BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. METHOD We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. RESULTS In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. CONCLUSIONS These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

中文翻译：

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胰高血糖素受体拮抗剂治疗具有保留射血分数的心力衰竭。


背景技术射血分数保留的心力衰竭（HFpEF）是一种新兴的主要未满足需求，也是心脏病学中最重大的临床挑战之一。 HFpEF 的发病机制与多种危险因素有关。高血压和与肥胖相关的代谢紊乱是 HFpEF 患者中观察到的两种最突出的合并症。尽管高血压引起的机械超负荷长期以来被认为是导致射血分数降低的心力衰竭的一个重要因素，但机械超负荷与代谢紊乱在 HFpEF 发病机制中的协同相互作用仍知之甚少。方法 我们通过对瘦 C57Bl/6J 或肥胖/糖尿病 B6.Cg-Lepob/J (ob/ob) 小鼠应用横向主动脉缩窄，然后对单- 核 RNA 测序和排名靠前的信号通路的靶向操作在 2 个实验组中受到不同程度的影响。结果 与主动脉横缩后 C57Bl/6J 瘦小鼠相比，横主动脉缩窄后的 ob/ob 小鼠表现出射血分数随时间降低的心力衰竭病理特征，但射血分数没有显着变化，但出现了特征性的射血分数变化。 HFpEF 的病理特征包括舒张功能障碍、心脏肥大恶化和病理重塑，以及运动不耐受的进一步恶化。单核RNA-seq分析显示，受到压力超负荷和肥胖/糖尿病双重压力的心肌细胞中存在显着的转录组重编程，这与仅受到压力超负荷或肥胖/糖尿病压力的心肌细胞明显不同。 此外，胰高血糖素信号传导被确定为与 HFpEF 相关的心肌细胞中受影响的首要信号传导途径。在 2 个独立的临床前模型中，胰高血糖素受体拮抗剂治疗显着改善了 HFpEF 相关病理特征的进展。重要的是，心肌细胞特异性的胰高血糖素受体基因缺失也显着改善了心脏功能，以应对压力超负荷和代谢应激。结论 这些发现确定心肌细胞中的胰高血糖素受体信号传导是 HFpEF 进展的关键决定因素，并为胰高血糖素受体拮抗剂作为该疾病的潜在疗法提供了概念验证支持。