低剂量培哚普利和厄贝沙坦联合治疗扩张型心肌病

扩张型心肌病(dilated cardiomyopathy,DCM)主要表现为慢性心力衰竭,因病因未明,尚无特殊的治疗方法,预后很差。坎地沙坦降低心力衰竭病死率和发病率评估中的CHARM-Added研究[1]报道将血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitors,ACEIs)和血管紧张素Ⅱ1型受体阻滞剂(angiotensin II type 1 receptorblockers,ARBs)联合治疗慢性心力衰竭,与单用ACEIs比较,可以更好改善心功能及预后,但代价是患者血肌酐水平明显增高,高钾血症发生率增加以及耐受性下降、终止治疗的患者增多。原因可能是因为联合大剂量的ACEIs…     

血管紧张素转换酶抑制剂联合血管紧张素Ⅱ受体阻滞剂治疗慢性心力衰竭的研究进展

慢性心力衰竭(chronic heart failure,CHF)是一复杂的临床综合征,由任何可以引起心室充盈和射血障碍的结构性或功能性心脏疾病所导致。其主要表现是呼吸困难和乏力,从而限制运动耐量;而体液潴留则导致肺淤血及外周水肿[1]。CHF在各国均是一个严重的公共卫生问题,有必要对CHF的发病机制及治疗措施进行广泛深入的研究。心脏重塑既是心力衰竭时心脏代偿的机制,也是进一步加重心力衰竭的过程。尽管有几个因素可以加速左心室重塑的过程,其中又以肾素-血管紧张素系统(renin-angiotensin system,RAS)的病理生理改变与心脏重塑的关系最为密切。…     

联用血管紧张素Ⅱ受体拮抗剂和β受体阻滞剂对扩张型心肌病的影响

为观察联用血管紧张素Ⅱ受体拮抗剂和β受体阻滞剂对扩张型心肌病的心脏结构及心功能的影响,本院及北京阜外心血管病医院采用以上两药治疗扩张型心肌病80例,总结如下: 1 资料与方法 1.1 观察对象:系我院5年中及北京阜外心血管病医院3年中收治的符合诊断标准的扩张型心肌病80例(男51例,女29例),年龄18～76岁(平均42±9.8岁)入选时心功能按NYHA分级标准为Ⅰ级31例,Ⅱ级33例,Ⅲ级16例。     

依那普利联合厄贝沙坦治疗扩张型心肌病的疗效观察——附38例报告

目的:观察依那普利联合小剂量厄贝沙坦治疗扩张型心肌病(dilated cardiomyopathy,DCM)的疗效.方法:78例DCM患者,随机分为对照组(40例)和观察组(38例),对照组予依那普利,观察组予依那普利联合小剂量厄贝沙坦治疗.观察并比较如下指标:治疗前1日、治疗12周及20周后2组患者血清血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)、醛固酮水平;治疗前1日及治疗20周后UCG检查指标、血压变化、6 min步行试验结果.结果:对照组治疗后12周血清AngⅡ、醛固酮水平均较治疗前降低,但20周后明显升高(P＜0.05);观察组治疗12周后及20周后AngⅡ、醛固酮水平下降(P＜0.05),与对照组治疗20周后比较,观察组AngⅡ及醛固酮水平较低(P＜0.05～0.01).治疗20周后,2组的左心室舒张末期内径和左心室收缩末期内径均下降,观察组治疗20周后与治疗前比较,LVEF显著提高(P＜0.05);2组治疗后血压明显下降(P＜0.05).治疗20周后2组的6 min步行距离均提高,观察组提高更明显(均为P＜0.05～0.01).结论:依那普利联合小剂量厄贝沙坦治疗能有效抑制"醛固酮逃逸"现象,改善DCM心衰患者的左心室收缩功能,提高患者的活动耐力.     

