Electrophysiological effects of Chinese medicine Shen song Yang xin （SSYX） on Chinese miniature swine heart and isolated guinea pig ventricular myocytes

Background Shen song Yang xin （SSYX） is a compound of Chinese medicine with the effect of increasing heart rate （HR）. This study aimed to evaluate its electrophysiological properties at heart and cellular levels. Methods The Chinese miniature swines were randomly assigned to two groups, administered with SSYX or placebo for 4 weeks （n=8 per group）. Cardiac electrophysiological study （EPS） was performed before and after drug administration. The guinea pig ventricular myocytes were enzymatically isolated and whole cell voltage-clamp technique was used to evaluate the effect of SSYX on cardiac action potential （AP）. Results SSYX treatment accelerated the HR from （141.8±36.0） beats per minute to （163.0±38.0） beats per minute （P=0.013） without changing the other parameters in surface electrocardiogram. After blockage of the autonomic nervous system with metoprolol and atropin, SSYX had no effect on intrinsic HR （IHR）, but decreased corrected sinus node recovery time （CSNRT） and sinus atrium conducting time （SACT）. Intra cardiac EPS showed that SSYX significantly decreased the A-H and A-V intervals as well as shortened the atrial （A）, atrioventricular node （AVN） and ventricular （V） effective refractory period （ERP）. In isolated guinea pig ventricular myocytes, the most obvious effect of SSYX on action potential was a shortening of the action potential duration （APD） without change in shape of action potential. The shortening rates of APD30, APD50 and APD9o were 19.5%, 17.8% and 15.3%, respectively. The resting potential （Em） and the interval between the end of APD30 and APD90 did not significantly change. Conclusions The present study demonstrates that SSYX increases the HR and enhances the conducting capacity of the heart in the condition of the intact autonomic nervous system. SSYX homogenously decreases the ERP of the heart and shortens the APD of the myocytes, suggesting its antiarrhythmic effect without proarrhythmia.

Effects of Chinese herbs on multiple ion channels in isolated ventricular myocytes

Background Shensong Yangxin （SSYX） is one of the compound recipe of Chinese materia medica. This study was conducted to investigate the effects of SSYX on sodium current （/Na）, L-type calcium current （/Ca.L）, transient outward potassium current （/to）, delayed rectifier current （/K）, and inward rectifier potassium currents （/K1） in isolated ventricular myocytes. Methods Whole cell patch-clamp technique was used to study ion channel currents in enzymatically isolated guinea pig or rat ventricular myocytes. Results SSYX decreased peak Na by （44.84±7.65）% from 27.21±5.35 to 14.88±2..75 pA/pF （n=-5, P〈0.05）. The medicine significantly inhibited the /Ca,L. At concentrations of 0.25, 0.50, and 1.00 g/100 ml, the peak/Ca,L was reduced by （19.22±1.10）%, （44.82±6.50）% and （50.69±5.64）%, respectively （n=5, all P〈0.05）. SSYX lifted the I-V curve of both /Na and /Ca,L without changing the threshold, peak and reversal potentials. At the concentration of 0.5%, the drug blocked the transient component of /to by 50.60% at membrane voltage of 60 mV and negatively shifted the inactive curve and delayed the recovery from channel inactivation. The tail current density of /K was decreased by （30.77±1.11）% （n=5, P〈0.05） at membrane voltage of 50 mV after exposure to the medicine and the time-dependent activity of /K was also inhibited. Similar to the effect on /K, the SSYX inhibited /K1 by 33.10% at the test potential of -100 mV with little effect on reversal potential and the rectification property. Conclusions The experiments revealed that SSYX could block multiple ion channels such as /Na /Ca,L, /k, /to and /K1, which may change the action potential duration and contribute to some of its antiarrhythmic effects.

