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Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction.

ABSTRACT: Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ?10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline [95% CI, -1.8 to -0.4] with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.

SUBMITTER: Demissei BG

PROVIDER: S-EPMC7033834 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction.

Demissei Biniyam G BG Hubbard Rebecca A RA Zhang Liyong L Smith Amanda M AM Sheline Karyn K McDonald Caitlin C Narayan Vivek V Domchek Susan M SM DeMichele Angela A Shah Payal P Clark Amy S AS Fox Kevin K Matro Jennifer J Bradbury Angela R AR Knollman Hayley H Getz Kelly D KD Armenian Saro H SH Januzzi James L JL Tang W H Wilson WHW Liu Peter P Ky Bonnie B

Journal of the American Heart Association 20200121 2

Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort o ...[more]

PMID: 31959034

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Project description:Anthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on-treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines.This report encompasses 121 women included in the 2×2 factorial, placebo-controlled, double-blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240-400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide, C-reactive protein, and galectin-3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy.Treatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta-blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear.URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134.

Project description:PurposeWe characterized the early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy (RT) and evaluated their associations with radiation dose-volume metrics including mean heart dose (MHD), V5, and V30.Methods and materialsIn a prospective longitudinal study of 87 patients with breast cancer, lung cancer, or mediastinal lymphoma treated with photon or proton thoracic RT, blood samples were obtained pre-RT and after completion of RT (median, 20 days; interquartile range [IQR], 1-35). High-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, placental growth factor (PIGF), and growth differentiation factor 15 (GDF-15) were measured. Associations between MHD, V5 and V30, and biomarker levels and associations between echocardiography-derived measures of cardiac function and biomarker levels were assessed in multivariable linear regression models. Analyses were performed according to the following subgroups: (1) breast cancer alone and (2) lung cancer and lymphoma combined.ResultsThe median (IQR) estimates of MHD ranged from 1.3 Gy (0.9-2.4) in breast cancer (n = 60) to 6.8 Gy (5.4-10.2) in mediastinal lymphoma (n = 14) and 8.4 Gy (6.7-16.1) in lung cancer (n = 13) patients (P < .001). There were no significant increases in biomarker levels from pre-RT to post-RT in breast cancer. In lung cancer/lymphoma, PIGF increased from a median (IQR) of 20 ng/L (16-26) to 22 ng/L (16-30) (P = .005), and GDF-15 increased from 1171 ng/L (755-2493) to 1887 ng/L (903-3763) (P = .006). MHD, V5, and V30 were significantly associated with post-RT PIGF and GDF-15 levels in multivariable models. Changes in biomarkers were not significantly associated with changes in echocardiography-derived measures of cardiac function.ConclusionContemporary thoracic RT induces acute abnormalities in vascular and inflammatory biomarkers that are associated with radiation dose-volume metrics, particularly in lung cancer and mediastinal lymphoma. Long-term follow-up studies are needed to determine the impact of these changes on the development of overt cardiac disease.

Project description:AimsCancer therapy-related cardiac dysfunction (CTRCD) is commonly reported, but its histopathology, mechanisms, and risk factors are not known. We aimed to clarify the histopathology and mechanisms of CTRCD to identify risk factors.Methods and resultsWe performed myocardial histopathological studies on 13 endomyocardial biopsies from CTRCD patients, 35 autopsied cancer cases with or without cardiac dysfunction, and controls without cancer (10 biopsies and 9 autopsies). Cardiotoxicity risk scores were calculated based on medication; and patient-related risk factors, fibrosis, and cardiomyocyte changes were scored; and p53 and H3K27ac histone modification were evaluated by histological score (H-score). In the biopsy cases, all histopathological changes and the p53 evaluation were significantly higher in the CTRCD group than in the controls [p53 H-score; 63 (9.109) vs. 33 (5.099), P < 0.05]. In patients with a short time between drug and disease onset (<4.2 years), fibrosis and p53 positively correlated (r = 0.76, P < 0.05), and in those with late onset disease (>4.2 years), cellular abnormalities and p53 trended to a positive correlation and cardiotoxicity risk scores and p53 positively correlated (r = 0.95, P < 0.05). A year after biopsy, the short-term group had significant recovery of ejection fraction compared with the long-term group (P < 0.05). The CTRCD group had a significantly worse overall survival prognosis than the control group [hazard ratio 7.61 (95% confidence interval 1.30-44.6), P < 0.05]. Autopsy cases with cancer treatment also had a high grade of histopathological changes, with even more severe changes in patients with cardiac dysfunction, and had increased p53 and H3K27ac expression levels, compared with controls. H-scores of p53 and H3K27ac showed a positive correlation in the CTRCD group in biopsy cases (r = 0.62, P < 0.05) and a positive correlation in autopsy cases.ConclusionsOur results indicate distinct morphological characteristics in myocardial histopathology associated with CTRCD. p53 and H3K27ac histone modification could be sensitive markers of CTRCD and suggest a mechanistic involvement of epigenetic changes.