厄贝沙坦与贝那普利治疗高血压非糖尿病肾病临床观察

慢性肾病常常伴有高血压,有较高发病率和病死率.2006年1月～2008年12月期间本院分别使用用厄贝沙坦和贝那普利治疗高血压慢性肾病,发现两者降压效果相当,均能较大程度降低非糖尿病肾病患者的蛋白尿,不增加血钾水平,同时显著降低血尿酸水平.现报告如下.     

培哚普利联合厄贝沙坦对扩张型心肌病大鼠心功能及心肌NF-kB活性的影响

[目的]观察培哚普利联合厄贝沙坦对扩张型心肌病(DCM)大鼠的心功能及心肌核因子-kB(NF-κB)活性的影响.[方法]通过腹腔注射阿霉素建立大鼠DCM模型.13周后,大鼠分为4组:A组为正常大鼠;B、C、D组均为DCM大鼠.A、B组不予药物干预,C组予以培哚普利,D组予以培哚普利联合厄贝沙坦.超声心动图测定左室射血分数(LVEF),ELISA方法检测血浆脑利钠肽(BNP)水平,免疫组化方法检测心肌NF-κB的活化.[结果]药物治疗3周后,与C组比较:①D组LVEF更明显升高(P＜0.01);②D组BNP水平更明显下降(P＜0.01);③D组NF-κB活性更明显减弱(P＜0.01);④BNP水平、NF-κB活性均与LVEF呈负相关(r=-0.85,P＜0.01;r=-0.80,P＜0.01),NF-κB活性与BNP水平呈正相关(r=0.90,P＜0.01).[结论]心肌NF-κB的过度活化,损害了心功能.培哚普利联合厄贝沙坦治疗DCM大鼠,较单用培哚普利更明显改善心功能,机制可能为更明显降低心肌NF-κB活性.     

血管紧张素Ⅱ受体1和受体2在小鼠肾脏输尿管芽中的表达

目的:探讨血管紧张素Ⅱ受体1和受体2在小鼠肾脏发育早期输尿管芽的表达及其与肾脏发育的关系。方法:实验于2005-05/2006-05在锦州医学院组织与胚胎学教研室完成。①取成年健康昆明系小白鼠24只,体质量25～30g,雌、雄(1∶1)同窝饲养,见雌鼠阴道栓出现计为胚龄0d。取胚龄12,14,15,16日胎鼠,各龄小鼠每组4只。剖腹取出肾脏,40g/L甲醛固定,制成切片5μm。②常规苏木精-伊红染色光镜下观察小鼠肾组织发育早期形态学变化。③采用免疫组织化学方法检测胚龄12,14,15,16d小鼠肾脏发育早期输尿管芽分支中血管紧张素Ⅱ受体1和受体2的含量。④体视学测量:每个动物的肾脏系统随机选取5张切片,按“S”形等间隔选取视野,采用方格测试系统,交点计数法测算血管紧张素Ⅱ受体1和受体2在输尿管芽阳性表达的体积密度。结果:①小鼠肾组织发育早期形态学观察:胚龄12d小鼠肾脏中可见输尿管芽及其分支。胚龄15d,输尿管芽周围出现了逗号小体、S小体,但未见成熟肾小体。胚龄16d的肾脏中可见出现了成熟肾小体、近曲小管和远曲小管。②小鼠肾脏组织免疫组织化学染色结果:在胚龄12d,血管紧张素Ⅱ受体1和受体2在输尿管芽中均有少量表达,胚龄15d,血管紧张素Ⅱ受体1达到高峰,胚龄16d血管紧张素Ⅱ受体1仅有微量表达;胚龄14d,血管紧张素Ⅱ受体2达到高峰,以后逐渐降低。结论:输尿管芽在小鼠后肾发生中有血管紧张素Ⅱ受体1和血管紧张素Ⅱ受体2表达,且血管紧张素Ⅱ受体1与诱导输尿管芽分支不断延长有关。     

