抑肽酶促进心肌缺血及再灌注后的功能恢复:药物对离体鼠心的影响

近年来,抑肽酶已广泛用于心脏直视手术中,具有显著减少术中及术后失血的作用。蛋白水解酶在心肌缺血性损害中起着重要作用,抑肽酶町以抑制心肌溶酶体酶的释放及其损伤效应,降低心肌ATP消耗,保护心肌的超微结构,但对缺血心肌功能恢复作用尚不清楚。作者采用改良的离体鼠心Langendorff装置,研究不同剂量抑肽酶对正常心肌的直接影响及大剂量抑肽酶对缺血心肌功能恢复的作用。     

以心肌肥厚为主要临床表现的法布里病母子案例分析

<正>法布里病(Fabry disease)是一种由GLA基因突变引起的X连锁溶酶体储存障碍,导致α- 半乳糖苷酶A活性缺乏,致使鞘糖脂在体液和全身细胞溶酶体中积累。出现皮肤、周围神经、肾脏、脑、眼、胃肠道及心血管等多器官系统的损害。其中,心脏受累的特征性表现为进行性心肌肥厚、心肌纤维化、心律失常和心力衰竭,称为Fabry心肌病,具有心脏猝死的潜在风险^[1]。本文报道以心肌肥厚为主要表现的法布里病母子病例,以提高对法布里病男女性发病的认识。     

非抗心律失常药物的致心律失常作用

非抗心律失常药物可致各种各样的心律失常。这些药物包括抗微生物药物(大环内酯类、喹诺酮类、抗疟药物、唑类抗真菌药物)、抗组胺药物、抗精神病药物、抗抑郁药物、抗惊厥药物、抗肿瘤药物、胃肠道药物,以及非抗心律失常的心血管药物。他们通过对心脏的直接或间接作用影响心肌离子和分子功能,从而在一定的外界条件下致心律失常发生。处理措施包括停药、纠正电解质紊乱、对症处理以及抗心律失常和辅助药物治疗。     

过氧化体增殖物激活型受体对心肌能量代谢调控的病理生理机制

过氧化体增殖物激活型受体是调节编码脂肪酸β－氧化相关酶类基因的重要转录调节因子，在调节心肌能量代谢中发挥重要作用。心肌肥厚和心力衰竭时心肌细胞过氧化体增殖物激活型受体α的表达和转录调控活性均降低，脂肪酸β－氧化的相关酶类基因（过氧化体增殖物激活型受体α的靶基因）的表达在转录水平降低，说明过氧化体增殖物激活型受体α可能通过信号转导途径影响心肌的能量代谢。过氧化体增殖物激活型受体γ激活剂可增加心肌细胞对葡萄糖的氧化和利用，减轻心肌缺血／再灌注损伤和心肌肥厚的程度，有潜在的心脏保护作用。但仍缺乏过氧化体增殖物激活型受体γ激活剂对心肌能量代谢的调控与心脏保护作用关系的研究报道。     

Ibuprofen对急性心肌缺血的有益作用

心肌缺血的早期病理过程与炎症有关,包括在缺血区释放激肽与前列腺素、白细胞浸润及血小板集聚,同时增加心肌溶酶体水解酶的释放。糖皮质激素可阻止急性梗塞的扩展,但非固醇类抗炎剂尚未证实有明显抗梗塞作用。消炎痛、抗炎酸与阿斯匹林能有效抑制心脏前列腺素的释放,但增加动脉压,故增加心肌需氧量,且不能在心肌缺血时明显稳定溶酶体膜。Ibuprofen是一非固醇类抗炎剂,可抑制前列腺素释放和稳定溶酶体膜,而无升压作用。本文旨在估价Ibuprofen对猫急性心肌缺血时缺血性损伤早期(初5小时)的作用,以及有关的生物学作用,包括溶酶体稳定、心肌的收缩能性及血管作用。     

