Pharmacological Activation of IKr Impairs Conduction in Guinea Pig Hearts

Activation of I_Kr Impairs Conduction. Introduction: The hERG (Kv11.1) potassium channel underlies cardiac I_Kr and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I_Kr results in impaired cardiac conduction. Methods and Results: Cardiac conduction was assessed in Langendorff‐perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 μM) prolonged the QRS rate dependently. A significant prolongation (16 ± 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I_Kr blocker E4031 (1 μM). While partial I_Na inhibition with flecainide (1 μM) alone prolonged the QRS (34 ± 3%, BCL 250 ms), the QRS was further prolonged by 19 ± 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di‐4‐ANEPPS a similar potentiation of the effect of NS3623 was observed. With di‐4‐ANEPPS, NS3623 prolonged the QRS significantly (26 ± 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity. Conclusion: Pharmacological activation of I_Kr by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I_Kr in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs. (J Cardiovasc Electrophysiol, Vol. 21, pp. 923‐929, August 2010)     

Transseptal Dispersion of Repolarization and Its Role in the Development of Torsade de Pointes Arrhythmias

Transseptal Dispersion and TdP . Objective: This study was designed to quantitate transseptal dispersion of repolarization (DR) and delineate its role in arrhythmogenesis using the calcium agonist BayK 8644 to mimic the gain of function of calcium channel current responsible for Timothy syndrome. Background: Amplification of transmural dispersion of repolarization (TDR) has been shown to contribute to development of Torsade de Pointes (TdP) arrhythmias under long‐QT conditions. Methods: An arterially perfused septal wedge preparation was developed via cannulation of the septal artery. Action potentials (APs) were recorded using floating microelectrodes together with a transseptal electrocardiogram (ECG). These data were compared to those recorded from arterially perfused canine left ventricular (LV) wedge preparations. Results: Under control conditions, the shortest AP duration measured at 90% repolarization (APD₉₀) was observed in right ventricular (RV) endocardium (181.8 ± 15 ms), APD₉₀ peaked close to midseptum (278.0 ± 32 ms), and abbreviated again as LV endocardium was approached (207.3 ± 9 ms). Transseptal DR averaged 106 ± 24 ms and T_peak–T_end 84 ± 7 ms (n = 6). TDR and T_peak–T_end recorded from LV wedge were 36 ± 9 ms and 34 ± 19 ms, respectively (n = 30). BayK 8644 increased transseptal DR to 123.2 ± 35 ms (n = 5) and induced early and delayed afterdepolarizations (3/5), rate‐dependent ST‐T‐wave alternans (5/5), and TdP arrhythmias (3/5). Conclusions: Our data indicate that dispersion of repolarization across the interventricular septum is twice that of the LV free wall, predisposing to development of TdP under long‐QT conditions. Our findings suggest that the coronary‐perfused ventricular septal preparation may be a sensitive model in which to assess the potential arrhythmogenic effects of drugs and pathophysiological conditions. (J Cardiovasc Electrophysiol, Vol. 21, pp. 441–447, April 2010)     

Electrocardiographic features in a patient with the coexistence of long QT syndrome and coronary vasospasm

A 20-year-old woman suffered from cardiopulmonary arrest due to ventricular fibrillation. The electrocardiogram after resuscitation showed prolonged QTc interval with bifid T wave. On the third hospital day, the QTc interval and the T-wave changes improved. However, the QTc interval was distinctively prolonged after administration of epinephrine, oral glucose load, and intracoronary acetylcholine (Ach) into the left coronary artery. Moreover, an injection of Ach into the right coronary artery provoked severe coronary spasm. This is a case of the coexistence of long QT syndrome (LQTS) and coronary vasospasm, which may give an important clinical implication for the treatment of LQTS.     

