; Fatty Acids; Fatty acid glycerol esters; Female; Functional disorder; Gold; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; HIV; Heart; Heart Diseases; Heart failure; Hormone Antagonists; Hour; Human; Hypertension; Individual; Inflammatory; Influentials; Injury; Intervention; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Lipids; Lipodystrophy; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolism; Methods; Modeling; Myocardial; Myocardial dysfunction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Ovarian; Ovarian Ablation; Patients; Physiological; Placebos; Plasma; Premenopause; Prevalence; Randomized; Reproducibility; Research; Rest; Risk; Risk Factors; Rodent; Rodent Model; Role; Sex Differences; Signal Transduction; Stress; Testing; Time; Tissues; Translating; Triglycerides; United States National Institutes of Health; Ventricular; Visit; Water; Woman; Work; base; cardiovascular disorder risk; comorbidity; diabetic; disorder risk; food restriction; heart function; human subject; impaired glucose tolerance; innovation; insight; lipid metabolism; lipidomics; male; men; novel; pre-clinical; prevent; protective effect; sex; sexual dimorphism; theories; western diet

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.

心肌脂肪变性的性别差异及其调控机制 功能障碍 肥胖在世界范围内已达到流行病的程度，并导致2型糖尿病患病率的平行上升。 糖尿病（T2 D），以及心血管疾病和死亡的相关风险。对心脏的风险 肥胖的失败比传统的风险因素如高血压和 冠状动脉疾病改变的底物代谢被认为是重要的贡献功能障碍， 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 明白一个越来越流行的理论涉及脂质过度储存（称为脂肪变性）和脂毒性损伤， 心肌细胞这些数据几乎完全是使用临床前啮齿动物模型得出的， 人类的转化研究还远远不够发达。尝试将这项工作转化为人类受试者， 仅限于患者组与各种潜在合并症的相关性。为了解决这一重大问题， 限制，我们提出了一种新的和创新的食物限制模型，可重复地导致一个短暂的， 在年轻健康个体中心肌甘油三酯含量的生理性增加。该实验 该方法将提供最可控的环境来测试心肌脂肪变性是否与心脏病直接相关。 功能障碍-独立于潜在的合并症。我们的初步数据表明，当暴露于 急性脂质过度储存，男性-而不是绝经前女性-发展LV舒张功能障碍。基于此 观察我们将：1）测试心脏脂肪变性引起的左心室功能障碍是性的假设， 通过比较急性禁食前后年龄匹配的男性和绝经前女性， 干预2)通过以下方法检验雌激素对心脏脂肪变性诱导的功能障碍具有保护作用的假设： 用GnRH拮抗剂抑制卵巢性激素，并重复禁食研究， 雌激素回加3)检测血浆和心肌脂肪酸组成是否具有性别二态性， 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功能的影响的重要机制 在其他健康的年轻人类受试者中发挥作用。研究结果也有望解决NIH的任务 关注性别对疾病风险的影响。总之，这些新颖和创新的研究将有助于 改变范式的诊断和治疗方法，以减少肥胖症患者的心脏病负担， 糖尿病