Luís A. Providência

Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury

AMPK activation during ischemia helps the myocardium to cope with the deficit of energy production. As AMPK activity is considered to be impaired in diabetes, we hypothesized that enhancing AMPK activation during ischemia above physiological levels would protect the ischemic diabetic heart through AMPK activation and subsequent inhibition of mitochondrial permeability transition pore (mPTP) opening. Isolated perfused hearts from normoglycemic Wistar or diabetic Goto-Kakizaki (GK) rats (n ≥ 6/group) were subjected to 35 min of ischemia in the presence of 10, 20, and 40 μM of A-769662, a known activator of AMPK, followed by 120 min of reperfusion with normal buffer. Myocardial infarction and AMPK phosphorylation were assessed. The effect of A-769662 on mPTP opening in adult cardiomyocytes isolated from both strains was also determined. A-769662 at 20 μM reduced infarct size in both Wistar (30.5 ± 2.7 vs. 51.8 ± 3.9% vehicle; P < 0.001) and GK hearts (22.7 ± 3.0 vs. 48.5 ± 4.7% vehicle; P < 0.001). This protection was accompanied by a significant increase in AMPK and GSK-3β phosphorylation. In addition, A-769662 significantly inhibited mPTP opening in both Wistar and GK cardiomyocytes subjected to oxidative stress. We demonstrate that AMPK activation during ischemia via A-769662 reduces myocardial infarct size in both the nondiabetic and diabetic rat heart. Furthermore, this cardioprotective effect appears to be mediated through inhibition of mPTP opening. Our findings suggest that improving AMPK activation during ischemia can be another mechanism for protecting the ischemic heart.

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.

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.

Carvedilol: Just Another Beta-Blocker or a Powerful Cardioprotector?

Beta-blockers have been used to treat ischemic heart disease, due to negative chronotropic and inotropic properties, thus inducing a decrease in myocardial consumption of oxygen and nutrients, allowing a better balance between nutritional needs and the supply provided by the coronary blood flow. Recent developments in cell biology allowed us to understand that not all beta-blockers are equal, as their intracellular mechanisms of action can be very different. This paper will focus on carvedilol, a non-selective beta-blocker with alfa-blocker properties, currently used to treat hypertension, heart failure and coronary artery disease. Effects of carvedilol on cardiac mitochondria, their relation to its antioxidant properties, and how these can improve cardiomyocyte resistance to aggression and cardiac function will be discussed. We will begin by depicting the effect of carvedilol on mitochondrial parameters, namely oxidative phosphorylation, calcium homeostasis and energy production. Then we will focus on the mitochondrial permeability transition (MPT) and how the antioxidant properties of carvedilol can be used to minimize oxidative stress, a powerful inducer of MPT. Carvedilol will also be highlighted as an enzyme modulator, focusing on its importance to prevent doxorubicin (DOX) cardiotoxicity. The mitochondrial-related mechanism of cardioprotection involving carvedilol will also be addressed, as we will discuss some clinical pieces of evidence showing the importance of mechanisms previously depicted. In conclusion, based upon its molecular mechanisms of action, carvedilol seems to be a unique beta-blocker. These unique characteristics can help us understand the positive impact of carvedilol on the prognosis of patients with heart disease.

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 …

Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.

Circumferential ascending aortic strain and aortic stenosis.

BACKGROUND Two-dimensional speckle tracking (2D-ST) echocardiography for the measurement of circumferential ascending thoracic aortic strain (CAAS) in the context of aortic stenosis (AS) is not elucidated. Purpose This study assesses the thoracic ascending aortic deformation using 2D-ST echocardiography in AS patients. Population and methods Forty-five consecutive patients with an aortic valvular area (AVA) ≤0.85 cm(2)/m(2) were included. Regarding aortic deformation, the global peak CAAS was the parameter used, and an average of six segments of arterial wall deformation was calculated. The corrected CAAS was calculated as the global CAAS/pulse pressure (PP). Aortic stiffness (β2) index was assessed according to ln(Ps/Pd)/CAAS. The sample was stratified according to the stroke volume index (SVI) as: Group A (low flow, SVI ≤35 mL/m(2); n = 19) and Group B (normal flow, SVI >35 mL/m(2); n = 26). RESULTS The mean age was 76.8 ± 10.3 years, 53.3% were male, the mean indexed AVA was 0.43 ± 0.15 cm(2)/m(2), and the mean CAAS was 6.3 ± 3.0%. The CAAS was predicted by SVI (β = 0.31, P < 0.01) and by valvulo-arterial impedance (Zva). The corrected CAAS was correlated with the M-mode guided aortic stiffness index (β1) (r = -0.39, P < 0.01), and was predicted by SVI, Zva, and systemic arterial compliance (β = 0.15, P < 0.01). The β2 index was significantly higher for the low-flow patients (16.1 ± 4.8 vs. 9.8 ± 5.3, P < 0.01), and was predicted by SVI (β -0.58, P < 0.01) and PP (β = 0.17, P < 0.01). Global CAAS was more accurate to predict low flow than Zva, systolic function and systemic vascular resistance. CONCLUSION In patients with moderate-to-severe aortic stenosis, SVI and LV afterload-related variables were the most important determinants of 2S-ST global CAAS.

