Protective Effect of Bisoprolol on Beta-1 Adrenoceptor Peptide-Induced Autoimmune Myocardial Damage in Rabbits

Idiopathic dilated cardiomyopathy is a severe disease of unknown etiology. Accumulating evidence suggests that agonist-like autoantibodies against the beta 1 adrenoceptor in the circulation of dilated cardiomyopathy may play an important role. The aim of this study was to evaluate the effects of the selective beta 1-adrenoceptor blocker, bisoprolol, on beta 1-adrenoceptor peptide induced autoimmune myocardial damage. In the animal model of autoimmune cardiomyopathy induced by active immunization of rabbits with beta 1-adrenoceptor peptide, bisoprolol was given at a dose of 3 mg/day throughout the study period. Our results showed high titer of anti-beta 1-adrenoceptor antibody in the immunized group throughout the study but not in the group receiving only bisoprolol. Cross-reactivity to beta 2 adrenoceptors was observed in some of the immunized rabbits, but disappeared almost entirely after 6 months. As compared to the beta 1-adrenoceptor peptide immunized group without bisoprolol treatment, bisoprolol treated beta 1-receptor peptide immunized group showed increase in the wall thickness and decreases in cavity dimension in anatomical measurements and only mild alterations in macro- and microscopic examinations. Thus, our study clearly demonstrated a beneficial effect of bisoprolol in rabbits who have developed autoimmune myocardial damage.     

Active immunization of combined beta1-adrenoceptor and M2-muscarinic receptor peptides induces cardiac hypertrophy in rabbits.

BACKGROUND: The high prevalence of patients with dilated cardiomyopathy (DCM) with anti-beta1-adrenoceptor and/or anti-M2-muscarinic receptor autoantibodies in their sera has been observed. However, the pathophysiological role of these autoantibodies in the development of cardiomyopathy is unknown. We previously reported an experimental model of early-stage DCM-like cardiomyopathy induced by immunizing rabbits for 1 year with synthetic peptides corresponding to the sequence of the second extracellular loop of either beta1-adrenoceptor or M2-muscarinic receptor. Because approximately half the sera of patients with DCM that recognize one of the two receptor sequences also recognize the second sequence, a model was created in rabbits simultaneously immunized with the synthetic peptides corresponding to the second extracellular loop of the beta1-adrenoceptor and M2-muscarinic receptor. METHODS AND RESULTS: All rabbits (n = 8) immunized with both peptides had a high titer of both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies in their sera, whereas none of the sera from control rabbits injected with saline (n = 9) was positive. No significant cross-reaction with peptides other than those used for immunization was found. The weight of the hearts of immunized rabbits increased significantly. The hearts of immunized rabbits showed marked concentric left ventricular hypertrophy with mild inflammatory cell infiltration. In these rabbits, mild or moderate interstitial fibrosis was also observed. In electron micrographs, immunized rabbits showed focal myofibrillar lysis, loss of myofilament, and a marked increase in the number of mitochondria and deposition of dense granules in both sarcoplasm and myofibrils. Conversely, one of the control rabbits showed scant mononuclear cell infiltration. However, in this control rabbit, no significant alteration was found by electron microscopy. CONCLUSION: Our results showed the coexistence of both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies in the sera has pathophysiological importance, shown by their ability to induce cardiac hypertrophy in rabbits.     

Effects of autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy on neonatal rat cardiomyocytes

