单纯缺血预处理对未成熟兔心脏的作用研究

目的 探讨缺血预处理（Ｉｓｃｈｅｍｉｃ Ｐｒｏｃｏｎｄｉｔｉｏｎｉｎｇ ＩＰＣ）对未成熟心脏全心缺血再灌注损伤的影响。方法 对经历５Ｍｉｎ缺血、１０Ｍｉｎ再灌注的幼兔（１４～２１天）心脏进行离体灌注,观察其在生理温度（３９℃）下接受３０Ｍｉｎ缺血、４０Ｍｉｎ再灌注的心肌酶释放、心肌能量及病理变化。结果 ＩＰＣ组全心缺血后心脏停跳持续时间显明延长（Ｐ〈０．０１）,心肌ＡＴＰ含量明显减少（Ｐ〈０．００     

Selective sensory denervation by capsaicin aggravates adriamycin-induced cardiomyopathy in rats

Capsaicin-sensitive sensory nerves that contain calcitonin gene-related peptide (CGRP) contribute significantly to cardioprotective mechanisms. In this study, the possible role of capsaicin-sensitive afferent nerves in the development of congestive heart failure was examined in an established model of adriamycin-induced experimental cardiomyopathy in rats. Systemic treatment with capsaicin was utilized to deplete sensory neuropeptides from cardiac afferent nerves. Echocardiography was applied to assess the cardiac function in adriamycin-treated rats pretreated with capsaicin or its vehicle. In control rats, adriamycin treatment produced a reduction in the fractional shortening of the left ventricle and an increase in the ratio of the left atrial diameter and the aortic diameter, indicative of a decreased myocardial contractility and heart failure only at 3–4 weeks post-treatment. In contrast, in capsaicin-pretreated rats, a deterioration of the cardiac function was already evident 1 week after the cessation of adriamycin administration, while the clinical signs associated with cardiomyopathy were more severe and displayed a significantly more rapid progression. Immunohistochemistry revealed a complete depletion of calcitonin gene-related peptide from cardiac sensory nerves after systemic capsaicin treatment. This study has demonstrated that elimination of capsaicin-sensitive afferent nerves promotes the development and progression of adriamycin-induced myocardial dysfunction. The results suggest that interfering with capsaicin/vanilloid receptor function and/or perturbation of the myocardial CGRP metabolism may open up new perspectives concerning prevention and/or alleviation of the pathological changes that follow adriamycin treatment.     

冷血停跳液单次灌注在心内直视手术中的应用

目的:探讨体外循环(Cardiopulmonary Bypass.CPB)心内直视手术中,单次灌注含钾冷血停跳液的心肌保护效果.方法:50例患者采用4:1血液晶体停搏液灌注.灌注量20 ml/kg,术中心电图不出现活动波形,则不再重复灌注.结果:患者CPB时间(76.78.±18.57)min,主动脉阻断时间(42.08±10.44)min.开放主动脉后心脏自动复跳48例(96%),复跳后除颤2例(4%),术后患者全部康复出院.结论:单次灌注含钾冷血停搏液心肌保护作用明显.     

Deferoxamine infusion during coronary artery bypass grafting ameliorates lipid peroxidation and protects the myocardium against reperfusion injury: immediate and long-term significance.

AIMS: Previous reports have demonstrated enhanced myocardial protection and better post-ischaemic recovery using the oxygen free radical scavenger deferoxamine (DEF) during cardioplegia. The aim of this study was to test whether, in patients undergoing coronary artery bypass grafting (CABG), DEF i.v. infusion can reduce reperfusion injury on a short- and long-term basis. METHODS AND RESULTS: Forty-five consecutive male patients were randomly allocated to two groups: in group D (n=25, age 60.8+/-8.6 years), 4 g of DEF were infused for 8 h starting immediately after the induction of anaesthesia; in group C (n=20, age 62.2+/-6.4 years) dextrose solution was given for the same time as placebo. Haemodynamic monitoring and measurement of oxygen free radical production [by measuring thiobarbituric acid reactive substances (TBARS)] were carried out before and after CABG. Left ventricular ejection fraction (EF) and wall motion score index (WMSI) were measured before and after CABG and 12 months later. Haemodynamic measurements were similar in both groups before and after CABG. TBARS peaked at 4.8+/-1.1 nmol/mL in group C, but remained unchanged (2.4+/-0.9 nmol/mL) in group D (P=0.01). At baseline, both the EF and WMSI were similar between the groups. Following CABG, EF increased more in group D (8.8+/-8.4%) than in group C (1.3+/-6.7%), P=0.008, while WMSI decreased more in group D (-0.7+/-0.3) than in group C (-0.2+/-0.2), P=0.0001. Dividing group D according to the pre-operative median EF value (38%), we observed that after 1 year follow-up, DEF infusion conferred more protection in patients with a lower EF (EF increased by 19.3+/-6.2%, WMSI decreased by -1.1+/-0.2) than in those with a higher EF (EF increased by 7.7+/-4.5%, WMSI decreased by -0.8+/-0.2), P=0.001, respectively. CONCLUSION: In patients undergoing CABG, DEF i.v. infusion ameliorates oxygen free radical production and protects the myocardium against reperfusion injury. Patients with a lower EF seem to benefit more by DEF i.v. infusion.     

