Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Am J Physiol Heart Circ Physiol. 2022 Oct 1;323(4):H797-H817. doi: 10.1152/ajpheart.00374.2022. Epub 2022 Sep 2.
Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF). HFpEF is more prevalent in females compared with males, but the underlying mechanisms are unknown. We previously showed that pressure overload (PO) in male felines induces a cardiopulmonary phenotype with essential features of human HFpEF. The goal of this study was to determine if slow progressive PO induces distinct cardiopulmonary phenotypes in females and males in the absence of other pathological stressors. Female and male felines underwent aortic constriction (banding) or sham surgery after baseline echocardiography, pulmonary function testing, and blood sampling. These assessments were repeated at 2 and 4 mo postsurgery to document the effects of slow progressive pressure overload. At 4 mo, invasive hemodynamic studies were also performed. Left ventricle (LV) tissue was collected for histology, myofibril mechanics, extracellular matrix (ECM) mass spectrometry, and single-nucleus RNA sequencing (snRNAseq). The induced pressure overload (PO) was not different between sexes. PO also induced comparable changes in LV wall thickness and myocyte cross-sectional area in both sexes. Both sexes had preserved ejection fraction, but males had a slightly more robust phenotype in hemodynamic and pulmonary parameters. There was no difference in LV fibrosis and ECM composition between banded male and female animals. LV snRNAseq revealed changes in gene programs of individual cell types unique to males and females after PO. Based on these results, both sexes develop cardiopulmonary dysfunction but the phenotype is somewhat less advanced in females. We performed a comprehensive assessment to evaluate the effects of slow progressive pressure overload on cardiopulmonary function in a large animal model of heart failure with preserved ejection fraction (HFpEF) in males and females. Functional and structural assessments were performed at the organ, tissue, cellular, protein, and transcriptional levels. This is the first study to compare snRNAseq and ECM mass spectrometry of HFpEF myocardium from males and females. The results broaden our understanding of the pathophysiological response of both sexes to pressure overload. Both sexes developed a robust cardiopulmonary phenotype, but the phenotype was equal or a bit less robust in females.
大约 50%的心力衰竭（HF）诊断可以归类为射血分数保留的心力衰竭（HFpEF）。HFpEF 在女性中比男性更常见，但潜在机制尚不清楚。我们之前的研究表明，雄性猫科动物的压力超负荷（PO）会引起具有人类 HFpEF 基本特征的心肺表型。本研究的目的是确定在没有其他病理应激源的情况下，缓慢进行性 PO 是否会在雌性和雄性中引起不同的心肺表型。雌性和雄性猫科动物在基线超声心动图、肺功能测试和血液采样后接受主动脉缩窄（带环）或假手术。手术后 2 和 4 个月重复这些评估，以记录缓慢进行性压力超负荷的影响。在 4 个月时，还进行了有创血流动力学研究。收集左心室（LV）组织进行组织学、肌原纤维力学、细胞外基质（ECM）质谱和单细胞 RNA 测序（snRNAseq）。两种性别之间的诱导压力超负荷（PO）没有差异。PO 也在两种性别中引起 LV 壁厚度和心肌细胞横截面积的类似变化。两种性别均保留射血分数，但男性在血流动力学和肺参数方面表现出稍强的表型。带环的雄性和雌性动物之间的 LV 纤维化和 ECM 组成没有差异。LV snRNAseq 揭示了 PO 后个体细胞类型基因程序的变化，这些变化在雄性和雌性中是独特的。基于这些结果，两种性别均出现心肺功能障碍，但女性的表型稍不先进。我们进行了一项全面评估，以评估在雄性和雌性射血分数保留心力衰竭（HFpEF）的大型动物模型中缓慢进行性压力超负荷对心肺功能的影响。在器官、组织、细胞、蛋白质和转录水平上进行了功能和结构评估。这是第一项比较雄性和雌性 HFpEF 心肌 snRNAseq 和 ECM 质谱的研究。该结果拓宽了我们对两种性别对压力超负荷的病理生理反应的理解。两种性别均发展出强大的心肺表型，但女性的表型相等或稍弱。
