Key result
Genetic variants or viral myocarditis explain ~46% of end-stage cardiomyopathy, enriched in transplant recipients.
Why the study?
Studies defining causes of advanced heart failure are often abandoned once treatable causes are excluded, leaving the genetic contribution to end-stage nonischemic cardiomyopathy requiring heart transplantation and its difference from ambulatory cases unclear.
Does DNA sequence analysis identify unrecognized genetic and viral causes of end-stage nonischemic cardiomyopathy requiring heart transplantation?
Observational (n=122)
No
Does DNA sequence analysis identify unrecognized genetic and viral causes of end-stage nonischemic cardiomyopathy requiring heart transplantation?
Comprehensive genetic and viral analysis of explanted hearts reveals that nearly half of 'idiopathic' end-stage cardiomyopathies have an identifiable pathogenic variant or viral origin, suggesting high-risk genetic profiles drive progression to end-stage disease.
Supports etiology evaluation via genetic/viral testing in unexplained end-stage cardiomyopathy; leaves open impact on management or outcomes.
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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Kim et al. (2023) conducted an observational in End-stage idiopathic nonischemic cardiomyopathy requiring heart transplantation (n=122). Whole exome and genome sequencing vs. Previously reported ambulatory adult dilated cardiomyopathy cohorts was evaluated on Prevalence of pathogenic or likely pathogenic cardiomyopathy gene variants. Pathogenic genetic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy, and causal variants were significantly more frequent in transplant patients compared to ambulatory patients (p<0.001).
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