Role of the changes in the sarcoplasmic reticulum in disorders of myocardial function]

Acute focal ischemia of the myocardium, acute hemodynamic overloading of the heart, coarctation of the aorta, and fibrillation of the heart were simulated on rabbits. The animals were studied for the contractile function of the myocardium, and potential work capacity of the heart was calculated according to a special formula. The rebbits were sacrificed at the acute period of the development of a pathological process, and the contractile myocardium was investigated by electron microscope. The studies of the bioelectric activity of the heart revealed periodically appearing disorders of the cardiac rhythm. The electron-microscopy investigation showed, apart from changes in the ultrastructure of cells of the contractile myocardium reflecting their hyperfunction, marked dilatation of small canals of the sarcoplasmic reticulum, right to the formation of cisterns containing sequesters of cells. It is established that the changes referred to above in the sarcotubular system were associated with potassium dysbalance. The conclusion was drawn that the above said changes in the sarcoplasmic reticulum was a stereotype reaction of the alterative heart at the level of ultrastructures developing according to the principle of a vicious circle.     

Changes in myocardial enzyme activity of patients with dilated cardiomyopathy and the relationship of these parameters to disturbed myocardial contractility and coronary atherosclerosis]

Endomyocardial biopsies from 20 patients with dilated cardiomyopathy (DCMP) were studied histochemically. The decrease of the mitochondrial enzyme activity and increase of the activity of lysosomal and hydrolytic enzymes were found. These alterations reflect degenerative processes in cardiomyocytes followed by activation of their degradation and utilization. This results in the decrease of the myocardium contractile volume and its contractile function damage. There was no correlation between the level of the enzyme activity in the myocardium and the degree of the contractile function activity. There was a tendency to the increase of the above changes in patients with early signs of coronary atherosclerosis.     

The effects of tetrandrine on the contractile function and microvascular permeability in the stunned myocardium of rats

The effects of tetrandrine (Tet) on the contractile function and microvascular permeability in stunned rat myocardium in vivo were studied. Stunned myocardium was induced by 15 (MS(15) group) or 20 (MS(20) group) min of myocardial ischemia plus 60 min of reperfusion. The following was shown. (1) FITC-BSA concentration was 166.0 +/- 7. 9 microg/g myocardium in the control group. The concentrations in ischemic myocardium increased by 35.4 and 45.6% in MS(15) and MS(20) groups respectively (p<0.05). (2) Administration of Tet (64.2 and 96. 3 micromol/kg, I.P.) 20 min before ischemia not only ameliorated the contractile function, but also reduced the FITC-BSA concentrations in ischemic myocardium. At 60 min after reperfusion, the contractile function parameters in Tet-treated groups were significantly superior to those in corresponding stunning groups. FITC-BSA concentrations in Tet-treated groups were lower than those in stunning groups. Then, there was already no significant difference in FITC-BSA concentrations between Tet-treated groups and the control group. The FITC-BSA concentrations at the end of experiments were correlated negatively with dp/dt(max) (r = -0.83, p<0.01). (3) Tet inhibited KCl-induced calcium influx in isolated cardiomyocytes. The results suggest that Tet given before ischemia may be involved in the reduction of microvascular permeability in stunned myocardium, which might be associated with its calcium channel blocking effect.     

Characteristics of the restructuring of the cardiomyocyte contractile apparatus in chronic ischemic heart disease

The contractile apparatus of cardiomyocytes was examined at the ultrastructural level in 20 heart biopsy specimens obtained during operations for aortocoronary bypass in patients with chronic ischemic heart disease (IHD). Myofilaments were found to have sustained compensatory-adaptive and destructive changes as well as changes indicative of impaired intracellular regenerations under conditions of chronic hypoxia and energy deficiency experienced by the muscle cells, with the result that myocardial contractility was substantially reduced. Together, these processes led to progressive restructuring of both the contractile apparatus of the cardiomyocytes and the cytoarchitectonics in general. This combined with signs of increasing hyperfunction of the contractile myocardium, which made the energy deficit worse and thus interfered with plastic processes in, and diminished the structural and functional capabilities of, the myocardium. On the other hand, distinct changes were noted in the cardiomyocytes that reflected their adaptation to the adverse conditions created by progressing coronary atherosclerosis. It is concluded that therapy for patients with chronic IHD should include measures aimed at promoting such adaptive changes.     

