The following article is something I wrote for my class in the Medical Sciences Master’s program for Medical Physiology and Pharmacology at the University or Florida.
Written by Isaac Chenevey
Medical Cardiovascular & Muscle Physiology
March 6, 2021
Long QT Syndrome
Long Q-T Syndrome (LQTS) is an inherited and rare condition of repolarization of the ventricles [2]. It is characterized where the QT interval is prolonged on the 12-lead electrocardiogram and raises the tendency of torsadogenic seizure failure and sudden cardiac death [1, 5]. LQTS is a large cause for sudden cardiac death among youth with two categories of the LQTS, acquired and inherited [14].
The genetic basis of Congenital LQTS is s single autosomal dominant mutation encoded for the cardiac ion channel or subunit ion channel, potentially causing arrhythmias and abrupt death for those with the heterozygous mutation [2]. LQTS is categorized into seventeen subtypes based on the mutation associated with fifteen genes that are autosomal prevalent, LQT1-15 [11]. In the 1990s, a sequence of linkage-analysis uncovered KCNQ1-encoded Kv 7.1 K+ channel, KCNH2-encoded Kv 11.1/hERG K+ channel, and SCN5A- encoded Nav 1.5 Na+ channel pore-forming α-subunits as genetic substratum for LQTS [5]. LQT1, a common subtype, impacts thirty to thirty-five percent of LQTS cases and occurs as a result of the gene KCNQ1 [11]. KCNQ1 loses its function of encoding the α subunit of potassium channel that is voltage-controlled by Kv7.1 in the cardiomyocytes cell membrane [11]. The Kv7.1 intercedes delayed rectifier potassium current, slow, and delayed activation. Kv7.1 comprises four α subunits which ensembles together with KCNE1 β-subunits to produce delayed rectifier potassium currents [4]. LQT1 gene on chromosome lpl5.5 where Harvey ras-1 gene is located, with two additional loci for LQT2 and LQT3 on chromosomes 7q35-36 and 3p21-24 [6]. The subunit of the KCNQ1 domain sensing voltage spanning segments S1-S6 are intracellular C- and N-terminus, and pore-forming α subunits [5, 7, 11]. The genetic basis described above resulting in LQTS displaying on the electrocardiogram surface as a symmetrical and broad-based T-wave having prolongation of QTc interval [4, 11].
Molecularly, the hERG gene (Human Ether-a-go-go-Related Gene) functions as a cardiac potassium channel and identified as the LQT2 gene at chromosomal region 7q35-36 [4,11]. hERG mutations are involved regulating potassium channels, responsible for the impeded repolarization [6]. The cardiac sodium channel SCN5A in the functional cardiac sodium channels have “altered properties”, with impeded inactivation and modified voltage dependence of channel inactivation, delaying myocardial sodium channel inactivation [6]. Extreme delays can reactivate L-type calcium and sodium channels, causing secondary depolarizations [6]. KvLQT1 (KCNQ1) and hERG (KCNH2) potassium ion channel proteins are the basis for LQT types 1 and 2, sodium channel protein NaV1.5 (SCN5A) for type 3 [13]. Depolarization of cardiac action potential results from rapid sodium influx (INa) causing phase 0, with phases 2 and 3 potassium efflux thru the slow (IKs) and rapid (IKr) causing the delayed rectifier current α subunits of IKs and IKr mutations; causing LQT1 and LQT2 diminishing total potassium current, delaying repolarization [13]. LQTS 1 and 2 phenotypes are not produced by heterozygous loss of function mutations indicating more complicated impacts at the RNA, genomic or protein level [13]. LQT3 results from gain of function in INa, leading to consistently slow sodium influx [13]. M1766L-SCN5A, the arrhythmia mutation, is dependent on the channel background specifically in respect to sodium channel polymorphism H558R, using intra-allelic complementation mechanisms [1]. The M1766L mutation (of H558) runs BrS1-like mutation (loss-of-function) while the M1766L (of R558) mutant channels run typically with increased late sodium current [1]. The full-length gene product of SCN5A polymorphism H558R causes a serious loss of function ion channels [1]. LQT locus, with a degree of heterogeneity distinct to LQT genes, can encode proteins that relate to regulate cardiac repolarization and arrhythmia causations [6].
LQTS pathophysiology reveals a dysfunction in the conduction of ions in the heart, or an increase in activity of the cardiac electrical conduction which results in the action potential pro-longed QT interval causing Torsades de pointes (TdP), resulting in sudden death [3]. Two identified delayed rectifier potassium currents are IKs and IKr; where IKs activates slowly during the repolarizing and plateau stages of the cardiac event, contributing to repolarization and calcium influx counter-balancing [3]. The ascending potassium current IKs, dependent of voltage, has a distinctive kinetic action with a vital role in repolarization [3]. The IKs are regulated by the stimulation of β-adrenergic receptors to regulate the action potential duration (APD) in the sympathetic action of the nerve [3,12]. There is an increase of ascending IKs current when there is sympathetic activation from adrenergic stimulation, which counter-balances the associated increase in the inward calcium current, which averts the delay of cardiac APD and permits for enough diastolic filling period amid the heart beats [3, 4]. When IKs are not adequately activated like the one witnessed in LQT1, the lack of counter-balance of the influx of calcium delays is possible and raises the chance of arrhythmia [3, 13].
The current treatment used for managing LQTS is β-adrenergic blockers, which are usually considered the first therapy for patients [11]. The commonly used and efficient β -blockers are nadolol and propranolol, rarely producing bradycardia specifically when the medication is slowly titrated over time [9]. More. Nadolol is usually preferred to reduce the event of life-threatening arrhythmias and consequently the percentage of abrupt death is diminished [10]. The β-blockers are preferred because they save lives and decreases cardiac failure very effectively [8, 9]. The mechanisms of the antiarrhythmic β-blockers entail shortening of the QT interval, modulating heart rate peak, and reducing adrenergic drivers [10]. The current prescription protocol of β-blockers is founded on analyzing retrospective data from wide LQT cases with the inclusion of patients with severe phenotypes [9]. Other treatment and therapies include gene-specific treatment in LQT3 disorder, heart transplant, the left cardiac sympathectomy, and implantable cardioverter-defibrillator [9].
Concluding, Long Q-T Syndrome is an inherited and rare condition of repolarization of the ventricles, leading to abrupt death of affected patients. The seventeen LQTS subtypes are based on the mutation associated with fifteen genes that are autosomal prevalent LQT1 to 15. Individuals are prone to ventricular tachyarrhythmias, manifesting as seizure, loss of consciousness, and abrupt death. The flow of ions in the heart, is disrupted or an increase in the system’s physiological activity of electrical conduction is present. Current clinical management for LQTS are β-blockers nadolol and propranolol as the preferred medication.
References
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