Effect of beta-adrenergic and renin-angiotensin system blockade on myocyte apoptosis and oxidative stress in diabetic hypertensive rats

Diabetes aggravates the clinical severity and represents an additional independent risk factor of hypertension. Since both diseases separately concur to cardiomyocyte apoptosis, a mechanism at least partly involving unbalanced oxidative stress, we investigated whether the combination of diabetes and hypertension potentiated cardiac cell death in experimental models, compared to either disease alone. We also evaluated the short-term effects of different drugs in these models. Streptozotocin-induced diabetic normotensive (WKY) or hypertensive (SHR) rats were treated for one week with a DA(2)/alpha(2) agonist (CHF-1024), a selective beta1 adrenergic blocker (metoprolol), an angiotensin II-receptor blocker (valsartan) or a radical scavenger (tempol). In separate experiments, isolated cardiomyocytes were cultured in high glucose medium (25 mM) containing the same drugs. Although the number of apoptotic cardiomyocytes and the myocardial density of oxygen radicals were higher in non diabetic hypertensive than in normotensive controls, diabetes raised these variables to comparable absolute levels in both strains. All drugs except metoprolol significantly reduced apoptosis and oxidative stress in the diabetic animals of both strains and in the isolated myocytes cultured with high glucose. In conclusion, hypertensive rat is no more susceptible than its normotensive control to acute apoptosis induced by diabetes. Oxidative stress might be considered the common trigger for cardiac myocyte apoptosis in both conditions.     

Scintigraphie myocardique et séquelles de myocardite : présentation d’un cas clinique

Acute and subacute myocarditis are well-defined pathological entities but it is often difficult to identify them because their clinical expression is variable and the diagnosis is histological showing myocardial inflammation associated with degeneration and/or necrosis. Often symptoms are similar to those of acute pericarditis with “chest-crushing” pain that mimics myocardial infarction and prompts practitioners to request angiography, especially when there are cardiovascular risk factors. We report the case of a 61-year-old patient with neither cardiac history nor cardiovascular risk factor who consulted for a long and self-limited atypical chest pain with normal clinical examination and electrocardiogram. Myocardial perfusion scintigraphy showed a non-reversible photopenic area suspected of being a nontransmural necrosis or an artifact. The discovery of inferolateral hypokinesis of left ventricle on echocardiography led to perform a coronary angiography which was finally normal. Cardiac MRI allowed to diagnose scars of a previous episode of myocarditis.     

Design of a trial evaluating myocardial cell protection with cariporide, an inhibitor of the transmembrane sodium-hydrogen exchanger: the Guard During Ischemia Against Necrosis (GUARDIAN) trial

Background  

Direct myocardial cell protection in patients with unstable angina or evolving myocardial infarction (MI) could prevent cell necrosis or reduce its extent, and minimize the risk of MI and death associated with percutaneous coronary interventions (PCIs) and coronary artery bypass surgery. The myocardial NHE plays a critical role in mediating the progression of ischemia to necrosis by promoting intracellular accumulation of sodium and calcium in exchange for hydrogen. Blockage of the system in various experimental models of ischemia and reperfusion had a strong antinecrotic effect. The present paper describes a trial that was intended to investigate the potential clinical benefit of cariporide, a potent and selective inhibitor of the NHE, in a large spectrum of at-risk patients.     

Diagnostic re-classification and prognostic risk stratification of patients with acute chest pain

Unstable angina and myocardial infarction are prevalent manifestations of acute coronary artery disease, combined in the term ‘acute coronary syndromes’. The introduction of sensitive markers for myocardial necrosis has led to confusion regarding the distinction between small myocardial infarctions and ‘true’ unstable angina, and the application of ever more sensitive markers has accelerated the pace at which patients with unstable angina are being re-classified to non-ST-segment elevation myocardial infarction. But in how many patients with acute chest pain is myocardial ischaemia really the cause of their symptoms? Numerous studies have shown that most have <5 ng/l high-sensitivity cardiac troponin, and that their prognosis is excellent (event rate <0.5% per year), incompatible with ‘impending infarction’. This marginalisation of patients with unstable angina pectoris should lead to the demise of this diagnosis. Without unstable angina, the usefulness of the term acute coronary syndromes may be questioned next. It is better to abandon the term altogether and revert to the original diagnosis of thrombus-related acute coronary artery disease, myocardial infarction. A national register should be the next logical step to monitor and guide the application of effective therapeutic measures and clinical outcomes in patients with myocardial infarction.

