Hibernating myocardium: Its pathophysiology and clinical role

Myocardial hibernation, as first defined by Rahimtoola, is a state of chronic contractile dysfunction in patients with coronary artery disease which is fully reversible upon reperfusion. Clinical conditions consistent with the existence of myocardial hibernation include unstable and stable angina, myocardial infarction heart failure, and anomalous origin of coronary arteries. The mechanisms of hibernation are not known. Morphological alterations have been described in the hibernating area of patients, but these information are strongly affected by the diagnostic criteria utilized to screen patients. It has been postulated that hibernation is an adaptive phenomenon occurring during ischemia. In this context, downregulation of contraction is not regarded as a consequence of energetic deficit, but as a regulatory event aimed at reducing energy expenditure, thereby maintaining integrity and viability. Thus, hibernation might bear a relationship to the phenomenon of low-flow perfusion-contraction matching, or repetitive stunning or preconditioning. Clear-cut evidence for the mechanism of hibernation in the clinical setting seems likely to remain elusive, because of the nature of the studies needed to document it. Current experimental evidence supports the view that hibernation, stunning, preconditioning, or their coexistence can be responsible for regional myocardial contractile dysfunction which is reversible upon reperfusion. These are all adaptive and protective phenomena independent of their terminology and strict definitions and do not always apply to the extremely complex situation of myocardial ischemia in man.     

Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant

Left ventricular biopsies from 21 patients with clinically diagnosed chronic hibernating myocardium (CHM) were examined by light- and electron microscopy. A mean of 27% of cardiomyocytes were structurally altered and were characterized as hibernating, because of reduced amount of myofibrils and increased glycogen content. Electron microscopy of these cells showed reduction of T-tubules and numerous small mitochondria, but few changes associated with degeneration, acute ischemia or apoptosis. The structural changes found in CHM are reminiscent of dedifferentiation rather than degeneration. The expression patterns of some structural proteins show resemblance with those in embryonic cardiomyocytes.Histochemically, mitochondrial NADH-oxidase and proton translocating ATPase activities were absent, whereas cytochrome c activity was present. Intracellular calcium distribution indicated normally bound sarcolemmal calcium and absence of excess mitochondrial calcium accumulation. Nuclear chromatin ranged from normal to dispersed with only a few nuclei that were clumped. These results suggest that cardiomyocytes from human CHM hearts are structurally altered, but viable, and lack morphologic and cytochemical characteristics suggestive of apoptosis or acute ischemia.     

Chronic hibernating myocardium: Interstitial changes

Chronic left ventricular dysfunctional but viable myocardium of patients with chronic hibernation is characterized by structural changes, which consist of depletion of contractile elements, accumulation of glycogen, nuclear chromatin dispersion, depletion of sarcoplasmic reticulum and mitochondrial shape changes. These alterations are not reminiscent of degeneration but are interpreted as de-differentiation of the cardiomyocytes. The above mentioned changes are accompanied by a marked increase in the interstitial space. The present study describes qualitative and quantitative changes in the cellular and non-cellular compartments of the interstitial space. In chronic hibernating myocardial segments the increased extracellular matrix is filled with large amounts of type I collagen, type III collagen and fibronectin. An increase in the number of vimentin-positive cells (endothelial cells and fibroblasts) compared with normal myocardium is seen throughout the extracellular matrix.The increase in interstitial tissue is considered as one of the main determinants responsible for the lack of immediate recovery of contractile function after restoration of the blood flow to the affected myocardial segments of patients with chronic left ventricular dysfunction.     

Cardiac expression of urocortin (Ucn) in diseased heart; preliminary results on possible involvement of Ucn in pathophysiology of cardiac diseases

Recently, several studies reported that urocortin (Ucn) had beneficial effects on cardiovascular system and was expressed both in the normal heart and in the heart of dilated cardiomyopathy (DCM), yet the relationship between high expression of Ucn and pathophysiology of Ucn in diseased heart has been discussed. Thus, the present study was designed to elucidate the expression of Ucn in the diseased heart by immunohistochemical approach using endomyocardial biopsy specimens. The involvement of immunoreactive Ucn in pathophysiology of cardiac disease was evaluated using endomyocardial biopsy specimens obtained from the patients with some heart diseases, including DCM and hypertrophic cardiomyopathy (HCM). Ucn was detected in all endomyocardial biopsy specimens of ventricular tissue obtained from the patients with such cardiac diseases, a specimens of atrial tissue, and normal heart specimens obtained from autopsy cases. In DCM patients, left ventricular end-diastolic pressure significantly elevated in severely stained group. On the contrary, in HCM patients, left ventricular ejection fraction was higher in the severely stained group. Ucn was expressed more abundantly in the diseased heart, especially in HCM and DCM, than in the normal heart. In conclusion, such close relationship between Ucn expression in the heart and cardiac function indicated that clinical features of Ucn resembled those of norepinephrine and Ucn could play a certain pathophysiological roles in the cardiac diseases.     