厄贝沙坦联合螺内酯治疗围生期心肌病临床研究

目的探讨厄贝沙坦联合螺内酯治疗围生期心肌病的治疗效果。方法40例经常规洋地黄、利尿剂、血管扩张药等治疗效果欠佳的围生期心肌病患者,给予口服厄贝沙坦75～225mg/d,螺内酯40mg/d,治疗4周后观察治疗前后心率、血压、心胸比、左室射血分数、左室舒张未期内径以及心功能的变化。结果治疗后心率、血压、心胸比以及左室舒张未期内径均明显下降（P〈0.05）,左室射血分数增加（P〈0.01）,心功能改善1～2级,药物不良反应少,患者耐受性好。结论厄贝沙坦联合螺内酯治疗围生期心肌病疗效好,不良反应少,值得临床推广。     

联合应用血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体拮抗剂对糖尿病肾病患者肾保护作用的临床研究

最新的研究表明,血管紧张素转换酶抑制剂(ACEI)和血管紧张素Ⅱ受体拮抗剂(ARB)均有肯定的肾脏保护作用,并且两药联合应用可相互补充,降低尿蛋白作用优于单用任何一种药物。糖尿病肾病是糖尿病最常见的慢性微血管并发症之一,也是糖尿病患者终末期的主要死因之一。在我国96%以上的糖尿病患者为2型糖尿病,发病后约经10～20年发展为糖尿病肾病,一旦发生糖尿病肾病,其进展至终末期肾功能衰竭的速度比一般肾脏疾病快14倍之多。因此预防和延缓糖尿病肾病发展可提高糖尿病患者的生活质量和生存率,减轻乃至消除蛋白尿是临床治疗的重点所在[1]。1资…     

运动联合培哚普利对自发性高血压大鼠大动脉顺应性的影响

目的:探讨运动训练联合血管紧张素转换酶抑制剂(培哚普利)对自发性高血压大鼠(SHR)高血压和大动脉硬化的影响,确定运动对于被降压药物调整为正常血压水平的高血压症的大动脉顺应性的影响.方法:7周龄SHR分为对照组,运动组,培哚普利投药组,培哚普利与运动并用组,观察8周,每周1次用tail-cuff方法测定大鼠的血压.15周龄时,用主动脉脉搏波传播速度来评估大动脉顺应性.结果:培哚普利完全抑制了血压的上升,运动也起到了一定的降压效果.同时培哚普利可以抑制大动脉顺应性的低下.单独运动对于大动脉顺应性的低下并没有起到抑制效果,而且在培哚普利投药的基础上加上运动也没有达到抑制的效果.结论:对于高血压进展期SHR,运动有一定的降压效果,但对于被培哚普利调整为正常血压水平的SHR的大动脉顺应性没有效果.     

呋喃唑酮诱发SD大鼠扩张型心肌病病理及神经内分泌研究

目的：建立一个可靠的、在病理及神经内分泌变化接近于人类扩张型心肌病的动物模型。方法：选择43只2周龄SD大鼠喂饲呋喃唑酮8周；检测体重、心脏重量、体表心电图、超声心动图、组织病理及心血管活性肽。结果：呋喃唑酮组体重减少，而心脏重量增加；心电图表现为QRS时限与Q—T间期延长；心脏超声示LVEDD、LVESD增大，而LVEF减小；组织病理示心脏重量增加，光镜与电镜下表现为典型的扩张型心肌病的病理变化；血浆心血管活性肽：血浆中ANP、AngⅡ、ET和TXB2增高，而PGF1α与血浆PGF1α／TXB2明显降低。结论：呋喃唑酮诱发SD大鼠扩张型心肌病动物模型不仅在活体形态学、组织病理而且在神经内分泌方面也与人类相符。     

159例扩张型心肌病心律失常分析

扩张型心肌病（DCM）心律失常的临床报告日见增多,本文通过对159例扩张型心肌病心律失常的发生率、种类以及与心功能、预后的关系进行分析,发现心律失常发生率高,且多样易变为其特点,异位心律和异位搏动是DCM主要的心律失常,异位心律的心功能和预后密切相关。     