INTRODUCTION: Immunoadsorption has been shown to improve cardiac performance and reduce mortality in patients with dilated cardiomyopathy. In this study, the underlying mechanism for these beneficial effects was investigated in cultured rat cardiomyocytes. METHODS AND RESULTS: Immunoadsorption was performed in patients with dilated cardiomyopathy (n=7). Antibody-induced complement-dependent cytotoxicity was investigated by colorimetric MTT. Autoantibodies against the beta(1)-adrenoceptor were detected by ELISA and purified. Column eluent from six patients exhibited a cytotoxic effect, three patients were positive for the beta(1)-adrenoceptor autoantibodies. The purified autoantibodies were able to visualize the beta(1)-adrenoceptors by immunocytofluorescence on rat cardiomyocytes, and also displayed partial agonist properties and induced a positive chronotropic effect, which were blocked by the beta(1)-selective antagonist bisoprolol and the peptide corresponding to the beta(1)-adrenoceptor. Column eluent from one patient induced apoptosis in nick end labelling test (8.1+/-1.7% vs. 2.9+/-1.2% in control, p<0.05). CONCLUSION: Autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy have a pathophysiological role, as shown by the complement-dependent cytotoxicity and chronotropic action on rat cardiomyocytes. This implies that removal of circulating autoantibodies might be part of the underlying mechanism for improved cardiac function.     

Antigen-specific effects of autoantibodies against sarcolemmal Na-K-ATPase pump in immunized cardiomyopathic rabbits

OBJECTIVES: We examine antigen-specific actions of autoantibodies directed against sarcolemmal Na-K-ATPase. BACKGROUND: Autoantibodies against some receptors or pumps were detected in patients with dilated cardiomyopathy. Although immunoglobulin adsorption therapy improved cardiac function in such patients, direct pathogenic effects of autoantibodies remain to be proven. METHODS: Japanese white rabbits were immunized once a month with purified Na-K-ATPase (NKA rabbits, n=10) or a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta rabbits, n=10), respectively. Control rabbits (n=10) received vehicle in the same manner. RESULTS: At 6 months, cardiac hypertrophy along with increased left ventricular end-diastolic pressure was observed in both NKA and beta rabbits, and inhibitory G protein level increased in both NKA and beta rabbits. Histological findings showed similar myocyte hypertrophy and interstitial fibrosis in both rabbits. Enzymatic activities of Na-K-ATPase were lower in NKA rabbits than in other groups. Immunoblotting showed that alpha3-isoform of Na-K-ATPase was selectively reduced in myocardium from NKA rabbits. CONCLUSIONS: Our present findings suggested that isoform-specific alterations of myocardial Na-K-ATPase activity were induced by immunizing rabbits. This was not secondary change due to cardiac hypertrophy. Thus, autoantibodies against sarcolemmal Na-K-ATPase have antigen-specific effect on the heart in vivo.     

钙网蛋白及基质金属蛋白酶在扩张型心肌病发病机制中的作用

目的 探讨扩张型心肌病与钙网蛋白（Calreticulin）、基质金属蛋白酶（MMPs）家族成员MMP-2和MMP-9之间的关系,为扩张型心肌病的预防和治疗提供理论论据.方法 试验分两组：扩张型心肌病组和对照组.分别收集14例扩张型心肌病患者及14例对照组全血及临床资料（年龄,性别,左房、右房、左室、右室舒张末期内径及左室射血分数等）,提取血浆,通过蛋白免疫印迹法（western blotting）测定血浆钙网蛋白的表达水平,通过明胶酶谱法（Gelatin-PAGE）检测各标本血浆中MMP-2和MMP-9活性.结果 ①扩张型心肌病组与对照组比较,两组间左房、左室舒张末期内径、左室射血分数和MMP-9活性的差异有统计学意义.②在扩张型心肌病组中,MMP-9活性与左室射血分数呈负相关（r＝-0.590,P＜0.05）,与左室舒张末径呈正相关（非正态分布等级相关：r＝0.396,P＜0.05）,但与左房、右房、右室舒张末径和室间隔厚度均无相关关系.对照组中,MMP-9与左房、右房、左室、右室舒张末径和室间隔厚度均无相关关系.③两组比较,MMP-2活性差异无统计学意义,与左房、右房、左室、右室舒张末径,左室射血分数和室间隔厚度之间均无相关关系.④钙网蛋白在扩张型心肌病组的表达升高,但与对照组相比,两者间的表达水平差异无统计学意义（P＞0.05）.结论 ①MMP-9在扩张型心肌病患者左室重构中起重要作用,MMP-9的活性可作为评估心功能情况的参考指标之一.②钙网蛋白在扩张型心肌病病理过程中未直接参与其疾病发展,但未排除通过其他途径作用于该病理过程.     

Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies

OBJECTIVES: Our study attempted to gain further understanding of the allosteric effects of human autoantibodies on beta1-adrenergic receptor (beta1-AR) function. BACKGROUND: Recently, we reported on the existence of activating anti-beta1-AR antibodies in patients with dilated cardiomyopathy (DCM 26% prevalence) or ischemic cardiomyopathy (ICM, 10% prevalence); however, their functional effects have not yet been thoroughly characterized. METHODS: In this study we detected functionally active receptor-antibodies in 8 out of 30 DCM patients. Their immunological and functional properties were analyzed using both synthetic receptor-peptides and intact recombinant human beta1-AR, and were compared with those of heterologous antibodies to selected beta1-AR domains generated in rabbits and mice. RESULTS: Rabbit, mouse, and human anti-beta1-AR against the second extracellular domain preferentially bound to a native receptor conformation and impaired radioligand binding to the receptor. However, their functional effects differed considerably: Rabbit and mouse antibodies decreased both basal and agonist-stimulated cAMP production, whereas the patient antibodies (n = 8) increased basal, and six of them also increased agonist-stimulated receptor activity (i.e., acted as receptor-sensitizing agents). Two out of eight human anti-beta1-AR increased basal but decreased agonist-stimulated receptor activity (i.e., acted as partial agonists). CONCLUSIONS: Antibodies against the same small beta1-AR domain can have very divergent allosteric effects, ranging from inhibitory to agonist-promoting activities. Activating autoantibodies were associated with severe cardiac dysfunction and thus might be involved in the development and/or course of human cardiomyopathy.     

Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces beta-adrenergic receptor desensitization and myocardial hypertrophy in vivo

Although immunoapheresis removing autoantibodies against the second extracellular domain of beta(1)-adrenergic receptors (ARs) improves cardiac function in patients with cardiomyopathy, the underlying mechanisms have not been defined. We examined the role of autoimmunity against the domain in the development of cardiac dysfunction in vivo. Japanese white rabbits were immunized with a synthetic peptide corresponding to the second extracellular loop of beta(1)-AR once a month with (beta+biso rabbits, n=10) or without (beta rabbits, n=13) bisoprolol treatment (2 mg/kg per day). Control rabbits received vehicle without bisoprolol treatment (n=13). Autoantibodies of IgG isotype against the domain were persistently detected in beta and beta+biso rabbits. Purified IgG from sera of beta and beta+biso rabbits increased cAMP production in a rabbit cardiac membrane preparation, which was blocked by bisoprolol. At 3 months, beta-AR uncoupling with increased G protein-coupled receptor kinase 5 (GRK5) expression was found in beta rabbits. At 6 months, left ventricular hypertrophy was noted with hemodynamic derangements in beta rabbits. This was accompanied by decreased beta(1)-AR density and increased inhibitory G protein and GRK5 expression, which were related to marked decrease in membrane cAMP production. These changes in beta rabbits at 6 months were prevented in beta+biso rabbits. There was no difference in the plasma norepinephrine concentration in the 3 groups over the observation period. Thus, autoimmunity against the second extracellular loop of beta(1)-ARs induced profound beta-AR desensitization and myocardial hypertrophy in vivo, associated with cardiac dysfunction. Sustained sympathomimetic-like actions of autoantibodies against the domain may be partly responsible for these changes.     

Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy

OBJECTIVES: We sought to define the clinical and long-term prognostic implications of autoantibodies that act against the second extracellular loop of beta1-adrenergic receptors (ARs) in patients with idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Although autoantibodies directed against various domains of beta-ARs are found in patients with IDC, only a subgroup against the second extracellular domain of beta1-ARs exerts intrinsic sympathomimetic-like actions on human beta-ARs. It is suggested that the autoantibodies take part in the pathophysiology of IDC and may affect long-term prognosis of patients with this disorder. METHODS: Sera from 104 patients with IDC were screened for autoantibodies that act against the second extracellular loop of beta1-ARs by enzyme-linked immunosorbent assay, using a synthetic peptide corresponding to the domain. Relations of the autoantibodies to clinical variables and long-term prognosis were assessed by multivariate analysis. RESULTS: Autoantibodies were detected in 40 patients (38%). Multifocal ventricular premature contractions (p < 0.01) and ventricular tachycardia (VT; p < 0.01) were more common in autoantibody-positive than in autoantibody-negative patients, although no differences in cardiac function or neurohormonal levels were demonstrated. The presence of autoantibodies (p = 0.001) and a low left ventricular ejection fraction (LVEF <30%; p = 0.02) were independent predictors of VT. Sudden death was independently predicted by the presence of autoantibodies (p = 0.03), as well as by LVEF <30% (p = 0.01), whereas total mortality was predicted only by LVEF <30% (p = 0.001). CONCLUSIONS: Autoantibodies directed against the second extracellular loop of beta1-ARs were closely related to serious ventricular arrhythmias in patients with IDC, and the presence of autoantibodies independently predicted sudden death. These autoantibodies may contribute to electrical instability in patients with IDC.     

Autoantibodies against the Beta- and Muscarinic Receptors in Cardiomyopathy

The sera of patients with idiopathic dilated cardiomyopathy and the Chagas' disease contain agonist-like autoantibodies directed against the beta 1-adrenoceptor and/or the muscarinic M2-receptor. The anti-beta 1-adrenoceptor antibodies could be directed against amino acid sequences of the first or second extracellular loop. In patients with dilated cardiomyopathy the first as well as the second extracellular loop was identified as an antibody epitope. In Chagas' disease the anti-beta 1-adrenoceptor antibody recognizes only 1 epitope on the second extracellular loop. The anti-beta 1-adrenoceptor antibodies acting like the beta-adrenergic agonist isoprenaline and exert a positive chronotropic effect in cultured rat cardiomyocytes. In contrast to isoprenaline the antibody caused no downregulation of the beta-adrenergic signal transduction cascade within 6 hours. The anti-M2 receptor antibodies recognize in both diseases an epitope on the second extracellular loop. The anti-M2-receptor antibody exert a negative chronotropic response in cultured cardiomyocytes. This antibody induced no downregulation of the muscarinic M2-receptor. The negative chronotropic effect was unabated for 6 hours. Based on these findings it is believed that the agonist-like autoantibodies that act against the beta 1-adrenoceptor and the muscarinic M2-receptor may play a role in the pathogenesis of dilated cardiomyopathy and Chagas' disease.     

自体骨髓单个核细胞移植治疗扩张型心肌病的临床研究

目的研究自体骨髓单个核细胞(ABMMNCs)经冠状动脉(冠脉)移植对扩张型心肌病(DCM)患者心功能的影响及其安全性。方法16例扩张型心肌病患者,按患者的意愿分成两组移植组(n=10)在药物治疗的同时,通过冠脉转运将ABMMNCs移植入心肌组织内;对照组(n=6)只进行相关的药物治疗;两组在术前和术后6个月分别行超声心动图及动态心电图检查。结果超声心动图检查显示移植组的左心室射血分数(LVEF)较术前明显增高,左心室舒张末期内径(LVDd)、左心室收缩末期内径(LVSd)较术前明显降低,左心房内径(LAD)也较术前明显降低。而对照组的LVEF,LVDd及LVSd虽然较6个月前有所改善,但差异无统计学意义(P>0.05)。术中及术后随访6~12个月均无恶性心律失常和其他合并症发生。结论ABMMNCs经冠脉移植,可以治疗扩张型心肌病,改善心脏功能,而且较为安全。     

