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  • methysergide It is important to know whether

    2019-06-06

    It is important to know whether pilsicainide can be used as a therapeutic agent for LQT2 patients; and if so, we should determine the types of LQT2 mutation carriers to whom pilsicainide could be administered. As shown in Fig. 8, we examined the effects of pilsicainide on two mutant hERG proteins, G601S and R752W, both of which are trafficking-defective. G601S locates in the pore region of hERG channels, while R752W in the intracellular domain. Pilsicainide at the clinical concentrations could facilitate the maturation of hERG channel proteins with the mutations in the pore region and in the intracellular domain; however, further experiments are necessary to determine which LQT2 mutation carriers will receive therapeutic benefits from pilsicainide.
    Conclusion Chronic treatment with 0.03–10μM pilsicainide for 48h enhanced the expression of WT-hERG proteins via delaying their degradation, increasing hERG channel expression and activity on the plasma membrane. Pilsicainide penetrates the plasma membrane, stabilizes WT-hERG proteins by acting as a chemical chaperone, and enhances WT-hERG channel currents without influencing phosphorylation of Akt or expressions of hsp family proteins. This mechanism may also be applicable to modulations of trafficking-defective mutant hERG proteins.
    Conflict of interest
    Funding sources
    Introduction Acetylcholine (ACh) is widely used for coronary spasm provocation tests in patients with vasospastic angina. J wave is characterized by dynamic morphological changes that show a hump, notch, or slur at the end of the QRS complex. A J wave observed particularly in inferior leads indicates a high risk of ventricular fibrillation (VF) in patients with vasospastic methysergide [1]. We report a case of aborted sudden cardiac death that presented with a J wave in a coronary spasm provocation test using ACh.
    Case report A 51-year-old man participated in a winter full marathon and experienced a cardiac arrest during the racing. He underwent by-stander cardiopulmonary resuscitation and was rescued without the use of an automated external defibrillator. He consulted a cardiology clinic, and vasospastic angina was suspected. He was referred to our hospital, where he underwent routine noninvasive cardiac examinations. Transthoracic echocardiography demonstrated no structural abnormalities. A 12-lead electrocardiography (ECG) in treadmill test revealed an ST-segment depression in the inferolateral leads (Fig. 1A). Coronary angiography (CAG) demonstrated a focal spastic lesion superimposed by an organic stenosis (75%) in segment 7 (Fig. 2A, B). Medication with an antiplatelet agent and calcium channel blockers was started. A bare metal stent (4.0×18mm) was implanted 2 months after the first CAG. Follow-up CAG was performed 4 months after the stent implantation. Provocation test induced no chest pain and stent-edge spasm (Fig. 2C). ECG demonstrated no ST-T changes but unmasked a J wave in the inferior leads. Short-coupled repetitive premature ventricular beats were observed according to an increase in ACh dose from 10 to 100μg (Fig. 1B). The patient underwent intensive medication and had not experienced a recurrence of the cardiac arrest during running since then.
    Discussion J wave is sometimes observed immediately before the onset of VF in patients with vasospastic angina [1]. However, de novo manifestation of J wave induced by ACh applied for coronary spasm provocation test is informative when considering the mechanisms of J waves. Although no evidence for life-threatening arrhythmia was obtained, ventricular tachyarrhythmia, as observed in Fig. 1B, is considered a cause of the aborted sudden cardiac death in this patient with a resuscitation history. ECG of Brugada syndrome, a family of J-wave syndromes, can be characterized by using class Ic antiarrhythmic agents. However, class Ic agents tend to mask J waves partly because of the QRS widening based on slowing of ventricular conduction. Therefore, pharmacological agents to evoke J waves have not been established yet.