Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paper shows comparative analysis of structural-metabolic changes of the ventricular cardiac hystiocytes during transitional restriction of blood supply, which leads to relapsing myocardium hypoperfusion, ischemia and even to cardiac infarction. We have established that an increase of the myocardium arrhythmogenicity, damage of myocardium electrophysiological activity and coronary deficiency are caused by pathologically intensified structural-metabolic heterogeneity of cardiomyocites. The chronic ischemic heart disease is worsening the situation by gradual accumulation of the metastructure changes of heart's working cells. It is possible to connect adaptable hypertrophy of cardiomyocites with compensatory redistribution of loading among them, what is accompanied with the deep reorganization of their metabolism and metastructure under the influence of neurohumoral factors, inadequate transport-trophic maintenance of the function, nonequal edema and fibrosis of the interstitium. The data obtained describe the formation of "prereadiness" of the myocardium to the fatal rhythm disturbance determined by interconnected structural-metabolic changes. Each of these pathological changes separately doesn't induce an impairment of myocardium electric stability but represents a necessary part in origin and development of the pathological process.
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PMID:[Structural and metabolic aspects of heterogenicity of the ventricular cardiac myocytes in coronary insufficiency]. 1472 32

This article reviews the fundamentals of myocardial energy metabolism and selectively outlines the use of several metabolically active drug therapies in the treatment of ischemic heart disease. These drugs - ranolazine, trimetazidine, dichloroacetate (DCA), glucose-insulin-potassium (GIK) solutions, and L-carnitine - have mechanisms of action distinct from traditional anti-ischemic drugs. These agents work by shifting myocardial energy metabolism away from fatty acids toward glucose as a source of fuel. Because these agents are well tolerated and do not affect heart rate or blood pressure, they conceivably could supplement traditional anti-ischemic drug therapy with little risk. The background, rationale for use, and published literature on each agent is reviewed, and the outcomes of pertinent clinical trials are discussed. In the case of ranolazine, data suggest benefit in the treatment of stable angina pectoris, particularly with sustained release formulations. Trimetazidine appears to have similar physiologic effects to ranolazine, and it is effective as monotherapy and as additive therapy in patients with chronic ischemic heart disease. DCA improves acidosis in critically ill patients and, likewise, improves myocardial hemodynamics in those with chronic coronary artery disease and congestive heart failure; however, its metabolism is variable and clinical data on its use in chronic ischemic heart disease are limited. GIK solutions have been shown to be beneficial in animal and human models of ischemia and acute myocardial infarction, and they offer an inexpensive means by which to improve the oxidation of glucose in the heart. Lastly, a large body of literature suggests a benefit with L-carnitine in a number of cardiovascular illnesses, including ischemic heart disease. Clinical trial data in acute myocardial infarction are promising and have prompted the initiation of a large-scale mortality trial.
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PMID:Role of metabolically active drugs in the management of ischemic heart disease. 1472 49

We studied the survival of human myoblast for cellular myocardial reconstruction in a porcine model of chronic myocardial ischemia with immune tolerance using transient immunosuppression. A porcine model of chronic cardiac ischemia was created in 10 pigs (DMEM medium-injected n = 4; myoblast transplanted n = 6) by clamping ameroid ring around left circumflex coronary artery. Three weeks later, 3 x 10(8) human myoblasts carrying lac-z reporter gene were transplanted in multiple sites (0.25 mL each) into the left ventricular wall. Immunosuppression was achieved with 5 mg/kg cyclosporine for 6 weeks after cell transplantation. After animals were euthanized between 6 and 30 weeks after cell transplantation; the heart was removed for histological studies. Discontinuation of immunosuppression after 6 weeks of cell transplantation did not result in donor cell rejection. The lac-z-positive donor cells were detected in porcine host cardiac tissue for up to 30 weeks posttransplantation, expressing human skeletal myosin heavy chain. The results highlight the effectiveness of transient immunosuppression for myoblast transplantation for cardiac repair.
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PMID:Effectiveness of transient immunosuppression using cyclosporine for xenomyoblast transplantation for cardiac repair. 1501 54

