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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