Autoantigen estimation and simple screening assay against cardiodepressant autoantibodies in patients with dilated cardiomyopathy

The objective of this study was to identify the cardiodepressant autoantibodies that could directly influence left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy (DCM), as well as to establish a simple screening method for these antibodies. Not only acute hemodynamic but also chronic prognosis improvements were reported with immunoadsorption in some patients with DCM. Various antibodies determined by immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (beta1-adrenergic [beta1-] receptors, muscarinic M2-acetylcholine [M2-] receptors, troponin I, or Na-K-ATPase) were measured in 104 patients with DCM. Cardiodepressant antibodies were also determined by ultrasonic echocardiography (UCG) of 18 day old chick embryos after adding the patients' purified immunoglobulin G, and the following clinical features were compared: age, gender, New York Heart Association class, LVEF, neurohumoral factors, arrhythmias, and other antibodies. We also checked the in vitro immunoadsorption effect against these cardiodepressant antibodies. Cardiodepressant antibodies were found in 63% of 104 patients with DCM and had no relation to other clinical parameters, except for some antibodies such as anti-beta1-receptor antibodies (81% vs. 52%, P < 0.01), anti-M2-receptor antibodies (83% vs. 48%, P < 0.01), or anti-Na-K-ATPase antibodies (85% vs. 55%, P < 0.01). However, cardiodepressant antibodies were similarly found in patients with and without antibodies against troponin I (56% vs. 64%). The LVEF of chick embryos measured by UCG in the presence of patient serum was improved after in vitro immunoadsorption. The ex vivo system using chick embryos was able to determine cardiodepressant antibodies. By multivariate analysis, antibodies against beta1- or M2-receptors was a predictor of these autoantibodies.     

卡维地洛对阿霉素心肌病兔氧化应激的影响

目的:研究卡维地洛对阿霉素心肌病兔氧化应激的影响,并探讨氧化应激与慢性心肌毒性之间的关系。方法:将40只日本长耳白兔随机分为对照组、阿霉素组、美托洛尔组和卡维地洛组,每组各10只。耳缘静脉注射阿霉素(每次1ml.kg-1,每周2次,共8周)建立阿霉素心肌病模型,对照组采用耳缘静脉注射0.9%氯化钠(每次1ml.kg-1,每周2次,共8周)。3周后,对照组和阿霉素组以0.9%氯化钠(5ml.kg-1.d-1)灌胃,美托洛尔组和卡维地洛组分别给予美托洛尔(5mg.kg-1.d-1)和卡维地洛(5mg.kg-1.d-1)灌胃。2个月后,超声心动图观察各组心脏结构变化,检测兔血清中丙二醛(MDA)、超氧化物岐化酶(SOD)和N末端前体脑钠肽(NT-proBNP)水平,并制备兔左室楔形心肌块的灌注模型,记录快频率程序刺激条件下室性心律失常的发生率。结果:与对照组比较,阿霉素组左室舒张末径(LVEDd)增大、左室射血分数(LVEF)降低(均P<0.05),血清SOD活性降低、NT-proBNP和MDA浓度升高,室性心律失常发生率增加(均P<0.05)。与阿霉素组比较,美托洛尔组无显著性变化,卡维地洛组LVEDd缩小、LVEF升高(均P<0.05),血清SOD活性增加、NT-proBNP和MDA浓度降低,室性心律失常发生率明显降低(均P<0.05)。结论:与美托洛尔比较,卡维地洛对阿霉素心肌病有保护作用,并能降低室性心律失常的发生,其机制与氧化自由基降低密切相关。     

Dobutamine gated blood pool scintigraphy predicts the improvement of cardiac sympathetic nerve activity,cardiac function,and symptoms after treatment in patients with dilated cardiomyopathy

