Prevention of disorders of the electric stability of the heart in experimental infarct using adaptation to hypoxia

It has been shown on rats preadapted to hypoxia in an altitude chamber that myocardial infarction induced by ligation of the coronary artery was accompanied by less disturbances in the electrical stability of the heart, namely by a twofold decrease in ventricular fibrillation threshold and a considerable decrease in the heart ectopic activity. Preliminary adaptation provided the maintenance of myocardial contractility in infarction.     

Computational modeling of acute myocardial infarction

Myocardial infarction, commonly known as heart attack, is caused by reduced blood supply and damages the heart muscle because of a lack of oxygen. Myocardial infarction initiates a cascade of biochemical and mechanical events. In the early stages, cardiomyocytes death, wall thinning, collagen degradation, and ventricular dilation are the immediate consequences of myocardial infarction. In the later stages, collagenous scar formation in the infarcted zone and hypertrophy of the non-infarcted zone are auto-regulatory mechanisms to partly correct for these events. Here we propose a computational model for the short-term adaptation after myocardial infarction using the continuum theory of multiplicative growth. Our model captures the effects of cell death initiating wall thinning, and collagen degradation initiating ventricular dilation. Our simulations agree well with clinical observations in early myocardial infarction. They represent a first step toward simulating the progression of myocardial infarction with the ultimate goal to predict the propensity toward heart failure as a function of infarct intensity, location, and size.     

Research progress of ghrelin on cardiovascular disease

Ghrelin, a 28-aminoacid peptide, was isolated from the human and rat stomach and identified in 1999 as an endogenous ligand for the growth hormone secretagogue-receptor (GHS-R). In addition to stimulating appetite and regulating energy balance, ghrelin and its receptor GHS-R1a have a direct effect on the cardiovascular system. In recent years, it has been shown that ghrelin exerts cardioprotective effects, including the modulation of sympathetic activity and hypertension, enhancement of the vascular activity and angiogenesis, inhibition of arrhythmias, reduction in heart failure and inhibition of cardiac remodeling after myocardial infarction (MI). The cardiovascular protective effect of ghrelin may be associated with anti-inflammation, anti-apoptosis, inhibited sympathetic nerve activation, regulated autophagy, and endothelial dysfunction. However, the molecular mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, and no specific therapeutic agent has been established. It is important to further explore the pharmacological potential of ghrelin pathway modulation for the treatment of cardiovascular diseases.     

Mechanisms of adaptation to physical exertion and the effect of carbon dioxide excess on their formation

4% CO2 addition to normoxic gas medium increased the activity, mass and functional capacity of the left ventricular myocardium, enhanced the stability of acetylcholine (AC) and noradrenaline (NA) storage in the myocardial tissues and stimulated myocardial response to these mediators during physical training of rats (swimming for 2 months). When the duration of the training period was prolonged to 3 months, CO2 had a decreasing effect on the myocardial activity, AC concentration and storage stability, as well as on the myocardial response to AC. The possibility of reducing signal and increasing metabolic CO2 effects during physical training is considered. The importance of intensified heart regulation by sympathetic and parasympathetic mechanisms during adaptation and the role of mechanism dissociation with the decrease in the degree of adaptation are discussed.     

Effect of adaptation to short-term stress exposure on the fibrillation threshold and ectopic activity of the heart in experimental myocardial infarct

Preliminary adaptation to short-term stress was shown to prevent the decrease in the heart fibrillation threshold and an increase in ectopic activity which is usually observed in experimental myocardial infarction. This protective effect involves an enhanced activity of the antioxidant system. Therefore, a synthetic antioxidant ionol was applied to prevent disturbances of the heart electrical stability in infarction. It was established that ionol completely prevents the decrease in the electrical threshold and the increase in ectopic activity of the heart in experimental infarction. Thus, it can be concluded that ionol possesses an antiarrhythmic effect.     

Increased Sensitivity to Heparin Following Acute Myocardial Infarction

In vivo increased sensitivity to heparin has been demonstrated in patients following an acute myocardial infarction. An intravenous injection of 10,000 units of heparin was given to each of 18 patients with recent myocardial infarction in order to compare them with 17 patients who were not suffering from any acute illness. The changes in whole blood clotting time, recalcified plasma clotting time and prothrombin time were greater and more prolonged in the patients with recent myocardial infarction. Of the three tests, the one-stage prothrombin time provided the simplest and the most precise measurement of heparin sensitivity. The reason for this was not clear: it is possible that it is related to shock and congestive heart failure which were complications of the clinical course following myocardial infarction.     

