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Genetic Contribution to End-Stage Cardiomyopathy Requiring Heart Transplantation
Yuri Kim1,2, Oddný Brattberg Gunnarsdóttir2, Anissa Viveiros3,4
1Division of Cardiovascular Medicine, Brigham and Women's Hospital (Y.K., B.M., C.E.S.).
Insights
Genetic sequencing identified causes in nearly half of end-stage cardiomyopathy patients, revealing a higher prevalence of genetic variants in heart transplant recipients compared to ambulatory cases. This aids in diagnosing heart failure and guiding family risk assessment.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Advanced heart failure often necessitates cardiac transplantation.
- Idiopathic cardiomyopathy is a common diagnosis when treatable causes are excluded.
- Unrecognized genetic causes may underlie end-stage cardiomyopathy.
Purpose of the Study:
- To investigate DNA sequence analyses for identifying unrecognized causes of end-stage nonischemic cardiomyopathy.
- To compare the prevalence of genetic causes in end-stage versus ambulatory cardiomyopathy cases.
Main Methods:
- Whole exome and genome sequencing were performed on 122 explanted hearts from adult and pediatric patients.
- Analysis included pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes.
- Nonhuman microbial sequences were assessed, and variant frequencies were compared across cardiomyopathy cohorts.
Main Results:
- Pathogenic/likely pathogenic cardiomyopathy gene variants were found in 44.3% of samples.
- The prevalence of causal genetic variants was significantly higher in end-stage cardiomyopathy than in ambulatory cases.
- Parvovirus genome sequences were detected in 28 samples, with two showing significantly higher levels.
Conclusions:
- Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy.
- Damaging gene variants are more frequent in transplant recipients than ambulatory patients.
- Genetic analyses can define the cause of end-stage cardiomyopathy, guiding management and risk stratification for patients and families.
Background:
Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to define causes are often abandoned, resulting in a diagnosis of end-stage idiopathic cardiomyopathy. We studied whether DNA sequence analyses could identify unrecognized causes of end-stage nonischemic cardiomyopathy requiring heart transplantation and whether the prevalence of genetic causes differed from ambulatory cardiomyopathy cases.
Methods:
We performed whole exome and genome sequencing of 122 explanted hearts from 101 adult and 21 pediatric patients with idiopathic cardiomyopathy from a single center. Data were analyzed for pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes and assessed for nonhuman microbial sequences. The frequency of damaging genetic variants was compared among cardiomyopathy cohorts with different clinical severity.
Results:
Fifty-four samples (44.3%) had pathogenic/likely pathogenic cardiomyopathy gene variants. The frequency of pathogenic variants was similar in pediatric (42.9%) and adult (43.6%) samples, but the distribution of mutated genes differed (P=8.30×10-4). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases (P<0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samples contained parvovirus genome sequences, including 2 samples with 6- to 9-fold higher levels than the overall mean levels in other samples.
Conclusions:
Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy. Damaging gene variants are significantly more frequent among transplant compared with patients with ambulatory cardiomyopathy. Genetic analyses can help define cause of end-stage cardiomyopathy to guide management and risk stratification of patients and family members.
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