Regenerative therapies in electrophysiology and pacing: introducing the next steps

The morbidity and mortality of cardiac arrhythmias are major international health concerns. Drug and device therapies have made inroads but alternative approaches are still being sought. For example, gene and cell therapies have been explored for treatment of brady- and tachyarrhythmias, and proof of concept has been obtained for both biological pacing in the setting of heart block and gene therapy for ventricular tachycardias. This paper reviews the state of the art developments with regard to gene and cell therapies for cardiac arrhythmias and discusses next steps.     

Regenerative Therapy in Peripheral Artery Disease

Patients with peripheral artery disease (PAD) and critical limb ischemia are the main candidates for limb amputations and have a poor life expectancy. Frequently, these patients are not eligible for either surgical or percutaneous interventions aimed at mechanical revascularization. Therefore, new strategies need to be identified to offer these patients a viable therapeutic option. Gene and cell therapy hold great promise for the treatment of peripheral vascular diseases because, in animal models, local delivery of growth factors and endothelial progenitor cells result in new blood vessel formation and regeneration of ischemic tissues. In this article, are reviewed phase I and phase II gene, and cell therapy clinical trials in patients with PAD.     

不同部位左心室内膜与外膜起搏对心力衰竭心脏的电生理作用差异

目的 评估左心室不同部位心内膜与外膜起搏对心力衰竭（心衰）犬心脏的电激动同步性以及复极离散度的影响及其差异.方法 12只比格犬,体重（12.5±1.7）kg.使用随机数字法平均分为2组（正常组和心衰组）.利用右心室心尖部快速起搏制作慢性心衰模型.左心室放置64极篮状电极导线进行电生理标测.通过左心室不同部位起搏（心底部心内膜与心外膜,心尖部心内膜与心外膜）记录并测量体表12导联心电图的QT间期、T波峰点与T波下降支最大斜率处切线与等电位线交点（Tp-e）间期,同时测定左心室心内膜整体激动时间以及各篮状电极记录的激动恢复间期及其复极离散度.结果 基础状态下,与正常心脏相比,心衰组QT间期、T波顶点与T波终点之间的时限Tp-e间期以及激动恢复间期均延长（P＜0.05）.心衰组中,与左心室心内膜起搏相比,相同部位的心外膜起搏时的QT和Tp-e间期均显著延长[QT：心底部（270±13）ms对（255±15）ms,（P＜0.01）;心尖部（275±12）ms对（257±11）ms,（P＜0.01）;Tp-e：心底部（50.2±8.3） ms对（42.7±4.5） ms,（P＜0.01）;心尖部,（52.9±10.1）ms对（45.6±9.3）ms,（P＜0.01）].心室激动恢复间期离散度无论在左心室心内膜还是在心外膜,近心底部起搏时较近心尖部起搏时显著减小.[心内膜起搏（4.1±0.5） ms对（5.8±0.7）ms,（P＜0.05）;心外膜起搏（4.7±0.6） ms对（6.2±0.9） ms,（P＜0.05）].在心衰心脏,左心室心外膜起搏时,左心室整体心内膜平均激动时间较心内膜起搏时明显延长（42.9±5.9）ms对（26.1±4.0）ms,（P＜0.001）].结论 左心室心内膜起搏较心外膜起搏有更好的心脏激动电同步性.心衰后,左心室心外膜起搏较心内膜起搏可致更长的复极时间以及更大的复极离散度.本研究结果提示左心室心内膜起搏较心外膜起搏可产生更好的电生理效应,有可能降低心衰心脏再     

Incremental programming of atrial anti-tachycardia pacing therapies in bradycardia-indicated patients: effects on therapy efficacy and atrial tachyarrhythmia burden.

