Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation

Based on extensive preclinical data, glycogen synthase kinase-3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b(-/-) embryoid bodies. While GSK-3alpha-deficient mice were born without a cardiac phenotype, no live-born Gsk3b(-/-) pups were recovered. The Gsk3b(-/-) embryos had a double outlet RV, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. The hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of three regulators of proliferation - GATA4, cyclin D1, and c-Myc. These studies, which we believe are the first in mammals to examine the role of GSK-3alpha and GSK-3beta in the heart using loss-of-function approaches, implicate GSK-3beta as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development. Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age.     

Percutaneous trans-apex intra-septal radiofrequency ablation of hypertrophic cardiomyopathy

A 70-year-old woman presented with severe hypertrophic obstructive cardiomyopathy (HOCM) (maximum ventricular septum thickness of 28?mm, peak pressure gradient (PG) in the left ventricular outflow tract (LVOT) of 153?mmHg). We performed percutaneous trans-apex intra-septal radiofrequency ablation (PTAISRA) of the interventricular septum under guidance of transthoracic echocardiography. At six-months follow up, the symptoms were significantly relieved; the septal thickness was reduced to 18?mm and the peak LVOT PG reduced to 44?mmHg. This case highlights a novel use of radiofrequency ablation for the treatment of HOCM. Long-term safety and efficacy merit evaluation.     

T cell-specific ablation of Fas leads to Fas ligand-mediated lymphocyte depletion and inflammatory pulmonary fibrosis

To study the role of Fas-Fas ligand (FasL) interaction-mediated apoptosis in lymphocyte homeostasis, we generated a mutant fas allele allowing conditional inactivation of the fas gene through Cre-mediated recombination. Experiments in which Fas was ablated in T cells, B cells, T and B cells, or in a more generalized manner demonstrated that the development of lymphoproliferative disease as seen in Fas-deficient mice requires Fas ablation in lymphoid and nonlymphoid tissues. Selective inactivation of Fas in T cells led to a severe lymphopenia over time, accompanied by up-regulation of FasL on activated T cells and apoptosis of peripheral lymphocytes. In addition, the mutant animals developed a fatal wasting syndrome caused by massive leukocyte infiltration in the lungs together with increased inflammatory cytokine production and pulmonary fibrosis. Inhibition of Fas-FasL interaction in vivo completely prevented the loss of lymphocytes and initial lymphocyte infiltration in the lungs. Thus, FasL-mediated interaction of activated, Fas-deficient T cells with Fas-expressing cells in their environment leads to break down of lymphocyte homeostasis and development of a lung disease strikingly resembling idiopathic pulmonary fibrosis in humans, a common and severe disease for which the mutant mice may serve as a first animal model.     

Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice.

Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.     

超声引导下经皮室间隔消融术治疗肥厚型梗阻性心肌病研究进展

对有症状的肥厚型梗阻性心肌病,如何有效解除左心室流出道梗阻是治疗的重点,依靠药物、双腔起搏的方法以减轻左心室流出道压力阶差可缓解症状,而减少室间隔厚度的方法包括外科间隔心肌切除术、经皮室间隔心肌化学消融术、室间隔射频导管消融术等,这些方法在减少室间隔厚度上均有明显效果。超声引导下经皮室间隔心肌热消融术作为一种侵入性较小、效果较好的治疗方法,在肥厚型心肌病的治疗中有较大应用前景。本文就超声引导下经皮室间隔消融术治疗肥厚型梗阻性心肌病的研究进展作一综述。     

Septal myectomy after previous septal artery ablation in hypertrophic cardiomyopathy

