Coordinating electrical activity of the heart: ankyrin polypeptides in human cardiac disease

Introduction: Over the past ten years, ankyrin polypeptides have emerged as players in cardiac excitation–contraction coupling. Once thought to solely play a structural role, loss-of-function variants of genes encoding ankyrin polypeptides have highlighted how this protein mediates subcellular localization of various electrical components of the excitation–contraction coupling machinery. Evidence has revealed how disruption of this localization is the primary cause of various cardiomyopathies, ranging from long-QT syndrome 4, to sinus node disease, to more common forms of arrhythmias.

Areas covered: The roles of ankyrin polypeptides in excitation–contraction coupling in the heart and the development of ankyrin-specific cardiomyopathies. How ankyrin polypeptides may be involved in structural and electrical remodeling of the heart, post-myocardial infarct. How ankyrin interactions with membrane-bound ion channels may regulate these channels' response to stimuli. New data, which offers the potential for unique therapies, for not only combating heart disease, but also for wider applications to various disease states.

Expert opinion: The ankyrin family of adapter proteins is emerging as an intimate player in cardiac excitation–contraction coupling. Until recently, these proteins have gone largely unappreciated for their importance in proper cardiac function. New insights into how these proteins function within the heart are offering potentially new avenues for therapies against cardiomyopathy.     

Effects of clonixin on the electrical activity of cardiac pacemaker cells.

1. The electrophysiological effects of clonixin, a non-steroidal analgesic, on cardiac pacemaker cells of spontaneously beating frog sinus venosus, were studied by intracellular recording of transmembrane potentials. 2. Results show that clonixin (Clx) between 1 x 10(-6) M and 3 x 10(-4) M, decreases the OS, APA, Vmax and frequency of primary and subsidiary cells, however pacemaker cells differ in their sensitivity to Clx. 3. At 2 x 10(-6) M, Clx completely blocked the spontaneous beating of primary cells. It is necessary to increase the Clx concentration about two orders of magnitude in order to attain a similar degree of blockade of subsidiary cells. 4. Previous or simultaneous superfusion with atropine does not modify Clx effects, thus a probable cholinergic mechanism of action for Clx is discarded. 5. When Clx concentrations were lower than 5 x 10(-4) M, their effects on both types of cells were partially reversed by a 100% increase of external calcium concentration. 6. BAY K-8644 which stimulates calcium influx through calcium L-type channels, reverted Clx effects on pacemaker cells. 7. It is suggested that Clx blocks calcium inward current which generates all or part of the upstroke of primary cells and subsidiary ones, respectively.     

The cardiac gap junction: a potential therapeutic target in the treatment of heart disease

Cardiac gap junctions have been implicated in maintaining cardiac conduction and function. In cardiac disease, expression of connexin 43, the most abundant ventricular gap junction protein, is markedly abnormal, a process termed gap junction remodeling. To date, however, the gap junction has not been directly targeted therapeutically in cardiac disease states. Therefore, we have developed novel and complementary experimental models to investigate whether loss of connexin 43 expression in the heart can be directly linked to the arrhythmic and functional complications of heart disease. In this article, we discuss how data from connexin 43 conditional and chimeric knock-out mice support the hypothesis that gap junction remodeling is a key molecular feature underlying the high incidence of sudden arrhythmic death and exacerbating the ventricular dysfunction associated with acquired heart disease.     

血栓通注射液辅治心绞痛型冠心病疗效观察

目的观察血栓通注射液辅治心绞痛型冠心病的疗效。方法将30例心绞痛型冠心病患者随机分为观察组和对照组各15例。观察组在常规西药疗法基础上加用血栓通注射液治疗,对照组只采用常规西药疗法。比较2组心绞痛症状及心电图疗效。结果观察组心绞痛症状总有效率及心电图总有效率均高于对照组,差异均有统计学意义(P<0.05)。结论血栓通注射液辅治心绞痛型冠心病疗效好,不良反应少,值得推广应用。     

Effect of bisoprolol on cardiac performance in coronary heart disease

Summary The effects of 5 and 10 mg bisoprolol once daily for 7 days on exercise ECG, myocardial perfusion and left ventricular function in 25 patients with stable coronary heart disease have been assessed in a double-blind, randomized, parallel group trial design.ST-segment depression during exercise was reduced by 56% by 5 mg bisoprolol and by 64% after 10 mg; the difference between the dose levels was significant. Heart rate, systolic and diastolic blood pressure and the rate-pressure product were reduced to similar extent both at rest and during exercise by both doses. Left ventricular thallium-201 scintigrams indicated a significant reduction in myocardial perfusion defects after 10 mg bisoprolol compared to baseline; however, the difference between the two active treatments was not significant. Left atrial and left ventricular diameters obtained by one-dimensional echocardiography, and the calculated shortening fraction, remained unchanged after bisoprolol, and so gave no evidence of a negative inotropic action.It is concluded that 5 mg bisoprolol was effective in once-a-day treatment of angina pectoris due to coronary heart disease, and a further improvement can be expected on increasing the dose to 10 mg.     