《抗疟药物使用规范》的解读

本文介绍了《抗疟药物使用规范》的制订和实施对我国疟疾患者个体生命健康和国家公共卫生安全的重要意义。本文在《抗疟药物使用规范》制订过程中,对如何以世界卫生组织相关的文件为指南,结合我国抗疟药物生产和供应的实际情况,以及我国在长期疟疾防治过程中积累的经验,并根据我国消除疟疾进程中的实际需求选择抗疟药物进行了说明。还对新制定的《抗疟药物使用规范》与世界卫生组织《疟疾治疗指南》第3版和原《抗疟药使用原则和用药方案》中抗疟药物使用剂量和疗程的差异进行了较为详细的描述,并对特殊情况下调整抗疟药物的剂量和疗程作了具体的解释,以便于临床医生和公卫医生在临床疟疾患者救治和消除疟疾进程中传染源控制时科学、合理、规范地使用抗疟药物。     

抗疟药物敏感性检测方法的研究进展

疟疾仍是一种严重危害人类健康的寄生虫病,多重抗药性恶性疟原虫株的扩散和间日疟原虫出现对氯喹及伯氨喹的耐药性,使全球消除疟疾面临严峻挑战。疟原虫对抗疟药物的敏感性检测为抗疟药物的合理使用和抗疟措施的制定提供了可靠的依据。该文对近年来抗疟药物敏感性检测方法进行了综述。     

脂肪酸代谢异常与糖尿病性心肌肥厚

正常心肌能量来源以脂肪酸为主,糖尿病时血中游离脂肪酸升高,心肌摄取脂肪酸也增加,开始时摄取的脂肪酸激活过氧化物酶体增殖物激活受体(PPAR)α调节的心肌脂肪酸代谢相关酶的活性和表达,增加心脏对脂肪酸的利用。而后由于心脏失代偿使相关酶的表达下调,脂肪酸β氧化减少;而同时糖尿病心肌糖代谢的异常也可抑制脂肪酸β氧化,使脂质中间代谢产物沉积,损害心脏的结构和功能,促进心肌肥厚的发生。     

心源性外泌体作为冠心病标志物和新靶点展望

心源性外泌体是由心脏细胞产生的包含大量生物活性分子的细胞外囊泡,它们是心脏细胞通讯的重要手段。冠心病患者心肌缺血缺氧损伤后4 h就可产生一些特殊的心源性外泌体组分,可作为早诊断的新标志物。心脏源性祖细胞等干细胞分泌的心源性外泌体,可以减少冠心病后心肌细胞凋亡,增加细胞管形成,减少纤维化的发展和改善心脏功能。这些心源性外泌体可装载对本病有治疗作用的药物,标记心肌靶向肽,发挥对缺血心肌的靶向治疗作用,现就此做一综述。     

卡托普利减轻心肌缺血再灌注损伤

作者分别在离体和在体条件下就卡托普利对缺血再灌注心脏心律失常及血液动力学的影响进行了研究，结果显示卡托普利对离体和在体心脏缺血再灌注性心律失常均有抑制作用，且可加速昏厥心肌的恢复。     

Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature

BACKGROUND: Hydroxychloroquine (HCQ) is extensively used in the long-term treatment of systemic lupus erythematosus (SLE). Although considered by clinicians to be relatively safe, serious side effects have been documented in the literature. Retinotoxicity has received the most attention, whereas neuromyotoxicity and cardiotoxicity have been described in isolated case reports. We present 2 cases of potential cardiotoxicity occurring in patients with SLE while receiving long-term HCQ therapy. OBJECTIVE: To review the incidence, presentation, and mechanism of serious antimalarial toxicity, and to discuss the impact of HCQ on cardiac health in SLE. METHODS: The authors reviewed the English-language literature from 1948 to December 2002 using Medline databases. RESULTS: In addition to our patients, there are 2 published cases of biopsy-proven HCQ cardiotoxicity in the English-language literature. Both occurred in patients with SLE. The literature indicates that antimalarial cardiotoxicity may be of particular importance in patients with SLE given their already increased cardiac risk due to primary heart disease and accelerated atherosclerosis. Endomyocardial biopsy reveals a constellation of findings including vacuolar myopathy, myeloid bodies, and curvilinear bodies. CONCLUSIONS: As HCQ use among SLE patients increases, clinicians should be alert to the possibility of antimalarial cardiotoxicity. The potential severity and reversibility of this complication underscore the importance of timely diagnosis. The cases presented here, one with biopsy and one without, illustrate the utility of endomyocardial biopsy in HCQ-treated SLE patients with cardiac complaints to ensure accurate diagnosis and appropriate management.     