OBJECTIVE: To review our institution's experience with patients who failed to benefit from septal artery ablation, which necessitated subsequent septal myectomy, and to examine reasons for ablation failure and outcome of myectomy after ablation. PARTICIPANTS AND METHODS: Of 550 patients who underwent septal myectomy at Mayo Clinic Rochester between January 1, 1999, and December 31, 2006, 16 (3%) had had a total of 22 previous septal artery ablations. This subset of 16 patients was analyzed and compared with a reference group of 120 patients whose septal artery ablations were performed at our institution during this period. Angiograms obtained during septal ablation were available for 13 (81%) of 16 patients in this series and were reviewed by 2 interventional cardiologists (R.A.N. and S.R.O.). These cardiologists also reviewed preoperative and postoperative echocardiography data, hospital course, and follow-up data to compile a list of characteristics that could have contributed to failed ablation. RESULTS: The median age of the patients at operation was 65 years (interquartile range [IQR], 52-72 years), and interval between ablation and myectomy was 409 days (IQR, 162-568 days). Angiograms revealed 2 failed procedures secondary to technical error. One patient had a relatively large first septal perforator with a large resting gradient. In 10 patients no septal perforators supplying the proximal septum were identified. Postoperatively, mitral regurgitation decreased from 3.00 to 1.00 (P less than .001), and left ventricular outflow tract gradient decreased from 75 mm Hg to 0 mm Hg (IQR, 0-29 mm Hg; P less than .001). Two patients died after surgery: 1 patient developed multiple-organ system failure on postoperative day 7, and 1 patient developed arrhythmia on postoperative day 21. Patients with previous septal artery ablation were older (P=.04), were more likely to have preoperative permanent pacemakers or implantable cardioverter-defibrillators (P=.05), were more likely to require postoperative pacemaker placement (P less than .001), and had higher operative mortality (P less than .001) than control patients. Fourteen patients survived the early recovery phase; 9 were followed up at a median of 1.88 years (IQR, 306 days to 3.3 years). All patients' symptoms improved. Median gradient of the left ventricular outflow tract was 13 mm Hg (IQR, 0-15 mm Hg) at follow-up with mild to moderate (1.6) mitral regurgitation. CONCLUSION: Septal myectomy performed after failed ablation improves gradient and provides excellent relief of symptoms but is associated with a higher incidence of morbidity and mortality.     

Long-term follow-up after percutaneous septal ablation in hypertrophic obstructive cardiomyopathy

OBJECTIVES: The aim of this study was to evaluate the longterm follow-up results of percutaneous transluminal septal myocardial ablation (PTSMA) in a large patient cohort. BACKGROUND: PTSMA by alcohol injection into septal branches has shown good acute and short-term results in symptomatic patients with hypertrophic obstructive cardiomyopathy. METHODS: A total of 100 consecutive symptomatic (NYHA class 2.8 +/- 0.6) patients underwent PTSMA. All patients had clinical and non-invasive follow-up at 3 months, 1 year, and annually up to 8 years. RESULTS: One patient died at day 2 after intervention due to fulminant pulmonary embolism following deep venous thrombosis, and eight patients required a permanent DDD-pacemaker due to post-interventional complete heart block. Acute reduction of the left ventricular outflow tract gradient was achieved from 76 +/- 37 to 19 +/- 21 mmHg at rest, from 104 +/- 34 to 43 +/- 31 mmHg during Valsalva maneuver, and from 146 +/- 45 to 59 +/- 42 mmHg post extrasystole (p < 0.0001, each). During follow-up (mean follow-up time: 58 +/- 14 months), three additional patients died (sudden death at 48 months, non-cardiac death at 49 months and stroke-related death at 60 months after the index procedure). All living patients showed clinical improvement to NYHA-class 1.4 +/- 0.6 (after 3 months, n = 99), 1.5 +/- 0.6 (after 1 year, n = 99), and 1.6 +/- 0.7 at final follow-up (n = 96; p < 0.0001, each). Non-invasive follow-up studies documented ongoing outflow tract gradient reduction, decrease of septal and left ventricular posterior wall thickness, and improvement of exercise capacity. CONCLUSIONS: PTSMA is an effective treatment for symptomatic patients with hypertrophic obstructive cardiomyopathy. Follow-up showed ongoing hemodynamic and clinical improvement without increased mortality and morbidity.     