     

Simulation of LV pacemaker lead in marginal vein: potential risk factors for acute dislodgement

Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design.     

Inability of dimethylthiourea to limit tissue necrosis during acute myocardial infarction in rabbits.

This study examined the effect of treatment with dimethylthiourea (DMTU), a highly cell-permeable scavenger of hydroxyl radicals, on tissue necrosis in rabbit hearts during myocardial ischemia and reperfusion. Sixty-two rabbits underwent 45 minutes of coronary occlusion with, or without, coronary reperfusion for 3 hours. A saline vehicle, or DMTU (500 mg/kg intravenously [iv]) was administered over 45 minutes starting either 10 minutes before or 10 minutes after coronary occlusion, or 10 minutes before coronary reperfusion. Anatomic risk zone size was assessed using microsphere autoradiography, and the area of necrosis was determined using tetrazolium staining. Cardiac hemodynamics and risk zone size were similar for all treatment groups. No differences were observed in the extent of tissue necrosis (normalized to risk zone size) for saline- and DMTU-treated rabbits subjected to 45 minutes (61.2 +/- 23.1% vs. 70.6 +/- 16.5%) or 225 minutes (82.8 +/- 5.4% vs. 78.3 +/- 5.9%) of permanent coronary occlusion without reperfusion. Similarly, tissue necrosis in rabbits with 45 minutes coronary occlusion followed by 3 hours reperfusion was not significantly reduced when DMTU was administered either 10 minutes before coronary occlusion, 10 minutes after coronary occlusion, or 10 minutes before coronary reperfusion (67.0 +/- 9.9%; 57.6 +/- 10.6%; 68.3 +/- 13.3%) compared to saline-treated controls (76.6 +/- 10.5%). These results demonstrate that the hydroxyl radical scavenger DMTU does not appear to influence the progression of myocyte injury in this experimental model of acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Applications and limitations of end-systolic measures of ventricular performance

The usefulness of end-systolic measures of left ventricular performance as a load-independent method of assessing of ventricular contractility has been studied in intact, conscious dogs. The end-systolic pressure-chamber diameter (P-D) relation was shown to be linear, unaltered by preload changes, and shifted in a parallel fashion by inotropic stimulation, whereas the end-systolic pressure-volume relation appeared to increase in slope with increased contractility. A simplified measure of end-systolic relations that does not require measurement of chamber volume or diameter, the end-systolic pressure-wall thickness ( WTh ) relation, was also linear and shifted with acute changes in inotropic state. During regional ischemia, the regional end-systolic WTh relation also may provide a relatively load-independent means of detecting regional depression of myocardial contractility. With chronic pressure overload hypertrophy in dogs, the end-systolic P-D relation was markedly shifted upward and to the left, which indicates hyperfunction of the left ventricle; however, end-systolic wall stress-diameter relations were identical before and after the development of hypertrophy, which suggests that myocardial contractility was unaltered. These findings and clinical studies of mitral regurgitation imply that for assessing resting left ventricular contractility in certain chronic conditions, the use of wall stress rather than pressure may be appropriate in the end-systolic framework. Further experimental studies are needed in the intact circulation to better characterize end-systolic relations before their full potential in the clinical setting can be realized.     