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.

The magnitude of the variation in glycemia: a new parameter for risk assessment in acute coronary syndrome?

INTRODUCTION AND OBJECTIVES The aim was to evaluate the relationship between the magnitude of the variation in the level of glycemia during hospitalization and in-hospital and long-term mortality and postdischarge endpoints in two groups of patients with acute coronary syndrome: those with and those without a previous diagnosis of diabetes. METHODS The study included 1210 patients admitted for acute coronary syndrome between May 2004 and July 2007. The study population was divided in two subgroups: patients with a previous diagnosis of diabetes (n=386) and nondiabetics (n=824). Each subgroup was further divided into four smaller groups according to the quartile of glycemia variation: diabetics (Q1: <46 mg/dl; Q2: 46-88 mg/dl; Q3: 88-164 mg/dl; Q4: >or=164 mg/dl) and nondiabetics (Q1: <14 mg/dl; Q2: 14-30 mg/dl; Q3: 30-60 mg/dl; Q4: >or=60 mg/dl). Patients were followed up for an average of 18 months after the occurrence of the acute coronary syndrome. RESULTS In diabetic patients, there was no relationship between the magnitude of the glycemia variation and in-hospital or postdischarge endpoints. In nondiabetics, no significant difference was observed in in-hospital mortality or morbidity, but statistically significant clinical differences were found during follow-up. Multivariate regression analysis showed that Q4 versus Q1, age >or=70 years, and previous antiplatelet or angiotensin-converting enzyme inhibitor therapy were independent predictors of postdischarge endpoints in the nondiabetic group. CONCLUSIONS In nondiabetic acute coronary syndrome patients, the magnitude of the variation in glycemia observed during hospitalization was a strong independent predictor of postdischarge clinical endpoints.

One-shot diagnostic and prognostic assessment in intermediate- to high-risk acute pulmonary embolism: The role of multidetector computed tomography

INTRODUCTION Contrast-enhanced multidetector computed tomography (MDCT) is useful for the diagnosis of pulmonary embolism (PE). However, current guidelines do not support its use for risk assessment in acute PE patients. OBJECTIVES We compared the prognostic impact of MDCT-derived indices regarding medium-term mortality in a population of intermediate- to high-risk PE patients, mostly treated by thrombolysis. METHODS Thirty-nine consecutive patients admitted to an intensive care unit with acute PE were studied. All patients had a pulmonary MDCT on admission to the emergency room as part of the diagnostic algorithm. We assessed the following MDCT variables: right ventricular/left ventricular diameter (RV/LV) ratio, arterial obstruction index, pulmonary artery-to-aorta diameter ratio and azygos vein diameter. A 33-month follow-up was performed. RESULTS Mean age was 59.1±19.6 years, with 80% of patients receiving thrombolysis. Follow-up all-cause mortality was 12.8%. Of the MDCT-derived variables, only the RV/LV ratio had significant predictive value, being higher in patients who suffered the endpoint (1.6±0.5 vs. 1.9±0.4, p=0.046). Patients with an RV/LV ratio ≥1.8 had 11-fold higher medium-term all-cause mortality (3.8% vs. 38.8%, p<0.001). Regarding this endpoint, the c-statistic was 0.78 (95% CI, 0.60-0.96) for RV/LV ratio and calibration was good (goodness-of-fit p=0.594). No other radiological index was predictive of mortality. CONCLUSIONS MDCT gives the possibility, in a single imaging procedure, of diagnosing and assessing the prognosis of patients with intermediate- to high-risk PE. Although further studies are needed, the simple-to-calculate RV/LV ratio has good discrimination and calibration for predicting poorer outcomes in patients with acute PE.