Echocardiographic Strain Analysis for the Early Detection of Myocardial Structural Abnormality and Initiation of Drug Therapy in a Mouse Model of Dilated Cardiomyopathy

This study aimed to evaluate the role of echocardiography-based strain analysis in the early diagnosis and guidance for management of dilated cardiomyopathy (DCM). Muscular dystrophy mice (which spontaneously develop DCM) and control (C57 BL/6 J) mice were sequentially evaluated by ultrasound biomicroscopy, conventional left ventricle (LV) measurement, two-dimensional (2-D) strain analysis and myocardial histologic analysis for 12 consecutive months. Significant alternation of LV remodeling and dysfunction could be detected by conventional echocardiography after 9 mo, by strain analysis after 5 mo and by histologic analysis after 4 mo. The global longitudinal systolic peak strain (PK) was the most sensitive strain marker for early detection of myocardial structural abnormality in the subclinical stage. Moreover, losartan administration before the PK decrease was associated with significantly preserved LV function. These results suggest that myocardial strain analysis (particularly longitudinal PK) is sensitive for the early detection of LV dysfunction in mice with dilated cardiomyopathy.     

Myoblasts and Embryonic Stem Cells Differentially Engraft in a Mouse Model of Genetic Dilated Cardiomyopathy

The functional and architectural benefits of embryonic stem cells (ESC) and myoblasts (Mb) transplantations into infarcted myocardium have been investigated extensively. Whereas ESC repopulated fibrotic areas and contributed to myocardial regeneration, Mb exerted their effects through paracrine secretions and scar remodeling. This therapeutic perspective, however, has been less explored in the setting of nonischemic dilated cardiomyopathies (DCMs). Our aim was to compare the integration and functional efficacy of ESC committed to cardiac fate by bone morphogenic protein 2 (BMP-2) pretreatment and Mb used as gold standard following their transplantation into the myocardium of a mouse model of laminopathy exhibiting a progressive and lethal DCM. After 4 and 8 weeks of transplantation, stabilization was observed in Mb-transplanted mice (P = 0.008) but not in groups of ESC-transplanted or medium-injected animals, where the left ventricular fractional shortening (LVFS) decreased by 32 ± 8% and 41 ± 8% respectively. Engrafted differentiated cells were consistently detected in myocardia of mice receiving Mb, whereas few or no cells were detected in the hearts of mice receiving ESC, except in two cases where teratomas were formed. These data suggest that committed ESC fail to integrate in DCM where scar tissue is absent to provide the appropriate niche, whereas the functional benefits of Mb transplantation might extend to nonischemic cardiomyopathy.Cell therapies are progressively emerging as promising tools for the treatment of heart failure. In an attempt to achieve cardiac cell-based replacement therapy in the setting of postischemic cardiomyopathies (ICM), a variety of adult cell types have been tested up to preclinical stages in small and large animal models, including skeletal myoblasts (Mb), muscle-derived stem cells, adipose-derived stem cells, bone marrow mononuclear cells, hematopoietic stem cells, circulating endothelial progenitors, mesenchymal stem cells, smooth muscle cells, cardiac stem cells, and most of these approaches have demonstrated some degree of efficacy.^{1,2,3,4,5,6,7} Except for some specific populations of cardiac stem cells, most categories of adult stem cells show partial or complete inability to produce bona fide cardiomyocytes and to participate to true myocardial tissue formation, with respect to homogeneity of electrical conduction.⁸ Their functional benefits would be linked, essentially, to the mechanical strengthening of the scar tissue, and/or to the promotion of myocardial cell survival through paracrine synthesis of trophic factors and/or improved local angiogenesis.^{1,4,7,8,9,10,11} Indeed, phase II randomized clinical trials developed using adult stem cells have provided encouraging but still limited results.