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1.
Amiodarone-Induced Thyroid Dysfunction: A Clinical Update.
Elnaggar, MN, Jbeili, K, Nik-Hussin, N, Kozhippally, M, Pappachan, JM
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2018;(6):333-341
Abstract
Amiodarone is one of the most commonly prescribed antiarrhythmic agents in clinical practice owing to its efficacy, even with high toxicity profile. The high iodine content and the prolonged biological half-life of the drug can result in thyroid dysfunction in a high proportion of patients treated with amiodarone even after cessation of amiodarone. Both hypothyroidism and hyperthyroidism are common side effects that mandate regular monitoring of patients with thyroid function tests. Amiodarone-induced hypothyroidism (AIH) is diagnosed and managed in the same way as a usual case of hypothyroidism. However, differential diagnosis and clinical management of amiodarone-induced thyrotoxicosis (AIT) subtypes can be challenging. With the aid of a case snippet, we update the current evidence for the diagnostic work up and management of patients with amiodarone-induced thyroid dysfunction in this article.
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2.
Nicorandil improves clinical outcomes in patients with stable angina pectoris requiring PCI: a systematic review and meta-analysis of 14 randomized trials.
Li, Y, Liu, H, Peng, W, Song, Z
Expert review of clinical pharmacology. 2018;(9):855-865
Abstract
Clinical trials concerning the effects of nicorandil in stable coronary artery disease (CAD) remain controversial. This study sought to evaluate the clinical outcomes of nicorandil following elective percutaneous coronary intervention (PCI). Areas covered: A meta-analysis including eligible randomized controlled trials (RCTs) with data on the nicorandil in stable CAD from Pubmed, EMBase, and Cochrane library (up to March 2018) was conducted. The primary end points were postprocedural incidence of myocardial infarction (MI) and contrast-induced nephropathy (CIN). The second end point was major adverse cerebrovascular and cardiovascular events (MACCE). Fourteen RCTs with a total of 1947 elective CAD patients were selected. Nicorandil significantly reduced the incidence of MI [n = 8; relative risk (RR) = 0.58; P = 0.001; I2 = 33.7%], and CIN (n = 5; RR = 0.36; P < 0.00001; I2 = 15.4%). However, There was no lowered risk of MACCE in nicorandil-treated patients [n = 10; odds RR = 0.75; P = 0.19; I2 = 0.0%]. Subsequent trial sequential analyses confirmed the effect of nicorandil on MI and CIN in PCI. Expert commentary: The present systematic review and meta-analysis suggests that nicorandil could improve clinical outcomes in terms of perioperative MI and CIN. However, the effect of nicorandil on the MACCE risk is not obvious. Future high-quality, large-scale clinical trials should majorly concern about the long-term clinical effect of nicorandil.
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3.
A Focus on Pharmacological Management of Catecholaminergic Polymorphic Ventricular Tachycardia.
Claudio, B, Alice, M, Daniel, S
Mini reviews in medicinal chemistry. 2018;(6):476-482
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a channelopathy characterized by adrenergic mediated ventricular arrhythmia. Untreated CPVT is a malignant syndrome with more than 50% of arrhythmic events and up to 25% of fatal or near-fatal cardiac events at 8 years follow-up. Prevention of sudden cardiac death starts with exclusion of competitive sports. Beta blockers (BB) are the cornerstone pharmacological therapy for the prevention of cardiac event in CPVT patients. Dose of BB should be highly tolerable, preferably nadolol. Efficiency of BB is undeniable but uncompleted. Therefore, on top of BB, one can propose the use of Calcium channel blockers or Class 1c antiarrythmic drugs. Indeed Flecainide allows reducing exercise- induced premature ventricular contraction and ventricular arrhythmia. Pharmacological management should be a stepwise approach with BB as the first line of choice. At each step of therapeutic changes, heart rhythm during exercise should be monitored by Holter monitoring and exercise testing. If the pharmacological management fails, left cardiac sympathetic denervation or implantation of cardioverter defibrillator should be considered.
