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Metabolic approach to therapy of acute and chronic forms of cardiac ischemia

            Both experimental and clinic study of last decade of the 20th century in the sphere of atherosclerosis were united by the aspiration of scientists to form a well-compose system of a unified pathogenic mechanism of shaping and progress of lesion of vessels and target organs. Latest achievements in spheres of molecular biology, control of local vascular reactivity, thrombosis and of proliferation processes made it possible to formulate a concept of damaged interrelation of a cell (endothelium) and of a vessel wall, which has a dynamic character (0.1. hearse, 1990) and to discover the interrelation of reduced myocardium contractile and metabolic functions in the area of its acute and chronic ischemia (H. Taegtmeyeretal, 1988). The term “Myocardium ischemia” (MI) describes various statuses conditioned by disparity of oxygen consumption by myocardium with the level of metabolism with a given status of cell oxidation. Numerous experimental studies dealt with the study of metabolic aftereffects of CI development including those resulting in cell necrosis. They served as a basis for the development of new methods of metabolic correction of statuses conditioned by the development of ischemia/reperfusion, and of new methods of therapy of chronic acute CI forms. Thus, CI (both with and without pain reaction) is based on intracell metabolic shifts resulting in the rise of anaerobic glycolysis, energetic phosphate content drop, medium overacidity, cell edema, mitochondria damage, etc. In line with this membrane phospholipases are locally activated with the growth of products of free radical lipid oxidation with secondary structural and conformational reformation of membranes. A parallel activation of blood cells (neutrophils, thrombocytes) also participate in the CI phenomena aggravation by separation various mediatory substances, which stimulate both growth of free radical products and rise of vasocontriction with secondary aggravation of disparity in oxygen supply and demand. From the clinical standpoint CI aftereffects depend on its spread (damage in single or in several vascular reservoirs), depth (duration of periods of complete or partial coronary circulation damage), conditioning in the end the development of either reversible or irreversible myocardium dysfunction. With a reversible damage of myocardium contractile function within the area of ischemia upon its reperfusion revival of cardiomyocytes contractility with its reperfusion is noted. All the above statuses are not accompanied with specific signs in ECG and are characterized by a retained function of mitochondria and of intracell energetic reserve as well as by existing blood circulation in th area of CI. In case of CI transformation into an irreversible form (necrosis) the function of mitochondria is always damaged, intracell concentration of calcium ions and of oxygen radicals are high while ATP is extremely low. Today the described pathologic mutations have become a clinical reality, although they were first ascertained in laboratory studies. It is just damaged function of left ventricle (apart of pain) serves for clinicians as a marker of myocardium disorders, which they can evaluate (as distinct from intracell metabolism shift and coronary circulation variation) with no changes in ECG. In case of stenocardia attacks on the background of non-occluding atherosclerosis (short-time ischemia followed by reperfusion) and angioplasty procedures cardiomyocytes function revives sufficiently quickly while with a more long period of myocardium infarction myocytes function revival is retarded (after thrombolysis and coronary angioplasty comparatively high reperfusion of a wide pre-ischemized area results in the activation of polymorphonucleous neutrophils, separating free oxygen radicals and triggering the chain of reaction of lipid free radical oxidation). It is just alteration of cell membranes due to the progress of free radical processes is now considered as one of pathologically significant factors of myocardium reperfusion damage with acute coronary syndromes and acute myocardium infarction (G.N. Pierce, M.P. Crubryt, 1995). The activation of lipoxygenasic way of arachidonic acid metabolism with formation of a whole class of leukotrienes having chemoattractant, vasocontriction and thrombocyte-activating effects is of high significance for the realization of the above processes. Some scientists assume that leukotrienes formation results in activation of free radical processes with myocardium ischemia/reperfusion. In this context during some experimental studies attempts were undertaken to study different effects on neutrophils activity and synthesis of leukotrienes with acute occlusion and reperfusion of coronary arteries (S. Hoshida et al., 1995), including with the use of a natural flavonoid Quercitrol, which is capable of blocking 5-lipoxygenase. The studies on creatures proved the preparation capability to reduce phenomena of ischemic and reperfusion damage of myocardium, to