Despite increasing pharmacological and mechanical treatment options, ischemic heart disease continues to be associated with considerable patient mortality and morbidity. The estimates of the direct and indirect costs associated with chronic stable angina amount to billions of dollars. Given the epidemiological and economic magnitude of the problem, the need for more effective therapies is self-evident. Based on current guidelines, the management of ischemic heart disease has progressively broadened to include risk factor modification, patient education, and pharmacological therapy. The latter includes i) classic antianginal agents such as beta-blockers, calcium antagonists, and nitrates, and ii) drugs for secondary prevention, such as aspirin, clopidogrel, statins, and angiotensin-converting enzyme inhibitors. Tailoring therapy to individual needs has become even more challenging because of the marked changes in the clinical profile of patients with chronic ischemic heart disease. Compared with the past, today's patients tend to be older, to have undergone revascularization procedures, and to frequently have associated illnesses, including heart failure and diabetes. Significant progress has been made in recent years in understanding the role of cardiac energy metabolism in the pathogenesis of myocardial ischemia. A better understanding of metabolic derangements associated with ischemia and reperfusion is translating into innovative therapeutic approaches. Optimization of cardiac energy metabolism is based on promoting cardiac glucose oxidation. This has been proved to enhance cardiac function and protect myocardial tissue against ischemia-reperfusion injury. A new class of metabolic agents, known as the 3-ketoacyl coenzyme A thiolase inhibitors (trimetazidine), is able to elicit an increase in glucose and lactate combustion secondary to partial inhibition of fatty acid oxidation, producing clinical benefits in patients with ischemic heart disease.
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PMID:["Persistent" angina: rationale for a metabolic approach]. 1507 76

Acute myocardial ischemia is a critical adverse effect potentially occurring during cardiac procedures. A peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1), betaARKct, has been successful in rescuing chronic myocardial ischemia. The present study focused on the effects of adenoviral-mediated betaARKct (Adv-betaARKct) delivery on left ventricle (LV) dysfunction induced by acute coronary occlusion. Rabbits received intracoronary delivery of phosphate-buffered saline (PBS) (n=9) or 5x10(11) viral particles of betaARKct (n=8). A loose prolene 5-0 Potz-loop suture was placed around the circumflex coronary artery (LCx) with both ends buried under the skin. Four days later, the suture was retrieved and pulled to occlude the LCx. Ischemia was confirmed by immediate ECG changes. LV function was continuously recorded for 45 min. Contractility (LVdP/dtmax), relaxation (LVdP/dtmin) and end diastolic pressure (EDP) were less impaired in the betaARKct group as compared to PBS (P<0.05, two-way ANOVA). betaAR density was higher in the ischemic area of the LV in the betaARKct group (betaARKct: 71.9+/-4.6 fmol/mg protein, PBS: 54.5+/-4.0 fmol/mg protein, P<0.05). Adenylyl cyclase activity was also improved basally and in response to betaAR stimulation. betaARK1 activation was less in the betaARKct group (P<0.05). Therefore, inhibition of myocardial betaARK1 may represent a new strategy to prevent LV dysfunction induced by acute coronary ischemia.
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PMID:Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1). 1588 Apr 49

Hibernation and stunning are phenomena which constitute a basis of dysfunction of the myocardium appearing as a consequence of chronic ischemic heart disease and of myocardial revascularization. Myocardial stunning is an acute derangement of contractility of ischemic myocardium at the moment of restoration of coronary blood flow by various interventions (bypass grafting, angioplasty, thrombolysis). Myocardial hibernation implies presence of chronically developing foci of reduced contractility located in the area of myocardium supplied by obstructed artery. There is a following difference between these phenomena: stunning is a complex of structural and metabolic disorders during the state of "ischemia-reperfusion" while hibernation is a process of adaptation of the myocardium to chronic ischemia consisting in switch of metabolism to alternative type of energy production (anaerobic glycolysis). Exploration of pathophysiology and morphology of hibernating and stunned myocardium is necessary for elaboration of methods of protection against ischemic injury.
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PMID:[Hibernation and stunning as manifestations of ischemic dysfunction of the myocardium]. 1623 97