^12,13 However, the applicability and therapeutic relevance of cell therapies remain under-explored for nonischemic heart failure (dilated cardiomyopathy (DCM), myocarditis), probably due to the progressive nature of the disease and extension of fibrotic remodeling, which make the targeting of a specific area more difficult than when considering a delineated scar formed upon myocardial infarction. A few preclinical studies have been carried out using Mb,^14,15 smooth muscle cells or ventricular heart cells¹⁶ in cardiomyopathic hamsters, or mesenchymal stem cells,¹⁷ mixed mesenchymal stem cells and Mb,¹⁸ or bone marrow cells in rat models of DCM.¹⁹ Among those studies, Mb seem to have the best potential of integration in the dilated myocardium, and represent a “gold standard” for cell-based therapy, although these cells are not able to differentiate into cardiomyocyte lineage.In contrast, embryonic stem cells (ESC) are pluripotent and can be readily committed towards the cardiogenic lineage in vitro. There is also increasing evidence that cardiac-committed ESC can engraft into the scar tissue within the infarcted myocardium and differentiate into cardiomyocytes, thereby operating a regeneration of the myocardium, eliminating fibrotic scar tissue, and promoting sustained improvement of left ventricular function.^{7,8,11,20,21,22,23,24,25,26} This confers the potential ability to rebuild true cardiac tissue, to replenish areas that have been depopulated following ischemic accidents or the progression of fibrosis.⁸ In contrast, this positive benefit is limited by the formation of teratomas²⁷ or if too many cells are in uncommitted state at the time of injection.²⁴In the present study, we have compared the integration and functional efficacy of the CGR8 line of murine ESC with the D7LNB1 line of murine Mb, in the myocardium of Lmna^H222P/H222P mice. This genetic model of laminopathy reproduces a human missense mutation in the Lamin A/C gene causing Emery-Dreifuss muscular dystrophy. This model exhibits a rapidly progressive and lethal DCM,²⁸ showing pathophysiological evolution and conduction defects comparable to the human situation. Of note, these animals are immunocompetent.The CGR8 cell line of ESC was chosen because it can be grown feeder-free, and it is efficiently committed toward cardiogenic differentiation in vitro upon treatment with bone morphogenic protein 2 (BMP-2),^23,24,29,30 a treatment that indirectly lowers the risk of teratoma formation in vivo by decreasing the proportion of pluripotent cells.^24,27 The committed CGR8 cells, whether selected or not, have been previously shown to efficiently improve cardiac function following injection into the scar tissue in animal models of postischemic heart failure.^7,8,23,24,25 The time window for the addition of BMP-2 is of crucial importance,³⁰ therefore we pretreated CGR8 ESC for a short period of time, and we designed the experiments using limited amounts of cells to reach a compromise between myocardial differentiation and risk of teratoma formation (3 × 10⁵ per heart, at four different sites).The Mb have been assayed, in the present study, as a gold standard for validating the injection procedure, the efficacy of the immunosuppression regimen, the natural evolution of the implanted cells, the immunohistological procedures. Comparisons between Mb and ESC in murine models of postischemic heart failure have pinpointed important intrinsic differences in the efficacies and persistence of these two cell types, which now deserve a comparison in a DCM model.¹¹ The D7 Mb cell line was originally derived from the dy/dy mouse model of laminin-2 deficient congenital muscular dystrophy.³¹ It was engineered to express β-Galactosidase (β-Gal) constitutively and named D7LNB1. It showed no modification in its ability to form myotubes in vitro and in vivo. In addition, unlike C2 or G8 murine Mb, D7LNB1 Mb cell line did not produce carcinomas in vivo.³² CGR8 ESC and D7 Mb originate from close parental strains of 129 mice derived from the same animals in the 1970''s (129P/Ola background for ESC, 129/ReJ background for D7), and they share identical markers.³³ To avoid immune rejection triggered by murine ESC³⁴ or Mb³⁵ further expressing β-Gal in allogenic contexts, recipient mice were immunosuppressed using Tacrolimus.³⁶ We compared the engraftment of committed ESC and D7LNB1 Mb in terms of functional benefits and fate of engrafted cells in vivo. Our results suggest that cardiac-committed ESC failed to engraft into the dilated myocardium of the Lmna^H222P/H222P mice model, whereas Mb have a higher transplantation efficiency and greater functional improvement of cardiac function in this genetic model of dilated heart failure.     

扩张型心肌病患者两种治疗方法前后microRNA-126 和microRNA-30a 水平表达的研究

目的 探讨microRNA-126（miRNA-126） 和microRNA-30a(miRNA-30a) 检测在扩张型心肌病（dilatedcardiomyopathy,DCM）患者诊断及预后评估的价值。方法 收集2014.2 ～ 2019.3 期间40 例DCM 患者,按治疗方法分为手术治疗组20 例和一般治疗组20 例,同期健康体检者20 例为对照组,采用qRT-PCR 法?检测治疗前后患者血清中miRNA-126 和miRNA-30a 的相对含量,并进行统计学分析。结果 ① DCM 患者与对照组血清miRNA-126 相对表达量为[1.40(0.44,3.28) vs 1.15（0.44,2.25）],miRNA-30a 为[2.37(0.70,4.25) vs 1.05（0.48,2.20）],差异无统计学意义（Z=-0.557,-1.662,P ＞ 0.05）。②治疗后,一般治疗组miRNA-126 为 1.35(0.66,2.00),miRNA-30a 为1.2(0.77,4.55)。手术治疗组miRNA-126 为 0.16(0.10,0.26),miRNA-30a 为0.20(0.14,0.33), 手术治疗组治疗前后miRNA-126,miRNA-30a 表达量差异有统计学意义（均Z =-3.059,均P ＜ 0.05）。一般治疗及手术治疗两者表达量差异有统计学意义（miRNA-126:Z = -3.806,P ＜ 0.05;miRNA-30a:Z = -3.24,P ＜ 0.05）。③ miRNA-126 与NT-proBNP 呈负相关;循环miRNA-30a 与NT-proBNP 呈正相关,与射血分数呈负相关。④ miRNA-126 的12 个月相对危险度为 0.768（95%CI 0.431~1.37,P ＞ 0.05）,miRNA-30a 的12 个月生存分析其相对危险度为1.141（95% CI 0.775~1.678,P ＞ 0.05）。结论 miRNA-126 和miRNA-30a 可为两种不同治疗方法的评价提供一定的参考价值。     

牛磺酸对扩张型心肌病大鼠左心室肌转化生长因子β_1表达的影响

目的　探讨牛磺酸对转化生长因子 β1(TGF β1)在扩张型心肌病大鼠左心室肌表达的影响。方法　将 60只大鼠分为三组 ,即正常对照组 (N组 )、扩张型心肌病模型组 (D组 )和牛磺酸治疗组 (T组 ) ,每组 2 0只 ,N组按常规喂养 ,D组在饮水中加呋喃唑酮饲养 ,T组除加呋喃唑酮饲养外同时注射牛磺酸 ,饲养 4周和 8周后分两批超声心动图检测大鼠心功能 ,病理学测量大鼠左心室内径和左心室游离壁厚度 ,HE和VG染色分别观察大鼠心肌细胞和间质胶原纤维的变化 ,免疫组化检测左心室肌TGF β1表达水平。结果　D组大鼠左心室内径增大、游离壁变薄 ,左心室收缩功能下降 ;心肌细胞肥大、间质纤维明显增生 ;左心室肌组织TGF β1表达水平明显增高 ,而T组大鼠左心室结构和功能正常 ,TGF β1表达水平较D组大鼠明显降低。结论　牛磺酸能下调扩张型心肌病大鼠左心室肌TGF β1水平 ,抑制心肌间质纤维化     

扩张型心肌病的诊断和治疗进展

扩张型心肌病(DCM)是一类以心腔扩大、心功能障碍为主要特征的原因不明的心肌疾病,病毒感染、遗传变异、免疫应答和心肌细胞凋亡增加均在DCM的发病中发挥重要作用。DCM起病隐匿,临床表现为进行性心力衰竭、心律失常、血栓栓塞甚或猝死。随着对该病认识的提高和新的检测方法的不