Chamber-enriched gene expression profiles in failing human hearts with reduced ejection fraction

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.

Contrasting Ionic Mechanisms of Impaired Conduction in FHF1 - and FHF2 -Deficient Hearts

“…Clinically, mutations in FHF1 have been linked to both idiopathic ventricular tachycardia 4 and Brugada syndrome. 5 Furthermore, reductions in FHF1 expression have been observed in diseased left atrial and left ventricular tissue, 3 while FHF2–4 levels are not significantly changed (Figure [E]). Thus, dysregulated FHF1 activity may play a mechanistic role in both heritable and acquired arrhythmic disorders.…”

“…FHF1–FHF4 transcript abundance in human cardiac chambers under normal and heart failure conditions (n=9–12 patient samples per cardiac chamber/condition). 3 F , Increased temperature leads to conduction slowing in Fhf1 KO (Fhf1 knockout) hearts. P wave ( top ) and QRS duration ( bottom ) plotted against temperatures at 37 °C or 43 °C.…”

“…Further, given that FHF1 expression is significantly reduced in the failing human atrial and ventricular tissue, our data suggest that FHF1 deficiency, through its effects on sodium currents, may be clinically operative and contribute to conduction slowing and the heightened arrhythmia burden observed in diseased hearts. 3…”

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy

“…Notably, the left ventricles (LV) of the failing hearts displayed prominently altered mRNA transcripts related to mitochondrial permeability and mitochondrial biogenesis, including BCL2L1, CAV2, COX10, DNAJA3, HSPA5, KRT8, PRDX3, PTCD2 , and etc. ( 25 ). These dramatic HFrEF-related transcriptional alterations in the left heart suggested a reciprocal relationship between mitochondrial dysfunction and cardiac pathology.…”

sMAP: An interactive microarray data analysis tool for early-stage researchers

“…Making sense of genomic data allows researchers to identify key disease pathways and find potential therapeutic targets. For example, gene expression profiling has recently uncovered associations between alcohol and neurodegenerative diseases [6], regulon expression in cognitive aging [7], and chamber-specific transcriptomics in heart failure patients [8].…”