BACKGROUND: We evaluated whether dobutamine gated blood pool scintigraphy (DOB-GBP) can predict improvement in cardiac sympathetic nerve activity and cardiac function after beta-blocker therapy in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: Twenty-two patients with DCM underwent DOB-GBP to measure left ventricular ejection fraction (LVEF) at rest, and during 5, 10, and 15 microg/kg/min of dobutamine infusion before therapy. Examinations were performed before and after 1 year of therapy. The heart/mediastinum count (H/M) ratio and total defect score (TDS) were determined for 123I-meta-iodobenzylguanidine images from anterior planar image and single-photon emission CT images. LVEF and left ventricular end-diastolic dimension (LVDd) were determined by echocardiography. After 1 year of treatment, the echocardiographic LVEF improved > 5% in 11 patients (group A), but did not improve in the remaining 11 patients (group B). Before treatment, TDS, H/M, LVEF, and LVDd were similar in both groups. However, there was a greater increase in the LVEF during dobutamine infusion in group A than in group B (21 +/- 8% vs 9 +/- 3%, p < 0.001). If a critical value of 15% for the DeltaLVEF was used to predict the improvement in LVEF after treatment, the sensitivity was 91% and specificity was 82%. The TDS, H/M ratio, LVDd, and New York Heart Association functional class improved in group A to a greater extent than in group B. CONCLUSIONS: DOB-GBP can be used to predict improved cardiac sympathetic nerve activity, cardiac function, and symptoms after treatment in patients with DCM.     

脉搏波传导速度与冠心病患者心肌重构及心功能之间关系的研究

目的 研究脉搏波传导速度与冠心病患者心肌重构及心功能之间的关系.方法 98例冠心病患者根据臂踝脉搏波传导速度（baPWV）的大小分为两组：baPWV正常组40例和baPWV增高组58例.每例均抽血行脑钠肽（BNP）检查,多普勒超声心动图测量室间隔厚度、左室后壁厚度及左室舒张末内径（LVDd）,计算左室质量指数（LVMI）和左室射血分数（LVEF）,比较两组各项指标的差异.结果 与冠心病baPWV正常组相比,baPWV增高组的LVMI、LVDd和BNP均升高,LVEF下降,差异有统计学意义（P＜0.05或P＜0.01）;且baPWV与LVMI、LVDd和BNP呈正相关（均P＜0.01）,与 LVEF呈负相关（P＜0.05）.结论 脉搏波传导速度与冠心病患者心肌重构及心功能损害有关,对冠心病患者心肌重构及心功能有良好的预测作用.     

抗心肌纤维化治疗家兔慢性心力衰竭的实验研究

目的 探讨姜黄素的抗心肌纤维化作用对家兔慢性心力衰竭(心衰)的影响.方法 30只新西兰大耳白兔随机分为对照组、心衰组、姜黄素组,每组10只.心衰组和姜黄素组采用主动脉瓣反流及主动脉缩窄法制作心衰模型,对照组做假手术但不造成主动脉瓣反流和主动脉缩窄.姜黄素组口服姜黄素(100 nag·kg-1·d-1),对照组和心衰组口服安慰剂.主动脉瓣反流术及其假手术前,主动脉缩窄术及其假手术后8周,所有动物做2次心脏超声检查.第2次超声检查后,取出心脏行基质金属蛋白酶(MMP)-2和MMP-9的免疫组织化学染色和Masson染色,观察MMP表达的改变和心肌纤维化情况.结果 前后2次超声结果 比较,心衰组左室射血分数和左室内径缩短分数显著下降,左室内径、左室后壁和室间隔厚度显著增大;姜黄素组上述指标也有显著改变,但程度较心衰组轻;对照组上述指标无显著改变.Masson染色显示,心衰组胶原含量高于姜黄素组和对照组(P<0.05);免疫组织化学染色显示,心衰组MMP-2和MMP-9的表达低于姜黄素组和对照组(P<0.05).结论 姜黄素通过提高MMP的表达可减轻心衰时的心肌纤维化,该作用可能是其改善心衰时心肌重构和心脏收缩功能的重要机制之一.抗纤维化治疗有可能成为心衰治疗的新方法 .     

