Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure

BACKGROUND: Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans. METHODS AND RESULTS: FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery. CONCLUSIONS: FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.     

肾动脉消融治疗慢性心力衰竭研究进展

慢性心力衰竭是一种复杂的临床症状群,是多种心血管疾病的共同转归。交感神经持续过度激活是其发生及发展的重要机制,多项临床及动物实验研究均表明,肾脏神经在交感神经活动中起着促进和传递的作用。2009年,Krum教授首次尝试利用导管靶向消融肾动脉周围的交感神经,从而降低全身过度激活的交感活性,达到治疗顽固性高血压的目的。这项新的治疗策略在有效地控制血压的同时还能有效降低心脏、肾脏以及肌肉组织等多个器官系统的交感神经活性,并能调节水盐代谢,改善心室重构和心脏功能,减轻机体高交感神经活性所导致的多器官损害。虽然其中具体的机制尚未明了,但我们有理由相信肾动脉消融在治疗高血压、慢性心力衰竭、代谢综合征等交感神经慢性过度激活的疾病有广阔的应用前景。     

A porcine model of ischemic heart failure produced by chronic placement of a tube in a coronary artery

BACKGROUND AND AIMS: Animal models of heart failure (HF) are useful to clarify the mechanism and to develop therapeutic interventions. To produce an easy ischemic HF model, we induced myocardial infarction (MI) in pigs by placing a tube in the coronary artery. METHODS: Twelve pigs underwent echocardiography and were randomly allocated to the myocardial infarction group (MI group) and the control group. In the MI pigs, a 4.2 F nylon tube was placed via the carotid artery in the left circumflex coronary (LCx) artery to induce MI. Three months thereafter, thoracotomy was performed in the both groups and left ventricular (LV) pressure-volume relation was evaluated. RESULTS: Body weight, LV dimension and function did not differ in the baseline state between the two groups. Three months after the tube placement, LV diameter was larger (47+/-3 vs. 42+/-2 mm) and its fractional shortening was lower in the MI group than the control group. In addition, aortic flow was decreased, LV ejection fraction was decreased (25+/-5 vs. 52+/-6%) and LV diastolic pressure was elevated (14+/-3 vs. 8+/-2 mmHg) in the MI group compared with the control group. The extent of MI was 26+/-5% of the LV in the MI pigs. CONCLUSION: The method of placing a tube in the coronary artery does not need thoracotomy or an additional procedure and enables the production of an ischemic HF model of pigs.     

Endothelial dysfunction and infarct-size relate to impaired EDHF response in rat experimental chronic heart failure

BACKGROUND: The rat coronary ligation model of chronic heart failure has been extensively used to investigate its pathophysiology including the role of endothelial dysfunction. Inconsistent results have been obtained concerning the role of endothelial dilative mediators nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). AIMS: Our aim was to investigate involvement of NO and EDHF in aortic endothelial dysfunction in this model and the influence of individual infarct sizes. Furthermore, we investigated whether it is justified to regard rats that failed to develop large infarct sizes as SHAM controls. METHODS: We performed coronary ligations and SHAM operations and studied acetylcholine (ACh)-induced relaxations and underlying endothelial mediators in isolated aortic rings 12 weeks after infarction. By then, cardiac and hemodynamic parameters were deteriorated in animals with large myocardial infarctions (large-MI, 35+/-3%), but not those with small myocardial infarctions (small-MI, 5+/-2%). RESULTS: Large-MI showed decreased ACh-induced relaxation compared to SHAM due to decreased contribution of EDHF which was inversely correlated with individual infarct-size. Interestingly, small-MI showed significantly increased ACh-induced relaxation compared to SHAM due to increased NO contribution. CONCLUSIONS: Our results suggest that impaired aortic endothelial dilatory function in large-MI is mainly due to an impaired EDHF response and strongly depends on individual infarct-size. In addition, endothelium-dependent relaxation of small-MI rats differed from SHAM, indicating that both groups may not be pooled to serve as controls. These results emphasize the importance of infarct-size and choice of the control group, and may explain inconsistencies in previous studies.     

