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Cardiomyopathy associated with cancer therapy.

ABSTRACT: Chemotherapy-associated cardiomyopathy is a well known cardiotoxicity of contemporary cancer treatment and a cause of increasing concern for both cardiologists and oncologists. As cancer outcomes improve, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors. Asymptomatic or symptomatic left ventricular systolic dysfunction in the setting of cardiotoxic chemotherapy is an important entity to recognize. Early diagnosis of cardiac injury through the use of novel blood-based biomarkers or noninvasive imaging modalities may allow for the initiation of cardioprotective medications or modification of chemotherapy regimen to minimize or prevent further damage. Several clinical trials are currently underway to determine the efficacy of cardioprotective medications for the prevention of chemotherapy-associated cardiomyopathy. Implementing a strategy that includes both early detection and prevention of cardiotoxicity will likely have a significant impact on the overall prognosis of cancer survivors. Continued coordination of care between cardiologists and oncologists remains critical to maximizing the oncologic benefit of cancer therapy while minimizing any early or late cardiovascular effects.

SUBMITTER: Yu AF

PROVIDER: S-EPMC5972392 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Cardiomyopathy associated with cancer therapy.

Yu Anthony F AF Steingart Richard M RM Fuster Valentin V

Journal of cardiac failure 20140821 11

Chemotherapy-associated cardiomyopathy is a well known cardiotoxicity of contemporary cancer treatment and a cause of increasing concern for both cardiologists and oncologists. As cancer outcomes improve, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors. Asymptomatic or symptomatic left ventricular systolic dysfunction in the setting of cardiotoxic chemotherapy is an important entity to recognize. Early diagnosis of cardiac injury through the us ...[more]

PMID: 25151211

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Project description:BackgroundCancer 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.MethodsWe 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.ResultsCCM 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).ConclusionsUnrecognized 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 registrationURL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Project description:Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry (n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10-8) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. SIGNIFICANCE: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors.See related commentary by Brown and Richard, p. 2272.

Project description:PurposeCurrent information regarding pregnancy-associated cardiomyopathy among women treated for childhood cancer is insufficient to appropriately guide counseling and patient management. This study aims to characterize its prevalence within a large cohort of females exposed to cardiotoxic therapy.MethodsThis is a retrospective cohort study of female cancer survivors treated at St. Jude Children's Research Hospital between 1963 and 2006, at least 5 years from diagnosis, ≥13 years old at last follow-up, and with at least one successful pregnancy. Pregnancy-associated cardiomyopathy was defined as shortening fraction <28 % or ejection fraction <50 % or treatment for cardiomyopathy during or up to 5 months after completion of pregnancy.ResultsAmong the 847 female cancer survivors with 1554 completed pregnancies, only 3 (0.3 %) developed pregnancy-associated cardiomyopathy and 40 developed non-pregnancy-associated cardiomyopathy either 5 months postpartum (n = 14) or prior to pregnancy (n = 26). Among those with cardiomyopathy prior to pregnancy (n = 26), cardiac function deteriorated during pregnancy in eight patients (three patients with normalization of cardiac function prior to pregnancy, three with persistently abnormal cardiac function, and two for whom resolution of cardiomyopathy was unknown prior to pregnancy). Patients that developed cardiomyopathy received a higher median dose of anthracyclines compared to those that did not (321 versus 164 mg/m(2); p < 0.01).ConclusionsPregnancy-associated cardiomyopathy in childhood cancer survivors is rare.Implications for cancer survivorsMost female childhood cancer survivors will have no cardiac complications during or after childbirth; however, those with a history of cardiotoxic therapies should be followed carefully during pregnancy, particularly those with a history of anthracycline exposures and if they had documented previous or current subclinical or symptomatic cardiomyopathy.

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Cardiomyopathy associated with cancer therapy.

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Cardiomyopathy associated with cancer therapy.

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