Differential effects of NADPH oxidase and xanthine oxidase inhibition on sympathetic reinnervation in postinfarct rat hearts

Superoxide has been shown to play a major role in ventricular remodeling and arrhythmias after myocardial infarction. However, the source of increased myocardial superoxide production and the role of superoxide in sympathetic innervation remain to be further characterized. Male Wistar rats, after coronary artery ligation, were randomized to vehicle, allopurinol, or apocynin for 4weeks. To determine the role of peroxynitrite in sympathetic reinnervation, we also used 3-morpholinosydnonimine (a peroxynitrite generator). The postinfarction period was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine, xanthine oxidase activity, NADPH oxidase activity, and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Sympathetic hyperinnervation was blunted after administration of allopurinol. Arrhythmic scores in the allopurinol-treated infarcted rats were significantly lower than those in vehicle. For similar levels of ventricular remodeling, apocynin had no beneficial effects on oxidative stress, sympathetic hyperinnervation, or arrhythmia vulnerability. Allopurinol-treated hearts had significantly decreased nerve growth factor expression, which was substantially increased after coadministration of 3-morpholinosydnonimine. These results indicate that xanthine oxidase but not NADPH oxidase largely mediates superoxide production after myocardial infarction. Xanthine oxidase inhibition ameliorates sympathetic innervation and arrhythmias possibly via inhibition of the peroxynitrite-mediated nerve growth factor pathway.     

An Anthelmintic Drug,Pyrvinium Pamoate,Thwarts Fibrosis and Ameliorates Myocardial Contractile Dysfunction in a Mouse Model of Myocardial Infarction

Metabolic adaptation to limited supplies of oxygen and nutrients plays a pivotal role in health and disease. Heart attack results from insufficient delivery of oxygen and nutrients to the heart, where cardiomyocytes die and cardiac fibroblasts proliferate – the latter causing scar formation, which impedes regeneration and impairs contractility of the heart. We postulated that cardiac fibroblasts survive metabolic stress by adapting their intracellular metabolism to low oxygen and nutrients, and impeding this metabolic adaptation would thwart their survival and facilitate the repair of scarred heart. Herein, we show that an anthelmintic drug, Pyrvinium pamoate, which has been previously shown to compromise cancer cell survival under glucose starvation condition, also disables cardiac fibroblast survival specifically under glucose deficient condition. Furthermore, Pyrvinium pamoate reduces scar formation and improves cardiac contractility in a mouse model of myocardial infarction. As Pyrvinium pamoate is an FDA-approved drug, our results suggest a therapeutic use of this or other related drugs to repair scarred heart and possibly other organs.     

ANTICOAGULANT DRUG TREATMENT OF CORONARY ARTERY DISEASE

Anticoagulant therapy of arteriosclerotic heart disease may prove to be most valuable when applied on a long-term basis for prevention of recurrent myocardial infarction. While its prophylactic value in impending infarction has not been established, at least the accepted treatment for the acute stage is already begun if an anticoagulant has been administered before an inevitable infarction occurs.The chief value of the anticoagulant, though, seems to lie in preventing cardiac mural thrombosis and extracardiac thromboembolism. It is by this effect, apparently, that mortality has been reduced by 50 per cent among survivors of myocardial infarction who receive continuous dicoumarin therapy.While the danger of hemorrhage is still present, it is being steadily reduced by increasing skill in the management of anticoagulant therapy, and for a long time the risk has been far outweighed by the reduction in coronary occlusion.Physicians have a duty to learn the use of anticoagulant therapy, obtain the facilities necessary for it, and apply it to patients who are able and willing to cooperate in prolonging their useful lives.     

Repair of Ischemic Heart Disease with Novel Bone Marrow-Derived Multipotent Stem Cells

Congestive heart failure is a growing, worldwide epidemic. The major causes of heart failure are related to irreversible damage resulting from myocardial infarction (heart attack). The long-standing axiom has been that the myocardium has a limited capacity for self-repair or regeneration; and the irreversible loss of cardiac muscle and accompanying contraction and fibrosis of myocardial scar tissue, sets into play a series of events, namely, progressive ventricular remodeling of nonischemic myocardium that ultimately leads to progressive heart failure. The loss of cardiomyocyte survival cues is associated with diverse pathways for heart failure, underscoring the importance of maintaining the number of viable cardiomyocytes during heart failure progression. Currently, no medication or procedure used clinically has shown efficacy in replacing the myocardial scar with functioning contractile tissue. Therefore, given the major morbidity and mortality associated with myocardial infarction and heart failure, new approaches have been sought to address the principal pathophysiologic deficits responsible for these conditions, resulting from the loss of cardiomyocytes and viable blood vessels. Recently, the identification of stem cells from bone marrow capable of contributing to tissue regeneration has ignited significant interest in the possibility that cell therapy could be employed therapeutically for the repair of damaged myocardium. In this review, we will discuss the currently available bone marrow-derived stem progenitor cells for myocardial repair and focus on the advantages of using recently identified novel bone marrow-derived multipotent stem cells (BMSC)     

