Background: Cancer therapy–induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. Methods: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. Results: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P ≤1.98e–04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P =7.36e–08), 0.7% of healthy volunteers ( P =3.42e–06), and 0.6% of the reference population ( P =5.87e–14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P =0.003) and impaired myocardial recovery ( P =0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P =0.0004 and P <0.002, respectively). Conclusions: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM. Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13.5% vs. 2.9%; p = 1.2 ×10-5), but similar between patients with ACM and DCM (19.4%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% confidence interval: -2.3% to -15.1%; p < 0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients. TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.

Objective To identify patients with type 2 myocardial infarction (MI) and patients with non-ischaemic myocardial injury (NIMI) and to compare their prognosis with those of patients with type 1 MI. Methods A retrospective observational study was performed in 1010 patients admitted to the emergency department of a university hospital with at least one troponin I test between 2012 and 2013. Participants were identified using laboratory records and divided into three groups: type 1 MI (rupture of atheromatous plaque), type 2 MI (imbalance between myocardial oxygen supply and/or demand) and NIMI (patients who did not meet diagnostic criteria for type 1 or type 2 MI). Clinical characteristics and 2-year outcomes were analysed. Results Patients with type 2 MI and NIMI were older, with higher proportion of women and more comorbidities than patients with type 1 MI. Absolute mortality and the adjusted risk for all-cause mortality in both groups were significantly higher than that of patients with type 1 MI (39.7%, HR: 1.41 95% CI 1.02 to 1.94, p=0.038 and 40.0%, HR: 1.54 95% CI 1.16 to 2.04, p=0.002, respectively). Patients with type 2 MI and NIMI tended to present more readmissions due to heart failure (16.5%, HR: 1.55 95% CI 0.87 to 2.76, p=0.133 and 12.3%, HR: 1.15 95% CI 0.70 to 1.90, p=0.580) and less readmission rates due to acute coronary syndrome (ACS) than patients with type 1 MI (2.1%, HR: 0.11 95% CI 0.04 to 0.31, p<0.001 and 4.3%, HR: 0.22 95% CI 0.12 to 0.41, p<0.001), Conclusions Patients diagnosed with type 2 MI and NIMI have higher rates of mortality and lower readmission rates for ACS compared with patients with type 1 MI.