Effect of Natural Cytokine Complex on Metabolism of Smooth Muscle Cells in Myocardial Arteries under Normal Conditions and during Hemodynamic Overload.

Histoenzymological methods were employed to examine the effects of systemically administered natural cytokine complex including IL-1, IL-2, IL-6, TNFα, MIF, and TGFß on metabolism of smooth muscle cells in intramural myocardial arteries under physiological conditions and during acute hemodynamic overload of the heart. Natural cytokine complex markedly inhibited metabolism of vascular smooth muscle cells under control conditions and during acute experimental aortal stenosis. In vascular smooth muscle cells, deceleration of tricarboxylic acid cycle, redistribution of the fluxes in glycolytic cascade and its inhibition, down-regulation of oxidation of free fatty acids and their metabolites, and inhibition of the shuttle systems and biosynthetic processes were observed. Inhibition of metabolism in the vascular wall of myocardial arteries correlated with a decrease in their tone and could be partially determined by a decrease in contractile activity of smooth muscle cells. These findings do not exclude the involvement of other factors and mechanisms in down-regulation of metabolism in vascular myocytes in response to increased cytokines levels of in the blood, including their direct effect on biochemical processes in cells.

Effects of Natural Cytokine Complex on the Myocardial Blood Flow in Normal and under Conditions of Increased Hemodynamic Load.

The effects of a natural complex of cytokines IL-1, IL-2, IL-6, TNF, MIF, and GTFß on myocardial blood flow were studied under control conditions and during acute experimental aortal stenosis. Systemic administration of the cytokine complex under control conditions led to moderate impairment of the blood flow in the myocardium associated with plethora and perivascular edema. The number of functioning vessels in the myocardium significantly increased under these conditions, which reflected enhancement of the coronary blood flow. The comparison of the myocardial blood flow under conditions of acute heart overload alone and in combination with systemic administration of the cytokine complex revealed similar changes. In both cases, moderate plethora in all compartments of the vascular network, moderate perivascular edema, and moderate blood stasis in the myocardial capillaries were seen. The only difference the increase in the density of functioning capillaries that was significantly more pronounced after cytokine administration. These data indicate that the increase in the blood cytokine level induced dilatation of myocardial vessels and intensification of blood flow in normal and under conditions of acute hemodynamic heart overload. Against the background of pronounced vasodilatation, the dyscirculatory changes in the myocardium were moderate. It was assumed that the increase in the duration or frequency of hypercytokinemia episodes can induce more severe blood flow disturbances in the myocardium.

Effect of Natural Cytokine Complex on the Structure and Metabolism of the Cardiac Conduction System in the Myocardium under Normally and Increased Hemodynamic Load.

Effect of natural complex of cytokines with activity of IL-1, IL-2, IL-6, TNF, MIF, and GTFß on the structure and metabolism of conduction cardiomyocytes was assessed in the control and under acute experimental aortic stenosis. After systemic administration of the cytokine complex in the control, structural abnormalities were revealed in a relatively low number of conduction cardiomyocytes; their relative number increased in the left ventricle and interventricular septum. When the complex was administered against the background of aortic stenosis, morphological changes in the conduction system were seen in a significant number of cells with their plasma imbibition, especially in the left ventricle and interventricular septum. Systemic administration of the natural cytokine complex inhibited the major metabolic processes in the conduction system, both in the control and under conditions of sharply increased hemodynamic load. In conduction cardiomyocytes, deceleration of glycolysis and citric acid cycle, inhibition of oxidation of free fatty acids and their metabolites, and suppression of shuttle mechanisms and biosynthetic reactions were observed. Increased blood levels of cytokines, primarily of the proinflammatory ones, can cause structural and metabolic disturbances in the cardiac conduction system and promote the development of arrhythmias, especially in case of sharply increased hemodynamic load.

Effect of the Natural Cytokine Complex on the Structure and Metabolism of Contractile Myocardium Normally and under Increased Hemodynamic Load.

Effect of natural complex of cytokines with activity of IL-1, IL-2, IL-6, TNF, MIF, GTFß on the structure and metabolism of contractile ventricular cardiomyocytes was assessed in the control and under conditions of acute experimental aortic stenosis. Systemic administration of the complex in the control had no significant effect on myocardial morphology with low number of damaged cardiomyocytes and low degree of structural damage. Administration of the cytokine complex against the background of aortic stenosis did not exert any additional alterative effect on cardiomyocytes, structural damage of contractual nature was moderate. Systemic administration of the natural cytokine complex had a pronounced inhibitory effect on metabolic processes in the myocardium of both ventricles both in the control and against the background of increased hemodynamic load. In cardiomyocytes, glycolysis and citric acid cycle were slowed down, oxidation of free fatty acids and their metabolic products was inhibited as well as shuttle mechanisms and biosynthetic reactions. Inhibition of energy-producing processes is the cause of the lack of the contractile function energy supply and can worsen the course of cardiovascular diseases and increase the risk of their complications in conditions, accompanied by increased blood cytokine level.

