Genome Analysis Unit, Amgen Research, 1120 Veterans BLVD, South San Francisco, CA, 94010, USA.
Department of Cardiometabolic Disorders, Amgen Research, One Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
Sci Rep. 2021 Jun 4;11(1):11839. doi: 10.1038/s41598-021-91214-2.
Heart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality. To explore the underlying mechanisms of HFrEF etiology and progression, we studied the molecular and cellular differences in four chambers of non-failing (NF, n = 10) and HFrEF (n = 12) human hearts. We identified 333 genes enriched within NF heart subregions and often associated with cardiovascular disease GWAS variants. Expression analysis of HFrEF tissues revealed extensive disease-associated transcriptional and signaling alterations in left atrium (LA) and left ventricle (LV). Common left heart HFrEF pathologies included mitochondrial dysfunction, cardiac hypertrophy and fibrosis. Oxidative stress and cardiac necrosis pathways were prominent within LV, whereas TGF-beta signaling was evident within LA. Cell type composition was estimated by deconvolution and revealed that HFrEF samples had smaller percentage of cardiomyocytes within the left heart, higher representation of fibroblasts within LA and perivascular cells within the left heart relative to NF samples. We identified essential modules associated with HFrEF pathology and linked transcriptome discoveries with human genetics findings. This study contributes to a growing body of knowledge describing chamber-specific transcriptomics and revealed genes and pathways that are associated with heart failure pathophysiology, which may aid in therapeutic target discovery.
射血分数降低的心力衰竭（HFrEF）占心力衰竭住院患者的 50%，其死亡率很高。为了探究 HFrEF 病因和进展的潜在机制，我们研究了非衰竭（NF，n=10）和 HFrEF（n=12）人心室四个腔室的分子和细胞差异。我们鉴定了在 NF 心脏亚区中富集且常与心血管疾病 GWAS 变体相关的 333 个基因。HFrEF 组织的表达分析显示左心房（LA）和左心室（LV）中广泛存在与疾病相关的转录和信号改变。常见的左心 HFrEF 病理学包括线粒体功能障碍、心肌肥厚和纤维化。氧化应激和心脏坏死途径在 LV 中很明显，而 TGF-β信号在 LA 中很明显。通过去卷积估计细胞类型组成，发现与 NF 样本相比，HFrEF 样本中左心的心肌细胞比例较小，LA 中的成纤维细胞和左心的血管周围细胞比例较高。我们鉴定了与 HFrEF 病理相关的基本模块，并将转录组发现与人类遗传学发现联系起来。这项研究有助于描述腔室特异性转录组学的知识体系不断发展，并揭示了与心力衰竭病理生理学相关的基因和途径，这可能有助于治疗靶点的发现。