Complete auriculoventricular block during chloroquine treatment

INTRODUCTION: The cardiac toxicity of antimalarial agents is rare, it includes conduction disorders which can be complicated by third atrioventricular block and hypertrophic cardiomyopathy. We report two observations of patients who presented a complete heart block after several years of treatment by chloroquine. CASE REPORT: Two patients followed for rheumatoid polyarthritis, treated by antimalarial agents for average 12 years and corticotherapy, presented a syncopal complete heart block which required an implantation of a pace maker. After having eliminated all the other underlying causes for complete heart block, the antimalarial agents were accused and were stopped. The clinical evolution after interruption of the treatment was favorable. CONCLUSION: Our observations illustrate rare cardiac side effects observed in our two patients after long-term treatment by antimalarial agents. The diagnosis of antimalarial agents responsibility was retained on clinical and biological arguments after having eliminated the other causes. The insidious character of these complications imposes vigilance during the use of long-term treatment by antimalarial agents.     

Quantifying dense bodies and lipofuscin during aging: a morphologist's perspective

Secondary lysosomes, residual or dense bodies containing lipofuscin or age pigment accumulate in post-mitotic and inter-mitotic cells during aging. The consensus is that the accumulation of this auto-fluorescent material is an index of cellular senescence. Biochemical and morphological studies have independently demonstrated marked age-related increases in the cell and tissue contents of lipofuscin. Most morphological studies on aging have been qualitative, have included only two or three age groups and have not yielded data that are easily correlated with biochemical analyses. One of the best documented age-related changes in hepatocytes and cardiac myocytes is the accumulation of dense bodies and lipofuscin inclusions. Independent stereologic studies reported two- to eightfold age-related increases in the dense body volume fraction of rat hepatocytes. Furthermore, we reported a fourfold increase in the dense body volume fraction of cardiac myocytes in rats between 6 and 30 months of age. These and other studies confirm the use of quantitative morphology to estimate the increases in dense body and lipofuscin inclusions as indices of age. Whether or not the accumulated lipofuscin compromises cell functions in senescent animals has not been adequately addressed. On the one hand, there is little evidence that several-fold increases in this subcellular compartment impair the functional capacities of either hepatocytes or cardiac myocytes. On the other hand, the age-related accumulation of immunoprecipitable, but catalytically inactive, lysosomal enzymes in both liver and heart muscle may be a reflection of increased lipofuscin deposits in the dense bodies.     

Long-term cell culture of adult mammalian cardiac myocytes: electron microscopic and immunofluorescent analyses of myofibrillar structure

Adult rat heart was dissociated into a single-cell suspension by a retrograde perfusion technique with collagenase and hyaluronidase in Krebs-Ringer phosphate buffer. Long-term culture of these isolated single cardiac muscle cells was established for up to 45 days. Transmission electron microscopy and immunofluorescence analysis with monoclonal antibodies to cardiac myosin were used to examine sequentially the external and internal structural organization of the cardiac myocytes. Most of the cardiac myocytes exhibited prominent alterations in their external and internal structural organization during the first two weeks of culture. As they attached to the substrate and spread out, the myocytes assumed various shapes and sizes, with the exception of a few which maintained their original cylindrical shape. Electron microscopy of 2 to 4-day cultures revealed that most of the muscle cells contained disorganized myofibrils and surface blebs with enclosed mitochondria and myofilaments, which were eventually extruded from the cytoplasm. With progressive culture, the cardiac myocytes appeared to lose myofibrillar material; fewer myofilaments or sacromere fragments with interfibrillar mitochondria were observed in the sarcoplasm. Such cells resembled cultured embryonic or neonatal cardiac myocytes. However, some muscle cells retained closely packed, well organized myofibrils characteristic of freshly dissociated or in vivo cardiac myocytes. Immunofluorescence microscopy demonstrated that the cultured cardiac myocytes were strongly myosin positive throughout their morphological changes and subsequent maintenance in culture. Two patterns of fluorescence were observed in these cells in correlation with the fine structural evidence for myofibrillar distribution. One pattern exhibited bright fluorescence near the central region of the cell with a more weakly diffuse fluorescence throughout the cytoplasm; the other pattern was characterized by bright fluorescence throughout the sarcoplasm. Most of the myocytes retained their contractility throughout the culture period excepting the initial 24 to 48 h of cell attachment and flattening. These studies demonstrate the feasibility of maintaining contractile cardiac muscle cells from adult rats for at least 1 1/2 months in monolayer culture, although some variability in myofibrillar organization has been observed.     