Quick adaptation of the myocardium and autonomic nervous regulation of the cardiac rhythm in 10- to 11-year-old children operating a computer

A study of quick adaptation of the myocardium of subjects operating a computer, depending on the adaptive capacities of the body, was conducted in 100 children with ages varying between 10 and 11 years using the electrocardiography method for the analysis of heart rate variability. Significant differences in the bioelectrical processes in the myocardium and autonomic nervous regulation of the cardiac rhythm (CR) were found in children with different adaptive capacities of the body. Quick adaptation to the operator activity in children with a good adaptive capacity is characterized by intensification of atrial activity and metabolic processes in the myocardium, as well as by a shortened duration of the cardiac cycle due to a shorter diastolic time, determined by increased sympathetic influences on the CR. In children with a decreased adaptive capacity, a decrease in the atrial excitability and myocardial metabolism, an increase in the systolic time, a decrease in the diastolic time, and an increase in parasympathetic influences on the CR are observed.     

Morphological aspects of apoptosis in heart diseases

It has been suggested that apoptosis may be responsible for a significant amount of cardiomyocyte death during acute myocardial infarction as well as for a progressive loss of surviving cells in failing hearts. Typical apoptosis can indeed be induced in cardiomyocytes at the experimental conditions. In actual heart diseases, in contrast, there is very little direct morphological evidence of apoptosis in cardiomyocytes occurring at any stage of myocardial infarction and heart failure, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. For that reason, the potential efficacy of therapeutic intervention to prevent apoptosis remains controversial. This review will survey available data from both animals and humans to critically assess the role of cardiomyocyte apoptosis during myocardial infarction and its relevance to myocardial remodeling and during progression to heart failure. Also considered will be nonmyocyte interstitial cells, which have received less attention than myocytes despite definitive evidence of their apoptosis in the infarcted heart and recent studies suggesting that blockade of apoptosis among these cells mitigates postinfarction cardiac remodeling and heart failure. We conclude from our survey that there are many hurdles to surmount before regulation of apoptosis can be clinically applied in the treatment of myocardial infarction and heart failure.     

alphaB-crystallin is phosphorylated during myocardial infarction: involvement of platelet-derived growth factor-BB

alphaB-crystallin is the most abundant low-molecular-weight heat shock protein in heart and recent studies have demonstrated that it plays a cardioprotective role during myocardial infarction both in vivo and in vitro. On the other hand, platelet-derived growth factor (PDGF), a potent serum mitogen, has been reported to improve cardiac function after myocardial infarction. In the present study, using a mouse myocardial infarction model, we investigated whether alphaB-crystallin is phosphorylated during myocardial infarction and the implication of PDGF-BB. Phosphorylation of alphaB-crystallin at Ser-59 was time dependently induced and plasma PDGF-BB levels were concomitantly increased. Moreover, PDGF-BB-stimulated phosphorylation of alphaB-crystallin was suppressed by SB203580, a specific inhibitor of p38 mitogen-activated protein (MAP) kinase, in primary cultured cardiac myocytes. Our results indicate that PDGF-BB induces phosphorylation of alphaB-crystallin via p38 MAP kinase during myocardial infarction.     

Conditional entropy approach for the evaluation of the coupling strength

A method that enables measurement of the degree of coupling between two signals is presented. The method is based on the definition of an uncoupling function calculating, by means of entropy rates, the minimum amount of independent information (i.e. the information carried by one signal which cannot be derived from the other). An estimator of the uncoupling function able to deal with short segments of data (a few hundred samples) is proposed, thus enabling the method to be used for usual experimental recordings. A synchronisation index is derived from the estimate of the uncoupling function by means of a minimisation procedure. It quantifies the maximum amount of information exchanged between the two signals. Simulations in which non-linear coordination schemes are produced and changes in the coupling strength are artificially induced are used to check the ability of the proposed index to measure the degree of synchronisation between signals. The synchronisation analysis is utilised to measure the coupling strength between the beat-to-beat variability of the sympathetic discharge and ventilation in decerebrate artificially ventilated cats and the degree of synchronisation between the beat-to-beat variability of the heart period and ventricular repolarisation interval in normal subjects and myocardial infarction patients. The sympathetic discharge and ventilation are strongly coupled and the coupling strength is not affected by manoeuvres capable of increasing or depressing sympathetic activity. The synchronisation is lost after spinalisation. The synchronisation analysis confirms that the heart period and ventricular repolarisation interval are well coordinated. In normal subjects, the synchronisation index is not modified by experimental conditions inducing changes in the sympathovagal balance. On the contrary, it strongly decreases after myocardial infarction, thus detecting and measuring the uncoupling between the heart period and ventricular repolarisation interval. Received: 29 October 1998 / Received in revised form: 4 March 1999     

