Apocynin attenuates isoproterenol-induced myocardial injury and fibrogenesis

Oxidative stress is mechanistically implicated in the pathogenesis of myocardial injury and the subsequent fibrogenic tissue remodeling. Therapies targeting oxidative stress in the process of myocardial fibrogenesis are still lacking and thus remain as an active research area in myocardial injury management. The current study evaluated the effects of a NADPH oxidase inhibitor, apocynin, on the production of reactive oxygen species and the development of myocardial fibrogenesis in isoproterenol (ISO)-induced myocardial injury mouse model. The results revealed a remarkable effect of apocynin on attenuating the development of myocardial necrotic lesions, inflammation and fibrogenesis. Additionally, the protective effects of apocynin against myocardial injuries were associated with suppressed expression of an array of genes implicated in inflammatory and fibrogenic responses. Our study thus provided for the first time the histopathological and molecular evidence supporting the therapeutic value of apocynin against the development of myocardial injuries, in particular, myocardial fibrogenesis, which will benefit the mechanism-based drug development targeting oxidative stress in preventing and/or treating related myocardial disorders.     

Perception of arterial hypertension and myocardial infarction in hypertensive and normotensive men and women

The research aims were to test perception of arterial hypertension and myocardial infarction in hypertensive and normotensive men and women as well as to test perception of arterial hypertension and myocardial infarction as predictors of blood pressure control in hypertensives. In the research 470 subjects of 4 general practices from Rijeka, Croatia participated, hypertensive group from the list of hypertensive patients without cardiovascular complications and other major chronic conditions, normotensive group from the list of patients without chronic conditions. Each group had 235 subjects, 128 men and 107 women. Perception of hypertension and myocardial infarction was measured as the result on semantic differential questionnaire. Factor analysis extracted evaluation, potency and activity factor. Blood pressure control was interpreteted on the five degrees scale. Statistical significance was defined under 5% (p < 0.05). Hypertensive subjects perceived hypertension as less negative and more active, while myocardial infarction was perceived as more potent term than by normotensives. Women perceived myocardial infarction as less negative, and less potent term than men. Both groups perceived myocardial infarction as more negative, potent and active term than hypertension. Normotensive women evaluated hypertension as more negative, and perceived myocardial infarction as less potent than other subjects. Well-controlled hypertension was correlated with a lower potency of hypertension and lower activity of myocardial infarction. Both conditions are perceived as more "male" diseases. As perception of hypertension and myocardial infarction is correlated with blood pressure regulation in hypertensives, and hypertension is major risk factor for myocardial infarction, family doctors should put additional effort in changing perception of cardiovascular diseases in their patients, especially in women.     

肠道菌群及其代谢产物对心肌纤维化影响与治疗的研究进展

心肌纤维化是多种心血管疾病,如冠心病、心肌梗死和心力衰竭等的终末期表现和主要致病因素。研究发现,免疫和炎症过程在心肌纤维化的发病机制中起决定性作用。近年来,人们发现肠道微生物在心肌纤维化的发病机制和发展中起着至关重要的作用。肠道菌群的失调可导致微生物的代谢产物转移到血液循环中,如短链脂肪酸、脂多糖和氧化三甲胺等。这些代谢物直接或间接地诱导组织损伤免疫和激活全身炎症反应,进而影响心肌纤维化。如何改变肠道菌群来改善心肌纤维化已成为当前的研究重点,包括饮食干预、使用抗生素、补充益生菌和益生元,以及粪便微生物群移植等。本综述旨在回顾肠道菌群及其代谢产物与心肌纤维化的相互作用,介绍通过干预肠道菌群改善心肌纤维化的研究进展,为心肌纤维化的治疗提供新思路。     

缩醛基毛冬青提取化合物R4对缺血缺氧心肌的保护作用

目的：研究缩醛基毛冬青提取化合物R4对缺血缺氧心肌的保护作用,以便为缩醛基毛冬青提取化合物R4的临床新用途提供实验依据。方法：采用小鼠常压耐缺氧实验、夹闭气管小鼠心电消失时间、垂体后叶素所致大鼠心肌缺血模型及大鼠冠脉结扎所致的心肌缺血模型,观察缩醛基毛冬青提取化合物R4对缺血缺氧心肌的保护作用。结果：缩醛基毛冬青提取化合物R4（1.0、2.0、4.0 mg/kg）均能显著延长小鼠常压耐缺氧条件下的存活时间,延长夹闭气管小鼠心电消失时间,缩醛基毛冬青提取化合物R4（0.75、1.5和3.0 mg/kg）能拮抗垂体后叶素引起的心电图变化,并能明显降低结扎冠脉所致大鼠的心肌梗塞范围。结论：缩醛基毛冬青提取化合物R4对缺血缺氧心肌具有明显保护作用,其效应与剂量呈相关性,其机制可能是通过扩张冠脉,增加心肌的供血供氧而发挥抗心肌缺血的作用。     

