Role of Oxidative Stress in the Mechanisms of Anthracycline-Induced Cardiotoxicity: Effects of Preventive Strategies.

Anthracycline-induced cardiotoxicity (AIC) persists as a significant cause of morbidity and mortality in cancer survivors. Although many protective strategies have been evaluated, cardiotoxicity remains an ongoing threat. The mechanisms of AIC remain unclear; however, several pathways have been proposed, suggesting a multifactorial origin. When the central role of topoisomerase 2ß in the pathophysiology of AIC was described some years ago, the classical reactive oxygen species (ROS) hypothesis shifted to a secondary position. However, new insights have reemphasized the importance of the role of oxidative stress-mediated signaling as a common pathway and a critical modulator of the different mechanisms involved in AIC. A better understanding of the mechanisms of cardiotoxicity is crucial for the development of treatment strategies. It has been suggested that the available therapeutic interventions for AIC could act on the modulation of oxidative balance, leading to a reduction in oxidative stress injury. These indirect antioxidant effects make them an option for the primary prevention of AIC. In this review, our objective is to provide an update of the accumulated knowledge on the role of oxidative stress in AIC and the modulation of the redox balance by potential preventive strategies.

Serum uric acid is associated with increased risk of posttransplantation diabetes in kidney transplant recipients: a prospective cohort study.

BACKGROUND: Serum uric acid (SUA) is associated with fasting glucose in healthy subjects, and prospective epidemological studies have shown that elevated SUA is associated with increased risk of type 2 diabetes. Whether SUA is independently associated with higher risk of posttransplantation diabetes mellitus (PTDM) in kidney transplant recipients (KTR) remains unknown. METHODS: We performed a longitudinal cohort study of 524 adult KTR with a functioning graft ≥1-year, recruited at a university setting (2008-2011). Multivariable-adjusted Cox proportional-hazards regression analyses were performed to assess the association between time-updated SUA and risk of PTDM (defined according the American Diabetes Association's diagnostic criteria). RESULTS: Mean (SD) SUA was 0.43 (0.11) mmol/L at baseline. During 5.3 (IQR, 4.1-6.0) years of follow-up, 52 (10%) KTR developed PTDM. In univariate prospective analyses, SUA was associated with increased risk of PTDM (HR 1.75, 95% CI 1.36-2.26 per 1-SD increment; P < 0.001). This finding remained materially unchanged after adjustment for components of the metabolic syndrome, lifestyle, estimated glomerular filtration rate, immunosuppressive therapy, cytomegalovirus and hepatitis C virus infection (HR 1.89, 95% CI 1.32-2.70; P = 0.001). These findings were consistent in categorical analyses, and robust in sensitivity analyses without outliers. CONCLUSIONS: In KTR, higher SUA levels are strongly and independently associated with increased risk of PTDM. Our findings are in agreement with accumulating evidence supporting SUA as novel independent risk marker for type 2 diabetes, and extend the evidence, for the first time, to the clinical setting of outpatient KTR.

Potential use of n-3 PUFAs to prevent oxidative stress-derived ototoxicity caused by platinum-based chemotherapy.

Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.

[The cardiovascular impact of cancer control therapy]. / Impacto cardiovascular secundario a la terapia para el control del cáncer.

Cardiovascular diseases and cancer account for 27 and 25% of mortality in Chile, respectively. In the last decades, survival of people with cancer has improved due to preventive programs, early detection strategies, advances in technology and development of new antineoplastic therapies. Consequently, a progressive number of cancer-surviving patients have been generated, who may develop cardiovascular diseases, secondary to the same cancer therapy. Cardio-Oncology has emerged as the necessary link between both specialties to promote the prevention and early detection of cardiac complications, in patients undergoing oncological therapies. The aim is to curb cardiovascular complications. Also, to acquire knowledge about the mechanisms and effects of drugs that lead to heart damage aiming to develop efficient cardioprotective therapies. In this article we review and propose a didactic organization and classification of the main cardiovascular effects of cancer control therapy. We recognize that there is still a knowledge gap in basic sciences about the mechanisms that underlie these alterations.

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).

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 ß-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 ß-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.

