Mechanisms of subcellular remodelling in post-infarct heart failure.

Occlusion of a coronary artery results in myocardial ischemia and subsequent myocardial infarction. Whenever the infarct size is more than 30% of the ventricular wall, the remaining myocardium attempts to compensate for the loss of muscle mass by changing the size and shape of cardiocytes in addition to developing cardiac hypertrophy, cardiac dilatation and congestive heart failure. This remodeling of the heart is associated with changes in the extracellular matrix including collagen proteins and is most probably due to the activation of both sympathetic nervous system and renin-angiotensin system as well as increased formation of various growth factors. Alterations in contractile function of the infarcted heart are associated with remodelling of the sarcoplasmic reticulum with respect to Ca(2+)-pump and Ca(2+)-release channels as well as contractile and regulatory proteins of the myofibrils. Myocardial infarction has also been shown to result in remodelling of the sarcolemmal membrane with respect to Ca(2+)-channels, Ca(2+)-transport systems, cardiac receptors and signal transduction mechanisms. Although information regarding remodelling of mitochondria in the infarcted heart is limited, alterations in energy yielding and Ca(2+)-accumulating systems are suspected. Accordingly, it is suggested that changes in cardiac contractile dysfunction due to myocardial infarction are associated with remodeling of both extracellular matrix and subcellular organelles in the heart.

Biphasic changes in heart performance with food restriction in rats.

To examine effects of food restriction resembling very-low-calorie dieting on heart performance, normal rats were fed 25% of ad libitum food intake for 14 days. Although heart weight decreased (P < 0.05) after 5 days, left ventricular systolic pressure as well as rates of pressure development and fall were increased (P < 0.05) at 7 days and decreased (P < 0.05) after 14 days. Systolic and diastolic blood pressures were also increased from 5 to 7 days and decreased after 14 days. The increased hemodynamic performance of heart was associated with a raised plasma norepinephrine concentration, which peaked at day 7 of food restriction; epinephrine concentration was increased (P < 0.05) also at day 7. An increased catecholamine synthesis was indicated by the raised (P < 0.05) plasma dopamine beta-hydroxylase activity at 3 days, but this was decreased (P < 0. 05) at 14 days. The concentration of dopamine in the heart was increased (P < 0.05) at 2-14 days, of norepinephrine at 7-14 days, and of epinephrine at 10 and 14 days. Food restriction thus appears initially to be associated with an enhanced catecholamine influence on the heart and is followed by a depressed cardiac performance.

Characteristics and mechanisms of tachyphylaxis of cardiac contractile response to insulin.

Although insulin is known to cause internalization of its own receptors, the physiological significance of this phenomenon is not clear. In the isolated rat heart we observed that the positive inotropic effect of 25 munits/ml insulin was completely abolished if the heart was preperfused with insulin for 10 min. This tachyphylactic response to insulin began to appear 3-4 min after starting preperfusion with insulin and was partially reversible after 30 min of washing. Preperfusion with insulin did not affect the action of vanadate, which has insulin-like effect on glucose transport, or the actions of the other positive inotropic agents, isoproterenol and ouabain. The presence of propranolol in the perfusion medium, unlike atenolol, phenoxybenzamine, guanethidine, verapamil or quinidine, modified the inotropic as well as tachyphylactic responses to insulin. The positive inotropic and tachyphylactic responses to insulin were not altered in hearts from reserpine-treated animals. Perfusion of heart with glucose-free solution abolished the tachyphylaxis due to insulin. Likewise, no tachyphylactic response to insulin was evident when iodoacetate, but not sodium fluoride, was added in medium containing glucose. These results suggest that ATP formed during glycolysis may play an important role in insulin-induced tachyphylaxis with respect to cardiac contractile activity.

Role of endothelin in heart function in health and disease.