Selective morphologic alterations of the cardiac conduction system in calves deficient in vitamin E and selenium.

Vitamin E and selenium (E-Se) deficiency causes necrosis of the contractile myocardium in many species but does not usually affect the cells of the conduction system. In the present study, experimental E-Se deficiency in cattle produced preferential degeneration and necrosis of Purkinje cardiocytes. Calves fed deficient diets for 127-137 days had sublethal damage characterized histologically by sarcoplasmic accumulation of lipopigment granules; ultrastructurally, these granules corresponded to cytolysosomes that had a heterogeneous ultrastructure. Alterations in necrotic cells included mitochondrial mineralization, sarcoplasmic condensation, and plasmalemmal fragmentation. Necrosis of Purkinje cells was followed by macrophagic penetration of the external lamina, phagocytosis of necrotic sarcoplasm, and repair by fibrosis. Furthermore, E-Se depletion of calves resulted in only minimal alterations in the contractile myocardium. In contrast, feeding supplements of polyunsaturated fatty acids to E-Se-deficient calves intensified the Purkinje cell damage but also resulted in widespread degeneration and necrosis of the contractile myocardium. Accumulation of lipopigment supports a pathogenetic role for lipoperoxidation in development of the cardiac lesions of E-Se deficiency. These lesions constitute a unique example of preferential damage to Purkinje cardiocytes. This model offers an attractive method of studying damage and repair to the cardiac conduction system.     

Changes in Passive But Not Active Mechanical Properties Predict Recovery of Function of Stunned Myocardium

The time course of alterations in active and passive mechanical properties of stunned myocardium during ischemia and throughout reperfusion has not been thoroughly quantified. This investigation tested the hypothesis that the amount of injury as well as the rate and extent of recovery of contractile function in postischemic, reperfused myocardium are directly correlated to changes in regional active and passive elastance and viscosity. A modified viscoelastic Voigt model was employed to quantify myocardial mechanical properties. Left ventricular pressure and segment length (in both ischemic and normal regions) were fit to the model consisting of an active elastic spring in parallel with a viscous damper and a passive elastic spring. The mechanical properties of myocardium from dogs which recovered (50%) baseline regional contractile function as determined by percent segment shortening (n=7) were compared to those from dogs that did not recover function (n=7). Both groups displayed decreased active elastance in the ischemic region during coronary artery occlusion, and this decrease was maintained in the nonrecovery group. Increases in viscosity of ischemic myocardium were observed in both groups during coronary occlusion but returned to control only in the recovery group. The nonrecovery group demonstrated increased passive elastance in the ischemic region during coronary occlusion and throughout the reperfusion period whereas the recovery group remained unchanged. We conclude that functional recovery of stunned myocardium is directly related to alterations in mechanical properties caused by ischemia and that changes in passive elastance during occlusion may predict the ability of ischemic myocardium to recover contractile function. © 1999 Biomedical Engineering Society. PAC99: 8719Rr, 8719Uv, 8710+e     

Rhythmoinotropic Myocardial Reactions in Rats with Postinfarction Cardiosclerosis against the Background of Streptozotocin-Induced Diabetes

We studied rhythmoinotropic reactions of the myocardium in rats with postinfarction cardiosclerosis and in rats with postinfarction cardiosclerosis against the background of streptozotocin-induced diabetes. Inotropic myocardial response in rats with postinfarction cardiosclerosis was signifi cantly inhibited after rest periods, while in streptozotocin diabetic rats the rhythmoinotropic myocardial reaction was comparable with the reaction of intact myocardium. The combination of postinfarction cardiosclerosis and diabetes paradoxically contributed to preservation of contractile function of the myocardium in rats.     

