Molecular Mechanisms of HFpEF-associated Atrial Fibrillation

HFpEF 相关心房颤动的分子机制

基本信息

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
项目类别：
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

项目摘要

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

项目概要据说，射血分数保留的心力衰竭（HFpEF）是目前未满足的最大需求。心血管医学。 HFpEF 患者特别容易发生心房颤动 (AF)，这是一种常见的疾病节律紊乱与较差的临床结果相关。换句话说，AF 和 HFpEF 共分离，严重加剧彼此，并代表一种普遍且独特的临床挑战，而没有有效的疗法。代谢性疾病，如肥胖、糖尿病和高血压，是 HFpEF 的常见合并症和 AF，表明代谢紊乱是这两种情况的共同机制。我们最近开发并验证了一种信息独特的 HFpEF 小鼠模型，并公布了以前在心脏病中从未报道过的机制。这些动物容易发生房颤，就像 HFpEF 患者。此外，我们收集的初步数据表明 AMPK 信号传导在这些小鼠的心房发生变化，并且与心房重塑相关，类似于在 HFpEF 患者中观察到的变化。如果得到证实，这是疾病引发的房颤的一种新机制，不涉及组织纤维化等。在这里，我们建议测试以下中心假设：AMPK 信号传导受损会导致病理性的 HFpEF 中的心房重塑，调节该通路将减轻 HFpEF 中的心房病理学和 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塑中的作用，专注于心房肌细胞肥大、Cx40介导的心房肌细胞通讯和HCN4介导的异位自动性。在转化目标中，我们将确定 AMPK 激活对心房衰减的影响重塑和房颤倾向