QT dispersion increases in patients with systemic lupus erythematosus

Although autopsy studies have documented that heart is affected in most of systemic lupus erythematosus (SLE) patients, clinical manifestations occur in less than 10%. QT dispersion, a new parameter that can be used to assess homogeneity of cardiac repolarization and autonomic function, has not been studied in SLE patients. The aim of our study was to evaluate the QT dispersion (QTd) in SLE patients without overt cardiac involvement. Eighty-three patients with a diagnosis of SLE (mean age 41±13) and age- and sex-matched 77 healthy control subjects (mean age 43±10) were enrolled in the study. All subjects had their complete history taken, laboratory examination, and transthoracic echocardiography (ECG). Patients with cardiac disease, hypertension, diabetes, or taking medications that may effect QTd or any ECG abnormalities were excluded. Resting 12-lead ECG were recorded for measurement of QTd. None of the patients and control subjects had overt cardiac involvement. The mean SLE duration was 86.5±15.4 months. QT dispersion was significantly greater in SLE patients than incontrol subjects (55.2±24.7 vs 20.7±5.3 ms, respectively; p<0.001). There was no correlation between QTd and duration of SLE, SLEDAI-K score, corticosteroid usage, and presence of anti SS-A antibody. QT dispersion is significantly increased in SLE patients without overt cardiac involvement. Our result suggests that prolonged QT dispersion can be a useful noninvasive and simple method for early detection of cardiac involvement in SLE patients.     

Impaired T-amplitude adaptation to heart rate characterizes I(Kr) inhibition in the congenital and acquired forms of the long QT syndrome

Introduction:  The QTc interval prolongation is not a perfect surrogate marker of the presence of an increased risk for arrhythmic events. In the search for alternative markers, we investigated the T-amplitude and QT interval adaptation to heart rate (HR) in patients with the congenital long QT syndrome (LQTS) and individuals with sotalol-induced QT prolongation.
Methods and Results:  Our investigation is based on the analysis of continuous 12-lead digital Holter recordings in: 49 LQT1 carriers, 25 LQT2 carriers, 37 healthy individuals off drugs and on 160 mg of sotalol, and 21 of them also on 320 mg of sotalol. The Holter recordings were used to investigate repolarization parameters and their HR dependency. A loss of HR dependency of the T-amplitude was found as a common feature in individuals with impaired I_kr kinetics: LQT2 carriers and subjects on sotalol. The T-amplitude/RR slope was significantly (P < 0.05) flatter in LQT2 (0.31 ± 0.27 μV/ms) than in both LQT1 (0.62 ± 0.40 μV/ms) and healthy individuals (0.55 ± 0.29 μV/ms). A dose-dependent reduction of the T-amplitude/RR slope was also observed in subjects on sotalol (160 mg dose: 0.26 ± 0.19 μV/ms; 320 mg dose: 0.21 ± 0.14 μV/ms). The QT/RR slope was less effective than T-amplitude/RR slope in differentiating between congenital and drug-induced repolarization delay.
Conclusions:  Impaired adaptation of T-amplitude to changing HR is a common electrocardiographic feature associated with KCNH2 mutation and I_kr blockade by sotalol. This ECG marker may play an important role in the future of the assessment of the penetrance of KCNH2 mutation and the identification of a drug effect on the I_kr kinetics.     

Increasing gap junction coupling reduces transmural dispersion of repolarization and prevents torsade de pointes in rabbit LQT3 model

Introduction: Increased transmural dispersion of repolarization (TDR) contributes importantly to the development of torsades de pointes (TdP) in long QT syndrome (LQTS). Intercellular electrical coupling via gap junctions plays an important role in maintaining TDR in both normal and diseased hearts. This study examined the effects of antiarrhythmic peptide AAP10, a gap junction enhancer, on TDR and induction of TdP in a rabbit LQT3 model.
Methods and Results: An arterially perfused rabbit left ventricular preparation and sea anemone toxin II (ATX-II, 20 nM) were used to establish a LQT3 model. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded. Changes in nonphosphorylated connexin43 (Cx43) were measured by immunoblotting. Compared with the control group, the QT interval, TDR, early afterdepolariztion (EAD), R-on-T extrasystole, and TdP increased sharply with augmented nonphosphorylated Cx43 in the LQT3 group (P < 0.001 for both). Interestingly, compared with the LQT3 group, 500 nM AAP10 reduced QT interval, TDR (P < 0.001 for both), and prevented EAD, R-on-T extrasystole, and TdP (P = 0.003, P = 0.001, P = 0.02) with a parallel decrease in nonphosphorylated Cx43 in the presence of ATX-II (P < 0.001).
Conclusion: Gap junction enhancer AAP10 is capable of abbreviating the QT interval, reducing TDR, and suppressing TdP in a rabbit LQT3 model probably via its effect by preventing dephosphorylation of Cx43. These data suggest that increasing intercellular coupling may reduce TDR and, therefore, prevent TdP in LQTS.     