limit myocardium infarction area and to prevent development of heavy ventricular arrhythmia. These data were proved also in latest clinical tests in patients with acute myocardium infarction. In accordance with the data of studies in our clinic the use of quercitrol reduced (in comparison with a control group) release of creatinephosphokinase and of its MB-isoferment into blood flow, which fact indirectly proves a cytoprotective effect of the preparation. A cytoprotective effect of quercitrol in patients with acute myocardium infarction was proved by alleviation of clinical disease progress within treatment period preventing uvuleplastics on vessel occlusion background, after operations with assisted blood circulation associated with cell overload by calcium ions. In line with this acute myocardium infarction may occur on the background of prior occluding coronary atherosclerosis with hemodynamically significant patch (or with several patches in a single or in several vessels), which fact may be considered as an aggravation of prior intracell ischemic shifts. In such patients sections with chronically reduced contractility were registered downstream vessel stenosis. These sections can restore its function with better blood flow after aorta and coronary vessels shunting operation or angioplasty. For the purpose of description of such myocardium status American scientist Sh. Rakhimtula (1989) had implemented term "hibernating myocardium". This status differs from postponed myocardium dysfunction after complete recovery of coronary artery permeability with no or residual stenosis, which was described by E. Brownwald, 1982). Such myocardium with a change metabolism was called “stunned myocardium”. Regardless coronary artery permeability was recovered or not, with the development of acute myocardium infarction (AMI) in the area of necrosis a number of events in re-modeling of left ventricle progresses with thinning of necrotized myocardium section and expansion of ventricle cavity. The described events significantly affect formation of clinically-significant cardiac insufficiency, reduce coronary blood flow in such patients and result in myocardium hyperfusion in other vascular areas, thus facilitating contractility damage progress and heart cavity expansion. Acute and chronic cardiac dysfunction caused by metabolic disorder on background of myocardium infarction is noted with a number of clinical statuses of patients with cardiac ischemia. All above described served as reason for studying metabolic effects of well-known drugs (beta-adrenoblockators, angiotensin-forming ferment inhibitors, calcium antagonists, angiotensin II receptor blockators) and of new preparations having properties of antioxidants and membrane protectors. It was shown that above indicated drugs have cytoprotecting and cardioprotecting effects with ischemia/reperfusion syndrome. In line with these term metabolic therapy is understood as the use of drugs affecting the heart with now effect on hemodynamics. With our undoubted interest to above-indicated drugs having metabolic activity we shall emphasize only clinically promising representatives of antioxidants and membrane protectors. A distinct feature of preductal effect with myocardium infarction is its capability to activate aerobic metabolism of myocardium cells, to reduce intracell acidosis, loss of energetic phosphates and improve left ventricle function (A. Desideri, L. Celegon, 1998). This is reflected in reduction of MI attacks by the data of Halter’s monitoring of ECG and of load testing, improvement of functional status of blood circulation system in patients with chronic cardiac ischemia. It is worth noting that anti-ischemia effect of this preparation is comparable with that of beta-blockators and of calcium antagonists, which, as distinct from preductal, essential affect hemodynamics indicators. Preductal may be also used as pre-operation preparatory drug for protecting myocardium during operation on heart (J.N. Fabiani et al., 1992). Quite new is its use in patients with acute cardiac ischemia forms including myocardium infarction. The studies carried out in our clinic discovered cytoprotecting and anti-arrhythmic effects of this preparation and its capability to reduce processes of early re-modeling processes of left ventricle cavity (A.N. Darkhomenko at al., 1996). However, in line with this (as distinct from neoton) the deficiency of intravenous dosage forms of both quercitrol and preductal, which could increase efficiency of therapeutic intrusion with acute coronary catastrophes, is a disadvantage of these drugs. We hope that a soluble dosage form of homemade quercitrol will appear very soon as nowadays it is being trial tested in some clinics within Ukraine. Thus, nowadays we have a possibility to provide a metabolic correction of damaged function of endothelium cells and cardiomyocytes with acute and chronic disorders of coronary blood circulation. Such a therapy cannot be applied as an independent therapy, but in combination with other preparations it will facilitate results of therapeutic intrusion.

Published: 15.06.1999