A comprehensive review of the literature has revealed that endothelins belong to a family of vasoactive peptides which are formed and released from the endothelium. By producing constriction of the coronary arteries and peripheral blood vessels, endothelins are known both to reduce coronary bloodflow and increase blood pressure and thus can be seen to affect heart function adversely. On the other hand, endothelins are capable of producing positive inotropic and chronotropic effects by directly affecting both the myocardium and nodal tissues. Prolonged actions of high concentrations of endothelins can be seen to induce relative hypoxia in the myocardium which will eventually result in heart dysfunction. The mechanisms of actions of endothelin on smooth muscle cells and cardiomyocytes include interaction with endothelin receptors on the cell surface, activation of phospholipase C through G-proteins, and increase in the intracellular concentration of Ca2+ through the increase in phosphoinositol turnover. Endothelins were found to exert no effects on sarcolemmal Na+,K(+)-ATPase, Na(+)-Ca2+ exchange and Ca2+ pump systems nor on the sarcoplasmic reticular Ca2+ pump system and myofibrillar ATPase activities in the rat heart. Marked elevation in the levels of plasma endothelins and down-regulation of endothelin receptors in ischemia-reperfusion injury, hypertension and chronic diabetes indicate a significant role of endothelins in the genesis of heart dysfunction under different pathological conditions.

Prostaglandins and heart disease.

The role of prostaglandins (PGs) in cardiac pathophysiology has been reviewed with special emphasis on clinically applied aspects. Several PGs are synthesized and released by the heart and coronary vessels. Their synthesis is altered by various factors such as physical manipulation of tissue, pharmacological treatments and pathological conditions such as myocardial over-reactivity and ischemia. The involvement of PGs in cardiac dysfunction remains controversial, although it has been proposed that various PGs such as PGI2 or PGB2 may play a role in disaggregating platelets, inhibiting thrombus progression and coronary vasodilatation. The balance between thromboxane A2 (TXA2), a proaggregatory agent released from platelets and PGI2 may have a role in the genesis and management of angina and myocardial infarction. The use of non-steroidal anti-inflammatory agents in these conditions remains controversial; their possible beneficial effects are believed to be due to inhibition of TXA2 synthesis whereas their failure to be effective may be a consequence of concomitant inhibition of PGI2 production. Modulation of endogenous PG synthesis and administration of exogenous PGs or their analogues appear to be two therapeutic approaches in the management of certain cardiac diseases. Accordingly, there is a great need for synthesizing stable and potent PG analogues as well as specific inhibitors of PG synthesis in addition to studying their pharmacology and therapeutics. In this review we have emphasized the involvement of PGs in the pathogenesis of some forms of cardiac disease and have highlighted some therapeutic implications of these substances for the treatment of heart disease.

Adrenochrome uptake and subcellular distribution in the isolated perfused rat heart.

Adrenochrome uptake and its subcellular distribution were examined using isolated perfused rat heart preparation. The heart was perfused for 30 min with a medium containing 1 to 50 mg/l of 14C-adrenochrome and the subcellular fractions were isolated to measure their radioactivities. A decline in contractile force, a rise in resting tension and an increase in adrenochrome uptake by the heart were seen to depend upon the time of perfusion and the concentration of adrenochrome in the medium. The sarcolemmal fraction had the highest uptake of adrenochrome and this was followed by the microsomal fraction; some accumulation of adrenochrome was also observed in the myofibrillar and mitochondrial fractions. Either 10 or 20 min reperfusion of the heart previously exposed to 25 mg/l of adrenochrome, resulted in approximately 50 or 37% of the radioactivity remaining in the heart; this indicates irreversible binding of adrenochrome to the tissue. Reperfusion of the heart showed restoration of the resting tension but the contractile force did not show any recovery. Propranolol and iproniazid, which have been shown to inhibit the adrenochrome induced cardiotoxicity, reduced adrenochrome uptake by the heart, and prevented adrenochrome-induced depression in contractile force and rise in resting tension. These results indicate that adrenochrome is taken up by the heart and induces cardiac disturbances through its action on different subcellular organelles in the myocardium.

Pathophysiology of cardiac dysfunction in congestive heart failure.

Although various factors, such as myocardial infarction, pressure overload and volume overload, result in the development of congestive heart failure (CHF), the pathogenesis of contractile dysfunction in this situation is poorly understood. Loss of cardiac muscle due to myocardial infarction appears to activate several humoral and hormonal pathways, including the renin-angiotensin and sympathetic systems which serve as adaptive mechanisms to maintain cardiovascular performance at early stages of failure. However, under chronic conditions, an altered hormonal profile produces deleterious effects and permits transition from the compensated heart to the failing heart. Since several risk factors--such as hypertension, hypercholesteremia, stress, diabetes, smoking, ageing, obesity and lack of exercise--precipitate ischemic heart disease, it is possible that development of CHF due to myocardial infarction may vary according to the nature of these pathogenetic entities. While a great deal of research work remains in this area of investigation, it is becoming evident that cardiac dysfunction is intimately associated with calcium handling abnormalities of cardiac cells. In view of the role of sarcolemma, sarcoplasmic reticulum and mitochondria in regulating the intracellular concentration of Ca2+ and the importance of myofibrillar interaction with Ca2+, it appears that Ca2+ handling and Ca2+ interaction abnormalities in the failing heart are due to remodelling of different subcellular organelles. Such a remodelling of the subcellular organelles may be due to changes in gene expression for different protein components or the interactions of proteins with phospholipids. Accordingly, it is proposed that new interventions, which could prevent the remodelling of subcellular organelles, be developed for improving the therapy of CHF.