不同缺血预处理对未成熟心肌细胞功能的影响

目的比较不同方法的缺血预处理对未成熟心肌细胞功能的影响。方法采用Langendorff离体心脏灌注模型。分为4组:缺血/再灌注(I/R)组,离体心脏灌注15min转为工作心15min后停灌45min,恢复灌注15min改为工作心30min;心脏缺血预处理(MIP)组:离体心脏灌注15min转为工作心15min后反复2次缺血5min/再灌注5min,然后重复I/R组缺血/再灌注方法;肾缺血预处理(RIP)组:反复三次阻断左肾动脉5min,放开5min,切取心脏,重复I/R组方法;双下肢缺血预处理(DLIP)组:反复3次捆扎双下肢5min,松开5min,切取心脏,重复I/R组方法。以血清肌酸激酶(CK)和乳酸脱氢酶(LDH)漏出率、心肌组织三磷腺苷(ATP)和丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性、心肌细胞内Ca2+含量、心肌线粒体Ca2+-ATPase活性及其Ca2+含量、心肌线粒体合成三磷腺苷能力[ATP]m作为观察指标。结果MIP、RIP及DLIP组ATP含量、SOD活性、心肌线粒体Ca2+-ATPase活性、[ATP]m均高于I/R组(P<0.01),MDA含量、CK、LDH漏出率、心肌细胞内Ca2+含量、心肌线粒体Ca2+含量均低于I/R组(P<0.01)。结论肾缺血预处理、双下肢缺血预处理与心脏缺血预处理有同等的心肌细胞保护作用。     

Pharmacological postconditioning with the phytoestrogen genistein

Estrogens are known to activate the phosphatidyl-inosityl 3-kinase (PI3K)/Akt pathway, which is central in the cardioprotection afforded by ischemic postconditioning. Therefore, our goal was to investigate whether a phytoestrogen, genistein, could induce a pharmacological postconditioning and to investigate potential mechanisms. We used low doses of genistein in order to avoid tyrosine kinases inhibition. Thus, pentobarbital-anesthetized rabbits underwent a coronary artery occlusion followed by 4 h of reperfusion. Prior to reperfusion, they randomly received an i.v. injection of either saline (Control), 100 or 1000 microg/kg of genistein (Geni(100) and Geni(1000), respectively), and 10 or 100 microg/kg of 17beta-estradiol (17beta(10) and 17beta(100), respectively). Infarct size (IS, % area at risk) was significantly reduced in Gen(100), Gen(1000) and 17beta(100) but not in 17beta(10) (6+/-2, 16+/-5, 12+/-3 and 29+/-7%, respectively) vs. Control (35+/-4%). A significant decrease in the percentage of TUNEL-positive nuclei within infarcted area was observed in Gen(100) and 17beta(100) vs. Controls. The estrogen receptor antagonist fulvestrant (1 mg/kg i.v.) and the PI3K inhibitor wortmaninn (0.6 mg/kg) abolished the cardioprotective effect of genistein. Western blots also demonstrated an increase in Akt posphorylation in Gen(100). In the same group, in vitro mitochondrial swelling studies demonstrated a significant inhibition of calcium-induced opening of mitochondrial transition pore vs. Controls. In conclusion, genistein exerts pharmacological postconditioning with a similar potency as 17beta-estradiol through a pathway involving activation of the estrogen receptor, of PI3K/Akt and mitochondrial preservation. Therefore, genistein should not be only considered as an inhibitor of tyrosine kinase but also as a cardioprotective estrogen.     

Stromal derived factor 1α: A chemokine that delivers a two-pronged defence of the myocardium

Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting.