β受体阻断药在心力衰竭合并房颤治疗中的再评价

β肾上腺素受体阻断药被认定为心力衰竭治疗领域的里程碑,在心力衰竭指南中,β肾上腺素受体阻断药为IA类推荐。但针对慢性心力衰竭的经典、大型RCT临床试验中,房颤患者所占比率不高。新近对于心力衰竭合并房颤患者应用β肾上腺素受体阻断剂的死亡率和住院率进行Meta-分析示:β肾上腺素受体拮抗剂未见有更多临床获益(即死亡率和住院率减低水平无统计学意义)。本文就心力衰竭定义、心力衰竭时交感神经系统激活、作用于交感神经系统的β肾上腺素受体阻断药药理作用及分类、β肾上腺素受体阻断药在心力衰竭并发房颤治疗中应用地位、心力衰竭并发房颤患者应用β肾上腺素受体阻断药存在的争议及其原因分析进行简要综述。     

β肾上腺素受体与心力衰竭

β肾上腺素受体中的β1和β2亚型是调节心脏功能最重要的两种蛋白。在此将阐述β肾上腺素受体亚型信号转导对心脏的生理功能与心力衰竭的关系,并综合介绍β肾上腺素受体系统中一些关键蛋白的基因多态性与心力衰竭的易感性、预后及药物治疗效果的关联。最后,将探讨如何应用功能选择理论和基因组学发现新的心衰治疗靶点和新药,为新药研发和个体化医疗提供思路。     

β-肾上腺素受体与乳腺癌相关性的研究进展

精神和情绪对于肿瘤的发生、发展具有重要作用。通常,在急性或慢性应激状态下,由交感神经系统介导的正常生理应激机制导致神经递质肾上腺素和去甲肾上腺素释放增多。对于恶性肿瘤患者,大量研究证实交感神经系统主要通过β-肾上腺素能受体途径介导的信号传导通路对肿瘤的进展和转移产生影响。乳腺癌患者多伴有焦虑预后不良而引起肾上腺素及去甲肾上腺素分泌增加,从而可能促进乳腺癌的进展和转移。本文就β-肾上腺素受体及其在其它恶性肿瘤中相关研究,着重探讨β-肾上腺素受体在乳腺癌中表达情况和使用β-肾上腺素受体阻断剂与乳腺癌预后的关系作以下综述,为进一步探究β-肾上腺素受体在乳腺癌中的作用机制提供相关理论依据。     

氟烷对慢性缺氧兔心肌β肾上腺素能受体的影响

用放射配基结合法和高效液相色谱电化学法分别测定氟烷对慢性缺氧免心肌β肾上腺素能受体（简称β受体）和血浆儿茶酚胺的影响。结果表明：慢性缺氧后兔心肌β受体密度明显下降,受体亲和力无明显变化,血浆肾上腺素、去甲肾上腺素明显升高。缺氧吸入氟烷后兔心肌β受体密度进一步下降,亲和力增加,血浆肾上腺素、去甲肾上腺素无进一步变化。常氧吸入氟烷后心肌β受体密度无明显变化,亲和力升高,血浆肾上腺素、去甲肾上腺素反而降低。结果提示,氟烷抑制常氧兔交感神经活动而不能抑制缺氧兔交感神经活动,氟烷不改变常氧兔心肌β受体密度,但降低缺氧兔心肌β受体密度。β受体密度降低与缺氧后升高的儿茶酚胺下调β受体数目有关,同时可能与氟烷改变了缺氧心肌细胞膜脂质流动性使受体易向膜内移动有关。     

持续和间断激动β-肾上腺素受体对心脏重塑的不同作用

心脏疾病常伴有交感神经系统过度激活及循环系统内儿茶酚胺水平增高,通过激动β-肾上腺素受体引起心脏重塑.β-AR激动剂异丙基肾上腺素常用来制备心脏重塑模型.然而β-AR不同的激动模式,脉冲式的间断激动与慢性持续激动对心脏重塑和心脏功能下降的影响是否不同,尚未见报道.为此,本研究比较了ISO间断给药与持续给药对小鼠心脏重塑...     

α，β－受体阻断剂对大鼠缺氧性脑血管扩张反应的影响

本实验采用堤式颅窗软脑膜微循环实验方法,利用去甲肾上腺素和α,β－受体阻断剂,研究了交感神经在缺氧性脑血管扩张反应（ＨＣＶ）中的作用。去甲肾上腺素（１０－７ｍｏｌ／Ｌ和１０－６ｍｏｌ／Ｌ）对软脑膜微动脉无明显作用。β－受体阻断剂普萘洛尔（局部用药,下同）对ＨＣＶ无明显影响,而用１０－６ｍｏｌ／Ｌ哌唑嗪阻断软脑膜微动脉α－受体可明显增强ＨＣＶ（由２１．５±９．８％增至３０．６±９．２％,Ｐ＜０．０１）。结果提示,正常情况下交感神经对脑血管影响较小,但在缺氧时,交感神经对脑血管有收缩作用。交感神经可能通过增加其末梢释放去甲肾上腺素,作用于α－受体,限制微劝脉扩张而在缺氧性脑血管扩张反应中起调节作用。     

β-受体阻滞剂在心力衰竭治疗中的应用

β受体阻滞剂是治疗心力衰竭的重要用药,已经在我国治疗心力衰竭用药中得到了普及。β受体阻滞剂治疗高血压、冠心病、快速心律失常等领域有着重要的作用。但是对于如何应用这一药物、选择哪类β受体阻滞剂、用法用量等在我国医学上还没有系统化、规范化的阐述,为此,本文探究β受体阻滞剂在治疗心力衰竭中的应用,以指导我院在临床中正确使用这一药物。     

β—肾上腺素能受体介导的心肌细胞凋亡

作为交感神经系统主要递质的去甲肾上腺素在多种心脏疾病中诱导心肌细胞凋亡,这种诱导作用主要由肾上腺素能受体（β－AR）介导,β－AR还介导心肌细胞凋亡的信号转导,这对于了解心脏疾病的发病机理有一定的临床意义。     

心交感神经对缺血心肌区血液中TXB2和6—酮—PGF1α浓度变化的影响

本实验在54只麻醉开胸犬,分别观察了心交感神经和α、β受体阻断剂对心肌缺血早期血小板功能变化的影响。结果表明,阻断冠脉后,心肌缺血区血液中TXB_2和6-酮-PGF_(1α)含量明显升高,血小板计数减少,随缺血时间延长,变化程度也增大。缺血心肌局部外敷2％利多卡因湿沙条或切除双侧星状神经节,分别阻断心交感神经的传入和传出效应,发现阻断冠脉后各参数变化程度明显减轻,与单纯阻断冠脉后各参数变化相比,有显著差异,P<0.01。切除星状神经节并由静脉输注去甲肾上腺素后再阻断冠脉,可重新恢复单纯阻断冠脉后的各参数变化,但输注生理盐水无影响。α和β受体阻断剂对上述参数的影响途径不同。α_2受体阻断剂育亨宾和非选择性α受体阻断剂酚妥拉明,可明显减轻TXB_2和6-酮-PGF_(1α)升高及血小板计数降低的程度,与单纯阻断冠脉后的各参数变化程度相比,有显著差异,P<0.01。但α_1受体阻滞剂哌唑嗪无此作用。和α_2受体阻断剂一样,β受体阻断剂心得安对缺血后上述参数的变化也具有明显改善效应。这些结果提示,心交感神经在血小板功能变化中具有重要作用;育亨宾和酚妥拉明是通过阻断血小板膜α_2受体发挥作用的;在输注心得安而未阻断血小板膜α_2受体时所看到对缺血后血小板功能参数的改善效应,提示β受体阻断剂可能     