Models and mechanisms of acute lung injury caused by direct insults

Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are life-threatening diseases that are characterized by acute onset, pulmonary inflammation, oedema due to increased vascular permeability and severe hypoxemia. Clinically, ARDS can be divided into ARDS due to direct causes such as pneumonia, aspiration or injurious ventilation, and due to extrapulmonary indirect causes such as sepsis, severe burns or pancreatitis. In order to identify potential therapeutic targets, we asked here whether common molecular mechanisms can be identified that are relevant in different models of the direct form of ALI/ARDS. To this end, we reviewed three widely used models: (a) one based on a biological insult, i.e. instillation of bacterial endotoxins; (b) one based on a chemical insult, i.e. instillation of acid; and (c) one based on a mechanical insult, i.e. injurious ventilation. Studies were included only if the mediator or mechanism of interest was studied in at least two of the three animal models listed above. As endpoints, we selected neutrophil sequestration, permeability, hypoxemia (physiological dysfunction) and survival. Our analysis showed that most studies have focused on mechanisms of pulmonary neutrophil sequestration and models with moderate forms of oedema. The underlying mechanisms that involve canonical inflammatory pathways such as MAP kinases, CXCR2 chemokines, PAF, leukotrienes, adhesions molecules (CD18, ICAM-1) and elastase have been defined relatively well. Further mechanisms including TNF, DARC, HMGB1, PARP, GADD45 and collagenase are under investigation. Such mechanisms that are shared between the three ALI models may represent viable therapeutic targets. However, only few studies have linked these pathways to hypoxemia, the most important clinical aspect of ALI/ARDS. Since moderate oedema does not necessarily lead to hypoxemia, we suggest that the clinical relevance of experimental studies can be further improved by putting greater emphasis on gas exchange.     

Value of positive myocardial infarction imaging in coronary care units.

Positive myocardial imaging was undertaken on 120 unselected patients admitted to a coronary care unit with clinical suspicion of acute myocardial infarction. Multipurpose mobile gamma-cameras were used for serial imaging after administration of 99mtechnetium-labelled imidodiphosphonate, a low-cost radiopharmaceutical that is 97% specific for myocardial necrosis, with myocardial uptake and blood clearance most suitable for myocardial imaging. The sensitivty of detection was 94% for patients whose infarction was unequivocal on the ECG; when the presence of raised enzyme concentrations was also used as a criterion for myocardial necrosis, the overall sensitivity for all 120 patients remained 94%. In 73 patients (61%), whose ECGs were unhelpful or difficult to interpret, scintigraphy allowed infarction to be diagnosed in 11 (15%) and to be excluded in five (7%). In 32 (44%) of this group whose ECGs were totally uninterpretable due to previous myocardial damage or disorders of electrical activation, scintigraphy provided confirmation of a diagnosis that otherwise rested only on whether enzyme concentrations were raised. Myocardial imaging is thus a useful technique that permits more definite diagnosis in patients for whom ECG and enzyme data are uncertain.     

急性脑梗死患者血清心肌酶学变化的临床意义及相关危险因素分析

目的:探讨急性脑梗死患者血清心肌酶学变化与预后的关系及导致急性脑梗死患者心肌酶学变化的相关危险因素。方法:回顾性分析临床及影像资料齐全且确诊的140例急性脑梗死患者(发病14天内),根据有无血清心肌酶学升高分为血清心肌酶学升高的急性脑梗死组A组(43例),血清心肌酶学正常的急性脑梗死组B组(97例),应用美国国立卫生研究院卒中量表评分(NIHSS)比较两组神经功能缺损情况,并对两组病人血清心肌酶学(包括天冬氨酸氨基转移酶(AST)、肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)、血糖、血脂、纤维蛋白原和血压等结果进行分析。结果:A组(31%)患者血清心肌酶学均增高,与B组比较均有显著性差异(P<0.01);发病后1天A、B两组患者临床神经功能缺损程度评分无显著性差异,发病后4、8、10天A、B两组患者临床神经功能缺损程度评分有显著性差异(P<0.01);A组高血压、糖尿病与B组比较有显著性差异(P<0.05);而血脂及纤维蛋白原两组比较无显著性差异。结论:急性脑梗死患者血清心肌酶学升高者预后不良;高血压、糖尿病是急性脑梗死患者血清心肌酶学升高的相关危险因素。     

Oxidative stress in cardiovascular disease: myth or fact?

