Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8
BACKGROUND: Adenosine triphosphate (ATP)-sensitive potassium cardiac channels consist of inward-rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9). OBJECTIVE: To examine the association of mutations in KCNJ8 with Brugada syndrome (BrS) and early repolarization syndrome (ERS) and to elucidate the mechanism underlying the gain of function of ATP-sensitive potassium channel current. METHODS: Direct sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch-clamp methods were used to study mutated channels expressed in TSA201 cells. RESULTS: The same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS probands but was absent in 430 alleles from ethnically matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole-cell patch-clamp studies showed a 2-fold gain of function of glibenclamide-sensitive ATP-sensitive potassium channel current when KCNJ8-S422L was coexpressed with SUR2A-wild type. Inside-out patch-clamp evaluation yielded a significantly greater half maximal inhibitory concentration for ATP in the mutant channels (785.5 +/- 2 vs 38.4 +/- 3 muM; n = 5; P <.01), pointing to incomplete closing of the ATP-sensitive potassium channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/corrected QT intervals, likely owing to their effect to induce an increase in L-type calcium channel current (I(Ca-L)). CONCLUSIONS: Our results support the hypothesis that KCNJ8 is a susceptibility gene for BrS and ERS and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in ATP-sensitive potassium channel current is due to reduced sensitivity to intracellular ATP.
High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based pacing in the Mode Selection Trial (MOST)
OBJECTIVES: We evaluated the incidence, predictors, and treatment of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based (VVIR) pacing in the Mode Selection Trial (MOST). BACKGROUND: Pacemaker syndrome, or intolerance to VVIR pacing, consists of cardiovascular signs and symptoms induced by VVIR pacing. METHODS: The definition of pacemaker syndrome required that a patient with single-chamber VVIR pacing develop either congestive signs and symptoms associated with retrograde conduction during VVIR pacing or a >or=20 mm Hg reduction of systolic blood pressure during VVIR pacing, associated with reproducible symptoms of weakness, lightheadedness, or syncope. RESULTS: Of 996 patients randomized to VVIR pacing, 182 (18.3%) met criteria for pacemaker syndrome in follow-up. Pacemaker syndrome occurred early in most patients (13.8% at 6 months, 16.0% at 1 year, increasing to 19.7% at 4 years). Baseline univariate predictors of pacemaker syndrome included a lower sinus rate and higher programmed pacemaker rate. Previous heart failure, ejection fraction, and drop in systolic blood pressure with VVIR pacing at implantation did not predict the development of pacemaker syndrome. Post-implantation predictors of pacemaker syndrome were a higher percentage of paced beats, higher programmed low rate, and slower underlying spontaneous sinus rate. Quality of life decreased at the time of diagnosis of pacemaker syndrome and improved with reprogramming to atrial-based pacing. CONCLUSIONS: Severe pacemaker syndrome developed in nearly 20% of VVIR-paced patients and improved with reprogramming to the dual-chamber pacing mode. Because prediction of pacemaker syndrome is difficult, the only way to prevent pacemaker syndrome is to implant atrial-based pacemakers in all patients.
A blind comparison of four non-invasive twelve-lead electrocardiogram algorithms for predicting susceptibility to ventricular tachycardia
INTRODUCTION: To reduce QT measurement error, a new method was tested in which high-gain, high-speed, simultaneous 12-lead electrocardiographic (ECG) recordings were obtained during a single cardiac cycle. To increase its predictive power, the utility of combining QTD with the QRS duration for predicting susceptibility to ventricular tachyarrhythmia (VT) was analyzed. METHODS AND RESULTS: A total of 113 patients referred for electrophysiological study underwent baseline simultaneous 12-lead ECG followed by electrophysiological study to determine VT inducibility. Twenty-six patients had inducible VT while 87 patients did not. QT intervals and the width of QRS complex were measured from a single cardiac cycle with high-gain (8 times normal) and high-speed (100 mm/second) 12-lead ECG recordings. This method resulted in 100% QT interval identification throughout all 12 leads for every patient. Receiver-operator characteristic curves (ROC) and the areas under the ROC curves (AUC) were used to quantitatively analyze the performance of four ECG variables (QTD3, QTD12, QTD12 + QRS and QTD3 + QRS). All four ECG variables were significantly increased in the patients with inducible VT as compared to those without inducible VT. The QTD3 algorithm was less useful than QTD12 in predicting inducible VT; however, the addition of QRS duration to all QTD algorithms enhanced VT detection. CONCLUSION: 1) QRS duration has an incremental benefit in the detection of VT when combined with QTD; 2) QTD12 + QRS duration provided the highest predictive power among the four tested algorithms; 3) high-gain, high-speed 12-lead ECG recordings reduced QT measurement error.
Cardiac arrest caused by trigeminal neuralgia [Case Report]
A 67-year-old man with a 12-year history of trigeminal neuralgia experienced multiple fainting episodes preceded by right facial pain. One episode resulted in cardiac arrest with successful resuscitation. Pacemaker insertion prevented further episodes of syncope despite the occurrence of pain. The fainting episodes and cardiac arrest are believed to be unusual manifestations of trigeminal neuralgia
Internal mammary artery angiography should be a routine component of diagnostic coronary angiography
Left internal mammary artery (LIMA) angiography was performed with diagnostic coronary angiography in 130 cases for which the coronary findings made use of the LIMA as a bypass graft a consideration. In 98% of the cases the approach to LIMA angiography was femoral with a 5F LIMA catheter first directed into the proximal subclavian and then advanced over a guidewire placed into the distal subclavian well beyond the origin of the LIMA. After withdrawing the wire the catheter was brought proximally to selectively cannulate and visualize the LIMA with nonionic contrast media. The only complication was a single transient occipital visual field loss. LIMA caliber too narrow to permit use as a graft was found twice, LIMA occlusion unrelated to prior surgery was found once, and LIMA occlusion related to prior surgery was found twice. Subclavian and/or vertebral stenosis was present five times. Large proximal branches of the LIMA best identified prior to surgery were present 12 times. Based on this experience, LIMA angiography 1) can be performed safely with a high degree of success, 2) demonstrates significant findings in 15% of cases, and 3) should therefore be performed whenever coronary angiographic findings make it appropriate to consider LIMA to coronary artery bypass grafting