Cardiac myosin binding protein-C: a novel sarcomeric target for gene therapy

Through its ability to interact with both the thick and thin filament proteins within the sarcomere, cardiac myosin binding protein-C (cMyBP-C) regulates the contractile properties of the myocardium. The central regulatory role of cMyBP-C in heart function is emphasized by the fact that a large proportion of inherited hypertrophic cardiomyopathy cases in humans are caused by mutations in cMyBP-C. The primary dysfunction in cMyBP-C-related cardiomyopathies is likely to be abnormal myofilament contractile function; however, currently, there are no effective therapies for ameliorating these contractile defects. Thus, there is a compelling need to design novel therapies to restore normal contractile function in cMyBP-C-related cardiomyopathies. To this end, concepts gleaned from various structural, functional, and biochemical studies can now be utilized to engineer cMyBP-C proteins that, when incorporated into the sarcomere, can significantly improve contractile function. In this review, we discuss the rationale for cMyBP-C-based gene therapies that can be utilized to treat contractile dysfunction in inherited and acquired cardiomyopathies.     

Age-related features of cardiac contractility and its adrenergic regulation in catecholamine damage to the myocardium

Studies on isolated rat hearts showed that in contrast to 8-month-old animals, in 26-month-old rats the contractile activity of the myocardium increases by the 3rd day after administration of toxic adrenalin doses (1 mg/kg i.m.). The maximum functional response of catecholamine injured hearts to stimulation of alpha- and beta-adrenoceptors reduced in both age groups, while the sensitivity of the myocardium to beta-adrenoceptor agonists in mature rats increased.     

Ca2+ sensitivity of stunned myocardium after skinning using retrograde infusion of detergent

Myofilament Ca2+ desensitization contributes to the contractile dysfunction of ischemic/reperfused ("stunned") myocardium. We examined the presence of reduced Ca2+ sensitivity of isometric force in chemically skinned fibers obtained from stunned myocardium using different modes of applying the detergent Triton X-100. Langendorff-perfused rat hearts underwent 20 min ischemia/20 min reperfusion, which caused a 35 +/- 3% decrease in left ventricular developed pressure, compared to continuously perfused control hearts. Stunned and control hearts were randomly allocated to two different permeabilization protocols: In group A, trabeculae were dissected and immersed in skinning solution containing 1% Triton X-100 for 20 min. Group B hearts remained fixed to the aortic cannula and skinning solution was infused retrogradely for 6 min prior to dissection of trabeculae. Extraction of cytosolic marker proteins was more complete in group-B than in group-A preparations. Group-A preparations from stunned hearts exhibited significant Ca2+ desensitization (pCa50 = 5.07 and 5.15 in stunned and control myocardium, respectively). In group B no such difference was observed, all preparations showing higher Ca2+ sensitivity and maximum force than group-A preparations (pCa50 = 5.32 in stunned versus 5.33 in control hearts). Prolonging group-A skinning to 150 min also abolished the difference in Ca2+ sensitivity between stunned and control myocardium. In conclusion, compared to a conventional protocol, skinning by perfusion results in more complete permeabilization and better preservation of myocardial contractile function. Ischemia/reperfusion at this moderate degree of contractile dysfunction induces Ca2+ desensitization at least partially by factors that can be extracted by thorough skinning.     

Morphological and functional features of the left ventricle in rabbits with experimental alcoholic cardiomyopathy

Against the background of chronic alcohol poisoning in rabbits a sharp decline is observed in the contractile power of the left ventricle, accompanied by a significant lengthening of the phases of isometric contraction and isometric relaxation. Morphological investigation of the heart revealed marked hypertrophy of the myocardium and intensification of intramyocardial lipolysis, leading to accumulation of acid lipids in the heart muscle. It may be that these lipids, requiring additional quantities of oxygen for their utilization, lead to the appearance of a state of relative hypoxia in the myocardium. Combined with the deficiency of diastole, this may lead to weakening of the contractile power of the heart and to the compensatory development of hypertrophy of the myocardium.Department of Pathological Physiology and Department of Internal Medicine, Patrice Lumumba Peoples' Friendship University, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. K. Kulagin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 3, pp. 358–360, March, 1980.     

An assessment of the reserve potentials of the heart by using volume loading with the exclusion of a portion of the left ventricular myocardium from contraction

The reserve possibilities of the heart in dosed exclusion of part of the contractile myocardium of the left ventricle were determined by the initial functional condition of the "intact" myocardium. Overexertion by volume in exclusion of part of the myocardium from contraction is dangerous due to exhaustion of the myocardial contractility reserve, relative diminution of coronary circulation with the gradual increase of exertion and overloading of the lesser circulation, which are a secondary cause of the reduction of the reserve possibilities of the heart.     

