³Ô¹ÏºÚÁÏ

An international team, including researchers from ³Ô¹ÏºÚÁÏ, has created the most detailed molecular map to date of hypertrophic cardiomyopathy, revealing biological pathways that could help pave the way for more personalised treatments.

Published in the study analysed gene activity in almost one million individual heart cells from patients with hypertrophic cardiomyopathy (HCM). The resulting molecular atlas enabled researchers to distinguish between different stages of HCM as well as genetic and non-genetic forms of the condition.

The international study brought together researchers from ³Ô¹ÏºÚÁÏ's National Heart and Lung Institute (NHLI), the Max Delbrück Center, Brigham and Women's Hospital, Harvard Medical School, the University of Alberta, Helmholtz Munich, TU Munich and Herz und Diabeteszentrum NRW.

By looking at individual cells from patients with hypertrophic cardiomyopathy, we were able to build a detailed picture of how the disease develops across different genetic causes and stages

Studying disease one cell at a time

HCM causes the heart muscle to become thickened and stiff, making it harder for the heart to pump blood effectively. While some people experience relatively mild symptoms, others develop serious complications including heart failure and abnormal heart rhythms.

To better understand why the disease affects patients differently, researchers analysed heart tissue from 47 patients spanning early- to end-stage HCM, including both genetic and non-genetic forms of the condition. The team then compared these samples with healthy donor hearts and tissue from patients with dilated cardiomyopathy (DCM), another common form of heart disease.

Using single-nucleus RNA sequencing, the researchers measured gene activity in individual cells, creating a comprehensive molecular atlas of HCM across different disease stages and genetic backgrounds.

The analysis revealed distinct molecular signatures linked to disease progression and genetic status. Patients with inherited forms of HCM showed patterns of gene activity associated with fibrosis and abnormal heart rhythms, helping researchers understand why genetically driven disease can often be more severe.

Professor of Cardiovascular Sciences at the NHLI and co-senior author of the study, said, “To develop better treatments for heart disease, we first need to understand how the disease works. By looking at individual cells from patients with hypertrophic cardiomyopathy, we were able to build a detailed picture of how the disease develops across different genetic causes and stages, with the hope that these insights will lead to more precise and informed treatments for patients in the future.”

Looking beyond heart muscle cells

The study also uncovered important changes in fibroblasts, cells responsible for maintaining the heart's structural framework.

Cardiomyopathies are often considered diseases of heart muscle cells, but the findings suggest that other cell types may play a much more significant role in disease progression than previously recognised. Researchers identified molecular changes in fibroblasts that could distinguish between disease stages and subtypes, highlighting potential new avenues for future research and treatment development.

The team also identified PRR16 as a potential contributor to the enlarged heart muscle cells that are characteristic of HCM.

Supporting future precision medicine

As part of the study, researchers developed artificial intelligence models using the gene expression data. The models were able to distinguish between early- and late-stage disease, identify genetic and non-genetic forms of HCM, and differentiate HCM from dilated cardiomyopathy.

The researchers hope the molecular atlas will serve as a valuable resource for the cardiovascular research community and help accelerate the development of more targeted treatments for patients with HCM.

Professor Norbert Hübner, co-senior author of the study from the Max Delbrück Center, said, “By mapping gene expression at single-cell resolution across disease stages and genetic subtypes, we've built a molecular signature of HCM's clinical spectrum. This should provide a foundation for future work on more targeted treatments.”

Alongside senior author Professor Michela Noseda and lead ³Ô¹ÏºÚÁÏ author , several other ³Ô¹ÏºÚÁÏ researchers contributed to the research as part of a large international collaboration.