Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States.
Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States.
Am J Physiol Heart Circ Physiol. 2023 Aug 1;325(2):H203-H231. doi: 10.1152/ajpheart.00038.2023. Epub 2023 May 19.
Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction in which patients develop symptoms of HF as a result of high left ventricular (LV) diastolic pressure in the context of normal or near normal LV ejection fraction (LVEF; ≥50%). Challenges to create and reproduce a robust rodent phenotype that recapitulates the multiple comorbidities that exist in this syndrome explain the presence of various animal models that fail to satisfy all the criteria of HFpEF. Using a continuous infusion of angiotensin II and phenylephrine (ANG II/PE), we demonstrate a strong HFpEF phenotype satisfying major clinically relevant manifestations and criteria of this pathology, including exercise intolerance, pulmonary edema, concentric myocardial hypertrophy, diastolic dysfunction, histological signs of microvascular impairment, and fibrosis. Conventional echocardiographic analysis of diastolic dysfunction identified early stages of HFpEF development and speckle tracking echocardiography analysis including the left atrium (LA) identified strain abnormalities indicative of contraction-relaxation cycle impairment. Diastolic dysfunction was validated by retrograde cardiac catheterization and analysis of LV end-diastolic pressure (LVEDP). Among mice that developed HFpEF, two major subgroups were identified with predominantly perivascular fibrosis and interstitial myocardial fibrosis. In addition to major phenotypic criteria of HFpEF that were evident at early stages of this model (3 and 10 days), accompanying RNAseq data demonstrate activation of pathways associated with myocardial metabolic changes, inflammation, activation of extracellular matrix (ECM) deposition, microvascular rarefaction, and pressure- and volume-related myocardial stress. Heart failure with preserved ejection fraction (HFpEF) is an emerging epidemic affecting up to half of patients with heart failure. Here we used a chronic angiotensin II/phenylephrine (ANG II/PE) infusion model and instituted an updated algorithm for HFpEF assessment. Given the simplicity in generating this model, it may become a useful tool for investigating pathogenic mechanisms, identification of diagnostic markers, and for drug discovery aimed at both prevention and treatment of HFpEF.
心力衰竭（HF）是发病率和死亡率的主要原因，尤其是在老年人和患有多种代谢合并症的患者中。射血分数保留的心力衰竭（HFpEF）是一种多系统器官功能障碍的临床综合征，患者由于左心室（LV）舒张末期压力升高而出现心力衰竭症状，但左心室射血分数（LVEF；≥50%）正常或接近正常。由于难以创建和再现该综合征中存在的多种合并症的稳健啮齿动物表型，因此存在各种无法满足 HFpEF 所有标准的动物模型。我们使用血管紧张素 II 和苯肾上腺素（ANG II/PE）的连续输注，证明了一种强烈的 HFpEF 表型，满足该病理学的主要临床相关表现和标准，包括运动不耐受、肺水肿、向心性心肌肥厚、舒张功能障碍、微血管损伤和纤维化的组织学迹象。舒张功能障碍的常规超声心动图分析确定了 HFpEF 发展的早期阶段，斑点追踪超声心动图分析（包括左心房（LA））确定了收缩-松弛周期障碍的应变异常。通过逆行心导管插入术和左心室舒张末期压力（LVEDP）分析验证舒张功能障碍。在发展为 HFpEF 的小鼠中，确定了两个主要亚组，主要表现为血管周围纤维化和间质心肌纤维化。除了该模型早期（3 天和 10 天）明显的 HFpEF 主要表型标准外，伴随的 RNAseq 数据还表明与心肌代谢变化、炎症、细胞外基质（ECM）沉积激活、微血管稀疏以及压力和容积相关的心肌应激相关的途径被激活。射血分数保留的心力衰竭（HFpEF）是一种新兴的流行疾病，影响多达一半的心力衰竭患者。在这里，我们使用了慢性血管紧张素 II/苯肾上腺素（ANG II/PE）输注模型，并制定了 HFpEF 评估的更新算法。鉴于生成这种模型的简单性，它可能成为研究发病机制、确定诊断标志物以及发现旨在预防和治疗 HFpEF 的药物的有用工具。
