Changes in blood metabolomes as potential markers for severity and prognosis in doxorubicin-induced cardiotoxicity: a study in HER2-positive and HER2-negative breast cancer patients.

BACKGROUND: We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined. METHODS: HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels. RESULTS: Cardiac injury and systolic dysfunction 2 weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment. CONCLUSIONS: The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity. TRIAL REGISTRATION: The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.

Sodium-Glucose Cotransporter 2 Inhibitors During Cancer Therapy: Benefits, Risks, and Ongoing Clinical Trials.

PURPOSE OF REVIEW: The goal of this paper is to summarize the data pertaining to the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) for the prevention of cardiotoxicity in patients receiving anthracyclines for cancer treatment. We discuss the potential efficacy of this class of medications, incorporating insights from existing literature and ongoing studies. RECENT FINDINGS: SGLT2i are a class of medications which were initially developed for treatment of Type 2 diabetes and later extended to treat heart failure with reduced and preserved ejection fraction regardless of diabetes status. There remains a need for effective and safe treatments to preventing cardiotoxicity in anthracycline-treated patients. It has been proposed that SGLT2i may provide protection against the cardiotoxic effects of anthracyclines. Some of the proposed mechanisms include beneficial metabolic, neurohormonal, and hemodynamic effects, renal protection, as well as a decrease in inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ion homeostasis. There is emerging evidence from basic science and observational studies that SGLT2i may play a role in the prevention of chemotherapy-induced cardiotoxicity. Randomized controlled trials are needed to conclusively determine the role of SGLT2 inhibitors as a cardioprotective therapy in patients receiving anthracyclines for the treatment of cancer.

Effect of Beta-Blocker on Long-Term Major Cardiovascular Events in High Atherosclerotic Risk Population.

PURPOSE: Beta-blocker is a frequently used medication in cardiovascular diseases. However, long-term benefit of beta-blocker in patients with preserved left ventricular ejection function (LVEF) on major adverse cardiovascular events (MACEs) is uncertain. METHODS: The Cohort Of patients with high Risk for cardiovascular Events (CORE-Thailand) was a prospective study that enrolled Thai patients with high atherosclerotic risk including multiple atherosclerotic risk factors and established atherosclerotic cardiovascular diseases. Baseline demographic data, co-morbidities and medication were recorded. Patients were followed for 5 years. Patients with LVEF<50% were excluded. Primary outcome was the effect of beta-blocker on the occurrence of MACEs including all-cause death, non-fatal myocardial infarction and non-fatal stroke (3P-MACEs). Propensity score matching was used to control confounding factors. RESULTS: There was a total of 8513 patients in the pre-matched cohort, 4418 were taking beta-blocker and 4095 were not. After adjustment of confounders, beta-blocker was an independent predictor of 3P-MACEs (adjusted HR 1.29;95% CI 1.12-1.49;p<0.001). After propensity score matching, 4686 patients remained in the post-matched cohort. Propensity score analysis showed consistent results in which patient taking beta-blocker had higher risk of 3P-MACEs (adjusted HR 1.29;95% CI 1.10-1.53;p=0.002). Subgroup analysis in patients with coronary artery disease (CAD) indicated that taking beta-blocker did not increase the incidence of 3P-MACEs (adjusted HR 0.99;95% CI 0.76-1.29) while those without CAD did (adjusted HR 1.51; 95% CI, 1.22-1.86;p-interaction=0.015). CONCLUSION: In patients with high atherosclerotic cardiovascular risk, taking beta-blockers had a higher risk of 3P-MACEs. Care should be taken when prescribing beta-blockers to patients without a clear indication. TRIAL REGISTRATION: TCTR20130520001 registered in Thai Clinical Trials Registry (TCTR) https://www.thaiclinicaltrials.org/ , date of registration 20 May 2013.

The long-term efficacy in blood transfusions, hematologic parameter changes, and complications after splenectomy in patients with transfusion-dependent thalassemia.