Effect of adrenochrome on adenine nucleotides and mitochondrial oxidative phosphorylation in rat heart.

Effects of adrenochrome, an oxidation product of epinephrine, on myocardial energy production were investigated by studying changes in adenine nucleotide content and mitochondrial oxidative phosphorylation activities in the isolated rat heart. Perfusion of the heart with 50 mg/L adrenochrome induced a marked decline in contractile force within 5 min and this was associated with a rapid decline in the myocardial ATP/AMP ratio. A significant decrease in ATP and ATP/ADP ratio as well as a significant increase in ADP and AMP content was observed at 10 min of perfusion with adrenochrome. Furthermore, mitochondrial oxidative phosphorylation activities were unchanged except that an increase in state 4 respiration and a decrease in RCI value were seen in the heart perfused with adrenochrome for 10 min. Autoradiography of the sections from hearts perfused with 14C-adrenochrome revealed the localization of a significant amount of radioactivity on mitochondria. Adrenochrome at concentrations of 20 mg/L or higher was found to inhibit the oxidative phosphorylation activities of heart mitochondria under in vitro conditions. The depressant effects of adrenochrome on mitochondrial oxidative phosphorylation were additive to those seen with calcium. These data suggest that adrenochrome in the presence of excess calcium in the myocardial cell may impair the process of energy production in mitochondria and this may result in contractile failure of hearts exposed to this cardiotoxic metabolite of epinephrine.

Pathophysiological aspects of myocardial hypertrophy.

Heart hypertrophy in response to increased workload is a complex process in which this organ adapts to the environment by increasing the muscle mass in terms of additional contractile units and formation of different types of contractile proteins (myosin isozymes). In addition, augmentation of membrane function with respect to calcium transport activities of sarcolemma and sarcoplasmic reticulum occurs at early stages of cardiac hypertrophy associated with hyperfunction of the myocardium. However, if cardiac hypertrophy is left unattended beyond a certain period, physiological hypertrophy is converted to pathological hypertrophy whereby the cardiac muscle is unable to generate an adequate amount of contractile activity. It appears that the sympathetic nervous system is activated for producing beneficial effects at early stages but an elevated level of sympathetic tone for a prolonged period could result in dysfunction of the cardiac muscle. The transition of physiological hypertrophy to pathological hypertrophy seems to be due to the occurrence of intracellular calcium overload in the myocardial cell as a consequence of defects in the membrane calcium transport systems. It is suggested that careful attention should be paid not only to removal of the stimulus responsible for cardiac hypertrophy but also to lowering sympathetic tone. Efforts should also be made to prevent the occurrence of intracellular calcium overload due to membrane defects.

Alterations of sarcolemmal Na+-Ca2+ exchange in catecholamine-induced cardiomyopathy.

Rats were injected intraperitoneally with 40 mg/kg body weight isoproterenol and the heart sarcolemma was isolated 3, 9 and 24 hours later. The heart/body weight ratio increased and varying degrees of change in cardiac ultrastructure were apparent at 9 and 24 hours after isoproterenol injection. Na+-dependent Ca2+ uptake activities of heart sarcolemma were depressed at 3, 9 and 24 hours; such alterations in 24 hour preparations were evident at different times of incubation and at different concentrations of Ca2+. No differences in Na+-induced Ca2+ release or Na+-K+ ATPase activities were observed between the control and experimental membranes. The control and isoproterenol-treated heart sarcolemmal preparations were minimally but equally contaminated by other subcellular organelles. Although there was no significant change in the phospholipid composition, the protein pattern as determined by gel electrophoresis was altered in sarcolemma at 24 hours of isoproterenol treatment. These results indicate an abnormality of heart sarcolemmal Na+-dependent Ca+ uptake during the development of catecholamine-induced cardiotoxicity. It is suggested that a depression in the ability of the cell to remove Ca2+ through the Na+-Ca2+ exchange in sarcolemma may contribute to the development of intracellular Ca2+ overload in catecholamine induced cardiomyopathy.

