Clinical, Genetic And Cellular Electrophyisiological Study On Brugada Syndrome

The Brugada syndrome has been an area of intensive investigation since its earliest description in 1992, both on a clinical and on a basic research level. In this study, we would make further investigations on risk stratification of Brugada syndrome,echocardiographic changes of Brugada syndrome,genetic characters and ionic mechanisms of the effects of isoproterenol on Brugada syndrome.Part I A cohort study of three years on 41 patients with a Brugada-type electrocardiogramObjective To investigate characteristics of LP in Chinese patients with BrS and its correlation with arrhythmia events in the current diagnostic criteria of BrS. Methods The signal-averaged electrocardiography (SAECG) was used to analyze characteristics of LP in 15 cases with ECG type I BrS and 26 cases with ECG type II or III BrS. The cohort study was conducted to observe the occurrence of arrhythmia and related events in BrS patients with positive LP and negative LP during a mean follow-up of period of 31.4±5.7 months. Results Positive LPs were present in 13 of 15 patients with type I BrS (86.7%),but LP was positive in only 2 subjects in the group of ECG type II or type III BrS(7.7%). The incidence of arrhythmia and related events were 86.7% (13 of 15 patients) in BrS patients with positive LP and 3.8% (1 of 26 patients) in BrS patients with negative LP, respectively (the relative risk (RR) was 22.5 and the 95% confidence interval(CI) was[3. 3,155.6], P<0.0001). Conclusion LP could be an effective factor predicting ventricular arrhythmia and one of useful markers for risk stratification in Chinese patients with BrrS. PartⅡInterventricular septum motion abnormalities: unexpected echocardiographic changes of Brugada syndromeBackground There remains controversy about whether Brugada syndrome has structural heart changes. We occasionally noted that a patient with BrS had a quite unusual regional wall motion abnormality at the basal segment of the interventricular septum (IVS) during echocardiographic examination. The unexpected finding promoted us to reexamine our patients with BrS by competing echocardiographic interrogation in the present study. Methods Patients with BrS (n=15), patients with complete right bundle branch block (RBBB) (n=15), and control subjects (n=15) were enrolled in this study. Two-dimensional echocardiography (2DE) was performed to obtain parasternal left ventricular long axis view on which M-mode scanning line was adjusted to be perpendicular to the basal segment of IVS for delineation of the segmental motion curve, with a simultaneously electrocardiographic tracing. Results 2DE revealed a rapid swing motion shifting toward the right ventricle of the IVS basal segment at early systole in 73.3% (11/15) patients with BrS, which was further confirmed on the M-mode curve evidenced by an early systolic notch toward the right ventricle. The position of the notch corresponded to C-point on the mitral motion curve, lasting for about 55 ms. There were no similar changes both in patients with RBBB and in the control subjects. Conclusions IVS basal motion abnormalities at early-systolic phase may be the novel finding of BrS.PartⅢGenetic study of the cardiac sodium channel gene SCN5A in Chinese with Brugada syndromeObjective To investigate mutations of SCN5A gene in Chinese Brugada syndrome.Methods 15 patients and their family members were screened for mutations by direct DNA sequeencing. Genomic DNAs were extracted from peripheral blood leukocytes. All 28 exons of SCN5A gene were amplified by PCR using 40 pairs of primers. The PCR products were sequenced directly. Results A novel single missence mutation, G5080A(R1628Q), was identified, which caused the change of the structure of S4 in domain IV ofαsubunit coding for cardiac sodium channel. This mutation was not found in 150 unrelated normal individules. Conclusions A new mutation in domain IV of SCN5A were found in Chinese Brugada syndrome.PartⅣStudies on ionic mechanisms of the effects of isoproterenol on Brugada syndrome Objective It has been reported that adrenergic beta stimulation attenuatedST-elevation and ventricular arrhythmia and electrical storm was suppressed by treatment with low-dose isoproterenol(Iso) in some cases of Brugada syndrome . However, there have been few systematic studies on ionic mechanisms of the effects of isoproterenol. Methods Single epicardial myocytes of right ventricle of the rabbits were isolated with enzymatic dissociation . The whole-cell patch clamp recording technique was used to observe the effect of 1μM Iso on action potential duration(APD), L-type calcium current (ICa,L) and transient outward potassium current (Ito) in epicardial myocytes of right ventricle of the rabbits. Results①1μM Iso significantly prolonged APD20, APD50 and APD90 from (151.3±11.8)ms,(268.7±27.3)ms and (380.9±34.6)ms to (195.4±13.3)ms, (324.5±32.8)ms and (423.5±42.1)ms (n=14, p<0.05), respectively.②At +60mV, Ito decreased from (11.4±1.7)pA/pF to(6.3±0.5)pA/pF(n=16,p<0.05 )after 1μM Iso. 1μM Iso downshifted the I-V curves of Ito without changes of their active, peak and reverse potentials; 1μM Iso turned the steady-state inactication curve to left and the curve of time recovery from inactivation of Ito moved right. V1/2,act and kact of Ito had no significant difference before and after 1μM Iso.③1μM Iso increased peak ICa,L from (-6.1±0.6)pA/pF to(-8.6±0.9)pA/pF ( n=10 , p<0.05 ), respectively. 1μM Iso downshifted the I-V curves of ICa without changes of their active, peak and reverse potentials. Conclusions Iso could prolonged APD, especially APD20 and APD50 ; Iso blocked Ito in a voltage dependent manner and probably inhibited Ito in its inactive state; Iso augmented ICa,L in a voltage dependent manner, which could be the important mechanisms of its suppressing ventricular arrhythmia and electrical storm of Brugada syndrome.