Project description:BackgroundObservational studies suggest that regular physical activity may reduce cardiovascular morbidity and cancer recurrence in survivors of breast cancer. The association between physical activity and cardiac function with breast cancer therapy is unknown.MethodsSelf-reported physical activity was assessed using the Godin Leisure-Time Exercise Questionnaire at repeated intervals in a longitudinal cohort study of 603 breast cancer participants treated with doxorubicin and/or trastuzumab. Multivariable regression models estimated associations between clinical variables and physical activity. Generalized estimating equations adjusted for prespecified variables estimated associations between baseline physical activity and longitudinal echocardiographic measures of systolic and diastolic function.ResultsPhysical activity was low at baseline, prior to cancer therapy initiation. More than half of participants reported no moderate-strenuous physical activity, and only 12.1% met guideline recommended levels of physical activity. Physical activity increased after chemotherapy completion; however, only 26.0% of individuals were sufficiently active 3 years after cancer diagnosis. Body mass index, hyperlipidemia and higher cancer stage were significantly associated with lower total physical activity at baseline. Higher baseline physical activity was very modestly associated with an attenuation in the absolute decline in left ventricular ejection fraction over time (β 0.4%, 95% CI 0.1, 0.7, P = .02 for each 10-unit increase in total activity). There tended to be a cardioprotective association with cardiotoxicity risk, although this was not statistically significant (HR 0.83, 95% CI 0.66, 1.04, P = .097).ConclusionsA small proportion of breast cancer patients and survivors are engaged in regular moderate-strenuous physical activity. While only modest associations between self-reported physical activity and left ventricular systolic function were observed, our findings do not exclude a cardioprotective benefit of exercise.

Project description:ObjectivesThis study sought to determine whether biomarkers ST2, growth differentiation factor (GDF)-15, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin I are elevated in patients infected with human immunodeficiency virus (HIV) and are associated with cardiovascular dysfunction and all-cause mortality.BackgroundHIV-infected patients have high rates of cardiovascular disease. Markers of myocardial stress may identify at-risk patients and provide additional prognostic information.MethodsBiomarkers and echocardiograms were assessed in 332 HIV-infected patients and 50 age- and sex-matched control subjects. Left ventricular systolic dysfunction was defined as ejection fraction <50%, diastolic dysfunction (DD) as stage 1 or higher, and pulmonary hypertension as pulmonary artery systolic pressure ≥35 mm Hg. Mortality data were obtained from the National Death Index.ResultsPatients with HIV had a median age of 49 years, and 80% were male. Compared with control subjects, HIV-infected patients had higher adjusted percent estimates of all biomarkers except ST2 and interleukin-6. Among HIV-infected patients, 45% had DD; only ST2 was associated with DD (relative risk [RR]: 1.36; p = 0.047). Left ventricular systolic dysfunction was rare in this cohort (5%). Pulmonary hypertension was present in 27% of HIV-infected patients and was associated with GDF-15 (RR: 1.18; p = 0.04), NT-proBNP (RR: 1.18; p = 0.007), and cystatin C (RR: 1.54; p = 0.03). Thirty-eight deaths occurred among HIV-infected patients over a median of 6.1 years. In adjusted analysis, all-cause mortality was independently predicted by ST2 (hazard ratio [HR]: 2.04; p = 0.010), GDF-15 (HR: 1.42; p = 0.0054), high-sensitivity C-reactive protein (HR: 1.25; p = 0.023), and D-dimer (HR: 1.49; p = 0.029). Relationships were unchanged when analyses were restricted to virally suppressed HIV-infected patients receiving antiretroviral therapy.ConclusionsAmong HIV-infected patients, ST2 and GDF-15 were associated with both cardiovascular dysfunction and all-cause mortality, and these variables may be useful at identifying those at risk for developing cardiovascular events and death.

Dataset Information

Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction.

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Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction.

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