Pedro Monteiro

Drug-induced Cardiac Mitochondrial Toxicity and Protection: From Doxorubicin to Carvedilol

Mitochondria have long been involved in several cellular processes beyond its role in energy production. The importance of this organelle for cardiac tissue homeostasis has been greatly investigated and its impairment can lead to cell death and consequent organ failure. Several compounds have been described in the literature as having direct effects on cardiac mitochondria which can provide a mechanistic explanation for their toxicological or pharmacological effects. The present review describes one classic example of drug-induced cardiac mitochondrial toxicity and another case of drug-induced mitochondrial protection. For the former, we present the case for doxorubicin, an anticancer agent whose treatment is associated with a cumulative and dose-dependent cardiomyopathy with a mitochondrial etiology. Following this, we present the case of carvedilol, a β-blocker with intrinsic antioxidant activity, which has been described to protect cardiac mitochondria from oxidative injury. The final part of the review integrates information from the previous chapters, demonstrating how carvedilol can contribute to reduce doxorubicin toxicity on cardiac mitochondria. The two referred examples result in important take-home messages: a) drug-induced cardiac mitochondrial dysfunction is an important contributor for drug-associated organ failure, b) protection of mitochondrial function is involved in the beneficial impact of some clinically-used drugs and c) a more accurate prediction of toxic vs. beneficial effects should be an important component of drug development by the pharmaceutical industry.

Metformin Protects the Brain Against the Oxidative Imbalance Promoted by Type 2 Diabetes

We aimed to investigate whether metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. This study analyzed the effect of metformin on oxidative stress markers (thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA) and carbonyl groups), hydrogen peroxide (H(2)O(2)) levels, non-enzymatic antioxidant defenses [reduced (GSH) and oxidized (GSSG) glutathione and vitamin E] and enzymatic antioxidant defenses [glutathione peroxidase (GPx), glutathione reductase (GRed) and manganese superoxide dismutase (MnSOD)] in brain homogenates of diabetic GK rats, a model of type 2 diabetes. For this purpose we compared brain homogenates obtained from untreated GK rats versus GK rats treated with metformin during a period of 4 weeks. Brain homogenates obtained from Wistar rats were used as control. The MDA levels, GPx and GRed activities are significantly higher in untreated GK rats, while TBARS levels, carbonyl groups, glutathione content and vitamin E levels remain statistically unchanged when compared with control rats. In contrast, MnSOD activity and the levels of H(2)O(2) are significantly decreased in untreated GK rats when compared with control animals. However, metformin treatment normalized the majority of the parameters altered by diabetes. We observed that metformin, besides its antihyperglycemic action, induces a significant decrease in TBARS and MDA levels, GPx and GRed activities and a significant increase in GSH levels and MnSOD activity. These results indicate that metformin protects against diabetes-associated oxidative stress suggesting that metformin could be an effective neuroprotective agent.

Metformin Prevents Myocardial Reperfusion Injury by Activating the Adenosine Receptor

Metformin improves cardiovascular outcomes in patients with type 2 diabetes compared with other glucose-lowering drugs. Experimental studies have shown that metformin can increase the intracellular concentration of adenosine monophosphate, which is a major determinant of the intracellular formation of adenosine. We hypothesize that metformin, given at reperfusion, can limit myocardial infarct size due to increased adenosine receptor stimulation. Isolated perfused hearts from Sprague-Dawley rats were subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion. Perfusion with metformin (50 μM) for the first 15 minutes of reperfusion reduced infarct size (percent area at risk) from 42% ± 2% to 19% ± 4% (n ≥ 6; P < 0.01), which was blocked by a concomitant perfusion with the adenosine receptor antagonist 8-p-sulfophenyltheophylline (100 μM; 43% ± 3%) or nitrobenzylthioinosine (a blocker of transmembranous adenosine transport; 1 μM; 45% ± 5%). In addition, intravenous administration of metformin (5 mg/kg) reduced infarct size in a rat in situ model of myocardial infarction (34% ± 6% vs. 62% ± 5%; P < 0.01), which was completely abolished by 8-p-sulfophenyltheophylline (61% ± 3%). We conclude that metformin, given at reperfusion, reduces infarct size in a rat model of myocardial infarction, which is critically dependent on adenosine receptor stimulation, probably via increased intracellular formation of adenosine.

Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidaemia

Non‐alcoholic fatty liver disease (NAFLD) and type 2 diabetes are associated with dyslipidaemia, inflammation and oxidative stress. However, the pathophysiology of NAFLD in type 2 diabetes with hyperlipidaemia is not fully known, as well as the utility of the commonly prescribed anti‐diabetic and lipid‐lowering drugs in ameliorating liver injury markers.