Pathogenesis of cardiac dysfunction in diabetes mellitus.

The use of insulin by diabetics has largely removed the threat of death from ketotic coma but cardiovascular dysfunction remains a major cause of death in patients with diabetes. Recent research has indicated a generalized membrane defect, which may cause abnormalities of calcium metabolism in nerves, cardiac and smooth muscle as well as endothelial cells and thus may lead respectively to the development of neuropathy, primary cardiomyopathy, microangiopathy and atherosclerosis in the diabetic population. Each of these pathogenic processes, which are associated with insulin deficiency, alone or in combination with others, may result in cardiac dysfunction in chronic diabetes. Activation of the sympathetic nervous system and abnormalities in catecholamine metabolism have been identified in diabetes; their involvement in the genesis of cardiac pump failure as well as large and small vessel disease is likely. The membrane defects as indicated by changes in both plasma membrane and glycocalyx in diabetic cardiomyopathy appear to be complex and may involve alterations in the metabolism of lipids and pyrimidine nucleotides. It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy; however, a concentrated research effort is required to understand the primary biochemical lesion in the pathogenesis of cardiac dysfunction in diabetes. In the meantime, a heightened awareness on the part of clinicians concerning the susceptibility of diabetic patients to cardiovascular problems may help in reducing mortality and morbidity in the diabetic population.

Influence of reducing agents on adrenochrome-induced changes in the heart.

To elucidate the role of oxidation products of catecholamines play in myocardial necrosis, we examined the effects that adrenochrome in the presence of some reducing agents and that autoxidized solution of adrenochrome have on the ultrastructure and force of contraction in the isolated rat heart. Addition of ascorbic acid (1 mM) or cysteine (0.5 mM) into a perfusion medium containing 25 mg/L of adrenochrome produced ultrastructural damage greater than that seen with adrenochrome alone, whereas addition of dithiothreitol (0.5 mM) did not. The rate of failure of the heart due to adrenochrome was accelerated by use of ascorbic acid and dithiothreitol. Reduction of adrenochrome into other oxidation products of catecholamines by these reducing agents was indicated by the results of spectral analysis studies. Myocardial damage or contractile failure did not occur if the adrenochrome solution was allowed to autoxidize for 24 hours before perfusion. These data indicate that oxidation products of epinephrine other than adrenochrome are involved in the genesis of catecholamine-induced cardiotoxicity. This effect may occur through the formation of cardiotoxic free radicals, as well as through interaction of these oxidation products with sulfhydryl groups.

Potential oxidative pathways of catecholamines in the formation of lipid peroxides and genesis of heart disease.

Effects of vitamin E, a fat soluble antioxidant, on the isoproterenol-induced changes in the lipid peroxide activity as determined by a quantitation of malondialdehyde (MDA) content in the myocardium were examined. Isoproterenol treatment (80 mg/kg given over two days in two equal doses) caused more than 100 percent increase in the MDA content which was prevented by pretreatment of the animals with vitamin E (alpha-tocopherol acetate, 10 mg/kg) for two weeks. Animals maintained on vitamin E deficient diet for 8 weeks were found to be more sensitive to isoproterenol-induced increase in the MDA content. A small increase in MDA content was also seen due to vitamin E deficiency alone. These changes were found to be reversible upon a 2 week feeding of the animals on the normal diet coupled with vitamin E treatment. Based on these data it is proposed that free radical mediated increase in lipid peroxide activity may have a role in catecholamine-induced heart disease.

How much gin in the tonic? The problems of writing a provincial medical history,.

This paper describes the problems and resources involved in writing a Canadian provincial medical history, (Manitoba Medicine: A Brief History). The first decision was whether it should be a scholarly or a popular history; The authors' background, and the realities of publishing dictated the latter. Resources available were local and easily accessible: archives and records, the Manitoba medical journals, a series of local medical journals (almost continuous for a century), and the Manitoba medical biographies, books variable in length, and content, but relating to a wide variety of physicians. Such a paper leads to a question- "Is local history merely trivial?" The answer to such a question is "no."