中年人群代谢综合征及其组分与心电图QT间期关系研究

目的探讨中年人群代谢综合征(metabolic syndrome,MS)及其组分与心电图QT间期的关系。方法2003—2006年对975名"宫内发育与成人疾病"队列人群(1948—1954年在北京协和医院出生的活产单子,其中男494名,女481名,年龄41~53岁)进行流行病学调查、身体测量、血生化指标测定及MS诊断,记录标准12导联心电图,用Bazett公式计算校正的QT间期(QTc)。采用稳态模式评估法计算胰岛素抵抗指数(HOMA-IR)。结果该中年人群心电图QT间期延长者262例(占26.9%),MS、HOMA-IR、中心性肥胖、高血压、高血糖、高三酰甘油(TG)、低高密度脂蛋白胆固醇(HDL-C)的检出率分别为19.7%,19.5%,42.5%,34.3%,26.3%,34.6%,31.1%。心电图QT间期延长与中心性肥胖、高血糖、高TG、胰岛素抵抗(IR)、MS及异常组分聚集有相关关系(P<0.05)。结论心电图QT间期延长与多项代谢异常组分、代谢异常聚集及代谢综合征有相关联系。     

Functional polymorphisms of the cytochrome P450 1A2 (CYP1A2) gene and prolonged QTc interval in schizophrenia

CYP1A2 is an important inducible enzyme involved in the metabolism of antipsychotics. This study examined two functional polymorphisms in the gene as potential markers in predicting prolongation of QTc interval in patients treated with antipsychotics. QT intervals were measured by 12-lead electrocardiography (ECG) for patients with a DSM-IV diagnosis of schizophrenia. Genomic DNA extracted from venous blood were genotyped for the two polymorphisms by PCR-RFLP. Statistically significant result for CYP1A2(*)1F was noted for all patients receiving chlorpromazine equivalent doses of above 300 mg and also for a further subgroup on antipsychotics known to be CYP1A2 substrates (p=0.007, mean QTc in ms for A/A: 395.5+/-15.1, A/C: 425.7+/-25.1, C/C: 427.3+/-20.7). For CYP1A2(*)1C, there was no statistically significant association between genotypes and mean QTc interval. Overall, there was a trend of those with the C allele of the CYP1A2(*)1F polymorphism having longer QTc intervals. The results of this study suggest that the CYP1A2(*)1F polymorphism may contribute to the risk of developing prolonged QT-interval in patients who are treated with higher doses of antipsychotics.     

抗精神病药物致代谢综合征及其组分与心电图QT间期的关系

目的 探讨抗精神病药物致代谢综合征(metabolic syndrome,MS)及其组分与心电图QT间期的关系.方法 对460例服用抗精神病药物的精神分裂症患者进行流行病学调查、身体测量、血生化指标测定及MS诊断,记录标准12导联心电图,用Bazett公式计算校正的QT间期(QTC).采用稳态模式评估法计算胰岛素抵抗指数(HOMA-IR).结果 抗精神病药物致代谢综合征人群心电图QT间期延长者124例,占27.0%,男女心电图QT间期延长检出率分别为21.7%、32.7%,差异有显著性(χ2=7.13,P<0.01).MS、HOMA-IR、中心性肥胖、高血压、高血糖、高TG、低HDL-C的检出率分别为39.3%,38.7%,35.4%,34.1%,31.3%,29.8%,27.0%.心电图QT间期延长与中心性肥胖、高血糖、高TG、胰岛素抵抗(IR)、MS及异常组分聚集有相关关系(χ2=4.95～13.63,P<0.05).结论 心电图QT间期延长与抗精神病药物所致多项代谢异常组分、代谢异常聚集及代谢综合征相关联.