Histoenzymological Characteristics of Smooth Muscle Cells in Myocardial Vessels: A Comparative Study under Conditions of Increased Left or Right Ventricular Afterload.

Histoenzymological methods were used to study metabolism of smooth muscle cells of intramural myocardial arteries during experimental aortic or pulmonary artery stenosis. Aortic stenosis was accompanied by changes in smooth muscles of the left ventricle manifested by deceleration of tricarboxylic acid cycle, inhibition of oxidation of free fatty acids and their metabolites, flux redistribution in the glycolytic cascade, and inhibition of shuttle systems and biosynthetic processes. Similar metabolic alterations were observed in vessels of the ventricular septum, but they were not revealed in vessels of the right ventricle (except glycolysis stimulation). Under conditions of pulmonary artery stenosis, histoenzymological alterations in vascular smooth muscle of both ventricles and ventricular septum were similar, which attested to acceleration of tricarboxylic acid cycle, stimulation of oxidation of the free fatty acids with their metabolites, acceleration of glycolysis, and activation of the shuttle systems and biosynthetic processes. Comparative analysis of histoenzymological alterations revealed substantial differences in the character of metabolic changes under conditions of increased left and right ventricular afterload, which can be caused by peculiarities in myocardial blood flow, severity of circulatory disorders, severity of hypoxia, and intensity of processes maintaining ionic homeostasis in vascular smooth muscles and transport across the histohematic barriers. The data attest to important metabolic role of glycolysis in vascular smooth muscles of the myocardium, especially under conditions of enhanced afterload of the right ventricle.

Histoenzymological characteristics of the heart conduction system: comparative study with left or right ventricle afterload.

Histoenzymological changes, indicating inhibition of the main metabolic processes, were found in the conduction cardiomyocytes of the left ventricle and ventricular septum in experimental stenosis of the aorta. The histoenzymological changes in the conduction system of both ventricles and ventricular septum were similar in experimental stenosis of the pulmonary artery and indicated primarily activation of glycolysis. The histoenzymological profile of conduction cardiomyocytes differed little in cases when the increase of the pressure load was complicated or not complicated by the development of heart failure, particularly in pulmonary artery stenosis. The histoenzymological changes in the conduction system in response to increased afterload differed significantly from those in the contractile myocardium and correlated with the level of cellular functional activity and sensitivity to the regulatory and alterative exposure. These data attest to minor role of metabolic shifts in conduction cell injuries with increasing afterload, primarily, of the right ventricle.

Histoenzymology of the contractile myocardium in experimental pulmonary stenosis.

Metabolism of contractile cardiomyocyte in experimental pulmonary stenosis complicated or not complicated by heart failure was studied by histochemical methods. In pulmonary stenosis not complicated by heart failure, intensification of glycolysis, more intense oxidation of free fatty acids and their metabolites, and acceleration of the citric acid cycle were found in the contractile cardiomyocytes. In pulmonary stenosis complicated by heart failure, glycogen content in the myocardium was sharply decreased. The histochemical enzyme profile of contractile cardiomyocytes is similar in pulmonary stenosis with and without heart failure. Comparative analysis of changes occurring in acute increase in afterload of the left or right ventricle suggested that in the latter case, metabolic abnormalities in the contractile cardiomyocytes are relatively unimportant in the pathogenesis of heart failure.

Histoenzymological characteristics of the contractile myocardium in experimental stenosis of the aorta.

Contractile cardiomyocyte metabolism was studied by histochemical methods in experimental stenosis of the aorta complicated and not by heart failure. Acceleration of the citric acid cycle, more intense oxidation of free fatty acids and their metabolites, glycolysis intensification, and higher activity of shuttle mechanisms were found in the contractile cardiomyocytes in stenosis of the aorta not complicated by heart failure. The presence of these metabolic shifts in the myocardium of all studied compartments suggests their association with not only more intense heart work, but also with the effects of total systems neurohumoral factors. Comparative study of myocardial metabolism in two variants of experimental stenosis of the aorta has revealed changes prognostically unfavorable for the development of heart failure. These changes include exhaustion of glycogen reserve, glycolysis inhibition, and metabolism shift towards biosynthetic processes. These data indicate an important role of glycolysis in support of myocardial contractile function during the acute phase of pressure overloading of the heart.

Pathomorphology of the heart conduction system: comparative study during increase in left or right ventricular afterload.

Pathomorphology of the peripheral compartments of the heart conduction system under conditions of increased left or right ventricular afterload is characterized by interstitial edema, hemorrhages, and reversible and irreversible focal lesions. The percentage of damaged conduction cardiomyocytes increases in the wall of hemodynamically overloaded ventricle and in the ventricular septum. These changes are more pronounced in cases when the afterload increase is complicated by heart failure development. Acute dilatation of the heart and distention of the myocardium are events of great specific significance in the genesis of the conduction system disorders developing under conditions of increased right ventricular afterload in comparison with those developing under conditions of increase left ventricular afterload. These data attest the presence of a pathomorphological base for the appearance of arrhythmias during the acute phase of pressure overload of the heart, especially in cases when it is aggravated by heart failure.

