A study published in the journal Science has challenged the idea that heart failure results from a common disease pathway, suggesting instead that individual genetics comes into play.
The research revealed that genetic variants activate specific pathways in cardiomyopathies, some shared and some distinct, that resulted in different cellular landscapes and transcriptional changes.
The investigators say their findings provide interventional opportunities to improve and personalize treatments for cardiomyopathies and heart failure.
“Our results show that different mutations evoked specific and some shared responses that lead to heart failure rather than triggering uniformly the same pathological pathways,” researcher Eric Lindberg, a PhD student at the Max Delbrück Center for Molecular Medicine in Berlin, Germany, told Inside Precision Medicine.
“These genotype-specific mechanisms such as differences in fibrotic responses may inform the design of precision targeted therapies that take into account each patient’s particular form of cardiomyopathy determined by the responsible individual gene defect.”
The team used a technique called single-nucleus RNA-sequencing (snRNAseq) transcriptional analysis to study cellular composition and molecular states in healthy and diseased hearts.
Ventricular tissue samples from 61 patients with genetic and idiopathic (mutation-negative) dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) were compared with those from 18 healthy donors.
The researchers studied multiple samples with pathogenic variants in DCM genes (LMNA, RBM20, and TTN), ACM genes (PKP2) and pathogenic variant–negative samples to determine genotype-stratified and common heart failure responses.
Machine learning was then employed to identify genotype-specific molecular responses.
From 881,081 nuclei isolated from left and right diseased and healthy ventricles, the team identified 10 major cell types and 71 distinct transcriptional states.