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| The gene PRR16 was more active — indicated by yellow dots — in cardiac tissue samples from people with hypertrophic cardiomyopathy (right) than those without the disease (left). A representative heart cell in each image is outlined in orange. Image Credit: Eric Q. Wei and Martin Beyer/HMS |
Scientific Frontline: Extended "At a Glance" Summary: Molecular Map of Hypertrophic Cardiomyopathy
The Core Concept: Researchers have mapped the molecular activity underlying hypertrophic cardiomyopathy (HCM), a disease causing thickening and stiffening of the heart muscle.
Key Distinction/Mechanism: By using single-nucleus RNA sequencing on nearly one million heart cells, the study distinguishes between genetic and nongenetic HCM, and early and late stages. It reveals that genetic HCM causes distinct molecular changes, such as proportional reductions in heart muscle cells and increased expression of genes related to arrhythmias and fibrosis, compared to nongenetic HCM.
Origin/History: The foundational research into the genetic and molecular basis of HCM began in 1990, led by the Seidman Lab, which ultimately paved the way for the first precision treatment (mavacamten) approved by the FDA in 2022.
Major Frameworks/Components:
- Single-nucleus RNA sequencing of heart tissue.
- Identification of the PRR16 gene as a contributor to cardiomyocyte enlargement.
- Characterization of fibroblast activity, specifically the reduced expression of collagen IV in early-stage HCM, which may destabilize the extracellular matrix.
- Use of an AI model trained on gene expression data to accurately categorize disease stages and subtypes.
Branch of Science: Cardiology, Genetics, Molecular Biology, Computational Biology.
Future Application: The detailed molecular signature provides a foundation for developing more targeted and precise treatments for the different stages and genetic subtypes of hypertrophic cardiomyopathy.
Why It Matters: The findings provide unprecedented insight into the specific cellular mechanisms driving HCM, demonstrating that the disease affects more than just heart muscle cells and opening new avenues for mitigating disease progression and heart failure.
“It’s enormously gratifying to see them feeling well”: Christine and Jonathan Seidman share the story of how fundamental discoveries in the lab led to the first approved precision treatment for patients with hypertrophic cardiomyopathy.
Video Credit: Rick Groleau
An international team led by researchers from Harvard Medical School, Brigham and Women’s Hospital, and the Max Delbrück Center for Molecular Medicine in Germany has created a detailed map of the molecular activity underlying hypertrophic cardiomyopathy (HCM), a common form of heart disease that causes the heart muscle to become thick and stiff and can lead to heart failure or sudden cardiac arrest.
The findings, published September 16 in Science Translational Medicine, provide insights into the changes that drive HCM, which could, in turn, inform current and future treatments.
“Charting the molecular landscape of hypertrophic cardiomyopathy is essential for advancing our understanding of the disease, improving patient care, and developing new therapeutic approaches,” said co-senior author Christine Seidman, the HMS Thomas W. Smith Professor of Medicine at Brigham and Women’s and professor of genetics at HMS.
“By looking across nearly 1 million heart cells, we’ve gained important insights into molecular changes that underlie HCM,” added Seidman, who directs the Cardiovascular Genetics Program at the Mass General Brigham Heart and Vascular Institute.
The work reveals differences between genetic and nongenetic HCM, as well as between early- and late-stage HCM. In fact, the authors said, the findings demonstrate that HCM caused by a genetic defect is distinct from nongenetic HCM, and the molecular changes seen in genetic HCM likely account for more arrhythmias and greater progression to heart failure than does nongenetic HCM.
The Seidman Lab—headed by Christine and co-senior author Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics in the Blavatnik Institute at HMS—has been a leader in HCM research for decades. Christine Seidman, a practicing cardiologist, brings her patient care experiences back to the lab, where they are complemented by Jonathan Seidman’s training in genetics. Beginning in 1990, their team made crucial discoveries about the genetic and molecular underpinnings of HCM that paved the way for the first precision treatment for the disease, called mavacamten (Camzyos), approved by the FDA in 2022.
The team behind the new study—co-led by cardiologist Yuri Kim, HMS assistant professor of medicine at Brigham and Women’s, and Eleonora Adami of the Hübner Lab at the Max Delbrück Center—characterized the cellular and molecular signatures of HCM.