Quinapril inhibits progression of heart failure and fibrosis in rats with dilated cardiomyopathy after myocarditis

The cardioprotective properties of quinapril, an angiotensin-converting enzyme inhibitor, were studied in a rat model of dilated cardiomyopathy. Twenty-eight days after immunization of pig cardiac myosin, four groups rats were given 0.2 mg/kg (Q0.2, n = 11), 2 mg/kg (Q2, n = 11) or 20 mg/kg (Q20, n = 11) of quinapril or vehicle (V, n = 15) orally once a day. After 1 month, left ventricular end-diastolic pressure (LVEDP), ±dP/dt, area of myocardial fibrosis, and myocardial mRNA expression of transforming growth factor (TGF)-1, collagen-III and fibronectin were measured. Four of 15 (27%) rats in V and two of 11 (18%) in Q0.2 died. None of the animals in Q2 or Q20 died. The LVEDP was higher and ±dP/dt was lower in V (14.1 ± 2.0 mmHg and +2409 ± 150/–2318 ± 235 mmHg/sec) than in age-matched normal rats (5.0 ± 0.6 mmHg and +6173 ± 191/–7120 ± 74 mmHg/sec; all p < 0.01). After quinapril treatment, LVEDP was decreased and ±dP/dt was increased in a dose-dependent manner (10.8 ± 1.8 mmHg and +3211 ± 307/–2928 ± 390 mmHg/sec in Q0.2, 9.4 ± 1.5 mmHg and +2871 ± 270/–2966 ± 366 mmHg/sec in Q2, and 6.6 ± 1.5 mmHg, and +3569 ± 169/–3960 ± 203 mmHg/sec in Q20). Increased expression levels of TGF-1, collagen-III and fibronectin mRNA in V were reduced in Q20. Quinapril improved survival rate and cardiac function in rats with dilated cardiomyopathy after myocarditis. Furthermore, myocardial fibrosis was regressed and myocardial structure returned to nearly normal in animals treated with quinapril.     

外泌体微小RNAs调控心肌线粒体稳态: 运动改善心力衰竭的新视角

外泌体(exosomes)是一类由细胞分泌到细胞外的囊泡,其携带了丰富的生物分子,如蛋白质、核酸和代谢产物等。微小RNA(microRNAs, miRNAs)是一类非编码RNA分子,在细胞分化、增殖和生存过程中发挥着重要的作用。运动可促进外泌体分泌,并促进其内容物miRNAs发挥生物学效应。近年来的研究发现,外泌体miRNAs与慢性心力衰竭关系密切,且运动会改变体液和组织中外泌体miRNAs的表达。外泌体miRNAs是心力衰竭诊断和预后的生物标志物,可以通过抑制心肌纤维化、促进心肌线粒体功能和增强心肌细胞存活等作用改善心力衰竭。本文对外泌体miRNAs在慢性心力衰竭中的作用以及运动通过外泌体miRNAs改善心力衰竭的线粒体机制进行综述,以期为心力衰竭的诊断和治疗提供依据。     

Gap junction remodeling and altered connexin43 expression in the failing human heart

Gap junctions (GJ) are important determinants of cardiac conduction and the evidence has recently emerged that altered distribution of these junctions and changes in the expression of their constituent connexins (Cx) may lead to abnormal coupling between cardiomyocytes and likely contribute to arrhythmogenesis. However, it is largely unknown whether changes in the expression and distribution of the major cardiac GJ protein, Cx43, is a general feature of diverse chronic myocardial diseases or is confined to some particular pathophysiological settings. In the present study, we therefore set out to investigate qualitatively and quantitatively the distribution and expression of Cx43 in normal human myocardium and in patients with dilated (DCM), ischemic (ICM), and inflammatory cardiomyopathies (MYO). Left ventricular tissue samples were obtained at the time of cardiac transplantation and investigated with immunoconfocal and electron microscopy. As compared with the control group, Cx43 labeling in myocytes bordering regions of healed myocardial infarction (ICM), small areas of replacement fibrosis (DCM) and myocardial inflammation (MYO) was found to be highly disrupted instead of being confined to the intercalated discs. In all groups, myocardium distant from these regions showed an apparently normal Cx43 distribution at the intercalated discs. Quantitative immunoconfocal analyis of Cx43 in the latter myocytes revealed that the Cx43 area per myocyte area or per myocyte volume is significantly decreased by respectively 30 and 55% in DCM, 23 and 48% in ICM, and by 21 and 40% in MYO as compared with normal human myocardium. In conclusion, focal disorganization of GJ distribution and down-regulation of Cx43 are typical features of myocardial remodeling that may play an important role in the development of an arrhythmogenic substrate in human cardiomyopathies.     