AIMS: Efficacy of pace-termination of atrial arrhythmias (ATP) may depend on atrial cycle length and regularity. Whether device programming of ATP therapies can improve ATP efficacy and alter atrial tachyarrhythmia burden is unknown. METHODS AND RESULTS: ATP efficacy was evaluated in 61 patients (39 males; 66 +/- 10 years) with a standard indication for pacing, 95% with a history of AT/AF. Each patient was implanted with a novel DDDRP pacemaker capable of delivering ATP therapy. ATP efficacy and AT/AF frequency and burden were compared within each patient during a period of nominal ATP programming (NP) followed by a period of aggressive incremental programming (IP). Adjusted ATP-termination efficacy was higher during IP than during NP (54.8% vs 37.9%, P < 0.05). No differences in AT/AF frequency (3.3 +/- 5.9 vs 3.2 +/- 6.9 day(-1)) or burden (18 +/- 28% vs 18 +/- 29%) were observed comparing NP with IP. The majority of episodes during both the NP (81%) and IP (77%) periods terminated within 10 min. Episodes lasting 24 h or more accounted for only 0.4% of the episodes in both groups. but accounted for 38% of the average burden during NP and 51% during IP. CONCLUSIONS: Device programming of ATP therapies can influence the number of treated episodes and the efficacy of ATP therapies although arrhythmic frequency and burden may not change. Total atrial arrhythmia burden is disproportionately influenced by long (>24 h) episodes.     

重组起搏基因质粒构建生物起搏器的实验研究

目的研究旨在构建重组起搏基因质粒pIRES2-EGFP-HCN2,并检测其在体外心房肌细胞及犬病态窦房结综合征(病窦)模型体内的表达。方法对含mHCN2cDNA的PTR载体进行转化和扩增,将所得mHCN2基因定向克隆到真核表达载体pIRES2-EGFP中,进行双酶切来鉴定克隆的正确性。将重组质粒用电穿孔法转染心房肌细胞,同时直接注射至犬病窦模型的窦房结区域,体表心电图监测犬窦房结功能改善情况,并通过荧光显微镜及RT-PCR检测重组质粒pIRES2-EGFP-HCN2在体内外的表达。而对照组仅注射生理盐水。结果构建了重组质粒pIRES2-EGFP-HCN2。荧光显微镜下可见转染后的心房肌细胞呈绿色荧光,其搏动频率较未转染的细胞明显增快[(180±11)次/min与(140±14)次/min,P<0.05]。注射组织的冰冻切片显示绿色荧光蛋白,RT-PCR显示了mHCN2基因片段,体表心电图显示犬窦房结功能改善[(150±13)次/min与(105±17)次/min,P<0.05]。而对照组始终未见到绿色荧光蛋白表达及窦房结功能改善。结论成功构建了重组质粒pIRES2-EGFP-HCN2,并在体外心房肌细胞及犬病窦模型体内成功表达,为生物起搏的研究奠定基础。     

The beneficial effect of biventricular pacing on ventricular tachycardia in a patient with non-ischemic cardiomyopathy

The effect of cardiac resynchronisation therapy on ventricular tachycardias (VT) has not been well established. This case-report demonstrates the favourable impact of biventricular pacing on ventricular arrhythmias. In 2004, a patient with dilated cardiomyopathy and ICD since 1999 was admitted to our Division for multiple VT. While left ventricular function was markedly reduced and mitral regurgitation was severe, he was asymptomatic for heart failure. Amiodarone was not administered on account of a documented proarrhythmic effect. The patient's ICD was upgraded to an ICD-biventricular system. After upgrading, a significant reduction in the number of VT was noted.     

Esophageal ECG recording--a valuable diagnostic tool in dual chamber pacing

The interpretation of the ECG of a dual chamber pacemaker necessitatesthe identification of atrial activity. This is a prerequisitefor the evaluation of pacemaker function and for the correctadjustment of programmable pulse generators. The assessmentof atrial capture in standard 12-lead ECGs is, however, sometimesrather difficult. Esophageal ECG recording by means of a reusableunipolar electrode, inserted transnasally, and connected toa standard ECG recorder, is a simple, rapid and inexpensivemethod for the reliable identification of P-waves. Clinical examples are presented to illustrate the value of thistechnique in determining atrial capture and as a tool for thedifferential diagnosis of pacemaker-involved tachycardias. Theuse ofesophageal ECG recording in the clinical follow-up ofpatients with dual chamber pacemakers isrecommended.     

