Molecular Mechanisms of HFpEF-associated Atrial Fibrillation

HFpEF 相关心房颤动的分子机制

• 批准号: 10545081
• 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/10545081
• 关键词: Adenosine Monophosphate; Animals; Arrhythmia; Atrial Fibrillation; Atrial Function; Attenuated; Cardiac Myocytes; Cardiovascular system; Cells; Clinical; Communication; Coupling; Data; Diabetes Mellitus; Disease; Doxycycline; EFRAC; Exercise; FRAP1 gene; Fibrosis; Functional disorder; Generations; Genes; Genetic; 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; 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; gain of function; in vivo; ivabradine; loss of function; mTOR inhibition; mortality; mouse model; novel; pharmacologic; pre-clinical; preservation; segregation; 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

项目摘要 据称，射血分数保留的心力衰竭（HFpEF）是心力衰竭患者中最大的未满足需求。 心血管内科HFpEF患者特别容易发生房颤（AF），这是一种常见的 心律紊乱与更差的临床结局相关。换句话说，AF和HFpEF共分离， 基本上使彼此恶化，并代表了普遍和独特的临床挑战， 治疗 代谢性疾病，如肥胖、糖尿病和高血压，是HFpEF和HFpEF的常见合并症。 和AF，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HFpEF小鼠模型， 以前从未报道过心脏病的机制。这些动物易患房颤， HFpEF患者。此外，我们收集的初步数据显示，AMPK信号转导受损， 这些小鼠的心房，并与心房重构类似的HFpEF患者中观察到的变化。 如果得到证实，这是一种新的疾病触发的AF机制，不涉及组织纤维化等。 在这里，我们提出测试的核心假设，受损的AMPK信号有助于病理性 HFpEF中的心房重构，调节该通路将减轻HFpEF中的心房病理和AF易感性。 HFpEF。 具体来说，我们将描述AMPK在HFpEF相关心房结构和电重构中的作用， 聚焦于心房肌细胞肥大、Cx40介导的心房肌细胞通讯和HCN 4介导的 异位自律性在平移目标中，我们将确定AMPK激活对衰减心房的影响 重构和AF易感性