Oxidative stress is a mechanism with a central role in the pathogenesis of atherosclerosis, cancer, and other chronic diseases. It also plays a major role in the aging process. Ischemic heart disease is perhaps the human condition in which the role of oxidative stress has been investigated in more detail: reactive oxygen species and consequent expression of oxidative damage have been demonstrated during post-ischemic reperfusion in humans and the protective role of antioxidants has been validated in several experimental studies addressing the pathophysiology of acute ischemia. Although an impressive bulk of experimental studies substantiate the role of oxidative stress in the progression of the damage induced by acute ischemia, not a single pathophysiologic achievement has had a significant impact on the treatment of patients and randomized, controlled clinical trials, both in primary and secondary prevention, have failed to prove the efficacy of antioxidants in the treatment of ischemic cardiovascular disease. This dichotomy, between the experimental data and the lack of impact in the clinical setting, needs to be deeply investigated: certainly, the pathophysiologic grounds of oxidative stress do maintain their validity but the concepts of the determinants of oxidative damage should be critically revised. In this regard, the role of intermediate metabolism during myocardial ischemia together with the cellular redox state might represent a promising interpretative key.     

Predicting the risk of cardiovascular disease: where does lipoprotein-associated phospholipase A(2) fit in?

Although an atherogenic lipoprotein phenotype has been well recognized as an important predictor of cardiovascular disease, recent studies have demonstrated a number of additional lipid-related markers as emerging biomarkers to identify patients at risk for future coronary heart disease. Among them, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), seems to be a promising candidate that might be added to the clinical armamentarium for improved prediction of cardiovascular disease in the future. Of particular note, Lp-PLA(2) is the only enzyme that cleaves oxidized low-density lipoprotein (oxLDL) in the subendothelial space, with further generation of proinflammatory mediators such as lysophosphatidylcholine (LysoPC) and oxidized fatty acid (oxFA), thereby probably linking two important features of atherogenesis, namely oxidation of LDL and local inflammatory processes within the atherosclerotic plaque. This overview aims to summarize our current knowledge based on observations from recent experimental and clinical studies. Emphasis has been put on potential pathophysiological mechanisms of action and on the clinical relevance of Lp-PLA(2) in a wide variety of clinical settings, including apparently healthy individuals, patients with stable angina or acute coronary syndromes, after myocardial infarction, and with subclinical disease. Although a growing body of evidence from epidemiological and clinical studies suggests that Lp-PLA(2) may represent an independent and clinically relevant long-term risk marker for coronary heart disease and, probably, also for stroke, the role of this enzyme in the setting of the acute coronary syndrome remains to be established.     

Prognosis in Acute Occupational Low Back Pain: Methodologic and Practical Considerations

Work-related or occupational low back pain (OLBP) is the leading cause of disability due to work-related conditions. The clinical course of this disorder is highly variable. Accurate prediction of disability outcomes in acute OLBP can lead to better selection of those likely to benefit from intensive interventions, identification of specific issues for intervention, and more efficient patient selection in clinical trials. The basis for disability prognostication has been developed through studies of outcomes in acute OLBP. These include investigations based on administrative data, workplace studies, and clinical studies in physicians' offices or workplaces. Each study design has inherent strengths and limitations that affect the accuracy of the resulting predictive models. Practical concerns for use of prognostic models in clinical settings include generalizability of results, feasibility of data collection and interpretation, acceptability to patients, cost, and linking prognosis to effective interventions. Ethical concerns include informed consent, confidentiality issues and inappropriate negative labeling. An informed choice of prognostic model and associated measures based on specific goals is needed to develop an appropriate application for a particular clinical or research situation. Future research may lead to greater use of these models, improving outcomes for workers with OLBP.     

beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning

Protein kinase A (PKA) activation has been implicated in early-phase ischemic preconditioning. We recently found that during ischemia PKA activation causes inactivation of cytochrome-c oxidase (CcO) and contributes to myocardial damage due to ischemia-reperfusion. It may be that beta-adrenergic stimulation during ischemia via endogenous catecholamine release activates PKA. Thus beta-adrenergic stimulation may mediate both myocardial protection and damage during ischemia. The present studies were designed to determine the role of the beta(1)-adrenergic receptor (beta(1)-AR) in myocardial ischemic damage and ischemic preconditioning. Langendorff-perfused rabbit hearts underwent 30-min ischemia by anterior coronary artery ligation followed by 2-h reperfusion. Occlusion-reperfusion damage was evaluated by delineating the nonperfused volume of myocardium at risk and volume of myocardial necrosis after 2-h reperfusion. In some hearts ischemic preconditioning was accomplished by two 5-min episodes of global low-flow ischemia separated by 10 min before coronary occlusion-reperfusion. Orthogonal electrocardiograms were recorded, and coronary flow was monitored by a drip count. Three hearts from each experimental group were used to determine mitochondrial CcO and aconitase activities. Two-hour reperfusion after occlusion caused an additional decrease in CcO activity vs. that after 30-min occlusion alone. Blocking the beta(1)-AR during occlusion-reperfusion reversed CcO activity depression and preserved myocardium at risk for necrosis. Similarly, mitochondrial aconitase activity exhibited a parallel response after occlusion-reperfusion as well as for the other interventions. Furthermore, classic ischemic preconditioning had no effect on CcO depression. However, blocking the beta(1)-AR during preconditioning eliminated the cardioprotection. If the beta(1)-AR was blocked after preconditioning, the myocardium was preserved. Interestingly, in both of the latter cases the depression in CcO activity was reversed. Thus the beta(1)-AR plays a dual role in myocardial ischemic damage. Our findings may lead to therapeutic strategies for preserving myocardium at risk for infarction, especially in coronary reperfusion intervention.     

Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling

Left ventricular (LV) remodeling and heart failure (HF) complicate acute myocardial infarction (AMI) even weeks to months after the initial insult. Apoptosis may represent an important pathophysiologic mechanism causing progressive myocardiocyte loss and LV dilatation even late after AMI. This review will discuss the role of apoptosis according to findings in animal experimental data and observational studies in humans in order to assess clinical relevance, determinants, and mechanisms of myocardial apoptosis and potential therapeutic implications. More complete definition of the impact of myocardiocyte loss on prognosis and of the mechanisms involved may lead to improved understanding of cardiac remodeling and possibly improved patients' care. Mitochondrial damage and bcl-2 to bax balance play a central role in ischemia-dependent apoptosis while angiotensin II and beta(1)-adrenergic-stimulation may be major causes of receptor-mediated apoptosis. Benefits due to treatment with ACE-inhibitors and beta-blockers appear to be in part due to reduced myocardial apoptosis. Moreover, infarct-related artery patency late after AMI may be a major determinant of myocardial apoptosis and clinical benefits deriving from an open artery late post AMI (the "open artery hypothesis") may be, at least in part, due to reduced myocardiocyte loss.     

Temporal relation of cardiac hypertrophy, oxidative stress, and fatty acid metabolism in spontaneously hypertensive rat

