Molecular Mechanisms of HFpEF-associated Atrial Fibrillation

HFpEF 相关心房颤动的分子机制

• 批准号: 10097363
• 负责人: THOMAS G GILLETTE
• 金额: $ 40.92万
• 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/10097363
• 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; Structure; 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