Prognostic value of CA125 in advanced heart failure patients

INTRODUCTION Serum levels of CA125 are often high in advanced heart failure (AHF) patients. AIM To determine the predictive value of CA125 in forecasting the occurrence of death or cardiac transplantation in an AHF population. METHODS 88 AHF patients referred for heart transplantation were divided into 2 groups based on CA125 levels: normal (CA125<38 U/mL) and elevated (> or = 38 U/mL). Events (death or heart transplant) were monitored over a period of 13+/-7 months after CA125 determination. RESULTS Patients with elevated CA125 (n=65) had significantly lower blood pressure, body mass index, serum sodium and peak exercise oxygen consumption, while B-type natriuretic peptide levels were significantly higher. The combined primary endpoint (death or heart transplant) rate was 39.4% and 62.3% in normal and elevated CA125 groups, respectively (p=0.029). Multivariate regression analysis showed that CA125 and sodium levels were the only independent predictors of the combined endpoint. CONCLUSION In AHF patients, plasma CA125 was an effective prognostic marker. Its determination may contribute to better risk stratification in this population.

Diabetes and cardiovascular disease: the road to cardioprotection

Diabetes is a metabolic disease whose incidence and prevalence has significantly increased in recent decades, mainly because of an increase in type 2 diabetes, which represents almost 90% of all cases of diabetes. The World Health Organization estimates that, by 2025, there will be 300 million diabetic patients (5.4% of the world population). Older patients are most affected by diabetes, as the disease prevalence increases with age, at least up until 75 years. The progressive aging of the global population could explain about half of the predicted increase of diabetic patients in the near future.1 Macrovascular disease (coronary artery disease, stroke, and peripheral vascular disease) is responsible for the majority of morbidity and mortality associated with type 2 diabetes. In the UK prospective diabetes study (UKPDS),2 the 10 year risk of all macrovascular complications was four times that of microvascular complications. Coronary artery disease is the leading cause of death among diabetic patients, and women have a higher cardiovascular risk than men. Diabetics have a worse prognosis after an acute coronary syndrome than non-diabetic patients. This was documented both for ST elevation and non-ST elevation acute myocardial infarction (AMI). The Framingham heart study has also shown a higher mortality rate, as well as reinfarction and heart failure rates, in diabetic patients, both during the acute phase and in the post-infarction period, even after data adjustment for other risk factors.1 Diabetic patients may, therefore, derive a greater benefit from therapies shown to be effective in treating ischaemic heart disease. The challenge is, therefore, to protect the heart of diabetic patients more effectively. Can we achieve this goal? To answer this question we must first understand why patients with diabetes have a higher cardiovascular risk. ### Preconditioning Preconditioning is the mechanism by which brief periods of sublethal ischaemia can render a …

Impact of Early Coronary Artery Bypass Graft in an Unselected Acute Coronary Syndrome Patient Population

Background— Performance of coronary artery bypass graft (CABG) during an acute coronary syndrome (ACS) is mainly used in high-risk patients. Although potentially life-saving, patients undergoing early CABG are traditionally associated with a worse outcome than those not requiring CABG. Is this really true in an unselected ACS population? The aim of this study was to evaluate, in an ACS population, if the performance of CABG during the index hospitalization influences in-hospital outcome. Methods and Results— Retrospective analysis of a nationwide database of 12 988 ACS patients admitted since 2002. Of those, 267 patients underwent CABG during the index hospitalization (group A) and 12 721 did not (group B). Group B patients were further divided in 2 subgroups: those submitted to percutaneous coronary interventions (PCI) (group B1; n=3948) during the index hospitalization and those not submitted to mechanical revascularization (group B2; n =8773). Patients from group A more frequently had diabetes, hypercholesterolemia, hypertension, and previous angina; they were also more often on cardiovascular medication before admission. Patients that underwent CABG were more often in Killip class IV at admission (4.8% versus 1.4% versus 2.0%); they also received more nitrates and catecholamines. Left ventricular function was better in group B1. Group A patients were more often on mechanical ventilation and intra-aortic pump and they had more in-hospital complications (31.1% versus 18.7% versus 17.3%), namely recurrent angina, re-infarction, and mechanical complications. They had a more severe coronary anatomy and the culprit lesion was more frequently on the left main (7.7% versus 0.5% versus 2.2%). However, their in-hospital mortality was significantly lower (1.1% versus 2.2% versus 6.8%; P<0.001). Multivariate analysis showed that performance of early CABG was an independent predictor of lower mortality (odds ratio of 0.12), as were the use of low-molecular-weight heparins, beta-blockers, and angiotensin-converting enzyme inhibitors. Conclusions— In unselected patients admitted for ACS, performance of early CABG, despite being performed in higher-risk patients, is associated with very low in-hospital mortality, even when compared with the mortality of lower-risk population not submitted to early CABG. Therefore, early performance of this procedure should be considered more often in eligible patients.

