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Biomedical subjects

Pedro Monteiro

Publications and source records attributed to Pedro Monteiro.

At least 19 recordsLinked to original sources
PubMed2006

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.

Adrenergic beta-Antagonists↗
PubMed2006

The YEASTRACT database: a tool for the analysis of transcription regulatory associations in Saccharomyces cerevisiae.

We present the YEAst Search for Transcriptional Regulators And Consensus Tracking (YEASTRACT; www.yeastract.com) database, a tool for the analysis of transcription regulatory associations in Saccharomyces cerevisiae. This database is a repository of 12 346 regulatory associations between transcription factors and target genes, based on experimental evidence which was spread throughout 861 bibliographic references. It also includes 257 specific DNA-binding sites for more than a hundred characterized transcription factors. Further information about each yeast gene included in the database was obtained from Saccharomyces Genome Database (SGD), Regulatory Sequences Analysis Tools and Gene Ontology (GO) Consortium. Computational tools are also provided to facilitate the exploitation of the gathered data when solving a number of biological questions as exemplified in the Tutorial also available on the system. YEASTRACT allows the identification of documented or potential transcription regulators of a given gene and of documented or potential regulons for each transcription factor. It also renders possible the comparison between DNA motifs, such as those found to be over-represented in the promoter regions of co-regulated genes, and the transcription factor-binding sites described in the literature. The system also provides an useful mechanism for grouping a list of genes (for instance a set of genes with similar expression profiles as revealed by microarray analysis) based on their regulatory associations with known transcription factors.

Binding Sites↗
PubMed2006

Hepatic UDP-glucose 13C isotopomers from [U-13C]glucose: a simple analysis by 13C NMR of urinary menthol glucuronide.

Menthol glucuronide was isolated from the urine of a healthy 70-kg female subject following ingestion of 400 mg of peppermint oil and 6 g of 99% [U-(13)C]glucose. Glucuronide (13)C-excess enrichment levels were 4-6% and thus provided high signal-to-noise ratios (SNRs) for confident assignment of (13)C-(13)C spin-coupled multiplet components within each (13)C resonance by (13)C NMR. The [U-(13)C]glucuronide isotopomer derived via direct pathway conversion of [U-(13)C]glucose to [U-(13)C]UDP-glucose was resolved from [1,2,3-(13)C(3)]- and [1,2-(13)C(2)]glucuronide isotopomers derived via Cori cycle or indirect pathway metabolism of [U-(13)C]glucose. In a second study, a group of four overnight-fasted patients (63 +/- 10 kg) with severe heart failure were given peppermint oil and infused with [U-(13)C]glucose for 4 hr (14 mg/kg prime, 0.12 mg/kg/min constant infusion) resulting in a steady-state plasma [U-(13)C]glucose enrichment of 4.6% +/- 0.6%. Menthol glucuronide was harvested and glucuronide (13)C-isotopomers were analyzed by (13)C NMR. [U-(13)C]glucuronide enrichment was 0.6% +/- 0.1%, and the sum of [1,2,3-(13)C(3)] and [1,2-(13)C(2)]glucuronide enrichments was 0.9% +/- 0.2%. From these data, flux of plasma glucose to hepatic UDPG was estimated to be 15% +/- 4% that of endogenous glucose production (EGP), and the Cori cycle accounted for at least 32% +/- 10% of GP.

Adult↗
PubMed2005

Valsartan improves mitochondrial function in hearts submitted to acute ischemia.