Sustained ventricular tachycardia following alcohol septal ablation for hypertrophic obstructive cardiomyopathy

A 49-year-old man with a history of hypertrophic obstructive cardiomyopathy (HOCM) presented in sustained monomorphic ventricular tachycardia (SMVT) 8 days post-alcohol septal ablation. A dual chamber implantable cardioverter defibrillator ICD was implanted and the patient experienced another episode of VT 3 weeks later, which was terminated by an ICD shock. This case demonstrates probable scar-induced reentrant VT post-alcohol septal ablation, a likely rare but hypothesized complication of this procedure.     

血管定位与选择方法在化学消融治疗肥厚梗阻型心肌病中的意义

目的评价化学消融左冠间隔支数量、大小、位置及侧支循环对消融效果的影响 [1 ]。方法对 16例肥厚梗阻型心肌病患者左冠前降支间血管的数量、大小、分布及侧支循环情况进行统计分析 ,然后用扩张球囊试阻断分支后观察心肌染色面积来判断心肌染色范围 ,测压差改变情况 ,确定消融分支的数量 ,进行化学消融。结果 16例造影后示第一支单阻断 8例 ,第二单支 3例 ,第一和第二同时消融的5例。 3例出现低血压 ,扩容后恢复正常 ,1例死于休克。术中及术后半年随访都达到减阻目的。结论冠状动脉间隔支存在数量、大小、分布及有无侧支循环的差异。用试阻断方法确定所选的分支及数量 ,放弃粗大及有明显侧支循环的分支可提高手术效果、降低并发症     

经皮经腔间隔心肌化学消融术治疗肥厚型梗阻性心肌病的近中期疗效观察

目的 评估经皮经腔间隔心肌化学消融术(PTSMA)治疗肥厚型梗阻性心肌病(HOCM)近中期疗效.方法 2006年7月至2009年6月,采用Sigwart法对19例(男14例,女5例)症状明显的肥厚型梗阻性心肌病患者进行PTSMA,所有患者均分别于术前、术后1周、术后30天及术后1年接受心脏彩色超声及心电图检查.结果 19例患者手术均成功.术前左心室流出道压差(LVOTPG)均明显高于术后1周、术后30天及术后1年,LVOTPG(92.5±32.4)mmHg vs(36.3±21.6)mmHg、(32.7±24.3)mmHg、(30.1±20.6)mmHg(P＜0.05或＜0.01).术前室间隔厚度(IVST)明显大于术后30天及术后1年,IVST(21.7±3.6)mm vs(15.4±4.2)mm、(13.4±2.8)mm(P＜0.05或＜0.01).17例患者术后心功能改善、临床症状明显减轻或消失.4例出现完全性右束支传导阻滞,其中1例术后即恢复,1例发生不完全左束支传导阻滞,无Ⅲ度房室传导阻滞发生.结论 PTSMA是HOCM一种安全、有效的治疗手段,IVST及LVOTPG均呈持续性下降.     

Reversible cardiomyopathy after radiofrequency ablation of lateral free-wall pathway-mediated incessant supraventricular tachycardia

Incessant supraventricular tachycardia leading to reversible cardiomyopathy has been reported. Cardiomyopathy usually only develops after prolonged episodes of tachycardia at a significant heart rate. Left ventricular free-wall pathways rarely cause fast and incessant tachycardia. Therefore cardiomyopathy has not been reported with left ventricular free-wall pathway-mediated supraventricular tachycardia. We report on two cases of left ventricular free-wall-mediated supraventricular tachycardia leading to reversible cardiomyopathy after radiofrequency ablation. These cases illustrate the difficulty in diagnosing tachycardia-mediated cardiomyopathy, as the tachycardia may be clinically silent. In addition, they emphasize the importance of making this diagnosis, as the cardiomyopathy is reversible.     

Histopathologic effects of endocardial and epicardial percutaneous radiofrequency catheter ablation in dilated nonischemic cardiomyopathy

We report the histological evaluation of both endocardial and epicardial radiofrequency (RF) ablation lesions in the explanted heart of a patient presenting with nonischemic dilated cardiomyopathy complicated by recurrent electrical storms. In this case, chronic RF lesions were almost transmural at the endocardial side, while remaining only superficial at the epicardial aspect, possibly because of the insulating interposed epicardial fat layer.     