NADPH oxidase-dependent oxidative stress in the failing heart: From pathogenic roles to therapeutic approach

Heart failure (HF) occurs when the adaptation mechanisms of the heart fail to compensate for stress factors, such as pressure overload, myocardial infarction, inflammation, diabetes, and cardiotoxic drugs, with subsequent ventricular hypertrophy, fibrosis, myocardial dysfunction, and chamber dilatation. Oxidative stress, defined as an imbalance between reactive oxygen species (ROS) generation and the capacity of antioxidant defense systems, has been authenticated as a pivotal player in the cardiopathogenesis of the various HF subtypes. The family of NADPH oxidases has been investigated as a key enzymatic source of ROS in the pathogenesis of HF. In this review, we discuss the importance of NADPH oxidase-dependent ROS generation in the various subtypes of HF and its implications. A better understanding of the pathogenic roles of NADPH oxidases in the failing heart is likely to provide novel therapeutic strategies for the prevention and treatment of HF.     

Long-term spectral analysis of heart rate variability — An algorithm based on segmental frequency distributions of beat-to-beat intervals

Reduced heart rate variability has been reported as a predictor of long-term mortality in recent myocardial infarction patients. However, it has not been systematically investigated whether the reduction in heart rate variability in those post myocardial infarction patients who later suffer death or severe arrhythmias is caused by a reduction of short-term variability of heart rate (such as respiratory arrhythmia) or whether the differences in long term variability (such as diurnal rhythm) are involved. In order to perform such an evaluation, a new algorithm has been developed which permits different wavelength components (including the long-term components due to diurnal rhythm) of heart rate variability to be approximated. In general, the method uses segmental frequency distributions of durations of intervals between successive normal cardiac beats. To assess the spectral components of heart rate variability, a scale of wavelength limits is used and for each limit of this scale, the algorithm excludes the rate changes of wavelength longer than the given bound. The method was applied to the analysis of electrocardiograms recorded in 14 post myocardial infarction patients who later suffered death or ventricular tachycardia, and in 14 other randomly selected patients with an uncomplicated course following acute myocardial infarction. The rate variability spectra obtained for both groups of patients were compared statistically and the results showed that the groups of positive and negative cases were most significantly distinguished when including both short- and long-term components of heart rate variability. Separate evaluation of different wavelength components showed that the very long-term components of heart rate variability were more powerful in distinguishing between positive and negative cases than the short term components.     

Regulation of noradrenergic function by inflammatory cytokines and depolarization

Although the sympathetic neurons innervating the heart are exposed to the inflammatory cytokines cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) after myocardial infarction, the effects of these cytokines on noradrenergic function are not well understood. We used cultured sympathetic neurons to investigate the effects of these cytokines on catecholamine content, the tyrosine hydroxylase co-factor, tetrahydrobiopterin (BH4), and norepinephrine (NE) uptake. CT-1, but not IL-6 or TNFalpha, suppressed NE uptake and catecholamines in these neurons, whereas CT-1 and, to a lesser extent, IL-6 decreased BH4 content. CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. The neurons innervating the heart are also activated by the central nervous system after myocardial infarction. We examined the combined effect of depolarization and cytokines on noradrenergic function. In CT-1-treated cells, depolarization caused a small increase in BH4 and NE uptake, and a large increase in catecholamines. These changes were accompanied by increased TH, GCH and NE transporter mRNAs. CT-1 and depolarization regulate expression of noradrenergic properties in an opposing manner, and the combined treatment results in elevated cellular catecholamines and decreased NE uptake relative to control cells.     

心肌再生途径的研究进展

心急梗塞等心脏疾病可造成心肌的损伤。相继会发生心室扩张、癍痕、心脏功能紊乱。目前时心脏疾病的治疗主要通过药物和器官移植,因药物治标不治本和移植器官匮乏限制了治疗的效果,严重影响病人的身体健康。最近研究发现,相关细胞因子或基因、干细胞移植可使损伤区心肌细胞和血管再生及诱导内源性干细胞转移,从而修复损伤心肌并恢复心脏功能。以上研究成果及其临床的应用将成为损伤性心肌有效的治疗途径。本文着重阐明了相关细胞因子、基因和干细胞移植时心肌再生作用机制的研究现状。