Pathomorphology of myocardial circulation: comparative study in increased left or right ventricle afterload.

Comparative study of pathomorphology of myocardial circulation under conditions of increased afterload of the left or right ventricles showed similar changes. All compartments of the coronary bed were plethoric, capillary blood stasis and perivascular edema, more pronounced in arterial vessels, were detected in both cases. These changes equally involved both ventricles and the ventricular septum. Significant differences consisted in local increase in the density of functioning capillaries. The increase was the maximum in hemodynamically overloaded ventricle and ventricular septum, presumably due to increase of their contractile activity. The density of functioning capillaries in the intact (vs. pressure overloaded) ventricle also increased, but to a lesser degree, which could be due to systemic neurohumoral effects. If increased afterload was complicated by the development of heart failure, circulatory disorders in the myocardium progressed. Significant increase in the density of functioning capillaries in all cardiac compartments indicated decreased vascular tone and exhaustion of coronary reserve. This was paralleled by a sharp arterial plethora in case of increased afterload of the left ventricle and sharp blood stasis in the microcirculatory bed in case of increased right ventricle afterload. Reduction of effective perfusion pressure in the presence of coronary dystonia can cause coronary insufficiency and myocardial ischemia in case of increased right ventricle afterload.

Sympathoadrenal system under conditions of increased left and right ventricular afterload.

Adrenergic plexuses in the myocardium and adrenal medulla were studied histochemically under conditions of increased left or right ventricular afterload. Under conditions of high afterload not accompanied by heart failure the density of sympathetic myocardial innervation remained unchanged in the loaded ventricle, but increased in the intact ventricle. Comparison of the state of the sympathoadrenal system under conditions of increased afterload complicated or uncomplicated by heart failure revealed common prognostically unfavorable changes: sharp decrease in the density of adrenergic nerve plexuses in the ventricular myocardium and activation of adrenal chromaffin cells.

Comparative pathomorphological study of contractile myocardium under conditions of increased left and right ventricular afterload.

Structural changes in the myocardium under conditions of increased left and right ventricular afterload were studied using polarization microscopy and histological, histochemical, and stereological methods. Increased afterload not complicated by heart failure was characterized by low number of damaged cardiomyocytes (3.3-6.5%) and moderate structural changes in the ventricular myocardium (contractures of different severity). Increased afterload complicated by heart failure was characterized by high ratio of damaged cardiomyocytes (5.6-19.2%) and severe reversible (grade I and II contractures) and irreversible (grade III contractures and lump degradation of myofibrils) structural changes. Irreversible damage to most cardiomyocytes included plasmatic impregnation, which was most pronounced in the subendocardial layer of ventricles operating under conditions of increased afterload. Comparative study showed that increased left and right ventricular afterload induces similar pathomorphological changes in the contractile myocardium. Our results indicate that increased afterload to the right or left ventricle is accompanied by the development of stereotypical structural changes in the myocardium. Profound and severe disturbances can cause heart failure.

Heart rhythm disturbances during the acute period of massive pulmonary embolism.

We studied the type, incidence, and dynamics of arrhythmia during the acute phase of massive pulmonary embolism complicated or uncomplicated by cardiac insufficiency. Complicated and uncomplicated massive pulmonary embolisms were accompanied by the appearance of individual and allorhythmic ventricular extrasystoles, respectively. The rise of right ventricular pressure to 70 mm Hg was critical for the development of allorhythmia. Allorhythmia started 3-268 sec after attaining critical ventricular pressure. Heart rhythm spontaneously recovered in 100 and 78% animals with uncomplicated and complicated massive pulmonary embolism, respectively. The duration of paroxysmal allorhythmia varied from 15 sec to 15 min. Electrophysiological processes in the myocardium were normalized with progression of uncomplicated massive pulmonary embolism: the incidence of single and, in particular, allorhythmic extrasystoles decreased, and electrocardiographic parameters returned to normal.

Structural and metabolic changes in cardiac conducting system during massive pulmonary embolism.

We studied structural and metabolic changes in ventricular conducting cardiomyocytes during the acute phase of massive pulmonary embolism complicated or uncomplicated by cardiac insufficiency. During massive pulmonary embolism without cardiac insufficiency, glycolysis in conducting cardiomyocytes of both ventricles was activated, and its contribution to energy formation increased. Massive pulmonary embolism complicated by cardiac insufficiency was accompanied by inhibition of glycolytic enzymes and damages to conducting cardiomyocytes of the left and right ventricles. Our findings indicate that the development of cardiac insufficiency during the acute phase of massive pulmonary embolism provides structural and morphological basis for impairment of electrophysiological properties of the myocardium.