化学消融治疗肥厚性梗阻型心肌病术中监测及护理配合

随着介入心脏病学的发展,化学消融是治疗肥厚性梗阻型心肌病(HOCM)的又一种方法。临床上对于症状明显的HOCM病人,药物治疗无效或副反应较大不能耐受者可用化学消融治疗[1]。它是将无水乙醇注入前降支的分支(间隔支),使间隔支发生坏死变薄,解除流出道梗阻以达到治疗的目的。由于     

心肌特异性hVEGF165真核表达载体的构建及鉴定

目的：构建MLC-2v启动子驱动的真核表达载体并鉴定特异性。方法：用MLC-2v启动子基因片段替代质粒pIRES2-EGFP的CMV启动子，而保留其增强子序列，并将目的基因hVEGF165分别克隆到两种启动子驱动的质粒，构建MEG-2v／pIRES2-EGFP-hVEGF165和pIRES2-EGFP-hVEGF165 2种质粒，瞬时转染心肌、内皮、平滑肌和成纤维细胞。结果：转染pIRES2-EGFP-hVEGF165，4种细胞均表达、目的基因及产物；而转染MLC-2v／plRES2-EGFP-hvEGF165，仅心肌细胞表达GFP和目的基因产物。结论：MLC-2v启动子驱动的质粒可心肌特异表达目的基因及蛋白。     

心肌声学造影在肥厚型梗阻性心肌病无水乙醇化学消融术中的应用

目的评价心肌声学造影(MCE)在经皮经冠状动脉心肌化学消融术(PTSMA)治疗肥厚型梗阻性心肌病的应用价值。方法 22例肥厚型梗阻性心肌病患者,术前超声观察二尖瓣前叶收缩期前向运动(SAM征)与室间隔接触点,脉冲多普勒测量左室流出道流速加速点,相应水平肥厚的室间隔确定为梗阻相关心肌(靶域)。术中行冠状动脉超声造影,根据室间隔支发出部位拟定消融血管;行MCE,若心肌显影范围与梗阻心肌范围吻合则确定该室间隔支为支配靶域的消融血管(靶血管),注入无水乙醇行PTSMA治疗。结果 22例患者术中,19例MCE心肌显影部位与术前靶域相吻合,直接行PTSMA治疗;2例MCE显示心肌显影区域小于靶域,更换靶血管后行PTSMA治疗;1例MCE显示非靶域显影而放弃消融治疗。21例患者术后即刻静息左室流出道压差(LVOTPG)下降达50%以上。PTSMA术后1、3、12个月IVST、LVOTG较术前减小(P0.05)。术后1个月SAM评分、二尖瓣反流评分较术前减小(P0.05),术后3个月、1年与术后1个月差异无统计学意义。结论 MCE在PTSMA术中能引导定位定量消融心肌,减少盲目消融导致的非靶域心肌损伤。     

16例肥厚型心肌病化学消融术后心肌酶谱分析与护理

目的通过观察室间隔化学消融术后患者不同时间段心肌酶谱的演变特点,以及相应不良事件的发生情况,探讨术后的护理方法。方法16例经心脏彩色多谱勒超声诊断为肥厚型心肌病经药物治疗无效的患者,在进行室间隔化学消融术后严密心电监护,心肌酶谱每4h测1次,共测6次,之后改为每天测1次,共测2次,记录术后0～8h,9～16h,17～24h及25～72h心肌酶谱变化情况,以及各时间段不良事件发生情况。结果16例患者术后0～8h心肌酶谱各项指标值较高,处于上升阶段,不良事件为44例。9～16h心肌酶谱指标开始有所下降,但数值仍高,不良事件为15例;17～24h心肌酶谱指标继续下降,数值降低,不良事件为1例;25～72h心肌酶谱数值基本接近正常数值,不良事件为2例。结论室间隔化学消融术后心肌酶谱的检测有利于指导制定术后的护理措施。