Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wildtype (p=0.0004 and p<0.002, respectively).ĬONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Adult CCM patients with TTNtv experienced more heart failure and atrial fibrillation (p=0.003) and impaired myocardial recovery (p=0.03) than those without. Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=3.42e-06), and 0.6% reference population (p=5.87e-14). POPULATION: Among nine prioritized genes CCM patients had more rare protein-altering variants than comparative cohorts (p≤1.98e-04). Adult CCM patients had cardiovascular risk factors similar to the U.S. RESULTS: CCM was diagnosed 0.4-9 years after chemotherapy 90% of these patients received anthracyclines. A prevalent CCM genotype was modeled in anthracycline-treated mice. Clinical characteristics and outcomes were assessed, stratified by genotypes. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas (TCGA) participants (n=2053), healthy volunteers (n=445), and ancestry-matched reference population. Cardiomyopathy genes, including nine pre-specified genes were sequenced. METHODS: We studied 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped breast cancer adults (n=73) and prospectively phenotyped children with acute myeloid leukemia (n=41). We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. These parameters incompletely account for substantial inter-individual susceptibility to CCM. BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders.
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