Showing papers by "Gan-Xin Yan published in 2002"
TL;DR: These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role forM cells in the development of reentrant TdP arrhythmias in LQTS.
Abstract: Background— Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood. Methods and Results— The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (n=14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7±0.9 ms/mm (controls) to 12.2±2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block a...
315 citations
TL;DR: Pharmacological activation of I(Ks) is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.
Abstract: Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current (I Ks) is impor...
54 citations
TL;DR: Agents that shorten the QT interval, including a potassium supplement, INa blockers and IKs agonists, have been proposed to be useful in the treatment of LQTS.
Abstract: Congenital and acquired long QT syndromes (LQTS) are diseases characterised by QT prolongation on the surface electrocardiogram (ECG) and a specific form of polymorphic ventricular tachycardia termed Torsade de Pointes (TdP). LQTS is caused by a net decrease in repolarising current, due to either gene mutation or drug action on late inward sodium current (INa), slowly activating delayed rectifier potassium current (IKs) and rapidly activating delayed rectifier potassium current (IKr). LQTS is associated with increased transmural dispersion of repolarisation (TDR) and phase 2 early afterdepolarisation (EAD), which are well-known risk factors for the development of TdP under conditions of QT prolongation. β-Adrenergic stimulation triggers the onset of TdP by inducing EAD and enhancing TDR. β-Adrenergic receptor blockade is the classic treatment for congenital forms of LQTS caused by gene mutation of ionic channels for IKs and IKr. Agents that shorten the QT interval, including a potassium supplement, INa bl...
11 citations
TL;DR: An 88-year-old woman was admitted with enterococcal bacteremia complicated by endocarditis and lumbar osteomyelitis for which she was treated with a 6-week regimen of intravenous ampicillin and gentamicin, finding the mechanisms responsible for marked QT prolongation were unclear.
Abstract: September 2002 PACE, Vol. 25, No. 9 An 88-year-old woman was admitted with enterococcal bacteremia complicated by endocarditis and lumbar osteomyelitis for which she was treated with a 6-week regimen of intravenous ampicillin and gentamicin. Her medical background included paroxysmal atrial fibrillation, moderate to severe aortic stenosis and hypertension. At the time of admission, her medications included amiodarone 100 mg daily, enalapril 10 mg daily, lansoprazole 30 mg daily, and ferrous sulfate 325 mg daily. Electrocardiogram (ECG) before admission showed normal sinus rhythm with a heart rate of 63 beats/min and normal QRS duration with a QT interval of 432 ms and U waves (Fig. 1). She had been receiving amiodarone therapy for paroxysmal atrial fibrillation for more than 6 months prior to this admission. One week into her admission, she developed progressive shortness of breath and was found to be in pulmonary edema. The ECG showed sinus tachycardia with a rate related left bundle branch block (LBBB). Serial cardiac enzymes were found to be elevated, and ECGs following the resolution of LBBB showed marked ST-segment changes with deep symmetrical T wave inversion, consistent with global subendocardial ischemia. QT interval was prolonged at 628 ms (Fig. 2). Electrolytes including serum magnesium were within normal limits and the average heart rate was 60–70 beats/min. The following day she reported sudden onset light-headedness with presyncope. The arrhythmia recorded at this time is shown in Figure 3. Subsequently, a 12lead ECG showed a further prolongation of QT interval to 699 ms. What caused the above ECG changes in this patient? How would you treat this patient, keeping in mind that a few weeks later her QT interval had returned to normal? Commentary There was a treatment dilemma in this case because the mechanisms responsible for marked QT prolongation were unclear. Amiodarone alone at such a low dose (100 mg, daily) is unlikely to have a significant effect on the QT interval, particularly under conditions of essentially normal serum electrolytes. Even at doses where it significantly prolongs the QT interval, amiodarone induced polymorphic ventricular tachycardia is rare. Endocardial or subendocardial ischemia alone is usually not associated with such marked QT prolongation, and ischemia induced polymorphic ventricular tachycardia is mostly triggered by extrasystoles with a short coupling interval and is not pause dependent. In clinical practice, fortunately, marked QT prolongation causing torsades de pointes (TP) is readily identifiable and is usually drug induced or secondary to electrolyte imbalance. Classical TP due to ischemia alone is uncommon as shown by Halkin et al. in a recent study where they encountered this arrhythmia in only 8 of 434 patients with uncomplicated myocardial infarction, and they referred to this as “infarct-related long QT syndrome.” Previous studies have demonstrated that ventricular myocardium is composed of three intrinsically distinct cell layers, epicardium, mid-myocardium (M cells), and endocardium. Endocardial ischemia may electrically uncouple injured cells with intrinsically short action potential duration (endocardium) from those with intrinsically long-action potential duration (M cells), resulting in QT prolongation. However, whether amiodarone can exaggerate the QT prolongation under certain pathophysiological conditions like endocardial ischemia is unproven. In view of the difficulty in deciding between ischemia and amiodarone as the cause of polymorphic ventricular tachycardia in this patient, treatment was directed to include both. Lidocaine and bblockers treated a presumed ischemic etiology. Coronary revascularization was considered, but, unfortunately, because of advanced age and associated comorbid factors, she was not thought to be a suitable candidate. Polymorphic ventricular tachycarEP ROUNDS