beta(1)-Adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a heart disease characterized by progressive depression of cardiac function and left ventricular dilatation of unknown etiology in the absence of coronary artery disease. Genetic causes and cardiotoxic substances account for about one third of the DCM cases, but the etiology of the remaining 60% to 70% is still unclear. Over the past two decades, evidence has accumulated continuously that functionally active antibodies or autoantibodies targeting cardiac beta(1)-adrenergic receptors (anti-beta(1)-AR antibodies) may play an important role in the initiation and/or clinical course of DCM. Recent experiments in rats indicate that such antibodies can actually cause DCM. This article reviews current knowledge and recent experimental and clinical findings focusing on the role of the beta(1)-adrenergic receptor as a self-antigen in the pathogenesis of DCM.     

Prediction of cardiac sympathetic nerve activity and cardiac functional outcome after treatment in patients with dilated cardiomyopathy: examination using dobutamine gated blood pool scintigraphy

OBJECTIVES: This study evaluated whether dobutamine gated blood pool scintigraphy can predict improvement of cardiac sympathetic nerve activity and cardiac function. METHODS: Sixteen patients(10 men and 6 women, mean age 59 +/- 13 years) with dilated cardiomyopathy underwent dobutamine gated blood pool scintigraphy to measure left ventricular ejection fraction (LVEF) using tracer at 0, 5, 10 and 15 micrograms/kg/min before treatment. Patients were divided into good responders (LVEF increase > or = 15%) 8 patients(GR Group) and poor responders(LVEF increase < 15%) 8 patients (PR Group) after treatment with beta-blocker or amiodarone with a background treatment of digitalis, diuretics and angiotensin converting enzyme inhibitor. I-123 metaiodobenzylguanidine(MIBG) imaging to evaluate cardiac sympathetic nerve activity and echocardiography were performed before and at one year after treatment. MIBG imaging was obtained 4 hours after tracer injection, and the heart/mediastinum count ratio(H/M ratio) calculated from the anterior planar image and the total defect score(TDS) from the single photon emission computed tomography image. LVEF and left ventricular endo-diastolic dimension (LVDd) were measured by echocardiography and New York Heart Association(NYHA) functional class was evaluated. RESULTS: The GR Group showed TDS decreased from 28 +/- 6 to 17 +/- 12(p < 0.05), H/M ratio increased from 1.79 +/- 0.26 to 2.07 +/- 0.32(p < 0.05), LVEF increased from 29 +/- 8% to 48 +/- 10%(p < 0.01), and LVDd decreased from 65 +/- 4 mm to 58 +/- 5 mm(p < 0.05). In contrast, the PR Group showed no significant changes in TDS, H/M ratio, LVEF and LVDd. NYHA functional class improved in both groups. The improvement was better in the GR Group than in the PR Group. CONCLUSIONS: Dobutamine gated blood pool scintigraphy is useful to predict the improvement of the cardiac sympathetic nerve activity and cardiac function, and symptoms after treatment in patients with dilated cardiomyopathy.     

中青年扩张型心肌病伴心力衰竭患者心功能的临床研究

目的探讨青年人扩张型心肌病伴或不伴心力衰竭与心脏功能关系及临床意义。方法对我院扩张型心肌病伴有心力衰竭患者65例（心力衰竭组）和不伴有心力衰竭患者58例（非心力衰竭组）给予超声心动图、心电图检查。比较两组心脏的大小、功能以及发生心律失常的情况。结果①心力衰竭组的左心室收缩末内径（LVESd）、左心室舒张末内径（LVEDd）、左心房内径（LAD）、左心室射血分数（LVEF）,左心室短轴缩短分数（LVFS）与非心力衰竭组比较,差异有统计学意义（P〈0.01）。②心力衰竭组在心电图上的QRS时限、肢导低电压、异常Q波、ST-T改变的比例略高于非心力衰竭组,差异无统计学意义（P〉0.05）。心力衰竭组的房性心律失常、室性心律失常和传导阻滞发生率与非心力衰竭组比较,差异有统计学意义（P〈0.01）。③心力衰竭组患者入院时心脏功能Ⅲ级、Ⅳ级分别占58.4%、21.5%。两组经住院治疗后,心脏功能较入院时明显改善（P〈0.05）。结论扩张型心肌病伴心力衰竭、心律失常时,LVEDd明显增大,LVEF显著降低,并与心脏功能有一定的相关性。早期诊断和治疗,除去心力衰竭诱发因素,能够改善心脏功能,提高患者的生活质量,改善预后。     