Extracellular matrix-derived peptides and myocardial repair

Repairing cardiac tissue remains one of the most challenging goals in tissue engineering. Here, we discuss ways whereby we sought to treat myocardial infarctions using extracellular-matrix derived peptides. Using an ischemia/reperfusion myocardial infarction rodent model, we targeted these extracellular matrix-derived peptides to the myocardial infarct site and were able to induce angiogenesis and alter the negative remodeling seen after an acute myocardial infarction. Our results indicate a potentially new strategy for repairing damaged tissue.Key words: extracellular matrix, myocardial infarction, tissue engineering, cardiac repair, angiogenesis     

Comparing Cognitive and Somatic Symptoms of Depression in Myocardial Infarction Patients and Depressed Patients in Primary and Mental Health Care

Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients.     

心肌酶和红细胞形态学参数与心肌梗死的相关性研究

目的:研究红细胞形态学参数对心肌梗死患者诊断作用及其与心肌酶谱的相关性。方法:选取40例心肌梗死患者,40例稳定型心绞痛组患者,40例健康对照组人群。对比分析稳定性心绞痛、急性心肌梗死(入院1h内)和对照组红细胞形态学参数(MCV、MCH、MCHC、RDW)、及心肌酶谱(CK-MB、c Tn I)。分析心肌梗死不同时间MCV、MCH、MCHC、RDW变化趋势。结果:稳定性心绞痛、心肌梗死组1 h内MCV、RDW明显高于正常对照组,差异有统计学意义(P0.05);稳定性心绞痛、心肌梗死组1 h内MCHC、MCH低于对照组,差异有统计学意义(P0.05)。心肌梗死组MCV、RDW在发病后1 h、24 h、48 h、7 d水平逐渐升高,各时间点间差异有统计学意义(P0.05)。心肌梗死组发病后1 h、24 h、48 h、7 d、14 d MCHC、MCH水平逐渐降低,各时间点间差异有统计学意义(P0.05)。RDW和CK-MB、c Tn I呈正相关性(P0.05)。RDW对心肌梗死诊断的灵敏度最高达到93.4%,特异度为69.7%,RDW对急性心肌梗塞的诊断临界值为14.04%。结论:RDW对心肌梗死的诊断具有较高的敏感性,可用于临床早期诊断心肌梗死,为临床诊断提供一新的诊断标准。     

Chronic beta-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties

Chronic beta-adrenoreceptor (beta-AR) activation increases left ventricular (LV) cavity size by promoting a rightward shift in LV diastolic pressure-volume (P-V) relations in association with increases in low-tensile strength myocardial (non-cross-linked) collagen concentrations. Because diastolic P-V relations are determined by chamber remodeling as well as by myocardial material properties (indexed by myocardial stiffness), both of which are associated with modifications in myocardial collagen cross-linking, we evaluated whether chamber remodeling or alterations in myocardial material properties govern beta-AR-mediated modifications in diastolic P-V relations. The effects of chronic administration of isoproterenol (Iso; 0.04 mg.kg(-1).day(-1) from 12 to 19 mo of age) to spontaneously hypertensive rats (SHRs) on LV cavity dimensions, LV diastolic P-V relations, myocardial collagen characteristics, myocardial stiffness constants [e.g., the slope of the LV diastolic stress-strain relation (k)], and LV chamber and myocardial systolic function were assessed. SHRs at 19 mo of age had normal LV diastolic P-V relations, marked myocardial fibrosis (using a pathological score), increased myocardial cross-linked (insoluble to cyanogen bromide digestion) type I and type III collagen concentrations, and enhanced myocardial k values. Iso administration to SHRs resulted in enlarged LV cavity dimensions mediated by a rightward shift in LV diastolic P-V relations, increased volume intercept of the LV diastolic P-V relation, decreased LV relative wall thickness despite a tendency to augment LV hypertrophy, and increased non-cross-linked type I and type III myocardial collagen concentrations. Iso administration resulted in reduced pump function without modification of intrinsic myocardial systolic function. However, despite increasing myocardial non-cross-linked concentrations, Iso failed to alter myocardial k in SHRs. These results suggest that beta-AR-mediated rightward shifts in LV diastolic P-V relations, which induce decreased pump function, are mediated by chamber remodeling but not by modifications in myocardial material properties.     