BACKGROUND: A splenectomy can reduce transfusion requirements in patients with thalassemia. However, the role of a splenectomy remains controversial because its efficacy has not yet been fully determined and there are concerns over potential complications. The purpose of this study was to assess the efficacy, potential changes in hematologic parameters, and any complications associated with splenectomy. METHODS: Medical records of 50 patients with transfusion-dependent thalassemia (TDT) who had undergone a splenectomy, along with those of 20 control subjects with intact spleens, were retrospectively reviewed. RESULTS: The primary outcomes indicate the efficacy of a splenectomy in reducing red cell transfusions. Fifty TDT post-splenectomy patients were included in this study, of which 28 (56%) were female. The median age of all patients was 20.5 (18-28 years of age). Twenty-seven patients (54%) transformed from TDT to non-transfusion-dependent thalassemia (NTDT) after the splenectomy; 100% with Hb H disease, 58.3% with beta-thalassemia/Hb E disease, and 23.5% with homozygous beta-thalassemia. According to multivariable logistic regression analysis, Hb H disease (adjusted OR 55.23, 95% CI 1.35-22.8.10) and receiving a splenectomy at > ten years of age (adjusted OR 25.36, 95% CI 1.62-396.47) were associated with higher responses. The prevalence of pulmonary hypertension and thromboembolic events were similar between the splenectomy patients and non-splenectomy patients. CONCLUSION: Splenectomy reduced transfusion requirements in TDT patients. The predictive factors as a response to a splenectomy included Hb H disease amongthose receiving a splenectomy at > ten years of age.

Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions.

Anthracyclines is an effective chemotherapeutic treatment used for many types of cancer. However, high cumulative dosage of anthracyclines leads to cardiac toxicity and heart failure. Dysregulation of mitochondrial dynamics and function are major pathways driving this toxicity. Several pharmacological and non-pharmacological interventions aiming to attenuate cardiac toxicity by targeting mitochondrial dynamics and function have shown beneficial effects in cell and animal models. However, in clinical practice, there is currently no standard therapy for the prevention of anthracycline-induced cardiotoxicity. This review summarizes current reports on the impact of anthracyclines on cardiac mitochondrial dynamics and mitochondrial function and potential interventions targeting these pathways. The roles of mitochondrial dynamics and mitochondrial function in the development of anthracycline-induced cardiotoxicity should provide insights in devising novel strategies to attenuate the cardiac toxicity induced by anthracyclines.

Changes in Mitochondrial Function and Cell Death Patterns in Peripheral Blood Mononuclear Cells during Trastuzumab Treatment Following Doxorubicin Chemotherapy.

Trastuzumab, a monoclonal antibody which works against human epidermal growth factor receptor 2 (HER2), possibly causes cardiotoxicity through mitochondrial dysfunction. The usefulness of isolated peripheral blood mononuclear cells (PBMCs) in the assessment of trastuzumab-induced cardiotoxicity remains uncertain. This study aimed to determine the temporal changes in mitochondrial function, oxidative stress, and cell death in the isolated PBMCs of HER2-positive breast cancer patients during breast cancer treatment and to compare the changes with HER2-negative breast cancer patients who did not receive trastuzumab therapy. Eighteen newly diagnosed HER2-positive breast cancer women who received sequential doxorubicin and trastuzumab were consecutively recruited. Age- and gender-matched controls with HER2-negative breast cancer were selected. Echocardiography was carried out, and blood samples for the study of cardiac biomarkers and PBMCs were collected periodically during treatment. Only one patient in our cohort developed asymptomatic left ventricular dysfunction during trastuzumab treatment. However, trastuzumab following doxorubicin aggravated subclinical cardiac injury, determined by cardiac troponin and echocardiography. Cellular and mitochondrial oxidative stress in isolated PBMCs remained unchanged throughout breast cancer treatment. Regarding mitochondrial respiration, the maximal respiration and spare respiration capacity was significantly increased in controls after doxorubicin treatment but not in patients who received trastuzumab therapy. Moreover, the percentage of apoptosis and necroptosis in isolated PBMCs was dramatically decreased in the control, compared to patients with trastuzumab treatment. In conclusion, trastuzumab caused subtle myocardial injury and impaired mitochondrial respiration and cell viability in isolated PBMCs.

Safety of Continuing Trastuzumab for Mild Cardiotoxicity: A Cardiovascular Magnetic Resonance Imaging Study.

The safety of continuing human epidermal growth factor receptor 2 (HER2)-targeted therapy in women with mild cardiotoxicity remains unclear. We performed a retrospective matched cohort study of 14 patients with human epidermal growth factor receptor 2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy, nested within the Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI (EMBRACE-MRI) trial. Among patients who developed cardiotoxicity and were treated with heart failure therapy, we compared those who had trastuzumab therapy interrupted to a matched cohort who continued trastuzumab therapy. By a median of 2.5 years of follow-up, no significant differences were present between the groups in the proportion with magnetic resonance imaging-measured left ventricular ejection fraction < 40%, magnetic resonance imaging-measured left ventricular volumes, left ventricular ejection fraction, edema, fibrotic markers, cardiopulmonary fitness, or quality of life.