扩张型心肌病的心肌组织细胞凋亡的研究

目的：研究扩张型心肌病（DCM）的心肌细胞凋亡及其与心功能的关系。方法：DCM组21例,其心肌组织14例来自右室心内膜心肌活检（EMB）亚组,7例来自死后尸检（尸检组）;对照组为5例死于非心血管疾病的尸检心肌组织。用原位细胞凋亡检测心肌组织凋亡细胞,计算凋亡指数（AI）。结果（1）DCM组的AI明显高于正常组（P＜0．01）,EMB亚组的AI明显低于尸检亚组（P＜0．01,但明显高于对照组（P＜0．01）。（2）DCM组中,心胸比（HTR）＜0．6、左室舒张末期内（LVDd)＜65mm和左室射血分数（LVEF）≥40％的患者AI均分别明显于低于HTR≥0．6、LVDd ≥65mm和LVEF＜40％的患者（P值均＜0．01）,但仍分别显著高于对照组（P值均＜0．01）。结论：DCM存在明显心肌细胞凋亡并随心功能恶化而程度加重,提示凋亡是DCM的心肌细胞丢失和心功能不全的重要机制。     

温肾活血方联合沙库巴曲缬沙坦治疗缺血性心肌病心力衰竭的疗效观察

目的探讨沙库巴曲缬沙坦(LCZ696)联合温肾活血方对缺血性心肌病心力衰竭病人生存质量及N末端-脑钠肽前体(NT-proBNP)、左室舒张末期内径(LVEDD)、左室射血分数(LVEF)的影响。方法选取2017年12月—2019年5月在重庆市中医院心内科就诊的90例缺血性心肌病心力衰竭病人,根据随机数字表法分为对照组和治疗A组、治疗B组,每组30例。对照组予基础抗心力衰竭治疗,治疗A组在对照组基础上口服沙库巴曲缬沙坦,治疗B组在治疗A组基础上加用温肾活血方治疗,3组均以治疗8周为1个疗程。比较各组治疗前后中医证候积分、美国纽约心脏病学会(NYHA)心功能分级、6 min步行试验距离和NT-proBNP、LVEF、LVEDD的变化。结果与对照组相比,治疗A组、治疗B组中医证候疗效更佳(均P<0.05),且NYHA分级提高更显著(P<0.05),NT-proBNP水平降低更明显(P<0.05),改善LVEF更为明显(均P<0.05)。治疗B组较对照组6 min步行试验距离增加(P<0.05),而治疗A组6 min步行试验距离较对照组比较差异无统计学意义(P>0.05);治疗B组在改善中医证候、改善6 min步行距离方面优于治疗A组(P<0.05)。而在改善NYHA分级、降低NT-proBNP、升高LVEF、缩小LVEDD方面治疗A组、治疗B组比较差异无统计学意义(P>0.05)。结论对缺血性心肌病心力衰竭病人在常规抗心力衰竭治疗基础上加用沙库巴曲缬沙坦可改善中医证候,提高NYHA分级,降低NT-proBNP,升高LVEF,降低LVEDD,但沙库巴曲缬沙坦在增加6 min步行距离方面与常规抗心力衰竭治疗比较改善不明显,在沙库巴曲缬沙坦基础上加用温肾活血方可明显改善病人6 min步行距离,并进一步改善中医证候。