Modulation of KCNQ1 current by atrial fibrillation-associated KCNE4 (145E/D) gene polymorphism

Background Atrial fibrillation is a common arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism （G/T） at position 1057 in the KCNE4 gene, resulting in a glutamic acid （Glu, E）/aspartic acid （Asp, D） substitution at position 145 of the KCNE4 peptide, was found in our laboratory to be associated with idiopathic atrial fibrillation （atrial fibrillation more frequent with KCNE4 145D）. However, the functional effect of the KCNE4 145E/D polymorphism is still unknown. Methods We constructed KCNE4 （145E/D） expression plasmids and transiently co-transfected them with the KCNQ1 gene into Chinese hamster ovary-K1 cells and performed whole-cell patch-clamping recording to identify the possible functional consequences of the single nucleotide polymorphism. Quantitative data were analyzed by Student＇s t test. Probability values less than 0.05 were considered statistically significant. Results A slowly activating, non-inactivating voltage-dependent current （（24.0±2.9） pA/pF, at ＋60 mV）） could be recorded in the cells transfected with KCNQ1 alone. Co-expression of wild type KCNE4 inhibited the KCNQ1 current （（7.3± 1.1 ） pA/pF））. By contrast, co-expression of KCNE4 （145D） augment the KCNQ 1 current （（42.9 ±3.7） pA/pF））. The V1/2 of activation for the KCNQI/KCNE4 （145D） current was shifted significantly towards the depolarizing potential compared to that for the KCNQ1 current （（-2.3±0.2） mv vs （-13.0±1.5） mv, P 〈 0.01）） without changing the slope factorK. Furthermore, KCNE4 （145D） also affected the activation and deactivation kinetics of KCNQ1 channels. Conclusion We provide experimental evidence that the KCNE4 （145E/D） polymorphism exerts the effect of ＂gain of function＂ on the KCNQ1 channel. It may underlie the genetic mechanism of atrial fibrillation. Further studies on the functional association between IKs and KCNE4 （145D） polymorphism in cardiac myocytes are suggested.

Clinical study of 39 Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy

Background There are few studies on the clinical profile of Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy （ARVD/C）. The purpose of this study was to describe the clinical characteristics of ARVD/C patients from China, particularly to define the features of electrocardiograph and treatment outcomes. Methods Thirty-nine patients hospitalized in Fu Wai Cardiovascular Hospital from 1998 to 2006 were included. The data were obtained from the medical archive and the follow-up records. Results Of these patients 33 were male and 6 female （age at the first presentation was （34.9 ± 9.8） years）. The most common symptoms were palpitation （62%） and syncope （44%）. Right precordial QRSd 〉 110 ms was detected in 69% of the patients, epsilon wave in 59%, and a ratio of QRSd in V1＋V2＋V3/V4＋V5＋V6 ≥ 1.2 in 82%. The most frequent features of electrocardiogram in patients without right bundle-branch block were T-wave inversions and S-wave upstroke in V1-V3 〉55 ms （96% and 90% of 28 patients, respectively）. Radiofrequency catheter ablation （RFCA） for ventricular tachycardia （VT） was successful in 15 （68%） of 22 patients. The recurrence rate of VT was 46% （7/15） during the follow-up of （16.7 ± 11.2） months. Seven patients had cardioverter/defibrillator （ICD） implanted plus drug therapy and 17 patients took antiarrhythmic drugs alone. During the follow-up of （35.6 ± 19.0） months, all patients with ICD implanted received at least one appropriate ICD shock. One patient died of ventricular fibrillation suddenly and one patient underwent heart transplantation for progressive biventricular heart failure during the drug therapy alone. Conclusions This study demonstrated the clinical and ECG features of the 39 ARVD/C Chinese patients. ICD provided life-saving protection by effectively terminating malignant arrhythmias, and the high recurrence of VT was the major problem of RFCA therapy.

Effects of Shensong Yangxin capsule on pacemaker channels encoded by human HCN4 gene

Shensong Yangxin （SSYX） is one of the compound recipes of Chinese materia medica including 12ingredients such as Panax ginseng, dwarf lilyturf tuber,nardostachys root, etc. Small-scale randomized multi-centre clinical trials suggested that SSYX reduced the number of ventricular extrasystoles in patients with or without structural heart disease.1 Besides excellent antiarrhythmic efficacy,2 SSYX also improved bradycardia in some patients, which was evidenced by animal studies3 as well.