胺碘酮联合β受体阻滞剂治疗急性心肌梗死并发快速心律失常的效果及对心功能影响

目的探讨急性心肌梗死并发快速心律失常患者应用胺碘酮联合β受体阻滞剂治疗的疗效及心功能变化。方法将我院收治的118例急性心肌梗死并发快速心律失常患者采用随机数字表法进行分组,对照组59例采用胺碘酮治疗,观察组59例在对照组的基础上加用β受体阻滞剂口服,比较两组临床疗效及心功能改善情况。结果观察组总有效率为91.53%,明显高于对照组的76.27%(P0.05);LVEF水平提高幅度,HR、LVEDD及LVESD水平降低幅度均优于对照组(P0.05)。结论胺碘酮联合β受体阻滞剂能有效改善急性心肌梗死并发快速心律失常患者的心功能情况,提高临床疗效。     

Calcium-Activated Potassium Current Modulates Ventricular Repolarization in Chronic Heart Failure

The role of I_KCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I_KCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I_KCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I_KCa blockade in all of the groups studied. I_KCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I_KCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I_KCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I_KCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.     

上胸段硬膜外阻滞治疗慢性心力衰竭合并房颤的临床研究

目的:比较上胸段硬膜外阻滞对有无合并房颤的扩张型心肌病心衰患者的疗效差异。方法:入选40例扩张型心肌病心衰患者,根据入院心电图有无房颤分为房颤组和非房颤组。所有患者均在抗心力衰竭常规治疗基础上,给予胸段硬膜外阻滞治疗4周,比较治疗前、后NYHA心功能分级、血浆N末端脑钠肽前体(NT-pro BNP)水平、左室射血分数(LVEF)、左室舒张期内径(LVEDD)及左房前后径(LAD)的变化情况。结果:与治疗前比较,两组患者经治疗后的NYHA心功能分级、NT-pro BNP、LVEF、LVEDD及LAD均明显改善(均P0.05),差异有统计学意义,但两组间各指标治疗前后的差值无统计学意义(P0.05)。结论:对于慢性心力衰竭合并房颤的患者而言,给予抗心力衰竭常规治疗基础上联合上胸段硬膜外阻滞治疗有效,且房颤的存在与否不影响上胸段硬膜外阻滞的疗效。     

Vascular Disease and Risk Stratification for Ischemic Stroke and All-Cause Death in Heart Failure Patients without Diagnosed Atrial Fibrillation: A Nationwide Cohort Study

Background

Stroke and mortality risk among heart failure patients previously diagnosed with different manifestations of vascular disease is poorly described. We conducted an observational study to evaluate the stroke and mortality risk among heart failure patients without diagnosed atrial fibrillation and with peripheral artery disease (PAD) or prior myocardial infarction (MI).

Methods

Population-based cohort study of patients diagnosed with incident heart failure during 2000–2012 and without atrial fibrillation, identified by record linkage between nationwide registries in Denmark. Hazard rate ratios of ischemic stroke and all-cause death after 1 year of follow-up were used to compare patients with either: a PAD diagnosis; a prior MI diagnosis; or no vascular disease.

Results

39,357 heart failure patients were included. When compared to heart failure patients with no vascular disease, PAD was associated with a higher 1-year rate of ischemic stroke (adjusted hazard rate ratio [HR]: 1.34, 95% confidence interval [CI]: 1.08–1.65) and all-cause death (adjusted HR: 1.47, 95% CI: 1.35–1.59), whereas prior MI was not (adjusted HR: 1.00, 95% CI: 0.86–1.15 and 0.94, 95% CI: 0.89–1.00, for ischemic stroke and all-cause death, respectively). When comparing patients with PAD to patients with prior MI, PAD was associated with a higher rate of both outcomes.

Conclusions

Among incident heart failure patients without diagnosed atrial fibrillation, a previous diagnosis of PAD was associated with a significantly higher rate of the ischemic stroke and all-cause death compared to patients with no vascular disease or prior MI. Prevention strategies may be particularly relevant among HF patients with PAD.     

Clinical Characteristics,Management, and Control of Permanent vs. Nonpermanent Atrial Fibrillation: Insights from the RealiseAF Survey

Background

Atrial fibrillation can be categorized into nonpermanent and permanent atrial fibrillation. There is less information on permanent than on nonpermanent atrial fibrillation patients. This analysis aimed to describe the characteristics and current management, including the proportion of patients with successful atrial fibrillation control, of these atrial fibrillation subsets in a large, geographically diverse contemporary sample.