Skeletal muscle disorders in heart failure.

Heart failure is associated with reduction of exercise capacity that cannot be solely ascribed to reduced maximal oxygen uptake (VdotO2max). Therefore, research has focused on changes in skeletal muscle morphology, metabolism and function. Factors that can cause such changes in skeletal muscle comprise inactivity, malnutrition, constant or repeated episodes of inadequate oxygen delivery and prolonged exposure to altered neurohumoural stimuli. Most of these factors are not specific for the heart failure condition. On the other hand, heart failure is more than one clinical condition. Congestive heart failure (CHF) develops gradually as a result of deteriorating contractility of the viable myocardium, myocardial failure. Is it possible that development of this contractile deficit in the myocardium is paralleled by a corresponding contractile deficit of the skeletal muscles? This question cannot be answered today. Both patient studies and experimental studies support that there is a switch to a faster muscle phenotype and energy metabolism balance is more anaerobic. The muscle atrophy seen in many patients is not so evident in experimental studies. Few investigators have studied contractile function. Both fast twitch and slow twitch muscles seem to become slower, not faster as might be expected, and this is possibly linked to slower intracellular Ca2+ cycling. The neurohumoural stimuli that can cause this change are not known, but recently it has been reported that several cytokines are increased in CHF patients. Thus, the changes seen in skeletal muscles during CHF are partly secondary to inactivity, but the possibility remains that the contractility is altered because of intracellular changes of Ca2+ metabolism that are also seen in the myocardium.     

Subcellular bases of cardiac disturbance in experimental informational neurosis

In experimental informational neurosis, accompanied by the development of stable arterial hypertension, tachycardia and dystrophic alterations in myocardium, the contractile protein ability to generate force and produce work as well as the power of the contractile process are significantly decreased and so is the intensity of Ca2+ transport through membranes of sarcoplasmic reticulum and mitochondria. Ca2+ content in these structures and energetic supply to the cardiac muscle do not change as compared with the control. Noradrenaline content in myocardium increases 5-fold compared with the control and 2.5-fold compared with the norm, while blood content falls to zero (sympathetic neuro-muscular contact is 'locked up' for noradrenaline outflow into the blood); dopamine content increases. Adenylate cyclase sensitivity to the stimulating effect of noradrenaline and NaF diminishes. Basal activity of phosphodiesterase increases, and its sensitivity to the inhibitory action of high calcium concentrations decreases. The disturbance in these systems may, on the one hand, be due to neural effects, and pressure overload of the heart, on the other hand, to the sharp rise in noradrenaline content in the myocardium and the change in the activity of cyclic adenosine monophosphate enzymes. It is suggested that similar changes may take place in the human myocardium and may underlie the cardiac weakness.     

Mechanism of action of nonachlazine on the blood supply and activity of the heart

Nonachlazine (10 mg/kg, intravenously) has a biphasic effect on cardiac activity. A short phase of weakening of cardiac activity is followed by a marked increase in the cardiac output and contractile function of the myocardium. The increase in the blood supply and activity of the heart coincides in time with the accumulation of noradrenalin in the myocardium and an increase in phosphorylasea. β-Adrenoblockers prevent the development of these effects. It is postulated that the effectiveness of nonachlazine in ischemic heart disease is connected with its ability to activate adrenergic mechanisms of glycogenolysis control, leading to switching of metabolism in the myocardium to the anaerobic pathway of energy liberation.     

Clinico-morphologic results of laser myocardial revascularization in ischemic heart disease]

Transmyocardial laser revascularization was applied in 58 patients with ischemic heart disease. The objective criterion of the method efficiency was an increase in myocardium perfusion due to newly formed blood vessels under influence of laser irradiation. The laser treatment has improved cardiac function and general condition of the patients. The surgery did not exert considerable influence on the contractile capacity of the myocardium in the patients treated.     