The effect of valsartan, an angiotensin II-type I receptor blocker, on the mitochondrial function, was studied using an ex vivo animal model (hearts from Wistar rats), perfused in a Langendorff system and then submitted to global acute ischemia. Parameters evaluated were: membrane electrical potential (DeltaPsi, using a tetraphenylphosphonium-TPP+-electrode), oxygen consumption by the respiratory chain (Clark-type O2 electrode), phosphorylation lag phase (time necessary to phosphorylate a fixed amount of ADP) and ATP/ADP ratio (adenine nucleotides quantified by high-pressure liquid chromatography-HPLC). Valsartan acts preferentially in the phosphorylation, increasing ATP/ADP ratios (succinate: 1.6+/-0.4 versus 0.5+/-0.1--P<0.05; ascorbate/N,N,N',N'-tetramethyl-P-phenylenodiamine-TMPD: 1.1+/-0.2 versus 0.4+/-0.1--p<0.05 versus ischemia in the absence of valsartan) and decreasing lag phase (glutamate/malate: 50.0+/-9.6 s versus 127.2+/-19.03 s-84.6+/-16.2% versus 215.3+/-32.2%; P=0.01; succinate: 111.8+/-33.1 s versus 275.73+/-45.99 s-168.2+/-49.8% versus 414.9+/-69.2%; P=0.02 or ascorbate/TMPD: 11.0+/-3.9 s versus 62.4+/-11.63 s-34.9+/-12.4% versus 198.1+/-36.9%; P=0.001 versus ischemia in the absence of valsartan). This enables a higher energy production in hearts submitted to acute ischemia, for which having energy becomes critical to preserve mitochondrial function. These mechanisms allow us to better understand valsartan cytoprotection in ischemic cardiomyopathy.

Acute Disease↗
PubMed2005

Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?

The cellular role of mitochondria includes ATP generation and the modulation of cytosolic calcium signals, besides being the "crossroads" for several cell death pathways. The maintenance of optimal mitochondrial functioning during the disease process increases the chances for survival. For example, ischaemia followed by reperfusion is known to negatively affect mitochondrial function, namely by inducing a deleterious condition called mitochondrial permeability transition (MPT). The MPT is responsible for mitochondrial dysfunction and can ultimately lead to cell death. Therefore, it seems important to protect mitochondrial function in cardiac disease. Carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, has a positive impact on cardiac mitochondria during in vitro, ex-vivo and in vivo models of cardiac dysfunction. Particularly, carvedilol was shown to inhibit MPT in isolated heart mitochondria and protect mitochondria against the oxidative damage induced by the xanthine oxidase/hypoxanthine pro-oxidant system. The observation that carvedilol acts as an inhibitor of mitochondrial complex-I is also of importance, since this mitochondrial system was proposed as cause of the cardiotoxicity associated with the anti-neoplasic drug doxorubicin. This review points out the major findings concerning the positive impact of carvedilol on mitochondrial function and its use in the treatment of myocardial diseases where oxidative stress is known to be involved.

Adrenergic beta-Antagonists↗
PubMed2005

Impact of imidapril on cardiac mitochondrial function in an ex-vivo animal model of global myocardial ischemia.

Imidapril is an angiotensin I converting enzyme inhibitor, a class of drugs with known cardioprotective activity. It is now known that this is due not only to their antihypertensive activity, but also to the fact that they decrease cellular and tissue levels of angiotensin II, a potent vasoconstrictor and inducer of myocardial fibrosis. These mechanisms may explain the good clinical results of this class of drugs in the treatment of coronary artery disease and heart failure, two diseases whose etiopathogenesis is closely related to the activation of the renin-angiotensin-aldosterone system. However, the impact of this class of drugs on cardiac mitochondrial function during acute myocardial ischemia is still largely unknown. With the aim of studying the effect of imidapril on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langerdorff system and then subjected to ischemia in the presence or absence of imidapril. We evaluated mitochondrial membrane electrical potential, respiratory chain O2 consumption, and rate and amplitude of mitochondrial swelling. We conclude that imidapril did not significantly change oxygen consumption by cardiac mitochondria, as assessed by the rate of respiratory state 3 (the state that corresponds to the active phosphorylation phase). However, imidapril significantly increased transmembrane electrical potential and, in ischemic cardiac mitochondria, was able to prevent the calcium-induced increase in the rate and amplitude of mitochondrial swelling, thus enabling better preservation of mitochondrial membrane structure, with consequent improvement of electrical potential after the phosphorylation cycle. These findings enabled a better understanding of the mechanisms behind the cytoprotection provided by imidapril during ischemic cardiomyopathy, clearly highlighting, at a cellular biology level, the importance of pharmacological modulation of cardiac mitochondrial function during acute ischemia.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Lupus myocarditis. Case report.

