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Advanced Dilated, Hypertrophic Cardiomyopathy Have Similar Transcriptional Profiles, Study Finds

NEW YORK — The transcriptional profiles of dilated cardiomyopathy and hypertrophic cardiomyopathy converge in advanced disease, a new single-nucleus analysis conducted by a Broad Institute-led team has found.

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) both cause heart failure, though differ in their presentations. DCM is marked by dilation of the left ventricle and systolic dysfunction, while HCM is characterized by a thickening of the left ventricle wall and is often linked to genetic alterations in sarcomere genes.

The researchers performed single-nucleus RNA sequencing to catalog the molecular changes that take place in these types of heart failure. As they reported in Nature on Wednesday, they found that the transcriptional profiles of DCA and HCM were largely similar at tissue and cell-type levels. They further uncovered a unique population of activated fibroblasts within a subset of DCM and HCM samples that were not present among non-failing hearts.

"In aggregate, our findings extend our understanding of the transcriptional and molecular basis of cardiomyopathies, results that will further inform the pathways and potential therapeutic targets for these morbid cardiac conditions," the Broad's Patrick Ellinor and colleagues wrote in their paper.

The researchers analyzed replicate left ventricle samples obtained from 11 individuals with DCM, 15 with HCM, and 16 individuals with non-failing hearts. All the DCM and HCM patients had advanced cardiomyopathy requiring transplantation.

In all, they examined more than 592,000 single nuclei, which, on the basis of their gene expression, clustered into 21 groups the researchers could identify based on cell type markers. The most common cell type was cardiomyocytes, followed by fibroblasts and endothelial cells. As compared to samples from non-failing hearts, DCM and HCM samples had decreased numbers of cardiomyocytes but increased numbers of vascular smooth muscle cells and activated fibroblasts.

The researchers uncovered few differentially expressed genes between the DCM and HCM samples but did note a number of genes were differentially expressed between them and non-failing hearts. Most of those genes, they noted, were expressed by fibroblasts. This suggested to the researchers that advanced cardiomyopathy — to the point of needing transplantation — converges to a common transcriptional profile.

Similar pathways were also up- or down-regulated among DCM and HCM samples, as compared to non-failing hearts. For instance, the complement cascade, neutrophil degranulation, and vitamin metabolism were downregulated among fibroblasts of DCM and HCM patients.

At the same time, the researchers noted an increase in activated fibroblasts that was nearly exclusive to samples from DCM and HCM patients. These activated fibroblasts exhibited increased expression of markers like POSTN, NOX4, and FAP, among others.

They then confirmed that such activated fibroblasts were present among separate cohorts of DCM and HCM patients but not found among controls with non-failing hearts. They further found that activated fibroblasts could also be detected among a cohort of HCM patients who were at an earlier stage of disease, suggesting that these cells could have a pathological role.

Additionally, they conducted a CRISPR-based knock-out screen of fibroblast transition upon TGFβ 1 stimulation to uncover a set of genes that, when lost, led to reduction of myofibroblast cell-state transition. These included the gene encoding the extracellular matrix protein prolargin, PRELP, and the collagen-linked gene COL22A1 as well as JAZF1.

"Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure," Ellinor and his colleagues wrote.