La question de savoir s'il est sûr de poursuivre le traitement par un médicament ciblant le récepteur 2 du facteur de croissance épidermique humain (HER2) en présence d'une légère cardiotoxicité chez la femme demeure controversée. Nous avons réalisé une étude de cohortes appariées rétrospective auprès de 14 patientes atteintes d'un cancer du sein positif pour le HER2 qui recevaient un traitement séquentiel par l'anthracycline et le trastuzumab, dans le cadre du programme EMBRACE-MRI ( E valuation of M yocardial Changes During Br east A denocarcinoma Therapy to Detect C ardiotoxicity E arlier With MRI ). Parmi les patientes ayant développé une cardiotoxicité et ayant reçu un traitement pour l'insuffisance cardiaque, nous avons comparé celles dont le traitement par le trastuzumab a été interrompu à une cohorte appariée ayant poursuivi ce traitement. Après un suivi médian de 2,5 ans, aucune différence significative n'avait été observée entre les groupes en ce qui concerne le pourcentage de patientes dont la fraction d'éjection ventriculaire gauche était inférieure à 40 % à l'imagerie par résonance magnétique (IRM), le volume ventriculaire gauche à l'IRM, la fraction d'éjection ventriculaire gauche, l'œdème, les marqueurs fibrotiques, la bonne forme physique de l'appareil cardio-pulmonaire ou la qualité de vie.

Predictive value of heart rate variability on long-term mortality in end-stage kidney disease on hemodialysis.

Autonomic disturbance is common in end-stage kidney disease (ESKD). Heart rate variability (HRV) is a useful tool to assess autonomic function. We aimed to evaluate the predictive value of HRV on all-cause mortality and explore the proper timing of HRV assessment. This prospective cohort study enrolled 163 ESKD on hemodialysis patients from April-December 2018. HRV measurements were recorded ten minutes before hemodialysis, four hours during hemodialysis, and ten minutes after hemodialysis. Clinical parameters and all-cause mortality were recorded. Cox-proportional hazard regression was used for statistical analysis. After a median follow up of 40 months, 37 (22.7%) patients died. Post-dialysis HRV parameters including higher very low frequency (VLF) (hazard ratio [HR], 0.881; 95%confidence interval [CI], 0.828-0.937; p<0.001), higher normalized low frequency (nLF) (HR, 0.950; 95%CI, 0.917-0.984; p = 0.005) and higher LF/HF ratio (HR, 0.232; 95%CI, 0.087-0.619; p = 0.004) were the independent predictors associated with lower risk for all-cause mortality. Higher post-dialysis normalized high frequency (nHF) increased risk of mortality (HR, 1.051; 95%CI, 1.015-1.089; p = 0.005). HRV parameters at pre-dialysis and during dialysis were not predictive for all-cause mortality. The area under receiver operating characteristic curve (AuROC) of VLF for survival was highest compared to other HRV parameters at post-dialysis period (AuROC 0.71; 95% CI; 0.62-0.79; p<0.001). In conclusion, post-dialysis HRV parameters predicted all-cause mortaliy in ESKD. VLF measured at post-dialysis exhibited best predictive value for survival in chronic hemodialysis patients.

Effect of renin angiotensin system inhibitors on long-term major cardiovascular outcomes in patients with high atherosclerotic cardiovascular risk.

The advantage of angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) in patients with preserved LV systolic function is uncertain. We aimed to investigate the effects of ACEI/ARB in high atherosclerotic risk patients without overt heart failure (HF) on long-term major cardiovascular outcomes (MACEs). The Cohort Of patients with high Risk for cardiovascular Events (CORE-Thailand) registry is a prospective, multicenter, observational, longitudinal study of Thai patients with high atherosclerotic risk. The patients with ejection fraction < 50% were excluded. Among 8513 recruited patients, there were 4246 patients included into final analysis after propensity score matching. At 5-years follow-up, Cox regression analysis showed that ACEI/ARB was significantly associated with reduced risk of all-cause mortality or non-fatal myocardial infarction, non-fatal stroke and HF hospitalization (HR 0.82, 95% CI 0.70-0.96, P = 0.011). The benefit was driven by the reduced all-cause mortality and HF. Subgroup analysis demonstrated that ACEI/ARB decreased risk of long-term MACEs in patients with diabetes (HR 0.77, 95% CI 0.63-0.94, P = 0.011) and patients not taking statin (HR 0.57, 95% CI 0.40-0.82, P = 0.002). We demonstrated that the use of ACEI/ARB was associated with reduced risk of long-term MACEs in a large cohort of high atherosclerotic risk patients. Reduction of all-cause mortality and HF were likely the main contributors to the benefit of ACEI/ARB.