Myocarditis is one of the many possible forms of cardiac involvement in systemic lupus erythematosus. Its clinical presentation ranges from asymptomatic patients with self-limited disease to fulminant heart failure that can lead to death. In most cases treatment consists of supportive care only. The authors present the case of a patient with lupus myocarditis.

Adolescent↗
PubMed2005

Impact of acute ischemia-reperfusion on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia.

INTRODUCTION: Cardiac mitochondria, as the major source of energy used by the heart, play an important part in the survival of cardiomyocytes undergoing ischemia followed by reperfusion. During ischemia, cardiac mitochondria represent one of the main cellular defense mechanisms, acting as a calcium-sequestering system and maintaining levels of energy production. However, when these cellular mechanisms are overcome, loss of mitochondrial integrity leads not only to the breakdown of energy production, but also to the release of pro-apoptotic factors, thus compromising the survival of cardiac cells. OBJECTIVES: To study the impact of acute ischemia-reperfusion (IR) on myocardial mitochondrial function in an ex-vivo model of global ischemia. METHODS: Wistar rat hearts were divided into two groups: control (165 minutes of perfusion with Krebs-Henseleit solution) and ischemia-reperfusion (IR - 10 minutes perfusion, followed by 35 minutes ischemia and 120 minutes reperfusion). Various parameters of mitochondrial function were assessed: respiratory control ratio (RCR) using a Clark-type oxygen electrode, oxidative stress (using the thiobarbituric acid reactive substances [TBARS] test), and mitochondrial swelling amplitude and calcium uptake, both determined by fluorimetric methods. RESULTS: All mitochondrial parameters were severely affected by IR. The IR group showed a significant decrease in RCR, which was independent of the respiratory substrate used, for each assay. There were no significant differences between the two experimental groups in TBARS production. The control group showed a trend for a decrease in mitochondrial swelling amplitude and an increase in calcium uptake compared to the IR group, in both the absence and presence of cyclosporin A. CONCLUSIONS: In this study, IR significantly altered mitochondrial function (RCR, mitochondrial swelling amplitude and intramitochondrial calcium uptake). This means that during acute myocardial ischemia, every effort should be made to avoid reperfusion injury, given its deleterious consequences for coronary artery disease patients.

Acute Disease↗
PubMed2004

Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia.

Trimetazidine is an anti-ischemic drug whose cytoprotective mechanisms are not yet fully understood (but until now mainly related to the trimetazidine-induced "metabolic shift" from lipid beta-oxidation to glucose aerobic oxidation). We studied the effect of trimetazidine on the mitochondrial function of ischemic Wistar rat hearts perfused with glucose, using a model of ex-vivo perfusion (Langendorff system). We measured the electrical potential of the mitochondrial membrane, O2 consumption by the respiratory chain, energy charges generated and the enzyme activities of the respiratory chain complexes. In this model, trimetazidine had a preferential action on the oxidative system (mainly on complex I), increasing its enzyme activity and decreasing O2 consumption after phosphorylation; this could decrease oxygen free radical production and increase mitochondrial integrity, thus allowing the maintenance of the electrical potential. These results allow us to better understand the cytoprotective effects of trimetazidine in coronary artery disease.

Adenosine Triphosphate↗
PubMed2004

Pulmonary embolism.

Pulmonary embolism (PE) is an important health problem and often a major clinical challenge, not only because of the low specificity of its clinical manifestations but also because of the increasing number of medical circumstances that are risk factors for this illness and the importance of early identification, since prompt and appropriate treatment can decrease mortality from this disease by about 25%. In recent years research on PE has been extensive, directed mainly at trying to determine and characterize its risk factors, establish new clinical probability algorithms, develop new diagnostic methods and put existing ones into perspective, seek new therapeutic approaches (pharmacological and non-pharmacological), and above all establish protocols that can guide the clinician from the stage of clinical suspicion to measures to prevent recurrence. It was the authors' aim to review the most significant literature on this subject, in order to produce a text that reflects the state of the art concerning PE and that can be used as a guide in the clinical approach to this pathology.

Diagnosis, Differential↗
PubMed2004

National Registry of Acute Coronary Syndromes: results of the hospital phase in 2002.