Impacto cardiovascular secundario a la terapia para el control del cáncer / The cardiovascular impact of cancer control therapy

Cardiovascular diseases and cancer account for 27 and 25% of mortality in Chile, respectively. In the last decades, survival of people with cancer has improved due to preventive programs, early detection strategies, advances in technology and development of new antineoplastic therapies. Consequently, a progressive number of cancer-surviving patients have been generated, who may develop cardiovascular diseases, secondary to the same cancer therapy. Cardio-Oncology has emerged as the necessary link between both specialties to promote the prevention and early detection of cardiac complications, in patients undergoing oncological therapies. The aim is to curb cardiovascular complications. Also, to acquire knowledge about the mechanisms and effects of drugs that lead to heart damage aiming to develop efficient cardioprotective therapies. In this article we review and propose a didactic organization and classification of the main cardiovascular effects of cancer control therapy. We recognize that there is still a knowledge gap in basic sciences about the mechanisms that underlie these alterations.

Viable Pregnancy in a patient with metastatic melanoma treated with double checkpoint immunotherapy.

Metastatic cancers during pregnancy have historically been associated with dismal outcomes, with greater rates of tumor progression in part because of diminished treatment alternatives. Immunotherapy with T-cell checkpoint inhibitors has significantly impacted the survival of several metastatic tumors. However, given their mechanism of action, immune-related adverse events can occur, especially with combined immunotherapy treatments. During pregnancy, checkpoint pathways have a major role, providing immune tolerance to the fetal allograft. Furthermore, evidence suggests that inhibition of this pathway may be associated with an increased risk of miscarriage. We describe, to our knowledge, the first case reported in the literature of a patient 7 weeks pregnant, diagnosed with metastatic melanoma and treated with nivolumab plus ipilimumab. We also present the associated immune-related side effects and their treatment, as well as the oncologic results that lead to favorable pregnancy outcome.

A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma.

LESSONS LEARNED: Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. BACKGROUND: Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. METHODS: We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination. RESULTS: The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). CONCLUSION: The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.

Effects of a novel ascorbate-based protocol on infarct size and ventricle function in acute myocardial infarction patients undergoing percutaneous coronary angioplasty.

INTRODUCTION: This study was designed to test the hypothesis that high-dose ascorbate prior to reperfusion followed by low chronic oral doses ameliorate myocardial reperfusion injury (MRI) in acute myocardial infarction patients subjected to primary percutaneous coronary angioplasty (PCA). MATERIAL AND METHODS: A randomized double-blind placebo-controlled and multicenter clinical trial was performed on acute myocardial infarction (AMI) patients who underwent PCA. Sodium ascorbate (320 mmol/l, n = 53) or placebo (n = 46) was infused 30 min prior to PCA. Blood samples were drawn at enrolment (M1), after balloon deflation (M2), 6-8 h after M2 (M3) and at discharge (M4). Total antioxidant capacity of plasma (ferric reducing ability of plasma - FRAP), erythrocyte reduced glutathione (GSH) and plasma ascorbate levels were determined in blood samples. Cardiac magnetic resonance (CMR) was performed at 7-15 days and 2-3 months following PCA. Ninety-nine patients were enrolled. In 67 patients, the first CMR was performed, and 40 patients completed follow-up. RESULTS: The ascorbate group showed significantly higher ascorbate and FRAP levels and a decrease in the GSH levels at M2 and M3 (p < 0.05). There were no significant differences in the infarct size, indexed end-systolic volume and ejection fraction at both CMRs. There was a significant amelioration in the decreased ejection fraction between the first and second CMR in the ascorbate group (p < 0.05). CONCLUSIONS: Ascorbate given prior to reperfusion did not show a significant difference in infarct size or ejection fraction. However, it improved the change in ejection fraction determined between 7-15 days and 2-3 months. This result hints at a possible functional effect of ascorbate to ameliorate MRI.

The population impact of obesity, sedentary lifestyle, and tobacco and alcohol consumption on the prevalence of type 2 diabetes: Analysis of a health population survey in Chile, 2010.

AIM: To estimate the impact of tobacco use, sedentary lifestyle, obesity and alcohol consumption on type 2 diabetes mellitus (T2DM) prevalence in the Chilean population. METHODS: The study-included 5,293 subjects with fasting glycaemia levels from the nationwide cross-sectional health survey in 2010, commissioned by the Ministry of Health, Chile. Crude and Adjusted Odds Ratio to T2DM and its corresponding 95% confidence interval were estimated through logistic regressions. Attributable fractions and population attributable fractions were estimated. RESULTS: T2DM prevalence was 9.5%. Sedentary lifestyles and obesity were significant risk factors for T2DM. 52,4% of T2DM could be avoided if these individuals were not obese, and at a population level, 23% of T2DM could be preventable if obesity did not exist. A 64% of T2DM is explained by sedentariness, and if people would become active, a 62,2% of the cases of diabetes could be avoided. INTERPRETATION: About 79% of T2DM cases in Chile could be prevented with cost-effective strategies focused on preventing sedentary lifestyle and obesity. It's therefore urgent to implement evidence-based public health polices, aimed to decrease the prevalence of T2DM, by controlling its risk factors and consequently, reducing the complications from T2DM.