Aspirin for primary prevention in patients with high cardiovascular risk: insights from CORE-Thailand registry.

Aspirin may be considered for primary prevention in non-elderly patients with high cardiovascular risk. However, contemporary management aimed at aggressive cardiovascular risk factor control may alter benefit-risk ratio of aspirin. Therefore, we aimed to examine the effect of aspirin for primary prevention on the long-term MACEs in a large cohort registry. Cohort Of patients with high Risk for cardiovascular Events (CORE-Thailand) registry is a prospective, multicenter, observational, longitudinal study of Thai patients with high atherosclerotic risk. Patients with established atherosclerotic cardiovascular diseases were excluded. Among 4259 patients with multiple cardiovascular risk factors, 1945 (45.7%) patients used aspirin. After propensity score matching, there were 3228 patients remained in post-matching analysis. During the median follow-up period of 58.2 months, we demonstrated that aspirin use increased risk of long-term MACEs in pre-matching cohort (unadjusted HR 1.76, 95% CI 1.43-2.17, P < 0.001) and post-matching cohort (HR 1.66 (1.31-2.10), P < 0.001). In addition, patients taking aspirin had a higher risk of bleeding than non-aspirin users in pre-matching cohort (unadjusted HR 2.28, 95% CI 1.09-4.75, P = 0.028). We demonstrated that aspirin was associated with increased risk of long-term MACEs in patients with multiple cardiovascular risk factors. Due to the non-randomized design, our results should be interpreted with caution.

Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer: a randomized controlled trial.

Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.

Prognostic Value of Ankle-Brachial Index in Prediction of Cardiovascular Events in an Asian Population with Multiple Atherosclerotic Risk Factors.

We aimed to evaluate the incremental prognostic value after incorporation of the ankle-brachial index (ABI) into the 10-year pool cohort equation (PCE) risk model in patients with multiple risk factors (MRFs). A total of 4332 MRFs patients were divided into 2 groups as ABI ≤.9 or >.9. The primary outcome was hard cardiovascular events (hCVE: including cardiovascular death, myocardial infarction, or ischemic stroke) over a median follow-up of 36 months. The Cox proportional hazards survival model, C-statistic, and net reclassification indices (NRI) were used. The occurrence of the primary outcome in the ABI ≤.9 group (3.7%) was significantly greater than in the ABI > .9 group (1.3%), P < .001. ABI is an independent predictor of hCVE in addition to the variables in the standard risk model (age, gender, and smoking status). ABI modestly improved the C-index when added to the PCE risk model (PCE .70 vs ABI+PCE .74). The addition of ABI to the PCE risk model did not significantly improve the classification of patients (NRI -.029; 95% CI: -.215 to .130). Despite ABI being one of the independent predictors of hCVE, integration of ABI into the PCE model did not improve the efficacy of risk reclassification in patients with MRFs.

Prognostic values of high sensitivity cardiac troponin T and I for long-term mortality in hemodialysis patients.

Previous studies using contemporary cardiac troponin (cTn) assays have shown conflicting results in predictability of mortality and major adverse cardiovascular events (MACEs) in hemodialysis patients. We aimed to evaluate the prognostic values of high-sensitivity cTnT (hs-cTnT) and hs-cTnI for long-term mortality and MACEs in asymptomatic chronic hemodialysis patients. 198 asymptomatic patients undergoing regular hemodialysis (age 62.4 ± 14.8 years) were enrolled. Pre-dialysis hs-cTnT and hs-cTnI levels were measured. The study outcomes were long-term all-cause mortality and MACEs. Median values of hs-cTnT and hs-cTnI were 61.1 ng/L (IQR 36.6-102.0) and 18.4 ng/L (IQR 9.5-36.6), respectively. During a median follow-up of 13.5 months, 30 (15.1%) patients developed MACEs, and 20 (10.1%) patients died. The patients in highest quartile of hs-cTnT level (≥ 102 ng/L) had increased risk of long-term mortality (HR 3.34; 95%CI 1.39-8.04, P = 0.005). However, hs-cTnI levels above highest quartile (≥ 36 ng/L) was not significantly associated with increased risk of all-cause mortality. Nevertheless, elevated level of hs-cTnT and hs-cTnI was associated with increased risk of MACEs. We demonstrated that higher level of hs-cTnT, but not hs-cTnI, was associated with increased risk of long-term mortality. Nevertheless, higher level of hs-cTnT and hs-cTnI both were associated with greater risk of long-term MACEs.