Nifekalant hydrochloride terminating sustained ventricular tachycardia accompanied with QT dispersion prolongation

Background Ventricular tachycardia （VT） and ventricular fibrillation are the main reasons causing sudden cardiac death.This study aimed to investigate the effects of nifekalant hydrochloride （NIF） on QT dispersion （QTd） in treating VT.Methods A total of 16 consecutive patients suffered sustained VT was included and then randomly divided into two groups according to the administration duration of NIF.In long-time group （group L）, patients were injected with NIF continuously for at least 12 hours after a bolus dose.The patients in short-time group （group S） were injected with NIF just for 1 hour.Results There were 7 of all 10 episodes of VT which were terminated by NIF, including 4 episodes in group L were stopped over 1 hour after continuous infusion of NIF.One patient suffered from torsade de pointes.Electrocardiography analysis indicated that QTd was significantly decreased 12 hours after stopping of infusing NIF compared with that when VT stopped （（45.4±22.1） ms vs.（73.4±33.2） ms, P 〈0.01）, and the corrected QTd （QTcd） decreased too （（47.8±22.9） ms vs.（78.3±36.5） ms, P 〈0.01 ）.There was a positive correlation between the increase in QTd and dose of administrating NIF （P 〈0.01）, so was QTcd （P 〈0.01）.Conclusions More administration of NIF indicates higher terminating rate of VT and more QTd prolongation.However,the safety is acceptable if several important issues were noticed in using NIF, such as serum potassium concentration,stopping side-effect related agents, and carefully observing clinical responses.

Beta2-adrenoceptor gene variant Arg16Gly is associated with idiopathic ventricular outflow-tract tachycardia

Background Imbalance of the sympathetic nervous system was involved in the pathogenesis of idiopathic ventricular outflow-tract tachycardia （IVOT）. We aimed to investigate whether the major genetic variants in β1-and β2-adrenoceptors and GNB3 C825T were associated with IVOT and verapamil sensitive idiopathic left ventricular tachycardia （ILVT）.Methods Patients with IVOT and ILVT from December 2005 to December 2007 were consecutively enrolled into this study. Controls were randomly selected from the community-based inhabitants. Five genetic variants, Ser49Gly and Gly389Arg in the β1-adrenoceptor, Arg16Gly and Gln27Glu in the β2-adrenoceptor and GNB3 C825T, were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis.Results A total of 227 patients with IVOT and 110 patients with ILVT were included. Genotyping revealed that the 16Gly allele of Arg16Gly variant of β2-adrenoceptor was associated with a higher risk of IVOT （OR：1.40, 95% CI： 1.12-1.75,P=0.003 in the addictive model and OR：. 1.62, 95% CI： 1.14-2.31, P=0.007 in the dominant model）. Patients with Gly16Gln27 haplotype also had a higher risk of IVOT （OR： 1.38, 95% CI： 1.11-1.73, P=0.012）. Other four variants,including Ser49Gly and Arg389Gly in β1-adrenoceptor, GIn27Glu in β2-adrenoceptor and GNB3 C825T, did not differ between patients with IVOT and controls. In patients with ILVT, no significant difference was found in these five variants compared with controls.Conclusions Arg16Gly in β2-adrenoceptor is significantly associated with IVOT in Chinese Han population. Major genetic variants in β1- and β2-adrenoceptor and GNB3 C825T may not be associated with ILVT. These data suggest a different arrhythmogenic mechanism in IVOT and ILVT.

Age-related changes in dispersion of atrial effective refractory period and its ionic mechanism in canines

Atrial fibrillation （AF） is the most common cardiac arrhythmia in man, and epidemiological study has shown the close relationship between the incidence of AF and aging. Although the effects of aging on atrial electrophysiolo have been investigated in humans and animal models, the electrophysiological changes that make the atria of aged individuals more susceptible to AF than those of adults remain poorly understood. AF is a reentrant arrhythmia, and the potential importance of dispersion of effective refractory period （ERP） for the induction and maintenance of reentry has long been recognized. In this study, we measured the dispersion of ERP and the underlying ionic mechanism in the atria of old and adult canines.

Flavivirus-like particles in the cardiac myocyte of a patient with arrhythmogenic right ventricular cardiomyopathy

Vires infection and subsequent myocardial damage and repairing were regarded as important aspects in the pathogenesis of dilated cardiomyopathy. Enterovirus and its association with myocarditis and dilated cardiomyopathy have been investigated extensively. Arrhythmogenic right ventricular cardiomyopathy （ARVC） is a relatively uncommon kind of cardiomyopathy which could cause malignant arrhythmia and sudden death in human. Although some ARVC patients have family history and some gene defects were found to be associated with ARVC, enterovims genome was shown in endomyocardial samples from the patients with ARVC and it suggested possible association between ARVC and vires infective myocarditis. Here, we present an electron microscopic evidence for a flaviviral infection of myocytes from a case of ARVC.