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  • SAR405 br Other drugs Overdose of diphenhydramine an H

    2019-05-07


    Other drugs Overdose of diphenhydramine (an H1 histamine receptor antagonist) is reported to induce a BrS phenotype [58,59]. Antihistamines are known to cause QT prolongation secondary to IKr inhibition. Cocaine is known to block the sodium SAR405 and thus to unmask a BrS phenotype [60]. Alcohol intoxication is also reported to induce a BrS phenotype [61]. Interestingly, a full stomach after a large meal is known to induce a BrS phenotype [62]. This response it believed to be due to increased parasympathetic tone. Any agent capable of producing an outward shift in the balance of current during the early phases of the epicardial AP is expected to be capable of creating or unmasking a BrS phenotype.
    Mechanism underlying drug-induced BrS Our working hypothesis regarding the mechanisms underlying induction of the drug-induced BrS phenotype is that these drugs produce an outward shift in the balance of current activity during the early phases of the epicardial AP, similar to the mechanism underlying the development of congenital BrS. Th is can be accomplished either by inhibition or reduction of depolarizing inward currents such as INa or ICa or augmentation of a repolarizing outward current such as Ito[25]. The outward shift of net current leads to the accentuation of the epicardial AP notch, which in turn causes loss of the AP dome in the right ventricular (RV) epicardium. The loss of the dome results in both epicardial and transmural dispersion of repolarization, which gives rise to an ST segment elevation and creates a vulnerable period within the RV wall. The epicardial dispersion of repolarization can result in phase 2 reentry, thus creating a closely coupled premature beat capable of capturing the vulnerable window and precipitating polymorphic VT [1,63,64]. BrS is a right ventricular disease because Ito is most prominent in the right ventricle. Ito is also much more prominent in the epicardium than in the endocardium, which is responsible for the prominent AP notch in the epicardium but not the endocardium. This heterogeneous distribution of Ito and the AP notch is responsible for inscription of the J wave [65]. Recent studies have proposed that delayed conduction in the RVOT is responsible for some cases of BrS [66,67]. A debate of the repolarization vs. depolarization hypothesis for BrS is the subject of a point counterpoint published in 2010 [68].
    Treatment for the drug-induced BrS Drug withdrawal is an effective treatment strategy in most cases of drug-induced BrS. In those cases in which additional measures are necessary, therapy is aimed at rebalancing the current activity during the early phases of the epicardial AP, either by increasing ICa or reducing Ito. The increase in ICa can be achieved with the administration of ISO, which is especially effective in suppressing drug-induced VF storms in BrS cases in the emergency room. ISO can also effectively suppress VF in drug-induced BrS. ICa augmentation can also be achieved with the phosphodiesterase III inhibitor, cilostazol. The reduction of Ito is best achieved using quinidine. Fig. 5 illustrates the ability of quinidine and ISO to suppress the BrS phenotype in experimental models of BrS. Quinidine also blocks INa, IKr, and IKs at therapeutic plasma levels, but its usefulness for the treatment of BrS is well established both in experimental studies and clinical cases [69].
    Conflicts of interest
    Acknowledgment
    Introduction Brugada syndrome (BS) is a cardiac disorder characterized by a typical electrocardiographic finding (type 1 Brugada ECG) in the right precordial leads. Since the first report in 1992 [1], BS has been recognized as a cause of sudden cardiac death (SCD) due to ventricular fibrillation (VF) in middle-aged individuals, especially men [2–7]. BS is responsible for 4% of all sudden deaths and for up to 20% of sudden deaths in individuals without structural cardiac disease [8]. Risk stratification in BS is still challenging, especially in asymptomatic cases. In general, BS patients who have been resuscitated from documented VF should receive an implantable cardioverter defibrillator (ICD) [9]. However, for individuals with Brugada-type ECG without documented VF, the best approach is still unclear. The value of inducibility of sustained ventricular arrhythmias with programmed electrical stimulation (PES) for risk stratification is still not clear. I have reviewed recent published data on the use of PES for identifying high-risk patients and discussed the value of PES for risk assessment in BS.