Klotho基因在慢性心力衰竭患者心肌中的表达

目的探讨慢性心力衰竭(CHF)患者心肌组织中Klotho基因的表达及其与心肌纤维化的关系。方法心肌组织样本取材于2013年8月至2014年8月在成都军区昆明总医院心脏外科建立体外循环的60例CHF患者,按照纽约心脏联合会(NYHA)心功能分级将其分为:NYHAⅠ级组、Ⅱ级组、Ⅲ级组,每组患者各20例。运用实时荧光定量反转录-聚合酶链反应(RT-PCR)检测Klotho基因表达量,同时采用酶联免疫吸附测定(ELISA)方法检测上述60例患者血清中Ⅰ型C端胶原前肽(PⅠCP)的浓度。并对正常心肌组织及CHF患者心肌组织进行HE染色。结果(1)HE染色显示CHF患者心肌胶原增生;(2)与NYHAⅠ级组比较,Klotho基因在NYHAⅡ级、NYHAⅢ级组的心肌组织中表达明显减少(均P0.05),且在NYHAⅢ级组中的表达较NYHAⅡ级组明显减少(P0.05);(3)NYHAⅢ级组患者血清中PⅠCP的含量高于Ⅱ级、Ⅰ级组(均P0.05),NYHAⅡ级组高于Ⅰ级组(P0.05)。结论 CHF患者心肌组织Klotho基因的表达减少可能与随着心功能恶化,其抗衰老作用及抗心肌纤维化作用逐渐减弱有关。     

Neurohumoral and hemodynamic effects of ibopamine in a rat model of chronic myocardial infarction and heart failure

Summary There is increasing evidence that both neurohumoral and hemodynamic factors play a role in disease progression in chronic heart failure (CHF). To examine the influence of the oral dopamine agonist ibopamine on these factors, we studied 20 rats with chronic myocardial infarction and CHF, and compared them with 20 normal rats. After 6 weeks, rats were randomly divided between control treatment (50%) or ibopamine (50%) for 3 weeks. At the end of the study, plasma and tissue neurohumoral parameters, as well as hemodynamics, were determined. In infarcted rats, the elevated plasma norepinephrine (PNE) levels were reduced by ibopamine (251±19 vs. 138±32 pg/ml; p<0.05). Other plasma neurohormones measured (epinephrine, renin, aldosterone, and angiotensin converting enzyme [ACE]) were not significantly increased in rats with myocardial infarction and were not affected by ibopamine. Cardiac (tissue) ACE was increased in infarcted rats (12.1±1.9 U/l/min) and was significantly lowered by ibopamine (9.6±1.0 U/l/min; p<0.05); renal ACE was unaffected. Blood pressure and heart rate were similar in the two groups and were not influenced by ibopamine treatment. In conclusion, in chronic myocardial infarction and CHF in rats, ibopamine reduces the elevated levels of PNE and cardiac ACE. Further research will be needed to determine whether this effect may lead to a favorable influence on disease progression in CHF.     

Correlation between serum levels of microRNA-21 and inflammatory factors in patients with chronic heart failure

As the leading cause of hospitalization and mortality worldwide, heart failure (HF) has caused significant burden on both individuals and the whole society. Thus, increasing knowledge about the phytopathology of HF is in demand for both diagnosis and treatment. Previous studies have shown that both microRNA 21 (miRNA-21) and inflammatory factors are closely related to the development of cardiac fibrosis, hypertrophy, and HF. However, whether there is any crosstalk between the 2 has not been examined. The current study evaluated the correlation between serum levels of miRNA-21 and critical inflammatory factors during the progress of chronic heart failure (CHF), providing new insights in understanding the physiopathology of CHF and identifying CHF biomarkers. In the presented study, serum level of miR-21, cardiac neurohormone, and critical inflammatory factors were measured and compared on 120 (67 male/53 female) CHF patients and 100 (58 male/42 female) health people with non-failing hearts. Echocardiography was also conducted to assess the severity of CHF. Correlations between different factors were calculated and tested for statistical significance. From our results, CHF patients showed significantly decreased serum levels of miR-21 while increased levels of inflammatory factors and cardiac neurohormone (P < .05). Levels of miR-21 negatively correlate with cardiac function while positively correlates with myocardial remodeling (P < .05). Levels of miR-21 negatively correlate with inflammation in CHF (P < .05). These findings indicate the potential crosstalk between serum miR-21 and inflammation during CHF progression, suggesting the potential of miR-21 in CHF diagnosis, severity indication, and treatment.     

