Association of Pathogenic/Likely Pathogenic Inherited Cardiomyopathy Variants With Heart Failure: A TOPMed Multiancestry Analysis

Naman S. Shetty, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Mokshad Gaonkar, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA.
Akhil Pampana, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA.
Nirav Patel, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA.
April P. Carson, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Bernhard Haring, Department of Medicine III, Saarland University Hospital, Homburg, Saarland, Germany; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York, USA.
Bruce M. Psaty, Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
Charles Kooperberg, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Eric Boerwinkle, Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Jerome I. Rotter, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
João A. Lima, Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Jorge R. Kizer, Cardiology Section, San Francisco Veterans Affairs Health Care System, and Departments of Medicine, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
Lisa Warsinger Martin, Department of Medicine, Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Kent D. Taylor, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Michael E. Hall, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Myriam Fornage, University of Texas Health Science Center at Houston, Houston, TX, USA.
Sanjiv J. Shah, Division of Cardiology, Department of Medicine and Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Stephen S. Rich, Center for Public Health, University of Virginia, Charlottesville, VA, USA.
Ramachandran S. Vasan, University of Texas School of Public Health San Antonio, San Antonio, TX, USA.
Rami Nassir, Department of Pathology, School of Medicine, Umm Al-Qura'a University, Saudi Arabia.
Peng Li, School of Nursing, University of Alabama at Birmingham, Birmingham, AL, USA.
Garima Arora, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
Pankaj Arora, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA. Electronic address: parora@uabmc.edu.

Document Type

Journal Article

Publication Date

8-22-2025

Journal

Mayo Clinic proceedings

DOI

10.1016/j.mayocp.2025.01.021

Abstract

OBJECTIVE: To evaluate the prevalence of pathogenic/likely pathogenic inherited cardiomyopathy variants and their association with heart failure in the (TOPMed) TransOmic for Precision of Medicine cohorts. METHODS: A retrospective cohort study using the TOPMed cohorts, including multi-ancestry US adults (≥18 years of age) with sequencing data, was conducted. Pathogenic/likely pathogenic inherited cardiomyopathy variant carrier status was determined based on ClinVar variants classified with two or more stars of evidence. Individuals without pathogenic/likely pathogenic variants were used as the reference group. The primary outcome was heart failure , adjudicated by an expert panel. Cox proportional hazards models assessed the association between carrier status and heart failure risk, adjusting for sex, study cohort, coronary artery disease, and genetic ancestry. Age was used as the timescale to account for the effect of variants since birth, and interval censoring was used to handle the uncertainty in the timing of heart failure events. RESULTS: Among 30,977 individuals (median age, 61.0 years; 71.3% female; 37.0% non-European ancestry), 229 (0.7%) were identified as pathogenic/likely pathogenic inherited cardiomyopathy variant carriers. There were 3,298 events of heart failure (35 in carriers and 3,263 in non-carriers). The heart failure incidence rate was higher in variant carriers (2.06 per 1000 person-years) compared with noncarriers (1.40 per 1000 person-years), with an adjusted hazard ratio of 1.68 (95% CI, 1.29-2.22). CONCLUSION: Approximately 1 in 140 US adults carry a cardiomyopathy variant, which increases heart failure risk. Targeted genetic screening may facilitate early identification and preventive interventions to reduce heart failure risk in carriers.

Department

Medicine

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