Reduced regional myocardial perfusion reserve is associated with impaired contractile performance in idiopathic dilated cardiomyopathy

Background. In idiopathic dilated cardiomyopathy (IDC) an imbalance between myocardial oxygen consumption and supply has been postulated. Subclinical myocardial ischaemia may contribute to progressive deterioration of left ventricular function. The relation between regional myocardial perfusion reserve (MPR) and contractile performance was investigated. Methods. Patients with newly diagnosed IDC underwent positron emission tomography (PET) scanning using both ¹³N-ammonia as a perfusion tracer (baseline and dypiridamole stress), and ¹⁸F-fluorodeoxyglucose viability tracer and a dobutamine stress MRI. MPR (assessed by PET) as well as wall motion score (WMS, assessed by MRI) were evaluated in a 17-segment model. Results. Twenty-two patients were included (age 49±11 years; 15 males, LVEF 33±10%). With MRI, a total of 305 segments could be analysed. Wall motion abnormalities at rest were present in 127 (35.5%) segments and in 103 (29.9%) during dobutamine stress. Twenty-one segments deteriorated during stress and 43 improved. MPR was significantly higher in those segments that improved, compared with those that did not change or were impaired during stress (1.87±0.04 vs. 1.56± 0.07 p<0.01.) Conclusion. Signs of regional ischaemia were clearly present in IDC patients. Ischaemic regions displayed impaired contractility during stress. This suggests that impaired oxygen supply contributes to cardiac dysfunction in IDC. (Neth Heart J 2009;17:470–4.)     

小剂量美托洛尔治疗扩张型心肌病充血性心力衰竭疗效评价

目的　评价小剂量美托洛尔治疗扩张型心肌病心力衰竭的临床疗效和安全性。　方法　将扩张型心肌病心力衰竭 4 0例 ,随机分为治疗组和对照组 ,对照组仅予常规治疗 ,治疗组在常规治疗的基础上加用美托洛尔 ;用超声心动图测定治疗前后左室射血分数 ( LVEF)和左室舒张末内径 ( LVDd) ,取治疗4周后的临床资料进行评价。　结果　治疗组总有效率 81 .8% ,明显高于对照组的 5 5 .6 % (χ2 =4 .71 ,P<0 .0 5 ) ,无严重不良反应 ,心功能、 LVEF、 LVDd治疗前后比较 ,治疗组优于对照组 ,治疗组具有显著或非常显著性差异 ( P <0 .0 5或 P <0 .0 1 )。　结论　小剂量美托洛尔能明显改善扩张型心肌病心力衰竭病人的心脏功能 ,安全有效。     

Effect of prolonged treatment with propionyl-L-carnitine on erucic acid-induced myocardial dysfunction in rats

The aim of this study was to evaluate the ability of propionyl-L-carnitine to prevent cardiac damage induced by erucic acid. Rats were fed for 10 days with normal or 10% erucic acid—enriched diets with or without propionyl-L-carnitine intraperitoneally injected, (1 mM/kg daily, for 10 days). The erucic acid diet produced increases in triglycerides (from 5.6 to 12.4 mg/gww, P < 0.01), and free fatty acids (from 2.0 to 5.1 mg/gww, P < 0.01), but no changes in phospholipids. When the hearts were perfused aerobically with an isovolumic preparation there was no difference in mechanical activity. On the contrary, when pressure-volume curves were determined, the pressure developed by hearts from the erucic acid-treated rats were reduced.Independent of diet, propionyl-L-carnitine treatment always produced positive inotropy. This was concomitant with improved mitochondrial respiration (RCI 5.1 vs 9.3, P < 0.01), higher tissue ATP content (10.3 vs 18.4 mol/gdw P < 0.01) and reduction of triglycerides (12.4 vs 8.0 mg/gww, P < 0.01). These data suggest that propionyl-L-carnitine, when given chronically, is able to prevent erucic acid-induced cardiotoxicity, probably by reducing triglyceride accumulation and improving energy metabolism.