奥美沙坦对心肌梗死后心力衰竭大鼠内皮素1和肾上腺髓质素水平的影响

目的探讨奥美沙坦对心肌梗死后心力衰竭大鼠血浆内皮素1(endothelin-1,ET-1)、肾上腺髓质素(adrenomedullin,ADM)水平的影响。方法 Wistar大鼠38只,随机分为对照组10只、假手术组10只、模型组9只、奥美沙坦组9只。采用结扎大鼠冠状动脉左前降支的方法制作心肌梗死后心力衰竭模型,灌胃法给药8周。超声心动图检测用药前后大鼠心功能,放射免疫法测定血浆ET-1、ADM水平。结果用药前,对照组与假手术组大鼠LVEF、ET-1、ADM水平差异无统计学意义(P>0.05);与假手术组比较,模型组和奥美沙坦组大鼠LVEF明显降低,差异有统计学意义(P<0.01)。用药后,与假手术组比较,模型组大鼠ET 1、ADM水平明显升高,差异有统计学意义(P<0.05,P<0.01);与模型组比较,奥美沙坦组大鼠LVEF明显改善,ET-1、ADM水平明显降低,差异有统计学意义(P<0.05,P<0.01)。结论应用奥美沙坦治疗可以改善心肌梗死后心力衰竭大鼠心功能,降低心力衰竭时升高的血浆ET-1、ADM水平,抑制慢性心力衰竭时肾素-血管紧张素系统以外的神经内分泌系统激活,对慢性心力衰竭心脏起到保护作用。     

慢性心力衰竭患者心率震荡检测及临床意义

目的观察慢性心力衰竭患者窦性心率震荡(HRT)现象的特征并探讨其临床意义。方法50例慢性心衰患者(心衰组)和30例非器质性心脏病患者(对照组)均接受24hHolter检查,分别计算HRT的初始值(TO)、震荡斜率(TS)及心率变异性的SDNN、SDANN、rMSSD值,并进行相关性分析。结果心衰组TO明显高于对照组(0.65±3.60%与-1.89±2.48%,P<0.01);心衰组TS明显低于对照组(2.96±1.23与10.24±4.47,P<0.001)。对照组TS与SDNN、SDANN、rMSSD的相关系数分别为-0.426、-0.385、-0.372(P均<0.05);心衰组TO与SDNN、SDANN、rMSSD的相关系数分别为0.489、0.465、0.436(P均<0.01),TS与SDNN、SDANN、rMSSD的相关系数分别为-0.745、-0.686、-0.597(P均<0.001)。结论慢性心衰患者中HRT现象明显减弱,TO与SDNN、SDANN、rMSSD值呈正相关,TS与SDNN、SDANN、rMSSD值呈负相关。     

Carvedilol in the treatment of elderly patients with chronic heart failure

Chronic heart failure (CHF) is common, and increases in incidence and prevalence with age. There are compelling data demonstrating reduced mortality and hospitalizations with adrenergic blockade in older patients with CHF. Despite this, many older patients remain under-treated. The aim of the present article is to review the potential mechanisms of the benefits of adrenergic blockade in CHF and the clinical data available from the large randomized studies, focusing particularly on older patients.     

Enhanced endothelin-1-induced contractions in mesenteric arteries from rats with congestive heart failure: role of ET(B) receptors

Studies of congestive heart failure (CHF) in man and in experimental CHF have demonstrated elevated circulating levels of endothelin (ET). In order to examine whether there are concomitant ET receptor alterations, the vasomotor effects of endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were examined in endothelium-intact and -denuded isolated mesenteric arteries from rats with CHF. CHF was induced by ligation of the left anterior descending coronary artery. Vasomotor responses were studied using small mesenteric arteries (approx. 250 microm in diameter, determined after normalisation). The antagonists IRL2500 and FR139317 were used in order to characterise the ET-1-induced response. In mesenteric arteries with intact endothelium, ET-1-induced contractions were more potent in CHF as compared to sham (pEC(50) 9.6+/-0.2 and 9.1+/-0.1, respectively, P<0.01). In endothelium-denuded arteries, there was no difference in potency of ET-1 between CHF and sham arteries, or in maximum contraction. In the presence of IRL2500, a selective ET(B)-receptor antagonist, ET-1 was more potent in endothelium-denuded arteries of CHF rats, while this difference was not seen in sham arteries. S6c had no consistent contractile or dilatory effect in CHF and sham rats. The results indicate that the enhanced contractile effects of ET-1 noted in CHF might be due to an attenuated endothelial function and that inhibition of smooth muscle cell ET(B) receptors increase the effects of contractile ET(A) receptors in CHF rats.     