Myocardial oxygen supply during hypocapnia and hypercapnia in the dog

It has been postulated that a coronary vasoconstriction during hypocapnia might be opposed by a compensating coronary vasodilatation due to impaired myocardial oxygen supply. The present study was performed first to examine whether a maximal decline in coronary sinus (CS) oxygen content was reached during hypocapnia. During hypercapnia a myocardial "over perfusion" has been demonstrated. The second purpose of the present study was to examine whether a myocardial "over perfusion" is essential to maintain a sufficient myocardial tissue oxygen supply during hypercapnia. Closed-chest dogs were anesthetized with pentobarbital and hypocapnia was induced by hyperventilation. Nitrogen gas and carbon dioxide could both be added to the inspiratory gas to create arterial hypoxemia (arterial SO2 65%) and hypercapnia, respectively. Arterial hypoxemia during hypocapnia increased myocardial blood flow (MBF) by 50%, while CS SO2 decreased significantly. The decrease in CS SO2 demonstrates a reserve capacity of myocardial oxygen extraction during hypocapnia, thereby ruling out any major coronary vasoconstriction during hypocapnia. Hypercapnia during normoxemia increased MBF, myocardial oxygen delivery, and CS SO2 substantially, but this was not observed when hypercapnia was created during arterial hypoxemia. From the present results we conclude that hypocapnia does not cause any major coronary vasoconstriction, while hypercapnia results in a myocardial "over perfusion," which is a luxury perfusion not essential to maintain sufficient myocardial oxygen supply during hypercapnia.     

Extracellular matrix-derived peptides and myocardial repair

Repairing cardiac tissue remains one of the most challenging goals in tissue engineering. Here, we discuss ways whereby we sought to treat myocardial infarctions using extracellular-matrix derived peptides. Using an ischemia/reperfusion myocardial infarction rodent model, we targeted these extracellular matrix-derived peptides to the myocardial infarct site and were able to induce angiogenesis and alter the negative remodeling seen after an acute myocardial infarction. Our results indicate a potentially new strategy for repairing damaged tissue.     

Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction

Mitochondria are important organelles in eukaryotic cells. Normal mitochondrial homeostasis is subject to a strict mitochondrial quality control system, including the strict regulation of mitochondrial production, fission/fusion and mitophagy. The strict and accurate modulation of the mitochondrial quality control system, comprising the mitochondrial fission/fusion, mitophagy and other processes, can ameliorate the myocardial injury of myocardial ischaemia and ischaemia-reperfusion after myocardial infarction, which plays an important role in myocardial protection after myocardial infarction. Further research into the mechanism will help identify new therapeutic targets and drugs for the treatment of myocardial infarction. This article aims to summarize the recent research regarding the mitochondrial quality control system and its molecular mechanism involved in myocardial infarction, as well as the potential therapeutic targets in the future.     

Changes in levels of lipid peroxides and activity of superoxide dismutase and catalase in diabetes associated with myocardial infarction.

Studies were carried out on the metabolism of lipid peroxides and antioxidative enzymes during diabetes and diabetes superimposed with myocardial infarction. Diabetes was induced using alloxan and myocardial infarction was induced by isoproterenol. In the case of diabetic animals there was a decrease in the levels of lipid peroxides in the heart while in the case of diabetes associated with myocardial infarction it was slightly elevated. The activity of superoxide dismutase and catalase showed a decrease in both the groups. Glutathione showed a fall in the case of diabetes and diabetes associated with myocardial infarction while taurine in heart and ceruloplasmin in the serum was elevated. Histopathological changes in the heart tissue showed some focal changes in the case of both diabetes and diabetes associated with myocardial infarction, but the degree of necrosis was much less than in the case of myocardial infarction.     

