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Heart failure in chemotherapy-related cardiomyopathy: Can exercise make a difference?

ABSTRACT: Medical therapies in oncology have resulted in better survival resulting in a large population who are at risk of early and late cardiac complications of chemotherapy. Cardiotoxicity related to chemotherapy can manifest decades after treatment with a threefold higher mortality rate as compared to idiopathic dilated cardiomyopathy. The leading cause of death in cancer survivors seems to be cardiac. Early detection and intervention could prevent progression of heart failure to end stage disease requiring advanced therapies such as implantation of ventricular assist devices or cardiac transplantation. This review focuses on the role of exercise in cardioprotection in this population. The current practice of depending on ejection fraction for diagnosis of heart failure is suboptimal to detect subclinical disease. It is also important to diagnose and treat early diastolic dysfunction as this tends to lead to heart failure with preserved ejection fraction. Hence we suggest an algorithm here that is based on using strain rate and tissue Doppler imaging modalities to detect subclinical systolic and diastolic dysfunction. Further research is warranted in terms of defining exercise prescriptions in this population. Human studies with multicenter participation in randomized controlled trials should be done to elucidate the intricacies of aerobic exercise intervention in cardiotoxicity dependent heart failure. It is also necessary to assess the utility of exercise interventions in the different chemotherapeutic regimens as they impact the outcomes.

SUBMITTER: Nair N

PROVIDER: S-EPMC4925806 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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Heart failure in chemotherapy-related cardiomyopathy: Can exercise make a difference?

Nair Nandini N Gongora Enrique E

BBA clinical 20160615

Medical therapies in oncology have resulted in better survival resulting in a large population who are at risk of early and late cardiac complications of chemotherapy. Cardiotoxicity related to chemotherapy can manifest decades after treatment with a threefold higher mortality rate as compared to idiopathic dilated cardiomyopathy. The leading cause of death in cancer survivors seems to be cardiac. Early detection and intervention could prevent progression of heart failure to end stage disease re ...[more]

PMID: 27413695

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Project description:Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p < 1 × 10-5 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci. Methods: We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases (N = 12) and control groups of patients treated with anthracycline +/- trastuzumab without HF (N = 282) and patients with HF that were never treated with anthracycline or trastuzumab (N = 690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6. Results: TRPC6 5' flanking variant rs57242572-T was significantly more frequent in cases compared to controls, p = 0.031, and rs61918162-T showed a trend for association, p = 0.065. The rs61918162 T-allele was associated with higher TRPC6 expression in the heart left ventricle. We identified a single TRPC6 rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction. Conclusions: Genetic variants that are associated with increased TRPC6 expression in the heart and rare TRPC6 missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.

Dataset Information

Heart failure in chemotherapy-related cardiomyopathy: Can exercise make a difference?

Publications

Heart failure in chemotherapy-related cardiomyopathy: Can exercise make a difference?

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