Hyperglycaemia at admission in acute coronary syndrome patients: prognostic value in diabetics and non-diabetics

Objective To evaluate the impact of admission glycaemia on short-term and long-term prognosis in diabetic and non-diabetic patients admitted for acute coronary syndromes (ACS), and to identify the independent predictors of post-ACS mortality in this population. Methods This study included 1149 consecutive patients admitted to a single coronary care unit for ACS between May 2004 and December 2006. Our population was divided into four groups according to the quartiles of glycaemia at admission [Q1 > 5.77 mmol/l, Q2 (5.77–7.0) mmol/l, Q3 (7.0–9.22) mmol/l and Q4 ≥ 9.22 mmol/l]. Diabetic (n = 396) and non-diabetic (n = 753) subgroups were then separately analysed. Results Hyperglycaemia at admission was associated with worse cardiovascular risk profile, high levels of necrosis and inflammation biomarkers and low left ventricle ejection fraction. Considering overall population, in-hospital, 30-day and 3-year mortalities were higher in more elevated glycaemia quartiles. In diabetic patients, there were no significant differences in mortality among glycaemia quartiles; however, in non-diabetic group higher admission glucose levels were associated with successively higher in-hospital and 3-year mortalities. After multivariate regression analysis, glycaemia at admission ≥ 5.77 mmol/l, age ≥ 72 years, Killip class [1 and troponin I ≥ 6.0 ng/ml were independent predictors of in-hospital mortality. Conclusion This study suggests that, in a broad ACS population, hyperglycaemia at admission is a short-term and long-term bad prognosis marker, particularly in non-diabetic patients, being a strong independent predictor of in-hospital mortality.

Learning curve and complications of minimally invasive transforaminal lumbar interbody fusion

OBJECT Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) has the potential advantage of minimizing soft-tissue damage and reducing recovery time compared to open procedures. A steep learning curve has been described for the technique. The aim of the present study was to define the learning curve that describes the progress of a single surgeon performing the MI-TLIF. METHODS One hundred fifty consecutive patients with degenerative lumbar disease who underwent 1- or 2-level MI-TLIF were included in the study. Operative time, corrected operative time per level, and complications were analyzed. The learning curve was assessed using a negative exponential curve-fit regression analysis. RESULTS One hundred ten patients underwent 1-level and 18 patients underwent 2-level MI-TLIF; the remaining 22 underwent a single-level procedure plus an ancillary procedure (decompression at adjacent level, vertebral augmentation through fenestrated pedicle screws, interspinous device at adjacent level). Negative exponential curves appropriately described the relationship between operative time and experience for 1-level surgery and after correction of operative time per level (R(2) = 0.65 and 0.57). The median operative time was 140 minutes (interquartile range 120-173 minutes), and a 50% learning milestone was achieved at Case 12; a 90% learning milestone was achieved at Case 39. No patient required transfusion in the perioperative period. The overall complication rate was 12.67% and the most frequent complication was a dural tear (5.32%). Before the 50% and 90% learning milestones, the complication rates were 33% and 20.51%, respectively. CONCLUSIONS The MI-TLIF is a reliable and effective option for lumbar arthrodesis. According to the present study, 90% of the learning curve can be achieved at around the 40th case.

Nicorandil protects cardiac mitochondria against permeability transition induced by ischemia-reperfusion

Ischemia followed by reperfusion is known to negatively affect mitochondrial function by inducing a deleterious condition termed mitochondrial permeability transition. Mitochondrial permeability transition is triggered by oxidative stress, which occurs in mitochondria during ischemia-reperfusion as a result of lower antioxidant defenses and increased oxidant production. Permeability transition causes mitochondrial dysfunction and can ultimately lead to cell death. A drug able to minimize mitochondrial damage induced by ischemia-reperfusion may prove to be clinically effective. We aimed to analyze the effects of nicorandil, an ATP-sensitive potassium channel agonist and vasodilator, on mitochondrial function of rat hearts and cardiac HL-1 cells submitted to ischemia-reperfusion. Nicorandil decreased mitochondrial swelling and calcium uptake. It also decreased reactive oxygen species formation and thiobarbituric acid reactive substances levels, a lipid peroxidation biomarker. We thus confirm previous reports that nicorandil inhibits mitochondrial permeability transition and demonstrate that nicorandil inhibits this process by preventing oxidative damage and mitochondrial calcium overload induced by ischemia-reperfusion, resulting in improved cardiomyocyte viability. These results may explain the good clinical results obtained when using nicorandil in the treatment of ischemic heart disease.