心脏彩超应用于心肌梗死后慢性心衰心脏同步性检测中的临床作用

目的：探讨心脏彩超应用于心肌梗死后慢性心衰心脏同步性检测中的临床作用。方法：2013年1月到2015年6月选择在我院进行诊治的心肌梗死患者92例,根据随机数字表法分为治疗组与对照组各46例,对照组给予介入手术治疗,治疗组在对照组治疗的基础上给予心脏再同步化治疗。结果：所有患者都介入治疗成功,介入后14d治疗组与对照组的LVESVI与LVEDVI值都明显都低于介入前(P<0.05),同时比较研究两组的LVESVI与LVEDVI值发现介入后14d治疗组值显著偏低 (P<0.05)。介入后14d治疗组与对照组的Trs-Avg-12值显著降低(P<0.05),并且对介入后14d治疗组进行观察,发现其Trs-Avg-12值比对照组显著要低(P<0.05);两组介入前后的Trs-Avg-6b组内与组间对比差异都无统计学意义(P>0.05)。所有患者介入后随访调查6个月,治疗组的慢性心力衰竭、再次心肌梗死、恶性心律失常和靶病变血管重建等主要心脏不良事件明显少于对照组(P<0.05)。结论：心肌梗死后慢性心衰心脏彩超显示多存在心室收缩不同步情况,心脏再同步化治疗辅助介入治疗能有效改善心功能,改善患者的心室收缩不同步情况,减少慢性心力衰竭等主要心脏不良事件的发生。     

阿霉素致大鼠心力衰竭干预起点探讨

目的探讨阿霉素导致大鼠心力衰竭心室结构演变和应用此模型进行心力衰竭治疗性试验时恰当的干预起点。方法以累积剂量达15mg/kg,3周内注射完毕的方法建立阿霉素致大鼠心力衰竭模型。分别于注射阿霉素前,注射后3、4、5、6周和7周在M型超声下观察左心室舒张末期内径(left ventricular end-diastolic dimension,LVEDd),左心室收缩末期内径(left ventricular end-systolic dimension,LVESd)和左心室射血分数(left ventricular ejection fraction,LVEF)变化;于注射阿霉素前,注射后6周,7周使用免疫酶联吸附法(ELISA)法检测血清脑利钠肽浓度。结果注射阿霉素7周后与注射阿霉素前比较,LVEF(69.6%±10.3%vs.78.7%±13.7%,P0.01),LVEDd[(0.67±0.03)cmvs.(0.52±0.02)cm,P0.01],LVESd[(0.41±0.17)cmvs.(0.30±0.02)cm,P0.01]和脑钠肽[(0.37±0.15)μg/Lvs.(0.18±0.06)μg/L,P0.01]差异有统计学意义。结论足量注射阿霉素7周后可作为阿霉素致大鼠心衰模型治疗性试验时干预的起点。     

对慢性心力衰竭患者进行院外干预的依从性及其效果

目的观察对慢性心力衰竭（CHF）患者进行院外干预的效果。方法：通过前瞻性随机对照方法,将215名出院的心力衰竭（HF）患者随机分为普通随访组和强化干预组,通过1年的随访观察,最终完成随访的患者共计205例。普通随访组仅进行常规的门诊随访,强化干预组患者接受电话咨询、专门的心力衰竭门诊随诊及定期健康宣教。结果：强化干预组和普通组相比较,限水限钠达标率和坚持每天监测体质量的比例大幅度增加（P〈0-01）,强化干预组利尿剂的使用率明显高于普通组（P〈0-01）,血管紧张素转换酶抑制剂（ACEI）／血管紧张素II受体拮抗剂（ARB）类药物、B受体阻滞剂的靶剂量达标率方面明显高于普通组（P〈0-01）,强化干预组左室射血分数高于普通随访组;与普通随访组相比,强化干预组氨基端脑钠肽前体（NT-pro-BNP）降低更明显（P〈0-05）,且6分钟步行试验优于普通组（P〈0-05）。两组再次入院和总心血管事件发生率有显著差异（3％伪．11％,P〈0-05）,强化于预措施显著降低了死亡和再住院联合终点事件的发生率。结论：对CHF患者进行院外强化干预,可以提高患者的自我管理能力,提高抗HF治疗药物的使用比例及二级预防药物的靶剂量达标率,降低再住院率和心血管事件发生率。     

