A mutation in the cardiac KV7.1 channel possibly disrupts interaction with Yotiao protein.

Here, we characterized the p.Arg583His (R583H) Kv7.1 mutation, identified in two unrelated families suffered from LQT syndrome. This mutation is located in the HС-HD linker of the cytoplasmic portion of the Kv7.1 channel. This linker, together with HD helix are responsible for binding the A-kinase anchoring protein 9 (AKAP9), Yotiao. We studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1 along with KCNE1 subunit and Yotiao protein, using the whole-cell patch-clamp technique. We found that R583H mutation, even at the heterozygous state, impedes IKs activation. Molecular modeling showed that HС and HD helixes of the C-terminal part of Kv7.1 channel are swapped along the C-terminus length of the channel and that R583 position is exposed to the outer surface of HC-HD tandem coiled-coil. Interestingly, the adenylate cyclase activator, forskolin had a smaller effect on the mutant channel comparing with the WT protein, suggesting that R583H mutation may disrupt the interaction of the channel with the adaptor protein Yotiao and, therefore, may impair phosphorylation of the KCNQ1 channel.

Non-invasive three-dimensional electrical activation mapping to predict cardiac resynchronization therapy response: site of latest left ventricular activation relative to pacing site.

AIMS: Pacing remote from the latest electrically activated site (LEAS) in the left ventricle (LV) may diminish response to cardiac resynchronization therapy (CRT). We tested whether proximity of LV pacing site (LVPS) to LEAS, determined by non-invasive three-dimensional electrical activation mapping [electrocardiographic Imaging (ECGI)], increased likelihood of CRT response. METHODS AND RESULTS: Consecutive CRT patients underwent ECGI and chest/heart computed tomography 6-24 months of post-implant. Latest electrically activated site and the distance to LVPS (dp) were assessed. Left ventricular end-systolic volume (LVESV) reduction of ≥15% at clinical follow-up defined response. Logistic regression probabilistically modelled non-response; variables included demographics, heart failure classification, left bundle branch block (LBBB), ischaemic heart disease (IHD), atrial fibrillation, QRS duration, baseline ejection fraction (EF) and LVESV, comorbidities, use of CRT optimization algorithm, angiotensin-converting enzyme inhibitor(ACE)/angiotensin-receptor blocker (ARB), beta-blocker, diuretics, and dp. Of 111 studied patients [64 ± 11 years, EF 28 ± 6%, implant duration 12 ± 5 months (mean ± SD), 98% had LBBB, 38% IHD], 67% responded at 10 ± 3 months post CRT-implant. Latest electrically activated sites were outside the mid-to-basal lateral segments in 35% of the patients. dp was 42 ± 23 mm [31 ± 14 mm for responders vs. 63 ± 24 mm non-responders (P < 0.001)]. Longer dp and the lack of use of CRT optimization algorithm were the only independent predictors of non-response [area under the curve (AUC) 0.906]. dp of 47 mm delineated responders and non-responders (AUC 0.931). CONCLUSION: The distance between LV pacing site and latest electrical activation is a strong independent predictor for CRT response. Non-invasive electrical evaluation to characterize intrinsic activation and guide LV lead deployment may improve CRT efficacy.

Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome.

Brugada syndrome (BrS) is an inherited cardiac arrhythmia characterized by ST-elevation, negative T-wave, and a high risk of sudden cardiac death (SCD) due to ventricular tachycardia. It is associated with mutations in over 20 genes but only SCN5A is recommended for routine genetic screening. This study was performed to estimate diagnostic yield and pathogenicity assessment of rare genetic variants in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome (BrS). Targeted genes panel sequencing of the five genes were screened using IonTorrent PGM with following Sanger confirmation. Detailed clinical evaluation of 75 unrelated BrS probands with a deep phenotyping of SCN5A (+) probands was performed. Twelve rare genetic variants (six missense, six truncating) were initially identified and classified as disease-causing. Reassessment of the clinical significance in the light of the current guidelines revealed: 2 Pathogenic (P) variants; 8 Likely Pathogenic (LP); two missense variants (p.G274S and p. S1778H) were re-classified later as a variant of uncertain significance (VUS). Unique VUS (p.Arg100Ser) was detected in the SCN4B gene. Lone Brugada-pattern was observed in 46% probands; 54% patients had concomitant arrhythmias. PR interval, the only electrocardiography parameter correlating with SCN5A-mutation, was longer (207 ± 24 ms) than normal in SCN5A (+) probands. SCD cases were registered in 31 families. Depression was the only recurring extra-cardiac complaint in SCN5A (+) probands; it was self-reported in five SCN5A (+) probands, and co-segregated with Brugada pattern in 2 families. After variants reassessment, the ratio of SCN5A (+) probands with Brugada syndrome accounts for 13% in Russian cohort.