Subcellular redistribution of la/SSB autoantigen during physiologic apoptosis in the fetal mouse heart and conduction system: a clue to the pathogenesis of congenital heart block

OBJECTIVE: In isolated congenital heart block, the mechanism by which maternal autoantibodies target the intracellular components of the Ro/La RNP complex is unclear. Previous studies have demonstrated that cultured fetal cardiac myocytes rendered apoptotic bind antibodies to 48-kd La/SSB. This study further investigated the subcellular distribution of the La antigen during apoptosis in the fetal mouse heart and conduction system. METHODS: The atrioventricular (AV) node, AV bundle, and sinoatrial (SA) node were identified in serial sections prepared from paraffin blocks of normal mouse fetuses on days 15, 17, and 19 of gestation. Apoptosis was detected by TUNEL assay. Under confocal microscopy, fluorescent labeling of fragmented DNA in apoptotic cells was assessed by TUNEL, and La protein localization was visualized simultaneously using a murine monoclonal antibody or affinity-purified human polyclonal anti-La antibodies. RESULTS: Apoptotic cells were detected in and at the periphery of the AV and SA nodes as well as in the fetal heart valve insertions and working myocardium. In contrast, no apoptosis was detected in the adult heart AV node or surrounding myocardium. As expected, the La antigen was predominantly immunolocalized to the nucleus in nonapoptotic cells. However, apoptotic cells showed a marked reduction of nuclear La and redistribution of La to the cytoplasm. High-resolution confocal microscopy revealed that in cells that had undergone apoptosis, La antigen asymmetrically clustered near the surface of TUNEL-positive nuclei and apoptotic bodies. CONCLUSION: These data provide the first in vivo demonstration of the subcellular translocation of La autoantigen during apoptosis in the fetal heart and the conduction system under physiologic conditions. This observation supports the hypothesis that subcellular redistribution of La in the normally developing heart facilitates the binding of cognate maternal antibodies and subsequent tissue damage.     

Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy

This study was designed to determine the morphological correlate of chronic heart failure. Myocardial tissue from eight patients undergoing transplantation surgery because of end-stage dilated cardiomyopathy was investigated by electron microscopy and immunocytochemistry using monoclonal antibodies against elements of the cytoskeleton: desmin, tubulin, vinculin, and vimentin. The tissue showed hypertrophy, atrophy of myocytes, and an increased amount of fibrosis. Ultrastructural changes consisted of enlargement and varying shape of nuclei, numerous very small mitochondria, proliferation of T tubules, and accumulation of lipid droplets and glycogen. The most obvious ultrastructural alteration was the decrease of myofilaments, ranging from rarefication to complete absence of sarcomeres in cells filled with unspecified cytoplasm. Immunocytochemistry showed that desmin was localized at the Z lines. In diseased myocardium, the amount of desmin was increased, but it was disorderly arranged. Tubulin formed a fine network throughout the myocytes and was significantly increased in cardiomyopathic hearts. Vinculin, a protein closely associated with the cytoskeleton, occurred not only at the sarcolemma and the intercalated disc but also within the myocardial cells. Ultrastructural changes and alterations of the cytoskeleton were severe in about one third of all cells. About one third of all cells showed moderately severe changes, and the remaining cells were normal. Vimentin was present in the interstitial cells and was increased in relation to the increase of fibrosis. We conclude that the increase of fibrosis, the degeneration of hypertrophied myocardial cells, and the alterations of the cytoskeleton are the morphological correlates of reduced myocardial function in chronic heart failure.     