The National Registry of Acute Coronary Syndromes (ACS) was designed to assess the situation in Portugal regarding the clinical profile, diagnostic and therapeutic management and medium-term prognosis of the entire clinical spectrum of ACS, as well as to evaluate compliance with clinical guidelines and to monitor temporal trends and the impact of actions implemented for its improvement. The National Registry of ACS is a continuous, observational and prospective clinical registry started on January 1, 2002, that includes 44 Departments of Cardiology distributed all over the country. During 2002, 7348 episodes were recorded. The mean age was 66 +/- 13 years and 69% were male. Admission diagnosis was ST-segment elevation acute myocardial infarction (STE-AMI) in 45.4%, non-ST-segment elevation acute myocardial infarction (NSTE-AMI) in 38.9% and unstable angina (UA) in 15.7% of the patients. Reperfusion therapy was performed in 60.5% of the STE-AMI cohort, mainly with fibrinolytic therapy (75% of patients undergoing reperfusion therapy). The great majority of the patients (99%) received oral antiplatelets during hospitalization and low molecular weight heparins were the preferred antithrombin therapy. The use of other drugs with a positive impact on prognosis, during hospital stay and on discharge respectively, was 68% and 67% for beta-blockers, 69% and 66% for ACE inhibitors and 74% and 79% for statins. The majority of patients (52%) underwent coronary angiography and coronary angioplasty was performed in 36% of patients with STE-AMI, 24% with NSTE-AMI and 29% with UA. In-hospital mortality was 10.2% in patients with STE-AMI, 5.6% with NSTE-AMI and 0.8% with UA. There was great variability in the rate of use of the main treatments among the participating centers. The results of the National Registry of ACS reveal that the overall diagnostic and therapeutic management of ACS in Portugal is similar to that observed in contemporary national and international clinical registries. Nevertheless, there is great variability among the participating centers.

Acute Disease↗
PubMed2004

Advantages in the use of carvedilol versus propranolol for the protection of cardiac mitochondrial function.

BACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria.

Animals↗
PubMed2004

Carvedilol protects ischemic cardiac mitochondria by preventing oxidative stress.

Ischemia negatively affects mitochondrial function by inducing the mitochondrial permeability transition (MPT). The MPT is triggered by oxidative stress, which occurs in mitochondria during ischemia as a result of diminished antioxidant defenses and increased reactive oxygen species production. It causes mitochondrial dysfunction and can ultimately lead to cell death. Therefore, drugs able to minimize mitochondrial damage induced by ischemia may prove to be clinically effective. We analyzed the effect of carvedilol, a beta-blocker with antioxidant properties, on mitochondrial dysfunction. Carvedilol decreased levels of TBARS (thiobarbituric acid reactive substances), an indicator of oxidative stress, which is consistent with its antioxidant properties. Regarding cell death by apoptosis, although ischemia did increase caspase-8-like activity, there were no changes in caspase-3-like activity, which is activated downstream of caspase-8; this may indicate that the apoptotic cascade is not activated by 60 minutes of ischemia. We conclude that carvedilol protects ischemic mitochondria by preventing oxidative mitochondrial damage, and, by so doing, it may also inhibit the formation of the MPT pore.

Adrenergic beta-Antagonists↗
PubMed2003

Carvedilol improves energy production during acute global myocardial ischaemia.

Cardiac mitochondria may become dysfunctional during ischaemia, thus compromising cardiomyocyte function. Carvedilol is an alpha(1)/beta-adrenoceptor antagonist with antioxidant, neuroprotective, cardioprotective and vascularprotective properties, and is used to treat hypertension, myocardial ischaemia and congestive heart failure. However, its impact on mitochondrial function during acute prolonged ischaemia is unknown. We aimed to study the effect of carvedilol on cardiac mitochondrial function during acute ischaemia, using Wistar rat hearts perfused with a Langendorff system, and then submitted to ischaemia in the presence and absence of carvedilol. We determined the electrical potential of the mitochondrial membrane, O(2) consumption by the respiratory chain, energy charge and the activity of the mitochondrial respiratory chain complexes. In our model, carvedilol had a preferential action on phosphorylation, increasing the mitochondrial energy charge (0.76+/-0.03 vs. 0.65+/-0.01 arbitrary units; P<0.05) and decreasing the phosphorylation lag phase (28.64+/-4.23 vs. 62.4+/-11.63 s; P<0.05) during ischaemia. The larger amount of energy available allowed the preservation of the electrical potential (201.2+/-2.45 vs. 186.66+/-3.36 mV;P<0.05), thus improving mitochondrial function during acute prolonged ischaemia.