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4.
Efficacy and safety of nicorandil on perioperative myocardial injury in patients undergoing elective percutaneous coronary intervention: results of the PENMIPCI trial.
Ye, Z, Lu, H, Su, Q, Long, M, Li, L
Drug design, development and therapy. 2018;:2591-2599
Abstract
BACKGROUND Previous studies have indicated that nicorandil can reduce perioperative myocardial injury (PMI) in patients undergoing elective percutaneous coronary intervention (ePCI), but this conclusion is still controversial. Additionally, studies reporting on the safety of nicorandil are lacking. Therefore, we performed this prospective study to evaluate the efficacy and safety of nicorandil on PMI in patients undergoing ePCI. METHODS One hundred and forty-six patients with coronary heart disease (CHD) scheduled to undergo ePCI were randomly assigned to the nicorandil group (n=74) or control group (n=72). The primary outcomes were the change in cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) at 12 and 24 hours after surgery. The secondary outcome was the incidence of major adverse cardiac events (MACE), which was a composite of cardiac death, nonfatal myocardial infarction, new heart failure or coronary revascularization. RESULTS There was no difference in age (54.76±5.93 vs 56.35±5.22) between the nicorandil group and the control group. In addition, no differences were observed in the cTnT and CK-MB levels between the two groups at admission (all P⩾0.05). Compared with those in the control group, the cTnT (0.15±0.12 vs 0.12±0.10 at 12 hours and 0.17±0.12 vs 0.13±0.10 at 24 hours) and CK-MB (15.35±8.23 vs 12.31±7.93 at 12 hours and 13.63±8.87 vs 11.13±5.71 at 24 hours) levels in the nicorandil group were significantly decreased after surgery (all P⩽0.05). Furthermore, nicorandil did not increase the incidence of MACE in the nicorandil group compared with the control group (12.16% vs 12.50%). CONCLUSIONS Nicorandil can reduce PMI in patients undergoing ePCI and does not increase the incidence of MACE. CLINICAL TRIAL REGISTRATION URL: http://www.chictr.org.cn/. Unique Identifier: ChiCTR-IOR-17012056.
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Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model.
Mehta, A, Ramachandra, CJA, Singh, P, Chitre, A, Lua, CH, Mura, M, Crotti, L, Wong, P, Schwartz, PJ, Gnecchi, M, et al
European heart journal. 2018;(16):1446-1455
Abstract
AIMS: Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced IKr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. METHODS AND RESULTS From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. CONCLUSION Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.
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6.
[Challenges in the management of amiodarone-induced thyrotoxicosis].
Tauveron, I, Batisse-Lignier, M, Maqdasy, S
Presse medicale (Paris, France : 1983). 2018;(9):746-756
Abstract
Amiodarone, a benzofuranic iodine-rich pan antiarrhythmic drug, is frequently associated with thyroid dysfunction. This side effect is heterogeneous and unpredicted, motivating regular evaluation of thyroid function tests. In contrary to hypothyroidism, amiodarone-induced thyrotoxicosis (AIT) is a challenging situation owing to the risk of deterioration of the general and cardiac status of such debilitating patients. Classically, AIT is either an iodine-induced thyrotoxicosis in patients with an abnormal thyroid (type I), or due to a subacute thyroiditis on a "healthy" thyroid (type II). Even if many studies tried to better identify the types of AIT, the diagnostic dilemma of type of AIT could be present, and many patients are treated by an association of antithyroid drugs (useful for type I AIT) with corticoids (useful for type II AIT). Being the main etiological factor in AIT, amiodarone is supposed to be stopped, but it could remain the only anti-arrhythmic option that is needed to be either continued or reintroduced to improve the cardiovascular survival. Recently, many studies demonstrated that amiodarone could be continued or reintroduced in patients with history of type II AIT. Nevertheless, in the other patients, amiodarone maintenance complicates the therapeutic response to the antithyroid drugs and increases the risk of AIT recurrence. Thus, amiodarone therapy is preferred to be interrupted. In such patients, thyroid ablation is recommended once AIT is under control.