Rate-responsive pacing as compared to fixed-rate VVI pacing in patients after ablation of the atrioventricular conduction system

In 44 patients with supraventricular arrhythmias various pacemakerswere studied after closed-chest ablation of the atrioventricularconduction system. There were 22 patients with a rate-programmableVVI pacemaker (Group I), 15 patients with an activity mode (ACTIVITRAX8400) (Group II) and seven patients with a QT-mode pacemaker(QUINTECH 911) (Group III). To study both physical work capacityand heart-rate behaviour, exercise testing was performed usinga treadmill. Sixteen patients in Group I (72·7% complainedof shortness of breath during exercise in comparison to fourpatients (26·7%) in Group II and three patients (42·9%)in Group III. Normal physical work capacity was observed inthree of 22 patients (13·6%) in Group I and in all patientsin Groups II and III. The heart rate both increased and decreasedmore rapidly at the onset and end of the stress test, respectively,in patients with activity-mode compared to patients with QT-modepacing systems. These data show that, despite successful His-bundleablation, both dyspnea and decreased work capacity are observedwhen VVI pacemakers are used. In contrast, the use of rate-responsivepacing systems leads to better cardiac performance.     

Regenerative medicine: Current therapies and future directions

Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies.     

脑钠肽对大鼠心脏重构和心电生理效应的作用

目的 观察大鼠长时间使用重组人脑钠肽(recombinant human B-type natriuretic peptide,rhBNP)后产生的心电生理效应和心脏重构效应,并与心肌梗死后大鼠进行对比.方法 雄性健康Wistar大鼠60只,分为3组:正常对照组、脑钠肽(B-type natriuretic peptide,BNP)处理组和心肌梗死组.以结扎左前降支的方法制作大鼠心肌梗死模型,正常对照组和BNP处理组进行假手术.BNP处理组予以国产冻干rhBNP(新活素)持续静脉微泵推注,连续输注7d.用超声心动图评估并对比3组大鼠心脏左心室质量,左心室缩短分数,左心室舒张末期直径.用24小时动态心电图监测记录并对比3组大鼠心率变异性(heart rate variability,HRV),PR间期,QRS间期,QTC间期等参数以及心律失常情况.结果 长时间rhBNP灌注可升高BNP处理组大鼠的心脏质量/体质量比,心肌梗死组也发生了类似的变化,与正常对照组比较差异有统计学意义(P＜0.05).BNP处理组和心肌梗死组QTC间期均拉长,与正常对照组比较差异有统计学意义(P＜0.05);SDNN都有明显降低,与正常对照组比较差异有统计学意义(P＜0.05).BNP处理组频率域分析显示低频带有振荡增高,与正常对照组比较差异有统计学意义[(0.08±0.02) ms2vs.(0.05±0.01) ms2,P＜0.05];低频/高频比率增高,与正常对照组比较差异有统计学意义(2.7±0.4 vs.1.3±0.2,P＜0.05).对比正常对照组,在BNP处理组和心肌梗死组大鼠观察到更多如频发室性期前收缩和室性心动过速等室性心律失常.结论 长时间使用rhBNP可能引发大鼠心脏重构效应和交感神经张力升高,进而诱发室性心律失常.     

Update on biological therapies for critical limb ischemia

Gene and stem cell therapies have been shown to be safe and well tolerated. Early trial results using these therapies have had promising results on important clinical end points such as wound healing, ischemic pain, and major amputation. Despite this, there have been no pivotal trials to date that have proved the benefit of biological therapy, although there are numerous pivotal trials in progress or about to initiate enrollment. Persistent obstacles exist with current study designs that complicate the ability to successfully perform clinical critical limb ischemia trials.     

Survivin与肝癌关系的研究进展

Survivin是一种凋亡抑制蛋白,具有调节细胞分化和抑制凋亡的双重功能.因其在人类大多数肿瘤中高表达,故成为近年来肿瘤基因治疗研究热点.此文就Survivin在肝癌中的研究进展作一综述.     

缺血性心脏病基因和细胞治疗的研究概况

基因和细胞治疗能有效地保护高危心肌,减少心肌炎症反应,挽救缺血、梗死心肌,并且已经初步应用于临床,成为目前治疗冠心病有潜力的方法,二者的联合治疗可能更有希望。