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Assessment of Myocardial Work in Cancer Therapy-Related Cardiac Dysfunction and Analysis of CTRCD Prediction by Echocardiography.

ABSTRACT: No study has examined myocardial work in subjects with cancer therapy-related cardiac dysfunction (CTRCD). Myocardial work, as a new ultrasonic indicator, reflects the metabolism and oxygen consumption of the left ventricle. The aim of this study was to test the relative value of new indices of myocardial work and global longitudinal strain (GLS) in detecting changes in myocardial function during the treatment of breast cancer by two-dimensional and three-dimensional echocardiography. We enrolled 79 breast cancer patients undergoing different tumor treatment regimens. Follow-up observation was conducted before and after chemotherapy. The effects of breast cancer chemotherapy and targeted therapy on the development of CTRCD [defined as an absolute reduction in left ventricular ejection fraction (LVEF) of >5% to <53%] were detected by two-dimensional and three-dimensional speckle tracking echocardiography. Our findings further indicate that LVEF, myocardial work index (GWI) and myocardial work efficiency (GWE) showed significant changes after the T6 cycle, and GLS showed significant changes after the T4 cycle (p < 0.05). The three-dimensional strain changes after T6 and T8 had no advantages compared with GLS. Body mass index (BMI), the GLS change rate after the second cycle of chemotherapy (G2v) and the 3D-GCS change rate after the second cycle of chemotherapy (C2v) were independent factors that could predict the occurrence of CTRCD during follow-up, among which BMI was the best predictor (area under the curve, 0.922). In conclusion, the current study determined that GLS was superior to GWI in predicting cardiac function in patients with tumors with little variation in blood pressure. BMI, G2v and C2v can be used to predict the occurrence of CTRCD.

SUBMITTER: Guan J

PROVIDER: S-EPMC8632001 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objectives: The aim of this study was to investigate whether echocardiographic assessment of myocardial work is a predictor of outcome in advanced heart failure. Background: Global work index (GWI) and global constructive work (GCW) are calculated by means of speckle tracking, blood pressure measurement, and a normalized reference curve. Their prognostic value in advanced heart failure is unknown. Methods: Cardiopulmonary exercise testing and echocardiography with assessment of GWI and GCW was performed in patients with advanced heart failure caused by ischemic heart disease or dilated cardiomyopathy (n = 105). They were then followed up repeatedly. The combined endpoint was all-cause death, implantation of a left ventricular assist device, or heart transplantation. Results: The median patient age was 54 years (interquartile range [IQR]: 48-59.9). The mean left ventricular ejection fraction was 27.8 ± 8.2%, the median NT-proBNP was 1,210 pg/ml (IQR: 435-3,696). The mean GWI was 603 ± 329 mmHg% and the mean GCW was 742 ± 363 mmHg%. The correlation between peak oxygen uptake and GWI as well as GCW was strongest in patients with ischemic cardiomyopathy (r = 0.56, p = 0.001 and r = 0.53, p = 0.001, respectively). The median follow-up was 16 months (IQR: 12-18.5). Thirty one patients met the combined endpoint: Four patients died, eight underwent transplantation, and 19 underwent implantation of a left ventricular assist device. In the multivariate Cox regression analysis, only NYHA class, NT-proBNP and GWI (hazard ratio [HR] for every 50 mmHg%: 0.85; 95% CI: 0.77-0.94; p = 0.002) as well as GCW (HR for every 50 mmHg%: 0.86; 95% CI: 0.79-0.94; p = 0.001) were identified as independent predictors of the endpoint. The cut-off value for predicting the outcome was 455 mmHg% for GWI (AUC: 0.80; p < 0.0001; sensitivity 77.4%; specificity 71.6%) and 530 mmHg% for GCW (AUC: 0.80; p < 0.0001; sensitivity 74.2%; specificity 78.4%). Conclusions: GWI and GCW are powerful predictors of outcome in patients with advanced heart failure.

Project description:AIMS:Increase of cardiac cAMP bioavailability and PKA activity through adenylyl-cyclase 8 (AC8) overexpression enhances contractile function in young transgenic mice (AC8TG). Ageing is associated with decline of cardiac contraction partly by the desensitization of ?-adrenergic/cAMP signalling. Our objective was to evaluate cardiac cAMP signalling as age increases between 2?months and 12?months and to explore whether increasing the bioavailability of cAMP by overexpression of AC8 could prevent cardiac dysfunction related to age. METHODS AND RESULTS:Cardiac cAMP pathway and contractile function were evaluated in AC8TG and their non-transgenic littermates (NTG) at 2- and 12 months old. AC8TG demonstrated increased AC8, PDE1, 3B and 4D expression at both ages, resulting in increased phosphodiesterase and PKA activity, and increased phosphorylation of several PKA targets including sarco(endo)plasmic-reticulum-calcium-ATPase (SERCA2a) cofactor phospholamban (PLN) and GSK3?/? a main regulator of hypertrophic growth and ageing. Confocal immunofluorescence revealed that the major phospho-PKA substrates were co-localized with Z-line in 2-month-old NTG but with Z-line interspace in AC8TG, confirming the increase of PKA activity in the compartment of PLN/SERCA2a. In both 12-month-old NTG and AC8TG, PLN and GSK3?/? phosphorylation was increased together with main localization of phospho-PKA substrates in Z-line interspaces. Haemodynamics demonstrated an increased contractile function in 2- and 12-month-old AC8TG, but not in NTG. In contrast, echocardiography and tissue Doppler imaging (TDI) performed in conscious mice unmasked myocardial dysfunction with a decrease of systolic strain rate in both old AC8TG and NTG. In AC8TG TDI showed a reduced strain rate even in 2-month-old animals. Development of age-related cardiac dysfunction was accelerated in AC8TG, leading to heart failure (HF) and premature death. Histological analysis confirmed early cardiomyocyte hypertrophy and interstitial fibrosis in AC8TG when compared with NTG. CONCLUSION:Our data demonstrated an early and accelerated cardiac remodelling in AC8TG mice, leading to the development of HF and reduced lifespan. Age-related reorganization of cAMP/PKA signalling can accelerate cardiac ageing, partly through GSK3?/? phosphorylation.

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.

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Assessment of Myocardial Work in Cancer Therapy-Related Cardiac Dysfunction and Analysis of CTRCD Prediction by Echocardiography.

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