Molecular Mechanisms of HFpEF-associated Atrial Fibrillation

HFpEF 相关心房颤动的分子机制

• 批准号: 10322371
• 负责人: THOMAS G GILLETTE
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322371
• 关键词: Adenosine Monophosphate; Alpha Rhythm; Animals; Arrhythmia; Atrial Fibrillation; Atrial Function; Attenuated; Cardiac Myocytes; Cardiovascular system; Cells; Clinical; Communication; Coupling; Data; Diabetes Mellitus; Disease; Doxycycline; EFRAC; Exercise; FRAP1 gene; Failure; Fibrosis; Functional disorder; Generations; Genetic; HCN4 gene; Health Expenditures; Heart; Heart Atrium; Heart Diseases; Heart failure; Homeostasis; Human; Hypertension; Hypertrophy; Imaging Techniques; Impairment; In Vitro; MLLT2 gene; Mediating; Medicine; Metabolic; Metabolic Diseases; Metformin; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Nodal; Obesity; Outcome; Pacemakers; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmacology; Physiological; Play; Predisposition; Prevalence; Protein Kinase; Regulatory Pathway; Reporting; Role; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Tissues; Transgenic Organisms; clinical translation; comorbidity; connexin 40; cyclic-nucleotide gated ion channels; effective therapy; in vivo; ivabradine; loss of function; mortality; mouse model; novel; pre-clinical; preservation; ventricular hypertrophy

PROJECT SUMMARY It is said that heart failure with preserved ejection fraction (HFpEF) is the single greatest unmet need in cardiovascular medicine. Patients with HFpEF are uniquely predisposed to atrial fibrillation (AF), a common rhythm disturbance that is associated with worse clinical outcomes. In other words, AF and HFpEF co-segregate, substantially exacerbate one another, and represent a prevalent and unique clinical challenge without effective therapies. Metabolic diseases, such as obesity, diabetes, and hypertension, are common comorbidities for both HFpEF and AF, suggesting that metabolic disturbance serves as a common mechanism underlying both conditions. We recently developed and validated a uniquely informative murine model of HFpEF and unveiled mechanisms never reported previously in heart disease. These animals are predisposed to AF, just as are patients with HFpEF. Further, we have collected preliminary data revealing that AMPK signaling is impaired in the atria of these mice and is associated with atrial remodeling similar to changes observed in HFpEF patients. If confirmed, this is a novel mechanism of disease-triggered AF, one that does not involve tissue fibrosis, etc. Here, we propose to test the central hypothesis that impaired AMPK signaling contributes to pathological atrial remodeling in HFpEF, and modulating this pathway will attenuate atrial pathology and AF predisposition in HFpEF. Specifically, we will delineate the role of AMPK in HFpEF-associated atrial structural and electrical remodeling, focusing on atrial myocyte hypertrophy, Cx40-mediated atrial myocyte communication, and HCN4-mediated ectopic automaticity. In a translational aim, we will determine the effect of AMPK activation on attenuating atrial remodeling and AF predisposition

项目总结 据说，心力衰竭伴保留射血分数(HFpEF)是 心血管医学。HFpEF患者特别容易发生心房颤动(AF)，这是一种常见的 节律紊乱与较差的临床结果相关。换句话说，AF和HFpEF是共同隔离的， 实质上相互加剧，并代表了一种普遍和独特的临床挑战，但没有有效的 治疗。 代谢性疾病，如肥胖、糖尿病和高血压，是两种HFpEF常见的并存疾病 和房颤，这表明代谢紊乱是这两种疾病的共同机制。 我们最近开发并验证了一种独特的信息丰富的HFpEF小鼠模型，并公布了 以前从未报道过心脏病的机制。这些动物容易患房颤，就像他们一样 HFpEF组2例。此外，我们收集的初步数据显示，AMPK信号在 与HFpEF患者中观察到的变化类似，这些小鼠的心房与心房重构有关。 如果得到证实，这是一种新的疾病触发的房颤机制，不涉及组织纤维化等。 在这里，我们建议检验AMPK信号受损导致病理改变这一中心假设 HFpEF的心房重构，调节这一通路将减轻心房病理和房颤易感性。 HFpEF。 具体来说，我们将描述AMPK在HFpEF相关的心房结构和电重构中的作用， 关注心房肌细胞肥大、Cx40介导的心房肌细胞通讯和HCN4介导的 超乎寻常的自动性。在翻译的目的中，我们将确定AMPK激活在减弱心房中的作用 房颤易感性与重构