Dependence of heart chamber dimensions and dynamics on chamber demands and myocardial properties

A heart chamber undergoes eccentric hypertrophy in response to a chronic elevation of stroke-displacement demand, and it undergoes concentric hypertrophy in response to a chronic elevation of systolic-pressure demand. Both of these adaptations, which occur in various combinations, involve two myocardial plastic properties, "stretch normalization" and "stress normalization". We have developed a model which predicts dimensions and dynamics of the left ventricle as functions of myocardial properties and of the loads to which the chamber is adapted. The model involves: a stress-normalization rule which describes how myocardial volume depends on average systolic pressure, cavity volumes and the responsiveness of growth to stress; a stretch-normalization rule which describes how the cavity volume of standard stretch relates to average end-diastolic and end-systolic volumes; and a pressure-volume-curve equation giving isometric pressures as functions of cavity volume and myocardial volume relative to standard-stretch cavity volume, and elastic properties including contractility. The model shows how the relations among average dimensions, dynamics and loads depend on myocardial properties, particularly contractility and the growth response to stress. These properties are the main determinants of myocardial performance. In addition to the load adaptations mentioned above, the model predicts eccentric hypertrophy incident to reduced contractility, chronic dilation incident to reduced growth response to stress, myocardial stricture incident to excessive growth response to stress, and concentric hypertrophy (similar to high-pressure adaptation) incident to deposition of inert material. It allows some refinements in the evaluation of myocardial performance and in the evaluation of the abnormal properties responsible for abnormal performance.     

大鼠心肌梗死模型构建和评价方法的改良

目的 优化和改良大鼠心肌梗死模型的构建和评价方法,提高模型的可靠性和稳定性.方法 取雄性SD大鼠结扎左冠状动脉前降支建立心肌梗死模型,在模型的构建过程中从麻醉、插气管、保温、手术操作、术后护理等环节进行优化和改进,并观察不同的麻醉方法和术后时间对心肌梗死程度的影响,用不同的染色方式进行心肌梗死模型的评价.结果 对比大鼠心肌梗死模型构建过程中各组大鼠麻醉时间、术后恢复以及心肌梗死面积的结果,戊巴比妥钠是更合适的麻醉药;结扎手术后时间对模型心肌梗死范围无明显影响（P＆gt;0.05）,但心肌缺血危险区面积随术后时间的延长明显减少（P〈0.01）;TTC与依文思蓝双重染色相对TTC染色能明显观察到心肌缺血危险区和梗死区范围.结论 优化和改进后的大鼠心肌梗死模型,提高了动物福利,制备和评价方法更加客观准确.     

Beating activity of heterokaryons between myocardial and non-myocardial cells in culture

Cultured mouse myocardial cells grown as monolayers fused upon treatment with HVJ (Sendai virus). The myocardial cells also fused with quail myocardial cells, neuroblastoma cells and non-excitable cells, such as KB cells. The beating activity of these heterokaryons was studied in the present work. Heterokaryons composed of myocardial cells from different species maintained spontaneous beating activity for 2 days or more. Those of one myocardial and one neuroblastoma cell maintained the activity for 22-26 h, while those of one myocardial and one non-excitable cell, such as KB cell, lost the activity within 2-4 h after addition of HVJ. Heterokaryons that had stopped spontaneous beating did not contract on application of electrical-field stimulation. The ration of non-myocardial cells in the heterokaryons increased in inverse proportion to the decrease in beating activity of the heterokaryons. Study of the rapid disappearance of beating activity in heterokaryons composed of one myocardial and one KB cell showed that both excitability of the cell membrane and myofibril organization were rapidly lost.     

The Protective Role of Interleukin-33 in Myocardial Ischemia and Reperfusion Is Associated with Decreased HMGB1 Expression and Up-Regulation of the P38 MAPK Signaling Pathway

Interleukin-33 (IL-33) plays a protective role in myocardial ischemia and reperfusion (I/R) injury, but the underlying mechanism was not fully elucidated. The present study was designed to investigate whether IL-33 protects against myocardial I/R injury by regulating both P38 mitogen-activated-protein kinase (P38 MAPK), which is involved in one of the downstream signaling pathways of IL-33, and high mobility group box protein 1 (HMGB1), a late pro-inflammatory cytokine. Myocardial I/R injury increased the level of IL-33 and its induced receptor (sST) in myocardial tissue. Compared with the I/R group, the IL-33 group had significantly lower cardiac injury (lower serum creatine kinase (CK), lactate dehydrogenase (LDH), and cTnI levels and myocardial infarct size), a suppressed inflammatory response in myocardial tissue (lower expression of HMGB1, IL-6, TNF-α and INF-γ) and less myocardial apoptosis (much higher Bcl-2/Bax ratio and lower cleaved caspase-3 expression). Moreover, IL-33 activated the P38 MAPK signaling pathway (up-regulating P-P38 expression) in myocardial tissue, and SB230580 partially attenuated the anti-inflammatory and anti-apoptosis effects of IL-33. These findings indicated that IL-33 protects against myocardial I/R injury by inhibiting inflammatory responses and myocardial apoptosis, which may be associated with the HMGB1 and P38 MAPK signaling pathways.     

Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-alpha receptor

Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-alpha (TNF-alpha), the role of TNF-alpha as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-alpha receptor mediates the myocardial depressive effects of TNF-alpha. Toll-like receptor 4 (TLR4) regulates cellular expression of proinflammatory mediators following lipopolysaccharide stimulation and may be involved in the tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-alpha response to hemorrhagic shock and TLR4's role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-alpha production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-alpha production and myocardial depression, and determined the roles of TNF-alpha and TNF-alpha receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-alpha (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-alpha response and attenuated myocardial depression (left ventricular developed pressure of 43.0 +/- 6.2 mmHg in TLR4 mutant vs. 30.0 +/- 3.6 mmHg in wild type, P < 0.05). TNF-alpha KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-alpha KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-alpha response during hemorrhagic shock and that TNF-alpha through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-alpha receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.     

Significance of sarcolemma damage in the pathogenesis of myocardial ischemia induced by pituitrin-isadrin and its correction using the antioxidant dibunol

The elevation of cardiomyocyte membrane permeability has been demonstrated during pituitrin-isadrin-induced myocardial ischemia. Preventive 7-day oral administration of an antioxidant dibunol (30 and 120 mg/kg) preserved sarcolemmal integrity, decreased myocardial membrane permeability to sulfacetamide sodium, and reduced peroxide and mechanical erythrocyte hemolysis. Inhibition of lipid peroxidation with an antioxidant dibunol improved myocardial injury and decreased the death rate of animals with catecholamine-induced myocardial ischemia. These data suggest the involvement of lipid peroxidation in the development of ischemic myocardial injury.     

眼镜蛇咬伤患者早期肝肾功能、心肌酶的变化

目的观察眼镜蛇咬伤患者早期肝、肾功能及心肌酶的改变,以探讨其临床意义。方法对30例眼镜蛇咬伤患者入院时即抽取静脉血2.0 ml,分离血清,按常规方法行肝、肾功能及心肌酶的测定,并与健康体检者进行比较。结果与对照组比较,眼镜蛇咬伤患者早期肝功能及心肌酶指标显著升高(P0.05);肾功能检测结果差异无显著性(P0.05)。结论通过对眼镜蛇咬伤患者肝、肾功能及心肌酶的测定,了解患者肝脏、肾脏、心肌损害程度,对指导临床治疗具有一定意义。     

Myocardial infarction and heart failure in the db/db diabetic mouse

Clinical studies have reported that the incidence and severity of myocardial infarction is significantly greater in diabetics compared with nondiabetics after correction for all other risk factors. The majority of studies investigating the pathophysiology of myocardial ischemia-reperfusion injury have focused on otherwise healthy animals. At present, there is a paucity of experimental investigations on the pathophysiology of heart failure in diabetic animals. We hypothesized that the severity of myocardial reperfusion injury and the development of congestive heart failure would be markedly enhanced in the db/db diabetic mouse. Accordingly, we studied the effects of varying durations of in vivo myocardial ischemia and reperfusion on the incidence of heart failure in db/db diabetic mice. Nondiabetic and db/db diabetic mice (10 wk of age) were subjected to 30, 45, or 60 min of left coronary artery occlusion and 28 days of reperfusion. Survival at 24 h of reperfusion was 100% in nondiabetic mice subjected to 30 min of myocardial ischemia and 88% in nondiabetic mice subjected to 45 min of myocardial ischemia. In contrast, survival was 53% in db/db diabetic mice subjected to 30 min of myocardial ischemia and 44% in db/db mice after 45 min of myocardial ischemia. Prolonged survival in nondiabetic mice was not significantly attenuated when compared during the 28-day follow-up period with all groups experiencing >90% survival. Prolonged survival was significantly decreased in db/db mice after both 30 and 45 min of myocardial ischemia compared with sham controls. Furthermore, we observed a significant degree or left ventricular dilatation, cardiac hypertrophy, and cardiac contractile dysfunction in db/db mice subjected to 45 min of myocardial ischemia and 28 days reperfusion. In nondiabetic mice subjected to 45 min of myocardial ischemia, we failed to observe any changes in left ventricular dimensions or fractional shortening. These studies provide a feasible experimental model system for the investigation of heart failure secondary to acute myocardial infarction in the db/db diabetic mouse.