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.
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PMID:H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart. 1637 98

Sudden cardiac death (SCD) is a major cause of mortality in the United States. Approximately 65% of cases of SCD occur in patients with underlying acute or chronic ischemic heart disease. The incidence of SCD increases 2- to 4-fold in the presence of coronary disease and 6- to 10-fold in the presence of structural heart disease. Ventricular fibrillation (VF) precipitated by ventricular tachycardia (VT) is a common mechanism of cardiac arrest leading to SCD. Triggers for SCD include electrolyte disturbances, heart failure, and transient ischemia. Although a large percentage of patients with out-of-hospital SCD do not survive, successful resuscitation to hospitalization has improved in recent years. One of the challenges for preventing SCD lies in identifying individuals at highest risk for SCD within a lower-risk population. The progression from conventional risk factors of coronary artery disease to arrhythmogenesis and SCD can be represented as a cascade of changes associated with levels of increasing risk. At the first level is atherogenesis, followed by changes in atherosclerotic plaque anatomy, which may be mediated by inflammatory processes. Disruption of active plaque formed during a transitional state initiates the thrombotic cascade and acute occlusion, after which acute changes in myocardial electrophysiology become the immediate trigger for arrhythmogenesis and SCD. Each level of the cascade offers different opportunities for risk prediction. Among the classes of risk predictors are clinical markers, such as ECG measures and ejection fraction. Transient risk markers, such as inflammatory markers, are potentially useful for identifying triggers for SCD. In the future, genetic profiling is expected to allow better assessment of individual risks for SCD.
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PMID:Epidemiology and stratification of risk for sudden cardiac death. 1645 Aug 7

This study investigates the long-term angiogenic effects of ANG-1 and VEGF in a swine chronic myocardial ischemia model. Four-weeks after gradual occlusion of the left circumflex coronary artery by ameroid constrictor, animals were injected with recombinant adenoviral vectors carrying either human ANG-1 (n=9), human VEGF(165) (n=10) or empty vector (n=7) into the left ventricle free wall supplied by the constricted artery. Left ventricular perfusion in animals that received AdANG-1 (3.25+/-0.16 ml/min/g, p<0.05) recovered robustly 4 weeks after gene transfer while ischemia persisted in the AdVEGF (1.09+/-0.13 ml/min/g) and empty vector (1.20+/-0.03 ml/min/g) groups. Microvascular densities in the left ventricles of animals that received AdANG-1 (19.61+/-1.76/0.572 mm(2) myocardial tissue, p<0.05) and AdVEGF (18.17+/-1.43/0.572 mm(2) myocardial tissue, p<0.05) were significantly higher than animals that received empty vector (13.53+/-0.92/0.572 mm(2) myocardial tissue) 12 weeks after gene transfer. ANG-1, but not VEGF, contributed to enhanced regional perfusion by increasing arteriolar density (1.9+/-0.4/0.572 mm(2) myocardial tissue vs. 0.7+/-0.2/0.572 mm(2) myocardial tissue, p<0.05) of large-sized (50-100 microm) arterioles. These data demonstrate that gene transfer of ANG-1 and VEGF enhances angiogenesis, but ANG-1 promotes sustained improvement of ventricular perfusion that expedites recovery of ischemic myocardium via arteriogenesis.
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PMID:Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model. 1654 66

During the search for cardioprotective mechanisms in a porcine model of chronic myocardial ischemia and hibernating myocardium, we discovered evidence for autophagy, which could be involved in the protection against apoptosis. Autophagy is a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which become sequestered in a double-membrane-bound vesicle, termed autophagosome, and subsequently degrade upon fusion with lysosomes. The dauer phase in C. elegans shares similarities with the induction of autophagy in chronically ischemic (hibernating) myocardium. In this sense, autophagy is an essential mechanism for survival which is activated by environmental stresses and confers stress resistance to the organism. Our study provided insight into understanding of the protective mechanism of autophagy in chronic ischemia.
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PMID:Autophagy: a novel protective mechanism in chronic ischemia. 1676 Jun 63


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