Methods and Results

Data from RealiseAF, an international, observational, cross-sectional survey of 10,491 patients with atrial fibrillation, were used to characterize permanent atrial fibrillation (N = 4869) and nonpermanent atrial fibrillation (N = 5622) patients. Permanent atrial fibrillation patients were older, had a longer time since atrial fibrillation diagnosis, a higher symptom burden, and were more likely to be physically inactive. They also had a higher mean (SD) CHADS₂ score (2.2 [1.3] vs. 1.7 [1.3], p<0.001), and a higher frequency of CHADS₂ score ≥2 (67.3% vs. 53.0%, p<0.001) and comorbidities, most notably heart failure. Physicians indicated using a rate-control strategy in 84.2% of permanent atrial fibrillation patients (vs. 27.5% in nonpermanent atrial fibrillation). Only 50.2% (N = 2262/4508) of permanent atrial fibrillation patients were controlled. These patients had a longer time since atrial fibrillation diagnosis, a lower symptom burden, less obesity and physical inactivity, less severe heart failure, and fewer hospitalizations for acute heart failure than uncontrolled permanent atrial fibrillation patients, but with more arrhythmic events. The most frequent causes of hospitalization in the last 12 months were acute heart failure and stroke.

Conclusion

Permanent atrial fibrillation is a high-risk subset of atrial fibrillation, representing half of all atrial fibrillation patients, yet rate control is only achieved in around half. Since control is associated with lower symptom burden and heart failure, adequate rate control is an important target for improving the management of permanent atrial fibrillation patients.     

心力衰竭合并房颤患者血浆脑钠肽水平及相关因素分析

目的:探讨心力衰竭合并房颤患者血浆脑钠肽水平变化及相关因素,为心血管疾病的临床诊断提供理论依据。方法:选取我院2011年1月-2013年1月收治的心力衰竭患者94例,分为窦性心律组和心房颤动组。分别抽取两组患者的血液样本并检测血浆中的BNP浓度,比较不同NYHA分级患者血浆内的脑钠肽水平的变化情况,记录左心房和左心室舒张末内径及房颤持续时间等。结果:心力衰竭合并心房颤动组与窦性心律组血浆BNP水平比较,心房颤动组高于窦性心律组;差异有统计学意义(P0.05);两组NYHA不同分级相互比较,Ⅱ级、Ⅲ级和Ⅳ级间的BNP水平,心房颤动组BNP水平均高于窦性心律组;差异显著具有统计学意义(P0.05);血浆BNP水平与患者年龄、左心房大小、左心室大小、房颤持续时间因素呈正相关(r分别为0.0.801,0.748,0.854和0.703,P0.05),与左心室射血分数呈负相关(r=-0.41,P0.05)。结论:BNP血浆浓度与心功能状态密切相关,BNP浓度的检测有助于临床心血管疾病的诊断。     

慢性心力衰竭合并心房颤动发病的相关机制研究

目的:慢性心力衰竭(Chronic Heart Failure,CHF)是心血管系统常见的疾病,威胁患者的生存周期及生活质量。本研究针对慢性心力衰竭合并房颤的临床特征,进一步探讨其发病机制,为临床治疗提供依据。方法:将80例慢性心力衰竭患者平均分为两组,心律正常的为窦性心律组,伴有心房颤动的作为房颤组。观察并比较两组的左心室射血分数(LVEF)和二尖瓣口舒张期流速(E/A)等心脏功能指标。结果:房颤组左心室射血分数(LVEF)为(0.42±0.08);二尖瓣口舒张期流速(E/A)为(0.65±0.22);左心房内径(LAD)为(53.4±8.2)mm。窦律组左心室射血分数(LVEF)为(0.45±0.09);二尖瓣口舒张期流速(E/A)为(0.72±0.17);左心房内径(LAD)为(46.7±7.9)mm。房颤组患者的LVEF和E/A值均低于窦律组,而LAD则明显高于窦律组,差异具有统计学意义(P0.05)。房颤组醛固酮、血管紧张素(AngII)、脑钠肽(BNP)及超敏C反应蛋白(hs-CRP)均高于窦律组,差异具有统计学意义(P0.05)。结论:慢性心力衰竭合并房颤的发病与患者体内神经内分泌体液系统水平和心脏结构功能有关,具体发病机制需进一步深入研究。     