Apoptosis of cardiomyocytes as extreme manifestation of regeneration and plastic insufficiency of myocardium

Alkaline dissociation of the myocardium from rats with modeled anthracycline cardiomyopathy revealed decreased absolute number of cardiomyocytes, disturbances in their intracellular regeneration, although no sings of necrosis were observed. Regeneration and plastic insufficiency of the myocardium due to structural changes in the nuclei and disturbances in myofibril reproduction resulting from selective suppression of synthesis of contractile proteins in the cardiomyocytes leads to the death of up to 30% cardiomyocytes.     

Role of myosin heavy chain composition in the stretch activation response of rat myocardium

The speed and force of myocardial contraction during systolic ejection is largely dependent on the intrinsic contractile properties of cardiac myocytes. As the myosin heavy chain (MHC) isoform of cardiac muscle is an important determinant of the contractile properties of individual myocytes, we studied the effects of altered MHC isoform expression in rat myocardium on the mechanical properties of skinned ventricular preparations. Skinned myocardium from thyroidectomized rats expressing only the β MHC isoform displayed rates of force redevelopment that were about 2.5-fold slower than in myocardium from hyperthyroid rats expressing only the α MHC isoform, but the amount of force generated at a given level of Ca²⁺ activation was not different. Because recent studies suggest that the stretch activation response in myocardium has an important role in systolic function, we also examined the effect of MHC isoform expression on the stretch activation response by applying a rapid stretch (1% of muscle length) to an otherwise isometrically contracting muscle fibre. Sudden stretch of myocardium resulted in a concomitant increase in force that quickly decayed to a minimum and was followed by a delayed redevelopment of force (i.e. stretch activation) to levels greater than prestretch force. β MHC expression dramatically slowed the overall rate of the stretch activation response compared to expression of α MHC isoform; specifically, the rate of force decay was ∼2-fold slower and the rate of delayed force development was ∼2.5-fold slower. In contrast, MHC isoform had no effect on the amplitude of the stretch activation response. Collectively, these data show that expression of β MHC in myocardium dramatically slows rates of cross-bridge recruitment and detachment which would be expected to decrease power output and contribute to depressed systolic function in end-stage heart failure.     

Hibernation and stunning as manifestations of ischemic dysfunction of the myocardium

Current information on hybernation and stunning which are the basis of myocardial dysfunction resulting from chronic ischemic heart disease and revascularization is provided. Myocardial stunning is an acute disturbance of a contractile function of ischemic myocardium at the moment of coronary circulation restoration done by various methods (coronary shunting, angioplasty, thrombolysis). Myocardial hybernation is a chronically developing foci of subnormal contractility in the region of stenotic artery. The difference between them is that stunning is a complex of structural and metabolic damages under the condition "ischemia-reperfusion" while hybernation is an adaptation of the myocardium to chronic ischemia by metabolism switching to anaerobic glycolysis. The study of pathophysiology and morphology of hybernating and stunned myocardium is necessary for developing methods of myocardium protection from ischemic damage.     

Skeletal muscle disorders in heart failure

Heart failure is associated with reduction of exercise capacity that cannot be solely ascribed to reduced maximal oxygen uptake (V˙O_2max). Therefore, research has focused on changes in skeletal muscle morphology, metabolism and function. Factors that can cause such changes in skeletal muscle comprise inactivity, malnutrition, constant or repeated episodes of inadequate oxygen delivery and prolonged exposure to altered neurohumoural stimuli. Most of these factors are not specific for the heart failure condition. On the other hand, heart failure is more than one clinical condition. Congestive heart failure (CHF) develops gradually as a result of deteriorating contractility of the viable myocardium, myocardial failure. Is it possible that development of this contractile deficit in the myocardium is paralleled by a corresponding contractile deficit of the skeletal muscles? This question cannot be answered today. Both patient studies and experimental studies support that there is a switch to a faster muscle phenotype and energy metabolism balance is more anaerobic. The muscle atrophy seen in many patients is not so evident in experimental studies. Few investigators have studied contractile function. Both fast twitch and slow twitch muscles seem to become slower, not faster as might be expected, and this is possibly linked to slower intracellular Ca²⁺ cycling. The neurohumoural stimuli that can cause this change are not known, but recently it has been reported that several cytokines are increased in CHF patients. Thus, the changes seen in skeletal muscles during CHF are partly secondary to inactivity, but the possibility remains that the contractility is altered because of intracellular changes of Ca²⁺ metabolism that are also seen in the myocardium.