Reduced lipofuscin accumulation in senescent rat brain by long-term acetyl-L-carnitine treatment

By using fluorescence microscopy and microfluorimetric techniques, the effects of ageing and of 11 months acetyl-L-carnitine (ALCAR) treatment on lipofuscin deposition within the cytoplasm of pyramidal neurons of rat prefrontal cortex and hippocampus (CA3 field) were assessed. No lipofuscin autofluorescence was observed in the nerve cell bodies of neurons under study in young rats (3 months of age), but lipopigment had accumulated in the same nerve cells of senescent rats (22 months of age). ALCAR administration significantly reduced the accumulation of lipofuscin within pyramidal neurons of the brain areas examined.     

Complete atrioventricular block following long term treatment with chloroquine

Antimalarial agents are routinely used in the management of connective tissues diseases and various skin disorders. Ophthalmologic, neurological and digestive side effects of antimalarial agents are well known. However, cardiac toxicity is uncommon. We report a 49-year-old patient, treated with chloroquine for 21 years for a systemic lupus erythematosus and a discoid lupus, who presented a complete atrioventricular block that required implantation of a cardiac pacemaker in emergency. This patient did not have significant cardiovascular past medical history. Investigations excluded known causes of atrioventricular block and chloroquine toxicity was diagnosed. This case report illustrates the cardiotoxicity of synthetic antimalarial agents. A regular cardiovascular monitoring (especially with electrocardiogram) could be useful in patients receiving long-term treatment with antimalarial agents.     

When should cardiologists suspect Anderson-Fabry disease?

Anderson-Fabry disease is a lysosomal storage disorder caused by α-galactosidase defects and progressive intracellular accumulation of globotriaosylceramide. The disease can be specifically treated with enzyme replacement therapy. Hemizygous men and heterozygous women can develop cardiac disease. Whereas men experience the most severe clinical phenotype, clinical presentation in women varies from asymptomatic to severely symptomatic. The characteristic cardiac phenotype is left ventricular hypertrophy mimicking sarcomeric hypertrophic cardiomyopathy or hypertensive heart disease. Early or prehypertrophy cardiac involvement may escape detection, unless electrocardiographic clues are present. The cardiac markers that raise suspicion of Anderson-Fabry disease include a short PR interval without a δ wave and a prolonged QRS interval, supraventricular and ventricular arrhythmias, and concentric left ventricular hypertrophy. Extracardiac features include renal failure, corneal deposits, and nervous, gastrointestinal, and cutaneous manifestations. Useful family data include cardiac and extracardiac traits in relatives and absence of male-to-male transmission. Symptoms are subtle, and the interval between the onset of symptoms and diagnosis may be as long as 20 years. As such, the diagnosis is typically late. Endomyocardial biopsy shows optically empty myocytes on light microscopy and dense osmiophilic bodies constituted of globotriaosylceramide on electron microscopy. Alpha-galactosidase A activity is reduced in hemizygous men but not in heterozygous women. Genetic testing is the gold standard for the diagnosis. In conclusion, a correct and timely diagnosis offers the possibility of disease-specific treatment that leads to sustained clinical benefits for cardiac and noncardiac signs and symptoms.     

Influence of agents that alter lysosomal function on fetal mouse hearts recovering from anoxia and substrate depletion

Recovery of fetal mouse heart myocytes from oxygen and substrate deprivation for 1 h is accompanied by complicated lysosomal and non-lysosomal vacuolar responses which can be subdivided temporally into four distinct phases that include production of lysosomal dense bodies; segregation of damaged subcellular organelles into vacuoles that initially lack lysosomal enzymes; delivery of lysosomal enzymes to these vacuoles through fusion with dense bodies, transforming them into lysosomal autophagic vacuoles and degradation of the sequestered organelles. These events are normally completed within 6 h of the resupply of oxygen and substrate. The progression of these events is influenced significantly by pharmacological interventions that alter lysosomal properties. Chloroquine inhibits all aspects of the lysosomally-related processes as well as the sequestration phase during recovery. Leupeptin delays the lysosomal degradation, presumably by slowing proteolysis. Hydrocortisone permits the engulfment phase and the appearance of lysosomal dense bodies but appears to prevent or postpone the delivery of lysosomal enzymes to many of the large vacuoles and to delay the degradation of sequestered organelles. These observations reveal that segregation of damaged organelles and lysosomally-mediated degradation of these subcellular structures are important events during recovery from ischemic-like injury, and that agents that interfere with normal lysosomal function can prevent or delay some or all of the lysosomal responses that are involved in the recovery process.