血栓通注射液辅治心绞痛型冠心病疗效观察

目的 观察血栓通注射液辅治心绞痛型冠心病的疗效.方法 将30例心绞痛型冠心病患者随机分为观察组和对照组各15例.观察组在常规西药疗法基础上加用血栓通注射液治疗,对照组只采用常规西药疗法.比较2组心绞痛症状及心电图疗效.结果 观察组心绞痛症状总有效率及心电图总有效率均高于对照组,差异均有统计学意义(P＜0.05).结论 血栓通注射液辅治心绞痛型冠心病疗效好,不良反应少,值得推广应用.     

Oxytocic polypeptides in human urine

The work of Gomes on the polypeptide in human urine which causes contraction of the rat uterus has been extended. Concentrates were prepared by means of paper pulp columns similar to those used by Rocha e Silva and his colleagues for the purification of bradykinin, and evidence was obtained for the presence of two different active substances not only in human urine but also in a preparation of bradykinin. The effect of human urine on the rat uterus is probably due to bradykinin itself or a mixture of similar substances.     

Beneficial effect of eplerenone on cardiac remodelling and electrical properties of the failing heart.

INTRODUCTION: The effect of chronic administration of eplerenone on cardiac remodelling and electrical properties was investigated in the failing heart of cardiomyopathic hamsters (TO-2) at five months of age. MATERIALS AND METHODS: Two-month-old hamsters were treated with eplerenone (200 mg/kg/day) administered into the chow for a period of three months. Measurements of membrane potential were performed with intracellular microelectrodes connected to a high impedance DC amplifier. The thickness of the ventricular wall as well as the area of fibrosis were measured. To investigate the influence of eplerenone on the electrogenic sodium pump myocytes were isolated from the ventricle and the pump current density was measured in voltage clamped cells using the whole cell clamp configuration. RESULTS: The results indicated that: 1) the width of the left and right ventricular wall was significantly reduced; 2) the heart weight/body weight ratio was decreased by 38+/-2.4% (n=24) (p<0.05); 3) the fibrotic area in the left ventricle (LV) was reduced by 12.6+/-2% (n=25) (p<0.05); 4) the incidence of cardiac arrhythmias was decreased from 58+/-3.8% (n=20) in the control to 40+/-4.1% (n=20) (p<0.05) in animals treated with eplerenone. Moreover, a significant reduction in the dispersion of the QT interval was found with the drug; 5) eplerenone increased the resting potential of ventricular fibres from 64.3+/-1.5 mV to 73.4+/-1.4 mV (n=30) (p<0.05), an effect related to the activation of an electrogenic sodium pump. The conduction velocity, in longitudinal direction, was enhanced from 50+/-2.2 cm/s (n=10) in the controls to 59+/-2.4 cm/s (n=13) (p<0.05) in animals treated with eplerenone. CONCLUSIONS: Eplerenone reduces cardiac remodelling, the incidence of cardiac arrhythmias and improves impulse propagation, an effect in part related to the antifibrotic effect of the drug but also to the activation of the electrogenic sodium pump.     

Effect of glimepiride on the electrical activity of isolated rabbit heart muscle.

The effect of glimepiride (CAS 93479-97-1) on the electrical threshold, conduction time, effective refractory period and automaticity of left atrium and right ventricle in the isolated rabbit heart was investigated and compared with those of chlorpropamide and glibenclamide. From the sulphonylureas investigated only glibenclamide diminished the electrical activity of rabbit heart muscle preparations. Chlorpropamide and glimepiride have a mild effect to change the basic parameters on the opposite direction. It seems that glimepiride does not have a significant effect on cardiac muscle in vitro.     

心脏超声筛查在胎儿先天性心脏病诊断中的应用价值

目的：比较常规超声检查与常规超声检查加胎心检查在胎儿先天性心脏病诊断中的应用价值,并分析胎儿先天性心脏病的危险因素。方法以2013年4月－2014年8月在我院健康检查的4000名孕妇为研究对象,按照数字数表法随机分为观察组和对照组。观察组采用常规超声检查＋胎心检查,对照组采用常规超声检查,比较两组的检查结果,对筛查出怀有先天性心脏病胎儿的孕妇进行危险因素调查。结果常规超声检查加胎心产前检查发现9例先天性心脏病胎儿,漏检1例,诊断准确率为90％。常规超声产前检查发现3例先天性心脏病胎儿,漏查2例,诊断准确率为40％,两组间差异具有统计学意义（ P＜0．05）。结论常规超声检查加胎心检查用于先天性心脏病筛查准确率高于常规超声检查对照组,值得临床推广。     

Ca2+-dependent signaling pathways in the heart: potential drug targets for cardiac disease

Ca2+ is an important secondary messenger and any alteration to intracellular Ca2+ signaling pathways or components of these pathways can have a profound physiological effect on any cell, particularly cardiomyocytes. Early approaches to investigate heart disease focused on many muscle proteins, however recent findings indicate that molecules considered as "non-muscle" proteins may be equally important players in etiology of many cardiac pathologies. Many of these "non-muscle" proteins play a role in Ca2+ cycling or Ca2+ -dependent signaling pathways in the heart. In this review we focus on Ca2+ -dependent pathways in normal, growing, and diseased hearts. Understanding of these unique signaling pathways may hold answers to many cardiac pathologies in children and adults.     

