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Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K_V currents and predisposes to ventricular arrhythmia.

ABSTRACT: KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (K_V) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5^-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5^+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte K_V current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( I_to,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( I_Kslow,1) (conducted by K_V1.5) and I_to,f (conducted by K_V4) and an increase in I_Kslow,2 (conducted by K_V2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where K_V2.1 was also detected in both Kcne5^-/0 and Kcne5^+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and K_V2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases I_K,slow2 by reducing K_V2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of K_V2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in K_V2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of K_V2.1 in mouse heart. Increased K_V current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K_V currents and predisposes to ventricular arrhythmia.

SUBMITTER: David JP

PROVIDER: S-EPMC6338634 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLeft atrial (LA) function following catheter or surgical ablation of de-novo long-standing persistent atrial fibrillation (AF) and its impact on AF recurrence was studied in patients participating in the CASA-AF trial (Catheter Ablation vs. Thoracoscopic Surgical Ablation in Long Standing Persistent Atrial Fibrillation).MethodsAll patients underwent echocardiography preablation, 3 and 12 months post-ablation. LA structure and function were assessed by 2-dimensional volume and speckle tracking strain measurements of LA reservoir, conduit, and contractile strain. Left ventricular diastolic function was measured using transmitral Doppler filling velocities and myocardial tissue Doppler velocities to derive the e', E/e', and E/A ratios. Continuous rhythm monitoring was achieved using an implantable loop recorder.ResultsEighty-three patients had echocardiographic data suitable for analysis. Their mean age was 63.6±9.7 years, 73.5% were male, had AF for 22.8±11.6 months, and had a mean LA maximum volume of 48.8±13.8 mL/m2. Thirty patients maintained sinus rhythm, and 53 developed AF recurrence. Ablation led to similar reductions in LA volumes at follow-up in both rhythm groups. However, higher LA emptying fraction (36.3±10.6% versus 27.9±9.9%; P<0.001), reservoir strain (22.6±8.5% versus 16.7±5.7%; P=0.001), and contractile strain (9.2±3.4% versus 5.6±2.5%; P<0.001) were noted in the sinus rhythm compared with AF recurrence group following ablation at 3 months. Diastolic function was better in the sinus rhythm compared with the AF recurrence group with an E/A ratio of 1.5±0.5 versus 2.2±1.2 (P<0.001) and left ventricular E/e' ratio of 8.0±2.1 versus 10.3±4.1 (P<0.001), respectively. LA contractile strain at 3 months was the only independent predictor of AF recurrence.ConclusionsFollowing ablation for long-standing persistent AF, improvement in LA function was greater in those who maintained sinus rhythm. LA contractile strain at 3 months was the most important determinant of AF recurrence following ablation.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT02755688.

Project description:PurposeTo determine whether left ventricular (LV) extracellular volume (ECV) expansion is associated with atrial fibrillation (AF) or AF-mediated LV systolic dysfunction (LVSD) while minimizing the influence of biologic and imaging methodologic confounders.Materials and methodsThis study examined the prevalence of LV ECV expansion in 137 patients with AF (mean age, 62 years ± 11 [standard deviation]; 92 male patients and 45 female patients; 83 paroxysmal and 54 persistent) who underwent preablation cardiovascular MRI. Biologic confounders were minimized by measuring the ECV fraction and excluding patients with severe LV hypertrophy, defined as wall thickness greater than 1.5 cm. Imaging confounders were minimized by using an arrhythmia-insensitive-rapid (AIR) cardiac T1 mapping pulse sequence. Other cardiac functional parameters, including LV ejection fraction (LVEF) and left atrial end-diastolic volume indexed to body surface area, were assessed using cine cardiovascular MRI. A substudy was conducted in 32 patients with no AF (mean age, 54 years ± 16) in sinus rhythm to establish control values and convert these values between the AIR sequence and literature-based modified Look-Locker inversion recovery (MOLLI) values.ResultsThe mean ECV was not significantly different (P > .05) between patients with AF with a normal LVEF (24.5% ± 2.8; n = 107), patients with AF with LVSD (24.5% ± 2.5; n = 30), and patients with no AF (24.4% ± 3.8; n = 32), but there was a significant interaction between ECV and CHA2DS2-VASc score (P = .045). Compared with the literature data obtained from healthy control patients scanned using MOLLI, 99.3% of patients with AF had ECV below the fibrosis cutoff point (32.8% when converted from MOLLI T1 mapping to AIR T1 mapping), including a subset of patients with AF (n = 28) with low CHA2DS2-VASc score (0/1 for men/women).ConclusionStudy results suggest that an LV ECV expansion is not associated with AF or AF-mediated LVSD. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Stillman in this issue.

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Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K_V currents and predisposes to ventricular arrhythmia.

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Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

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OmicsDI is part of the ELIXIR infrastructure

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Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K_V currents and predisposes to ventricular arrhythmia.