Amelioration of persistent left ventricular function impairment through increased plasma ascorbate levels following myocardial infarction.

PURPOSE: Percutaneous coronary angioplasty (PCA) has been demonstrated to reduce mortality and morbidity and thereby improve the prognosis of patients undergoing acute myocardial infarctions (AMIs). However, this procedure paradoxically increases the initial damage as the result of a condition known as 'myocardial reperfusion injury'. Oxidative stress may contribute to the mechanism of this injury. The goal of the present study was to ascertain whether high plasma ascorbate levels could ameliorate the reperfusion injuries that occur after the successful restoration of blood flow. METHODS: Patients from three clinical centers of the public health system were included in the study. The groups were formed by either-sex patients with a diagnosis of ST-segment elevation myocardial infarction with an indication for primary PCA. Only the patients who presented with their first myocardial infarction were enrolled. Ascorbate was administered through an infusion given prior to the restoration of the coronary flow, which was then followed by oral treatment with vitamin C (500 mg/12 hours) plus vitamin E (400 IU/day) for 84 days. The left ventricular ejection fraction (LVEF) was determined by using cardiac magnetic resonance on days 6 and 84 following the onset of the reperfusion. In addition, the microvascular function was assessed by an angiographic evaluation using the Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG). The results were grouped according to the plasma ascorbate concentration achieved immediately following the onset of reperfusion into either the HA group (high ascorbate, >1 mmol/l) or the LA group (low ascorbate, <1 mmol/l). The biochemical parameters were analyzed throughout the protocol. RESULTS: The LVEF of the HA group was significantly higher than that of the LA group, values on day 84 in the HA group were 33% higher than those of the LA group. The amelioration of the LVEF was accompanied by an improvement in the microvascular dysfunction, after PCA, 95% of the patients in the HA group achieved a TMPG of 2-3, in the LA group only 79% of patients showed a TMPG of 2-3. CONCLUSIONS: These data are consistent with the protective effect of high plasma levels of ascorbate against the oxidative challenge caused by reperfusion injury in patients subjected to PCA following an AMI. Further studies are needed to elucidate the mechanism accounting for this beneficial antioxidant effect.

Public Health Perspectives on Aquaculture.

Nearly half of all seafood consumed globally comes from aquaculture, a method of food production that has expanded rapidly in recent years. Increasing seafood consumption has been proposed as part of a strategy to combat the current non-communicable disease (NCD) pandemic, but public health, environmental, social, and production challenges related to certain types of aquaculture production must be addressed. Resolving these complicated human health and ecologic trade-offs requires systems thinking and collaboration across many fields; the One Health concept is an integrative approach that brings veterinary and human health experts together to combat zoonotic disease. We propose applying and expanding the One Health approach to facilitate collaboration among stakeholders focused on increasing consumption of seafood and expanding aquaculture production, using methods that minimize risks to public health, animal health, and ecology. This expanded application of One Health may also have relevance to other complex systems with similar trade-offs.

The effectiveness of antioxidant vitamins C and E in reducing myocardial infarct size in patients subjected to percutaneous coronary angioplasty (PREVEC Trial): study protocol for a pilot randomized double-blind controlled trial.

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of mortality worldwide. Oxidative stress has been involved in the ischemia-reperfusion injury in AMI. It has been suggested that reperfusion accounts for up to 50% of the final size of a myocardial infarct, a part of the damage likely to be prevented.Therefore, we propose that antioxidant reinforcement through vitamins C and E supplementation should protect against the ischemia-reperfusion damage, thus decreasing infarct size.The PREVEC Trial (Prevention of reperfusion damage associated with percutaneous coronary angioplasty following acute myocardial infarction) seeks to evaluate whether antioxidant vitamins C and E reduce infarct size in patients subjected to percutaneous coronary angioplasty after AMI. METHODS/DESIGN: This is a randomized, 1:1, double-blind, placebo-controlled clinical trial.The study takes place at two centers in Chile: University of Chile Clinical Hospital and San Borja Arriarán Clinical Hospital.The subjects will be 134 adults with acute myocardial infarction with indication for percutaneous coronary angioplasty.This intervention is being performed as a pilot study, involving high-dose vitamin C infusion plus oral administration of vitamin E (Vitamin-treatment group) or placebo (Control group) during the angioplasty procedure. Afterward, the Vitamin-treatment group receives oral doses of vitamins C and E, and the Control group receives placebo for 84 days after coronary angioplasty.Primary outcome is infarct size, assessed by cardiac magnetic resonance (CMR), measured 6 and 84 days after coronary angioplasty.Secondary outcomes are ejection fraction, measured 6 and 84 days after coronary angioplasty with CMR, and biomarkers for oxidative stress, antioxidant status, heart damage, and inflammation, which will be measured at baseline, at the onset of reperfusion, 6 to 8 hours after revascularization, and at hospital discharge. DISCUSSION: The ischemia-reperfusion event occurring during angioplasty is known to increase myocardial infarct size. The cardioprotective benefits of high doses of vitamin C combined with vitamin E have not been fully explored. The PREVEC Trial seeks to determine the suitability of the therapeutic use of vitamins C and E against the reperfusion damage produced during angioplasty.Patient recruitment opened in February 2013. The trial is scheduled to end in March 2016. TRIAL REGISTRATION: ISRCTN56034553.

