Abstract
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.
Highlights
Heart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality
TGF-beta signaling (ACVR1, ACVR1B, INHA, IRF7, KRAS, MAP2K1, MAP2K3, MAP3K7, MAPK13, MAPK3, NKX2-5, NRAS, PIAS4, PMEPA1, RAF1, RRAS, SERPINE1, SKI, SMAD2, SOS2, TAB1, TFE3, TGFB1, TGFB3, UBB, VDR, ZNF423) was identified in the left atrium (LA), where we observed a significant increase in fibroblasts populations, but not the left ventricle (LV). mRNA transcripts associated with mitochondria biogenesis (CAV2, COX10, DNAJA3, PRDX3, PTCD2, RAB3A, TFAM) and mitochondrial permeability (BCL2L1, HSPA5, KRT8) were altered in the LV but not the LA of the failing heart (Fig. 6b)
For each chamber we defined a set of enriched genes involved in the progression of several cardiovascular diseases: GWAS signals for atrial fibrillation were associated with 41 right atrium (RA)-Enriched genes, whereas GWAS signals for dilated cardiomyopathy were associated with Ventricles-Enriched MYH7, FHL2, TNNC1 and TNNI3 genes
Summary
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. Given that the diverse spectrum of disorders affecting the heart can only occasionally be traced to a specific single genetic mutation, it is important to determine changes within cardiac tissue at the molecular, cellular and genetic level in order to identify both genes and pathways that could influence heart failure progression. To better understand the underlying mechanisms of HFrEF etiology and progression, we performed a systematic analysis combining the precision of single cell technology together with global transcriptome profiling of all four heart chambers from 10 non-failing (NF) and 12 HFrEF donors (Fig. 1). We characterized the heterogenous nature of HFrEF among patients and across cell types and explored the underlying gene regulatory network, signaling pathways and genetic associations (Fig. 1)
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