丁基苯酞对心力衰竭大鼠心房颤动的影响及作用机制

为探讨丁基苯酞(DL-3-N-butylphthalide,NBP)对心肌梗死诱导的心力衰竭(heart failure,HF)大鼠心房结构重塑和心房颤动形成的影响,本研究将心力衰竭模型大鼠随机分为丁基苯酞组(NBP)、模型组(Model)和假手术组(Sham)。将丁基苯酞用大豆油溶解,制成10 mg/mL的丁基苯酞溶液。丁基苯酞组按照80 mg/kg体重对SD大鼠进行灌胃,模型组和假手术组用等量的大豆油灌胃。假手术组大鼠接受相同手术但未结扎左前降支冠状动脉。分别检测大鼠的超声心动图、心房颤动诱导性试验及心房纤维化,并检测TNF-α、TGF-β1、NF-κB、Nrf2和HO-1的蛋白表达。研究显示,应用丁基苯酞治疗4周后,NBP组大鼠心功能显著改善(p<0.05);NBP组大鼠心房颤动诱导能力和持续时间显著降低(p<0.05);NBP组大鼠心房纤维化程度显著减轻(p<0.05)。丁基苯酞显著抑制TNF-α,NF-κB和TGF-β1的蛋白表达,并上调Nrf2和HO-1的蛋白表达。并且,NBP对TNF-α/NF-κB/TGF-β1和纤维化的抑制作用可能与Nrf2/HO-1信号通路的激活有关。因此,丁基苯酞有望成为预防房颤的上游治疗中的有效药物。     

Deleterious cardiovascular effect of exosome in digitalis‐treated decompensated congestive heart failure

Heart failure (HF) is a medical condition inability of the heart to pump sufficient blood to meet the metabolic demand of the body to take place. The number of hospitalized patients with cardiovascular diseases is estimated to be more than 1 million each year, of which 80% to 90% of patients ultimately progress to decompensated HF. Digitalis glycosides exert modest inotropic actions when administered to patients with decompensated HF. Although its efficacy in patients with HF and atrial fibrillation is clear, its value in patients with HF and sinus rhythm has often been questioned. A series of recent studies have cast serious doubt on the benefit of digoxin when added to contemporary HF treatment. We are hypothesizing the role and mechanism of exosome and its biological constituents responsible for worsening the disease state and mortality in decompensated HF patients on digitalis.     

慢性心力衰竭合并心房颤动发病的相关机制研究

目的：慢性心力衰竭（Chronic Heart Failure,CHF）是心血管系统常见的疾病,威胁患者的生存周期及生活质量。本研究针对慢性心力衰竭合并房颤的临床特征,进一步探讨其发病机制,为临床治疗提供依据。方法：将80例慢性心力衰竭患者平均分为两组,心律正常的为窦性心律组,伴有心房颤动的作为房颤组。观察并比较两组的左心室射血分数（LVEF）和二尖瓣1：7舒张期流速（E／A）等心脏功能指标。结果：房颤组左心室射血分数（LVEF）为（0．42±0．08）;二尖瓣口舒张期流速（E／A）为（0．65±0．22）;左心房内径（LAD）为（53．4±8．2）min。窦律组左心室射血分数（LVEF）为（0．45±0．09）;二尖瓣口舒张期流速（E／A）为（0．72±0．17）;左心房内径（LAD）为（46．7±7．9）min。房颤组患者的LVEF和E／A值均低于窦律组,而LAD则明显高于窦律组,差异具有统计学意义（P〈0．05）。房颤组醛固酮、血管紧张素（AngII）、脑钠）]k（BNP）TZ超敏c反应蛋白（hs-CRP）均高于窦律组,差异具有统计学意义（P〈0．05）。结论：慢性心力衰竭合并房颤的发病与患者体内神经内分泌体液系统水平和心脏结构功能有关,具体发病机制需进一步深入研究。