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  • Any abnormality causing a loss of function in the

    2019-06-10

    Any abnormality causing a loss-of-function in the IKs macromolecular complex may lead to adrenergic-induced imbalance in ventricular repolarization currents and consequent QTc prolongation, which is identified based on the defective response of IKs to PKA stimuli due to mutations in KCNQ1 (-G269S, -A341V, and -K557E) [51,61,63], KCNE1-P127T [32], and Yotiao-S1570L [74]. Importantly, the role that IKs plays during adrenergic stimulation may explain why 88% of the cardiac events in LQT1 patients in the above study occurred during exercise and emotional stress [20].
    Acquired LQT1 In addition to congenital pathology, LQTS can also be induced by a variety of stimuli, such as QT-prolonging medications, emotional stress, and strenuous exercise, especially under certain circumstances (risk factors). Of all triggers, QT-prolonging medications (e.g., antiarrhythmics, antihistamines, antibiotics, antidepressants, antipsychotics, and antiemetics) are the most common cause of acquired LQTS (aLQTS), which is believed to be related to drug-induced IKr channel block [71]. Due to unique pore structural properties (spacious inner cavity and aromatic drug-binding sites in the S6 domain facing the inner cavity), the IKr channel displays an unusual susceptibility to a wide range of structurally diverse compounds that interact with the pore. Risk factors for aLQTS include electrolyte disturbances (e.g., hypokalemia, hypomagnesemia), bradycardia, gender, heart disease, and liver insufficiency. Moreover, genetic mutations in major LQTS-related genes including KCNQ1 have also been shown to be involved in aLQTS [75–78]. Siebrands et al. reported that the KCNQ1-A344V mutation increased the susceptibility of IKs channel to a local anesthetic bupivacaine, while the mutation per se did not cause a severe clinical phenotype of LQT1 [77]. Veerman et al. reported that the KCNQ1-K422T mutation per se had a mild clinical phenotype of LQT1, but additional fluoxetine or norfluoxetine resulted in more prominent QTc prolongation in the mutation carriers [78]. Electrophysiological study demonstrated that both fluoxetine and norfluoxetine inhibited KCNQ1/KCNE1 currents in HEK293 order enba [78]. The above studies suggest that loss-of-function in IKs caused by KCNQ1 mutation not only can predispose patients to congenital LQT1, but can be also associated with acquired LQT1. Normal cardiac repolarization critically depends on the interplay of multiple ion currents, and these provide some redundancy or “reserve”, which protects against excessive QT prolongation and allows for an LQTS mutation to remain clinically silent or mild. The lesions in these repolarizing mechanisms can reduce “repolarization reserve” and therefore increase the risk for aLQTS [71]. The loss-of-function in IKs, which is a major repolarization current, occurs due to a KCNQ1 mutation and decreases the repolarization reserve [16,17,71,77]. However, this may be insufficient to elicit a full-blown LQT1 phenotype, especially at rest. When a pathologic trigger such as an IKs-blocking and/or IKr-blocking medication is present, the superimposition of lesions will produce marked AP prolongation and lead to acquired LQT1. In fact, the adrenergic-induced latent LQT1 is a type of aLQTS, which is triggered by sympathetic stimuli.
    Conclusions Uncovering the molecular pathogenesis of LQT1 is helpful, and even mandatory, for precise diagnosis, risk stratification, and management of LQT1 patients. Although some progress has been achieved in investigating the genotype-phenotype correlation through protracted and unremitting efforts, our current understanding of the molecular pathogenesis remains incomplete and sometimes fails to allow for translating the genotype-phenotype correlation into clinical reality. Moreover, neither the localization of a KCNQ1 mutation nor its cellular electrophysiological effect is sufficient to predict the impact on clinical manifestations. The reasons why individuals (even from the same family) carrying the same mutation (e.g., KCNQ1-A341V and KCNQ1-R231C) exhibit diverse cardiac phenotypes clinically remain unknown. The findings to date indicate that mechanisms underlying LQTS are not only multifactorial, but are also involved in pathway crosstalk. Some recent studies show that protein kinase C and the parasympathetic nervous system are also involved in the control of clinical phenotypes in LQT1 [79,80], which brings in a new view to uncovering pathogenic mechanisms underlying the inherited arrhythmia. In addition, the use of induced pluripotent stem cells may better elucidate the clinical heterogeneity in LQTS, especially in cases that have compound mutations.