ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.

BACKGROUND: Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K(+) channel (I(K-ATP)), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis that genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS. METHODS AND RESULTS: Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC50 that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC50 from 8.5 ± 2 mM to 13.4 ± 5 µM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by -18.0 mV (p<0.01) and increased late I(Na) from 0.14% to 2.01% of peak I(Na) (p<0.01). CONCLUSION: Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in I(K-ATP) when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.

Electrophysiological characterization of cardiac veins in humans.

BACKGROUND: The coronary sinus is a complex structure with a surrounding myocardial coat and muscle bundles that course within it. The purpose of this study was to evaluate the electrical activity of the coronary sinus (CS), great cardiac vein (GCV) and related structures, such as the Vein of Marshall (VOM). METHODS AND RESULTS: Data obtained from adult ( n = 114) and pediatric patients ( n = 16) were analyzed. The width of atrial electrograms (EGMs) within the CS at a basic pacing cycle length of 600 ms was 46 +/- 7.4 ms (mean +/- SD) vs. 29.7 +/- 6.3 ms in the GCV ( p < 0.01). With decremental pacing the width of the EGM within the CS at 300 ms increased to 66.6 +/- 8.5 ms ( p < 0.1 compared to CS EGM at pacing cycle length of 600 ms). The width of the EGM within the GCV increased from 29.7 +/- 6.3 ms at a pacing cycle length of 600 ms to 34.6 +/- 6.0 at 300 ms ( p = NS). There were no significant differences in the atrial EGM width between CS and GCV in the pediatric patients. CONCLUSIONS: We conclude that atrial electrograms are wider in the CS but not in the GCV. This finding can be explained by the presence of a myocardial coat around the CS. The rate response characteristics of the atrial electrograms within the CS are consistent with a lack of tight coupling between muscle bundles and the CS musculature. Further, the absence of such differences in pediatric patients could partly explain relative differences in types of supraventricular arrhythmias seen in different age groups.

Influence of age and gender on the mechanism of supraventricular tachycardia.

OBJECTIVES: The objective of this study was to determine the impact of age and gender on the mechanism of paroxysmal supraventricular tachycardia (PSVT). BACKGROUND: Previous studies have indicated that PSVT mechanism may be influenced by age and gender, but contemporary data are limited. METHODS: In 1,754 patients undergoing catheter ablation of 1,856 PSVTs between 1991 and 2003, the mechanism was classified as atrioventricular reentrant tachycardia (AVRT), atrioventricular nodal reentrant tachycardia (AVNRT), or atrial tachycardia (AT). Patients with inappropriate sinus tachycardia, atrial flutter, atrial fibrillation, and age <5 years were excluded. RESULTS: The mean age was 45 +/- 19 years (range 5-96), and the majority were women (62%). Overall, AVNRT was the predominant mechanism (n = 1,042 [56%]), followed by AVRT (n = 500 [27%]) and AT (n = 315 [17%]). There was a strong relationship between age and PSVT mechanism; the proportion of AVRT in both sexes decreased with age, whereas AVNRT and AT increased (PM < .001 by ANOVA). The majority of patients with AVRT were men (273/500 [54.6%]), whereas the majority of patients with AVNRT and AT were women (727/1,042 [70%] and 195/315 [62%], respectively). The distribution of PSVT mechanism was significantly influenced by gender (P < .001). In women, 63% had AVNRT, 20% had AVRT, and 17.0% had AT. In men, 45% had AVNRT, 39% had AVRT, and 17% had AT. AVNRT replaced AVRT as the dominant PSVT mechanism at age 40 in men and at age 10 in women. CONCLUSIONS: The mechanism of PSVT in patients presenting for ablation is significantly influenced by both age and gender.

Alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo.

We previously reported that alpha(2)-adrenergic receptor (alpha(2)-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses beta-adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of alpha(2)-AR stimulation on reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface electrocardiogram, and renal sympathetic nerve activities were recorded simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for controls, 50% for the beta-blocker group, 72% for the alpha(1)-blocker group, and 12.5% for the alpha(1) + beta-blockers group (unopposed alpha(2)-adrenergic activation). Direct alpha(2)-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the alpha(2)-adrenergic antagonist yohimbine. Increases in renal sympathetic nerve activity were associated with left anterior descending coronary artery ligation and reperfusion (33 +/- 1.5 and 62 +/- 1.7% over baseline, respectively) in controls. Similar patterns were observed among all experimental groups irrespective of the incidence of VT/VF on reperfusion. We conclude that alpha(2)-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.