The researchers used single-nucleus RNA sequencing to analyze heart tissue from 47 patients spanning early- to end-stage HCM, including people with genetic and nongenetic forms of the disease. They compared these gene expression profiles with data from healthy donor hearts and heart tissue affected by dilated cardiomyopathy, a condition in which the left ventricle balloons, thinning the chamber’s walls.
The data gathered from these nearly 1 million individual heart cells allowed the creation of the map, which details altered gene activity according to disease stage and genetic status.
Genetic HCM showed proportionally fewer heart muscle cells than nongenetic HCM and healthy donor tissue. The researchers also identified the gene PRR16 as a potential contributor to the cardiomyocyte (heart cell) enlargement that is characteristic of HCM. In addition, genetic HCM samples had elevated expression of genes related to cardiac arrhythmias and fibrosis, features that contribute to disease progression.
The team found distinct features for early-stage HCM compared with late-stage HCM. Fibroblasts—which produce and maintain the extracellular matrix that surrounds cells—expressed less collagen IV, a deficit that the researchers say would likely destabilize the matrix.
In a final step, the researchers showed that an AI model trained on their gene expression data could accurately distinguish early- and late-stage HCM, separate HCM from dilated cardiomyopathy, and correctly identify patients with genetic versus nongenetic HCM. The model was able to make the same distinctions based on gene expression data from fibroblasts alone.
“This was a surprising finding,” said Kim, “because cardiomyopathies are usually thought of as diseases of heart muscle cells only.”
“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,” added co-senior author Norbert Hübner at the Max Delbrück Center. “This should provide a foundation for future work on more targeted treatments.”
Funding: This study was supported in part by the Beznos Family Fund; Boehringer Ingelheim Fonds; the British Heart Foundation (BBC/F/21/220106, FS/CRTF/23/24444, SP/19/1/34461, RE/18/4/34215, RE/24/130023); the British Heart Foundation Centre for Research Excellence, Imperial College London; the British Medical Association Foundation Josephine Lansdell Grant; the Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research) (81Z0600106, 81Z0600105); the Canadian Institutes of Health Research (PJT-451105, PJT-462950); the Chan Zuckerberg Initiative (2019-002431, 2019-202666, 2021-237882); the Erich and Hanna Klessmann Foundation; the German Research Foundation (SFB-1470 Project B03); Imperial College Healthcare NHS Trust Biomedical Research Centre Funding (PA7460); the Medical Research Council UK; the NIHR Imperial Biomedical Research Centre; the National Science Foundation Engineering Research Center on Cellular Metamaterials (EEC-1647837); the Pathfinder Cardiogenomics Programme of the European Innovation Council of the European Union (DCM-NEXT, 101115416); the Rosetrees Trust (PGS23/100028); the Sir Jules Thorn Charitable Trust (21JTA); and the Wellcome Trust (226083/Z/22/Z).
Disclosures: Christine Seidman reports serving as scientific advisor for Maze Therapeutics and Tenaya Therapeutics and on the board of directors for Burroughs Wellcome Fund and Merck.
Published in journal: Translational Medicine
Title: The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes
Authors: Eleonora Adami, Yuri Kim, Sean L. Zheng, Nikolay Shvetsov, Corinna Losert, Henrike Maatz, Syndi Barish, Gabriela Venturini, Natalia López Anguita, Qi Shi, Meraj Neyazi, Martin Beyer, Eric Q. Wei, Amanda Adam, Abhilash Suresh, Daniel Reichart, Eric Lindberg, Kemar J. Brown, Viktoria Strohmenger, David Saul, Anna Gärtner, Michael Lee, Lukas Mach, Jan Lukas Robertus, Joshua M. Gorham, Jan Haas, Laura A. Liebig, Christoph Lippert, Benjamin Meder, Anna Myronova, Giannino Patone, Sam N. Barnett, James S. Ware, Fabio De Robertis, Antonis Pantazis, Jan Gummert, Anissa Viveiros, Huachen Chen, Jorge Ruiz-Orera, Norbert Frey, Barbara A. McDonough, Richard N. Mitchell, Robert F. Padera, Sharlene M. Day, Carolyn Y. Ho, Neal K. Lakdawala, Hendrik Milting, Matthias Heinig, Gavin Y. Oudit, Michela Noseda, Jonathan G. Seidman, Norbert Hübner, and Christine E. Seidman
Source/Credit: Harvard Medical School
Edited by: Scientific Frontline
Reference Number: med091826_01