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7.
Effect of Na+-channel blockade on the three-dimensional substrate of atrial fibrillation in a model of endo-epicardial dissociation and transmural conduction.
Gharaviri, A, Verheule, S, Eckstein, J, Potse, M, Krause, R, Auricchio, A, Kuijpers, NHL, Schotten, U
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2018;(suppl_3):iii69-iii76
Abstract
AIMS: Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that increase its stability. Both clinical and experimental studies showed a concomitant loss of antiarrhythmic drug efficacy in later stages of AF. The mechanisms underlying this loss of efficacy are not well understood. We hypothesized that structural remodelling may explain this reduced efficacy by making the substrate more three-dimensional. To investigate this, we simulated the effect of sodium (Na+)-channel block on AF in a model of progressive transmural uncoupling. METHODS AND RESULTS In a computer model consisting of two cross-connected atrial layers, with realistic atrial membrane behaviour, structural remodelling was simulated by reducing the number of connections between the layers. 100% of endo-epicardial connectivity represented a healthy atrium. At various degrees of structural remodelling, we assessed the effect of 60% sodium channel block on AF stability, endo-epicardial electrical activity dissociation (EED), and fibrillatory conduction pattern complexity quantified by number of waves, phase singularities (PSs), and transmural conduction ('breakthrough', BT). Sodium channel block terminated AF in non-remodelled but not in remodelled atria. The temporal excitable gap (EG) and AF cycle length increased at all degrees of remodelling when compared with control. Despite an increase of EED and EG, sodium channel block decreased the incidence of BT because of transmural conduction block. Sodium channel block decreased the number of waves and PSs in normal atrium but not in structurally remodelled atrium. CONCLUSION This simple atrial model explains the loss of efficacy of sodium channel blockers in terminating AF in the presence of severe structural remodelling as has been observed experimentally and clinically. Atrial fibrillation termination in atria with moderate structural remodelling in the presence of sodium channel block is caused by reduction of AF complexity. With more severe structural remodelling, sodium channel block fails to promote synchronization of the two layers of the model.
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8.
Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
Liin, SI, Yazdi, S, Ramentol, R, Barro-Soria, R, Larsson, HP
Cell reports. 2018;(11):2908-2918
Abstract
Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic KV7.1 and KV7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on KV7.1 and KV7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of KV7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in KV7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how KV7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target KV7.1 channels.
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9.
Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.
Hu, RM, Tester, DJ, Li, R, Sun, T, Peterson, BZ, Ackerman, MJ, Makielski, JC, Tan, BH
Channels (Austin, Tex.). 2018;(1):176-186
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Abstract
INTRODUCTION Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. METHODS AND RESULTS A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. CONCLUSION SCN5A-N406K channel displays both "gain-of-function" in late INa and "loss-of-function" in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both "gain-of-function" and "loss-of-function" of the mutant sodium channel.
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10.
The role of mexiletine in the management of long QT syndrome.
Li, G, Zhang, L
Journal of electrocardiology. 2018;(6):1061-1065
Abstract
Congenital long QT syndrome (LQTS) is a hereditary cardiac disorder characterized by QT-interval prolongation and T-wave abnormalities on electrocardiogram (ECG), and is associated with an increased risk of torsade de pointes and sudden cardiac death. Beta-blocker medication is effective in most patients except those with a very slow heart rate. Increased late sodium currents (INa-L) can result in bradycardia-dependent QT prolongation. Mexiletine, an inhibitor of INa-L, is not only effective in treating type-3 LQTS, but also shows the promise in managing LQTS patients of other genotypes with markedly prolonged QT interval at slow heart rates.