慢性心力衰竭合并肌肉衰减综合征的研究进展

肌肉衰减综合征是一种与年龄增长相关,以进行性全身骨骼肌质量减少、肌肉强度下降和肌肉功能减退为主要特征的临床综合征。慢性心力衰竭是心血管疾病中影响患者生存率的重要疾病之一。越来越多的研究发现慢性心力衰竭可能造成或加重肌肉衰减综合征的进展,其机制涉及营养不良、运动量下降、炎症反应、氧化应激及激素变化等。目前的治疗策略主要包括运动干预、营养支持和药物治疗。本文就近年慢性心力衰竭合并肌肉衰减综合征的发病机制及治疗方案等方面的研究进展进行综述。     

超声心动图在评估犬慢性心力衰竭模型中的作用

目的探讨超声心动图在评估犬慢性心力衰竭模型中的作用。方法对10只比格犬进行快速右心室起搏,起搏前及起搏4周停止起搏后进行多普勒超声心动图和血流动力学检查。结果快速右心室起搏4周后,所有犬都出现气促、四肢浮肿等情况,并有不同程度的胸、腹腔积液。超声心动图示左室EF、FS较起搏前显著降低（P<0.01）,分别为（0.63±0.05）vs（0.42±0.10）和（0.33±4.50）vs（0.19±6.19）;血流动力学检测示犬左室±dp/dtm ax较起搏前均显著降低（P<0.01）,分别为[（9846±415）vs（3330±307）mmHg/s]和[（-7925±3558）vs（-2260±113）mmHg/s]。起搏前后犬左室EF和FS值与+dp/dtm ax值呈良好的正相关（P<0.01）。结论通过超声心动图和血流动力学指标的相关性分析,表明超声心动图在评价心力衰竭动物模型上是无创、便捷、重复性好的方法。     

Characteristics and prognosis of patients with acute myocardial infarction in relation to occurrence of congestive heart failure

Congestive heart failure is one of the major symptoms accompanyingacute myocardial infarction (AMI). The study aimed to describethe occurrence, characteristics and prognosis of congestiveheart failure in AMI and to compare post-MI patients with andwithout congestive heart failure. The methods used includedbaseline characteristics, initial symptoms, electrocardiogram(ECG), mortality during hospitalization and one year follow-upin consecutive patients with AMI admitted to Sahlgrenska Hospital,Göteborg, Sweden. Congestive heart failure was observed in 51% of the cases. Patientswith congestive heart failure were older, more frequently hada history of previous cardiovascular disease, and, less frequentlyhad chest pain on admission to hospital. They had a higher occurrenceof life-threatening ventricular arrhythmias during initial hospitalization,and their mortality during one year follow-up was 39% as comparedto 17% in patients without congestive heart failure (P<0.001).This difference remained significant when correcting for differencesat baseline. Patients with severe congestive heart failure hada one year mortality of 47% vs 31% in patients with moderatecongestive heart failure (P<0.01). Signs and symptoms of congestive heart failure occur in everysecond patient admitted to hospital due to AMI, and indicatea bad prognosis, which is directly related to the severity ofcongestive heart failure.     

Impact of hospitalization for acute coronary events on subsequent mortality in patients with chronic heart failure

Aims: We explored the impact of having a hospital admission for anacute coronary syndrome (ACS) on the subsequent prognosis amongpatients with chronic heart failure (CHF). Methods and results: A total of 7599 patients with CHF, New York Heart AssociationClasses II–IV, were randomly assigned to candesartan orplacebo. We assessed the risk of death after a first ACS usingtime-updated Cox proportional hazard models adjusted for baselinepredictors. During a mean follow-up of 3.3 years, 1174 patientsexperienced at least one ACS. Myocardial infarction (MI) wasthe first ACS in 442 subjects and unstable angina (UA) in 732.After these events, 219 (49.5%) and 167 (22.8%) patients diedduring follow-up. The early risk of death was more pronouncedafter MI: 30.2% died within 30 days compared with 3.6% afterUA. After an ACS event, the risk of death declined steadilyover time, although 18 months after an MI the risk was stilltwice that of patients without an ACS. Conclusion: Patients with CHF, who develop an ACS, have markedly increasedsubsequent mortality, particularly in the early phase afteran MI.