Methylglyoxal activates the human transient receptor potential ankyrin 1 channel

Methylglyoxal (MG) is an endogenous carbonyl compound that is produced in large quantity under hyperglycemic conditions, which are believed to contribute to the development of diabetic neuropathy. However, the mechanism by which this occurs and the molecular targets of MG are unclear. In the present study, we investigated the effect of MG on transient receptor potential ankyrin 1 (TRPA1) activation in human TRPA1-expressing HEK293 cells. MG activated TRPA1-expressing HEK293 cells, but failed to activate human capsaicin-sensitive transient receptor potential vanilloid 1 (TRPV1)-expressing HEK293 cells or mock-transfected HEK293 cells. MG also induced calcium (Ca²⁺) influx in a concentration-dependent manner, and the concentration-response curve indicates that the effect of MG has an EC50 of 343.1 ± 17.3 μM. Interestingly, the time course in the intracellular Ca²⁺ concentration ([Ca²⁺]i) in human TRPA1-expressing HEK293 showed considerable differences in response to MG and cinnamaldehyde. Furthermore, we examined four endogenous carbonyl compounds, including MG, glyceraldehyde, glycolaldehyde, and glyoxal; only MG notably activated TRPA1-expressing HEK293 cells. These results may provide insight into the TRPA1-mediated effects of MG on diabetic neuropathy.     

美托洛尔治疗风湿性心脏病心力衰竭的临床效果分析

目的 探讨β1受体阻滞剂美托洛尔治疗风湿性心脏病引发心力衰竭的临床效果.方法 选取本院收治的36例风湿性心脏病患者,随机分为对照组与治疗组,对照组18例给予常规强心、利尿、扩血管治疗,治疗组18例在对照组治疗基础上给予美托洛尔口服,始服剂量为12.5 mg,2次/d,每2周剂量加倍直至目标剂量.半年随访治疗,观察比较两组患者的心功能改善情况.结果 治疗组患者的总有效率高于对照组,再住院率和病死率明显低于对照组,差异有统计学意义（P＜0.05）.两组患者的左室舒张末内径（LVD）、左室收缩末内径（LVS）、心率、舒张压均降低,左室射血分数（LVEF）均升高,治疗组改善效果明显优于对照组（P＜0.05）.结论 在常规治疗基础上加用β1受体阻滞剂美托洛尔治疗风湿性心脏病心力衰竭,安全简便,提高了临床疗效.     

Effect of verapamil and diltiazem on calcium-dependent electrical activity in cardiac Purkinje fibres.

The effects of verapamil and diltiazem on normal action potentials, abnormal automaticity at depolarized membrane potential and oscillatory afterpotentials were compared in sheep cardiac Purkinje fibres. Concentrations of verapamil and diltiazem exerting the same action on abnormal automaticity due to slow action potentials, caused different effects on action potential characteristics and on oscillatory afterpotentials. Diltiazem significantly shortened action potential duration whereas verapamil slightly lengthened it (NS). Diltiazem appeared to be more effective than verapamil in preventing the development of oscillatory afterpotentials induced by barium or by strophanthidin. In 50% of barium-treated preparations, verapamil caused the appearance of spontaneous activity due to enhanced normal diastolic depolarization, while diltiazem had no such effect. The observed differences were explained in terms of the different effects of the two drugs on currents other than the slow inward current, since diltiazem was more potent than verapamil in depressing Vmax.     

Sarcoplasmic reticulum and cardiac oxidative stress: an emerging target for heart disease

The sarcoplasmic reticulum (SR) is a major player in maintaining cardiac function, as it is intimately involved in the regulation of Ca²⁺-movements on a beat-to-beat basis. SR dysfunction due to abnormalities in SR protein content has been reported in different cardiac diseases such as ischaemic heart disease, myocardial infarction, congestive heart failure and various cardiomyopathies; thus the genes expressing the SR Ca²⁺-pump, Ca²⁺-channels, calsequestrin, phospholamban and other regulatory proteins are considered important targets for drug development. In our experience, ischaemic preconditioning (IP) and pharmacological therapies, such as anti-oxidants, β-adrenergic receptor blockers, angiotensin receptor (AT-1) blockers, angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers are effective therapies that improve cardiac performance in the failing heart by improving SR function. Accordingly, this paper is intended to shed light on the knowledge in the field of cardiac therapy targeted to improve and protect SR function.