A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement.

OBJECTIVES: This study was designed to assess whether the reinforcement of the antioxidant system, through n-3 fatty acids plus antioxidant vitamin supplementation, could reduce the incidence of post-operative atrial fibrillation. BACKGROUND: Therapy to prevent post-operative atrial fibrillation remains suboptimal. Although oxidative stress plays a key role in the pathogenesis of this arrhythmia, antioxidant reinforcement has produced controversial results. METHODS: A total of 203 patients scheduled for on-pump cardiac surgery were randomized to placebo or supplementation with n-3 polyunsaturated fatty acids (2 g/day) (eicosapentaenoic acid:docosahexaenoic acid ratio 1:2), vitamin C (1 g/day), and vitamin E (400 IU/day). The primary outcome was the occurrence of post-operative atrial fibrillation. Secondary outcomes were the biomarkers related to oxidative stress and inflammation. RESULTS: Post-operative atrial fibrillation occurred in 10 of 103 patients (9.7%) in the supplemented group versus 32 of 100 patients (32%) in the placebo group (p < 0.001). Early after surgery, placebo patients presented with increased levels of biomarkers of inflammation and oxidative stress, which were markedly attenuated by antioxidant supplementation. The activity of catalase, superoxide dismutase, and glutathione peroxidase in atrial tissue of the supplemented patients was 24.0%, 17.1%, and 19.7% higher than the respective placebo values (p < 0.05). The atrial tissue of patients who developed atrial fibrillation showed NADPH oxidase p47-phox subunit protein and mRNA expression 38.4% and 35.7% higher, respectively, than patients in sinus rhythm (p < 0.05). CONCLUSIONS: This safe, well-tolerated, and low-cost regimen, consisting of n-3 polyunsaturated fatty acids plus vitamins C and E supplementation, favorably affected post-operative atrial fibrillation, increased antioxidant potential, and attenuated oxidative stress and inflammation. (Prevention of Post-Operative Atrial Fibrillation: Pathophysiological Characterization of a Pharmacological Intervention Based on a Novel Model of Nonhypoxic Pre-Conditioning; ISRCTN45347268).

Biosynthesis and bioavailability of long-chain polyunsaturated fatty acids in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has a high occurrence in most countries. Recent studies estimate its prevalence to be near 30% in United States, Italian and Japanese general adult populations. NAFLD commonly presents along with obesity and insulin resistance (IR), pathologies that share with NAFLD metabolic and inflammatory components. These conditions, particularly NAFLD, are associated with alterations in the bioavailability of long-chain polyunsaturated fatty acids (LCPUFAs). In the human population, the bioavailability of LCPUFAs depends both on endogenous biosynthesis and diet amount of preformed LCPUFAs. However, the lower liver LCPUFAs product/precursor ratio namely (20:5n-3+22:6n-3)/18:3n-3, 20:4n-6/18:2n-6 present in common Western diets, makes critical an adequate pathway activity to ensure minimum bioavailability of LCPUFAs in most Western populations. The key step of this biosynthesis involves Δ5 and Δ6-desaturases, whose activities are altered in NAFLD. During the disease, the presence of molecular activators of these two enzymes does not correlate with the scarce LCPUFAS biosynthesis observed. The key to this apparent contradiction, or at least part of it, could be explained on the basis of the possible sensitivity of the desaturases to oxidative stress; a metabolic condition strongly linked to inflammatory pathologies such as NAFLD, obesity and IR and that, according to latest research, not only would be consequence but also possibly a cause of these diseases. The present review is focused on the relationship between NAFLD and the bioavailability of LCPUFAs, with special reference to the role that oxidative stress could play in the modulation of the liver fatty acid desaturase activity.