Common Ancestry-specific Ion Channel Variants Predispose to Drug-induced Arrhythmias

Background: Multiple reports associate the cardiac sodium channel gene ( SCN5A ) variants S1103Y and R1193Q with type 3 congenital long QT syndrome (LQTS) and drug-induced LQTS. These variants are, however, too common in ancestral populations to be highly arrhythmogenic at baseline: S1103Y allele frequency is 8.1% in Africans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current (I Na-L ) in cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) but the role of these variants in modulating repolarization remains poorly-understood. Methods: We determined the effect of S1103Y on QT intervals among Africans in a large electronic health record. Using iPSC-CMs carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current (I Kr ) blocker dofetilide, and I Na-L and I Kr at baseline. Results: In 1479 African subjects with no confounding medications or diagnoses of heart disease, QT in S1103Y carriers was no different from that in non-carriers. Similarly, baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared to isogenic cells with the reference allele (SS cells). However, I Na-L was increased in SY and YY cells and the I Na-L blocker GS967 shortened APD in SY/YY but not SS cells (p<0.001). I Kr was increased almost 2-fold in SY/YY cells compared to SS cells (tail current: 0.66±0.1 vs 1.2±0.1 pA/pF, p<0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nM [IQR 1.5-9.3], n=11) and YY (4.2 nM [1.7- 5.0], n=5) than in SS cells (249 nM [22.3-2905], n=14, p<0.001 and p<0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased I Kr and increased dofetilide sensitivity. Conclusions: These common ancestry-specific variants do not affect baseline repolarization, despite generating increased I Na-L . We propose that increased I Kr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with I Kr block in variant carriers. Our findings further emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

Aborted Cardiac Arrest in LQT2 Related to Novel KCNH2 (hERG) Variant Identified in One Lithuanian Family

Congenital long QT syndrome (LQTS) is a hereditary ion channelopathy associated with ventricular arrhythmia and sudden cardiac death starting from young age due to prolonged cardiac repolarization, which is represented by QT interval changes in electrocardiogram (ECG). Mutations in human ether-à-go-go related gene (KCNH2 (7q36.1), formerly named hERG) are responsible for Long QT syndrome type 2 (LQT2). LQT2 is the second most common type of LQTS. A resuscitated 31-year-old male with the diagnosis of LQT2 and his family are described. Sequencing analysis of their genomic DNA was performed. Amino acid alteration p.(Ser631Pro) in KCNH2 gene was found. This variant had not been previously described in literature, and it was found in three nuclear family members with different clinical course of the disease. Better understanding of genetic alterations and genotype-phenotype correlations aids in risk stratification and more effective management of these patients, especially when employing a trigger-specific approach to risk-assessment and individually tailored therapy.

Comparative Characteristics of Beta-Blockers in Patients with Congenital Long QT Syndrome

Congenital long QT syndrome is a pathology that requires special attention and knowledge about the safety and effectiveness of various medications. Prolongation of the QT interval due to congenital or acquired causes is an important factor in the development of an unfavorable life forecast with the formation of an elongated QT syndrome. With an unfavorable course, patients suffer from loss of consciousness, episodes of tachycardia. Often, stable polymorphic ventricular tachycardia develops. The risk of sudden cardiac death in this pathology can vary from 0.33% to 5%. In people who have suffered an episode of cardiac arrest, and do not have a permanent prescribed antiarrhythmic therapy, the mortality rate reaches 50% within 15 years. Preventive administration of antiarrhythmic drugs is not always effective. A positive result of treatment depends on the severity of long QT syndrome and its genotype. Beta-blockers are often prescribed to patients of different ages with various cardiac pathologies, including for the prevention of arrhythmia in long QT syndrome. Beta-blockers differ in various pharmacokinetic and pharmacodynamic parameters (lipophilicity/hydrophilicity, selectivity, presence/absence of internal sympathomimetic activity), which, along with the variant of the disease genotype, can affect their effectiveness and safety in the considered pathology. This review article presents the results of major studies on the safety and effectiveness of different groups of beta blockers in various variants of long QT syndrome. The preferred beta-blockers for various genotypes of the syndrome were determined, and a comparative characteristic of beta-blockers for their safety and preventive effectiveness was given.

Management of Congenital Long-QT Syndrome: Commentary From the Experts

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.