Drug-induced Fatal Arrhythmias: Acquired long QT and Brugada Syndromes

Since the early 1990s, the concept of primary “inherited” arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc. Among these, long QT and Brugada syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. To date, more than 10 different genes have been reported to be responsible for each syndrome. More recently, it was recognized that long QT syndrome can be latent, even in the presence of an unequivocally pathogenic mutation (silent mutation carrier). Co-existence of other pathological conditions in these silent mutation carriers may trigger a malignant form of ventricular arrhythmia, the so called torsade de pointes (TdP) that is most commonly brought about by drugs. In analogy to the drug-induced long QT syndrome, Brugada type 1 ECG can also be induced or unmasked by a wide variety of drugs and pathological conditions; so physicians may encounter patients with a latent form of Brugada syndrome. Of particular note, Brugada syndrome is frequently associated with atrial fibrillation whose therapeutic agents such as Vaughan Williams class IC drugs can unmask the dormant and asymptomatic Brugada syndrome. This review describes two types of drug-induced arrhythmias: the long QT and Brugada syndromes

遺伝子診断に基づく不整脈疾患群の病態解明および診断基準・重症度分類・ガイドライン作成に関する研究

厚生労働科学研究費補助金研究成果報告書研究区分: 厚生労働科学研究費補助金 疾病・障害対策研究分野 難治性疾患等克服研究（難治性疾患政策研究）課題番号: H27-難治等(難)-一般-032研究年度: 2015報告書区分: 総括文献番号: 201510099A研究代表者: 堀江 稔（滋賀医科大学・医学部・教授

遺伝性不整脈疾患の診断基準・重症度分類・診療ガイドライン等の作成に関する研究

厚生労働科学研究費補助金研究成果報告書研究区分: 厚生労働科学研究費補助金 疾病・障害対策研究分野 【補助金】 難治性疾患等克服研究（難治性疾患克服研究）課題番号: H26-難治等(難)-一般-040研究年度: 2014報告書区分: 総括文献番号: 201415075A研究代表者: 堀江 稔（滋賀医科大学・医学部・教授

先天性QT延長症候群の家族内調査による遺伝的多様性の検討と治療指針の決定

厚生労働科学研究費補助金研究成果報告書研究区分: 厚生労働科学研究費補助金 疾病・障害対策研究分野 難治性疾患等克服研究（難治性疾患克服研究）課題番号: H23-難治-一般-088研究年度: 2012報告書区分: 総括文献番号: 201231067A研究代表者: 堀江 稔（滋賀医科大学・医学部・教授

Molecular medicine of inherited arrhythmias

科学研究費補助金研究成果報告書研究種目: 基盤研究(B)研究期間: 2002～2003課題番号: 14370225研究代表者: 堀江 稔（滋賀医科大学・医学部・教授

Pueraria mirifica, an estrogenic tropical herb, unveiled the severity of Type 1 LQTS caused by KCNQ1-T587M

After taking an estrogen-containing supplement derived from a tropical plant Pueraria mirifica, a 24-year-old woman presented marked QT prolongation and repetitive torsade de pointes. The patient was found to carry a heterozygous KCNQ1-T587M mutation. This is the first report on Pueraria mirifica-related acquired long QT syndrome

Plasma level of oxidized low-density lipoprotein is an independent determinant of coronary macrovasomotor and microvasomotor responses induced by bradykinin

AbstractObjectivesWe examined the relationship between coronary endothelium-dependent vasodilation in response to bradykinin (BK) and plasma levels of oxidized low-density lipoprotein (oxLDL) in subjects with normal coronary arteries.BackgroundIt is unclear whether the plasma oxLDL level is a determinant of coronary endothelial function. Bradykinin plays an important role in regulating resting coronary tone and flow-mediated coronary vasomotion.MethodsCoronary blood flow (CBF) in the left anterior descending (LAD) coronary artery was assessed by quantitative angiography and a Doppler flow wire in 94 consecutive subjects with normal coronary arteries. The plasma oxLDL level was measured by enzyme-linked immunosorbent assay using DLH3R, a specific antibody against oxLDL.ResultsPlasma levels of oxLDL in diabetic subjects (n = 13) were higher than those in non-diabetic subjects (n = 81). Plasma levels of oxLDL correlated with body mass index (BMI). Bradykinin at doses of 0.2, 0.6, and 2.0 μg/min caused dose-dependent increases in diameter and CBF in the LAD coronary artery. By a univariate analysis, oxLDL levels significantly correlated with epicardial (r = −0.30, p < 0.0001) and resistant (r = −0.36, p = 0.003) coronary vasodilator responses to BK at 2.0 μg/min, whereas total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were not associated with these coronary responses. In a stepwise multivariate analysis, oxLDL levels were significantly correlated with epicardial and resistant coronary vasomotor responses to BK, independent of age, gender, smoking status, other lipid levels, BMI, hypertension, and diabetes.ConclusionsThe plasma level of oxLDL is an appropriate surrogate for assessing coronary endothelial-dependent vasomotor function as estimated by responses to BK compared with conventional risk factors for atherosclerosis