Left ventricular hypertrophy is an adaptive response to hypertension, and an independent clinical risk factor for cardiac failure, sudden death, and myocardial infarction. As regression of cardiac hypertrophy is associated with a lower likelihood of cardiovascular events, it is recognized as a target of antihypertensive therapy. This necessitates identification of factors associated with the initiation and progression of hypertrophy. Oxidative stress and metabolic shift are intimately linked with myocardial hypertrophy, but their interrelationship is not clearly understood. This study proposes to identify the temporal sequence of events so as to distinguish whether oxidative stress and metabolic shift are a cause or consequence of hypertrophy. Spontaneously hypertensive rat (SHR) was used as the experimental model. Cardiac hypertrophy was apparent at 2 months of age, as assessed by hypertrophy index and brain natriuretic peptide gene expression. Enhanced myocardial lipid peroxidation accompanied by nuclear factor-kappa B gene expression in one-month-old SHR suggests that oxidative stress precedes the development of hypertrophy. Metabolic shift identified by reduction in the expression of peroxisome proliferator-activated receptor-alpha, medium chain acyl CoA dehydrogenase, and carnitine palmitoyltransferase 1β was seen at 4 months of age, implying that reduction of fatty acid oxidation is a consequence of hypertrophy. Information on the temporal sequence of events associated with hypertrophy will help in the prevention and reversal of cardiac remodeling. Investigations aimed at prevention of hypertrophy should address reduction of oxidative stress. Both, oxidative stress and metabolic modulation have to be considered for studies that focus on the regression of hypertrophy.     

Oxidative stress in acute pancreatitis: lost in translation?

Abstract

Oxidative stress has been implicated in the pathogenesis of acute pancreatitis, a severe and debilitating inflammation of the pancreas that carries a significant mortality, and which imposes a considerable financial burden on the health system due to patient care. Although extensive efforts have been directed towards the elucidation of critical underlying mechanisms and the identification of novel therapeutic targets, the disease remains without a specific therapy. In experimental animal models of acute pancreatitis, increased oxidative stress and decreased antioxidant defences have been observed, changes also detected in patients clinically. However, despite the promise of studies evaluating the effects of antioxidants in these model systems, translation to the clinic has thus far been disappointing. This may reflect many factors involved in the design of both preclinical and clinical evaluations of antioxidant therapy, not least the fact that most experimental studies have focussed on pre-treatment rather than post-injury assessment. This review has examined evidence relating to the involvement of oxidative stress in the pathophysiology of acute pancreatitis, focussing on experimental models and the clinical experience, including the experimental techniques employed and potential of antioxidant therapy.     

Early identification of patients at low risk of death after myocardial infarction and potentially suitable for early hospital discharge.

OBJECTIVES--To find (a) whether data available shortly after admission for acute myocardial infarction can provide a reliable prognostic indicator of survival at 28 days, and (b) whether such an indicator might be used to identify patients at low risk of death and suitable for early discharge. DESIGN--Retrospective analysis of data collected on patients admitted to a coronary care unit for acute myocardial infarction. A validation sample was selected at random from these patients. SETTING--Coronary care units in Perth, Western Australia. SUBJECTS--6746 patients aged under 65 and resident in the Perth Statistical Division who during 1984-92 were admitted to a coronary care unit with symptoms of myocardial infarction. MAIN OUTCOME MEASURES--Sensitivity and specificity of several models for predicting survival at 28 days after myocardial infarction, and detailed performance characteristics of a particular model. RESULTS--Patients with a pulse rate of 100 beats/min or less, aged 60 or under, and with symptoms typical of myocardial infarction, no past history of myocardial infarction or diabetes, and no significant Q wave in the admission electrocardiogram had a very high chance of survival at 28 days (99.2%). These patients made up one third of all patients studied. CONCLUSION--The prognostic index identifies patients very soon after admission who are at low risk of death and potentially eligible for early discharge from hospital or the coronary care unit. Computing the index does not need complex cardiac investigations.     

Association between dental health and acute myocardial infarction.

Known risk factors for coronary heart disease do not explain all of the clinical and epidemiological features of the disease. To examine the role of chronic bacterial infections as risk factors for the disease the association between poor dental health and acute myocardial infarction was investigated in two separate case-control studies of a total of 100 patients with acute myocardial infarction and 102 controls selected from the community at random. Dental health was graded by using two indexes, one of which was assessed blind. Based on these indexes dental health was significantly worse in patients with acute myocardial infarction than in controls. The association remained valid after adjustment for age, social class, smoking, serum lipid concentrations, and the presence of diabetes. Further prospective studies are required in different populations to confirm the association and to elucidate its nature.