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Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial).

ABSTRACT: BACKGROUND:Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a ?-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the ?-blocker effect, could prevent related cardiotoxicity. However, carvedilol's antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo. METHODS/DESIGN:We designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing. DISCUSSION:We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo. TRIAL REGISTRATION:ISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.

SUBMITTER: Carrasco R

PROVIDER: S-EPMC7001267 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial).

Carrasco Rodrigo R Ramirez María Cristina MC Nes Kjersti K Schuster Andrés A Aguayo Rubén R Morales Marcelo M Ramos Cristobal C Hasson Daniel D Sotomayor Camilo G CG Henriquez Pablo P Cortés Ignacio I Erazo Marcia M Salas Claudio C Gormaz Juan G JG

Trials 20200204 1

<h4>Background</h4>Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a β-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the β-blocker effect, could prevent related cardiotoxicity. However, carvedilol's antioxidant effects are pr ...[more]

PMID: 32019575

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Project description:ObjectivesWe aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity.BackgroundDoxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists.MethodsLeft ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques.ResultsFive days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists.ConclusionsThese data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

Project description:BackgroundPast clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.Methods33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.FindingsA 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.InterpretationDementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers.Trial registrationNCT02541929.FundingHNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Project description:BackgroundTrastuzumab is highly effective for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer but is associated with a decline in left ventricular ejection fraction.ObjectivesThe purpose of this study was to determine whether angiotensin-converting enzyme inhibitors or beta-blockers reduce the rate of trastuzumab-induced cardiotoxicity (left ventricular ejection fraction decrease >10%, or >5% if below 50%) and limit treatment interruptions.MethodsIn this double-blind, multicenter, placebo-controlled trial, cardiotoxicity and treatment interruptions in patients with HER2-positive breast cancer treated with trastuzumab for 12 months were evaluated over a 2-year period. Patients were stratified by anthracycline use and then randomized to receive lisinopril, carvedilol, or placebo.ResultsThe study included 468 women, age 51 ± 10.7 years. For the entire cohort, cardiotoxicity was comparable in the 3 arms and occurred in 32% of patients on placebo, 29% on carvedilol, and 30% on lisinopril. For patients receiving anthracyclines, the event rates were higher in the placebo group (47%) than in the lisinopril (37%) and the carvedilol (31%) groups. Cardiotoxicity-free survival was longer on both carvedilol (hazard ratio: 0.49; 95% confidence interval: 0.27 to 0.89; p = 0.009) and lisinopril (hazard ratio: 0.53; 95% confidence interval: 0.30 to 0.94; p = 0.015) than on placebo. In the whole cohort, as well as in the anthracycline arm, patients on active therapy with either angiotensin-converting enzyme inhibitor or beta-blockers experienced fewer interruptions in trastuzumab than those on placebo.ConclusionsIn patients with HER2-positive breast cancer treated with trastuzumab, both lisinopril and carvedilol prevented cardiotoxicity in patients receiving anthracyclines. For such patients, lisinopril or carvedilol should be considered to minimize interruptions of trastuzumab. (Lisinopril or Coreg CR in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab; NCT01009918).

Project description:Doxorubicin (DOX), an effective chemotherapeutic drug, causes cardiotoxicity in a cumulative and dose-dependent manner. The aim of this study is to investigate the effects of hot-water extract of Capsella bursa-pastoris (CBW) on DOX-induced cardiotoxicity (DICT). We utilized H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells to evaluate the effects of CBW on DOX-induced cell death. Superoxide dismutase (SOD) levels, reactive oxygen species (ROS) production, and oxygen consumption rate were measured in H9c2 cells. C57BL/6 mice were treated with DOX and CBW to assess their impact on various cardiac parameters. Human-induced pluripotent stem-cell-derived cardiomyocytes were also used to investigate DOX-induced electrophysiological changes and the potential ameliorative effects of CBW. UPLC-TQ/MS analysis identified seven flavonoids in CBW, with luteolin-7-O-glucoside and isoorientin as the major compounds. CBW inhibited DOX-induced death of H9c2 rat cardiomyocytes but did not affect DOX-induced death of MDA-MB-231 human breast cancer cells. CBW increased SOD levels in a dose-dependent manner, reducing ROS production and increasing the oxygen consumption rate in H9c2 cells. The heart rate, RR interval, QT, and ST prolongation remarkably recovered in C57BL/6 mice treated with the combination of DOX and CBW compared to those in mice treated with DOX alone. Administration of CBW with DOX effectively alleviated collagen accumulation, cell death in mouse heart tissues, and reduced the levels of creatinine kinase (CK) and lactate dehydrogenase (LDH) in serum. Furthermore, DOX-induced pathological electrophysiological features in human-induced pluripotent stem-cell-derived cardiomyocytes were ameliorated by CBW. CBW may prevent DICT by stabilizing SOD and scavenging ROS. The presence of flavonoids, particularly luteolin-7-O-glucoside and isoorientin, in CBW may contribute to its protective effects. These results suggest the potential of CBW as a traditional therapeutic option to mitigate DOX-induced cardiotoxicity.

Project description:IntroductionMaternal-infant equilibrium occurs when cord blood docosahexaenoic acid (DHA) is less than or equal to maternal DHA at delivery. Equilibrium may be an indicator of sufficient DHA for optimal fetal and infant neurodevelopment. The purpose of this study was to test the effect of maternal DHA supplementation on equilibrium status and fetal neurodevelopment.MethodsWomen enrolled between 12 and 20 weeks gestation and were randomized to 200 or 800 mg DHA/day until delivery. Maternal red blood cell (RBC) phospholipids were measured at enrollment, 32 weeks, delivery, and in cord blood at delivery. Fetal neurodevelopment was measured at 32 and 36 weeks gestation. Intent-to-treat analyses were conducted to test differences in equilibrium status by group. Fetal outcomes were assessed by equilibrium status and group.ResultsThree hundred women enrolled and 262 maternal-infant dyads provided blood samples at delivery. No maternal-infant dyads with maternal RBC-DHA ≤ 6.96% at delivery achieved equilibrium. The incidence of equilibrium was significantly higher in the 800 mg group. There was no effect of maternal group or equilibrium status on fetal neurodevelopment.ConclusionThe significance of maternal-infant DHA equilibrium remains unknown. Ongoing research will test the effect of treatment group, equilibrium, and nutrient status on infant behavior and brain function.ImpactPregnant women who received a higher dose of docosahexaenoic acid (DHA) were more likely to achieve maternal-infant DHA equilibrium at delivery. Equilibrium status had no effect on fetal neurodevelopment in this sample. While DHA is crucial for early life neurodevelopment, the significance of achieving maternal-infant equilibrium above the lower threshold is uncertain. There is a lower threshold of maternal DHA status where maternal-infant DHA equilibrium never occurs. The lack of equilibrium associated with low maternal DHA status may indicate insufficient maternal status for optimal placental transfer.

Dataset Information

Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial).

Publications

Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial).

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