Animals↗
PubMed2003

Carvedilol: relation between antioxidant activity and inhibition of the mitochondrial permeability transition.

OBJECTIVES: The mitochondrial permeability transition (MPT) is an event related to severe oxidative stress (for example, during myocardial ischemia and reperfusion) and excessive mitochondrial calcium accumulation, also being implicated in cell death. In this study, we compared the effect of carvedilol on the cardiac MPT induced by calcium and phosphate (Ca/Pi) and calcium/carboxyatractyloside (Ca/Catr). Oxidative stress plays a major role in MPT induction by Ca/Pi, leading to the oxidation of protein thiol groups, in contrast with Ca/Catr, where such oxidation is secondary to MPT induction and is not caused by oxidative stress. MATERIALS AND METHODS: Mitochondria were isolated from rat hearts and parameters related to MPT induction were evaluated (n = 5 for each inducer): mitochondrial swelling and oxidation of protein thiol groups (both measured by spectrophotometry). RESULTS: Using Ca/Pi, carvedilol protected mitochondria from MPT induction, particularly in its high conductance form. Its effect was demonstrated by analyzing the decrease in mitochondrial swelling amplitude. Simultaneously, we observed inhibition of protein thiol group oxidation (p < 0.001). By contrast, carvedilol did not show any protective effect with Ca/Catr. CONCLUSIONS: Carvedilol was only effective against the MPT when the oxidation of protein thiol groups was the cause and not the consequence of the MPT phenomenon. The results clearly show that during myocardial aggressions (ischemia and reperfusion, for example), the protective effect of carvedilol is primarily due to an antioxidant mechanism, inhibiting the production and effects of reactive oxygen species.

Animals↗
PubMed2003

Pyruvate improves mitochondrial bioenergetics in an ex-vivo animal model of myocardial ischemia.

Pyruvate is an energy substrate with known cardioprotective activity. We know now that this is due not only to its antioxidant activity, but also to its reduction of intracellular acidosis, modulation of intracytosolic calcium and improvement of cardiomyocyte contractility. However, the role of cardiac mitochondria in such positive effects has only recently begun to be understood and the exact mechanisms of the effect of pyruvate on mitochondria are still largely unknown. Aiming to study the effect of pyruvate on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langendorff system and then subjected to ischemia in the presence and absence of pyruvate. We evaluated the mitochondrial membrane electrical potential, the respiratory chain O2 consumption (and respiratory control ratio) and the energy charges generated with different energy substrates. We conclude that pyruvate has some effect on the mitochondrial oxidative system (by non-significantly improving the respiratory control ratio), but its main action is on the phosphorylation system, significantly decreasing the time taken to complete a phosphorylation cycle (lag phase) and improving ATP production (increase in energy charge), thus allowing better maintenance of mitochondrial membrane structure, with consequent improvement of the electrical potential after a phosphorylation cycle. These findings have enabled better understanding of the mechanisms behind pyruvate cytoprotection in ischemic cardiomyopathy, clearly highlighting the essential role of cardiac mitochondria in this process.

Animals↗
PubMed2003

Mitochondria: role in ischemia, reperfusion and cell death.

Recent advances in the knowledge of the biochemical basis of myocardial ischemia have enabled a better understanding of the complex sequence of events occurring in ischemic cardiomyopathy, whatever its manifestations. This has clearly highlighted the important role played by cardiac mitochondria in these events. At first only associated with energy production, mitochondria have been clearly shown to have other important functions, like the maintenance of calcium homeostasis, as well as ischemic and non-ischemic preconditioning, and also modulation of cellular life and death. The aims of this review are twofold: firstly, to review the current knowledge on mitochondrial morphology and structure, and how these can be affected by ischemia and ischemia-reperfusion; and secondly, to summarize the role of cardiac mitochondria in cardioprotection and modulation of cell death mechanisms.

Cell Death↗