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Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions.

ABSTRACT: Cardiac arrhythmias associated with intracellular calcium inhomeostasis are refractory to antiarrhythmic therapy. We hypothesized that late sodium current (I _Na) contributed to the calcium-related arrhythmias. Monophasic action potential duration at 90% completion of repolarization (MAPD₉₀) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca²⁺]_i) by using Bay K 8644, and the increase became greater in hearts treated with a combination of ATX-II and Bay K 8644 compared to Bay K 8644 alone. The prolongations caused by Bay K 8644 and frequent episodes of ventricular tachycardias, both in absence and presence of ATX-II, were significantly attenuated or abolished by late I _Na inhibitors TTX and eleclazine. In rabbit ventricular myocytes, Bay K 8644 increased I _CaL density, calcium transient and myocyte contraction. TTX and eleclazine decreased the amplitude of late I _Na, the reverse use dependence of MAPD₉₀ at slower heart rate, and attenuated the increase of intracellular calcium transient and myocyte contraction. TTX diminished the phosphorylation of CaMKII-? and Na_v 1.5 in hearts treated with Bay K 8644 and ATX-II. In conclusion, late I _Na contributes to ventricular arrhythmias and its inhibition is plausible to treat arrhythmias in hearts with increased [Ca²⁺]_i.

SUBMITTER: Wei XH

PROVIDER: S-EPMC5430524 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions.

Wei Xiao-Hong XH Yu Shan-Dong SD Ren Lu L Huang Si-Hui SH Yang Qiao-Mei QM Wang Ping P Chu Yan-Peng YP Yang Wei W Ding Yan-Sheng YS Huo Yong Y Wu Lin L

Scientific reports 20170420 1

Cardiac arrhythmias associated with intracellular calcium inhomeostasis are refractory to antiarrhythmic therapy. We hypothesized that late sodium current (I Na) contributed to the calcium-related arrhythmias. Monophasic action potential duration at 90% completion of repolarization (MAPD90) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca2+]i) by using Bay K 8644, an ...[more]

PMID: 28428622

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Project description:Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity.The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.01 ?M) blocker of INa-L.VT/VF were induced either by local aconitine injection (50 ?g) in the left ventricular muscle of adult (3-4 months) male rats (N = 21) or by arterial perfusion of 0.1 mM hydrogen peroxide (H2O2) in aged male rats (24-26 months, N = 16). The left ventricular epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of action potentials were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 ?M) against EAD/DAD-mediated VT/VF were then determined.Aconitine induced VT in all 13 hearts studied. Activation map (N = 6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (cycle length [CL] 84 ± 12) that degenerated to VF (CL 52 ± 8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 of 13 hearts (P < .001). Preexposure to GS967 for 15 minutes before aconitine injection prevented initiation of VT/VF in 5 of 8 additional hearts (P < .02). VF reoccurred within 10 minutes on washout of GS967. Microelectrode recordings (N = 7) showed that VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86 ± 14 ms (NS from VT CL) that preceded the VF. GS967 shortened APD, flattened the slope of the dynamic APD restitution curve, and reduced APD dispersion from 42 ± 12 ms to 8 ± 3 ms (P < .01). H2O2 perfusion in eight fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in five hearts (P < .02).The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs, and focal VT/VF. Suppression of EADs, DADs, and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.

Project description:Background Unlike T-wave alternans (TWA), the relation between QRS alternans (QRSA) and ventricular arrhythmia (VA) risk has not been evaluated in hypertrophic cardiomyopathy (HCM). We assessed microvolt QRSA/TWA in relation to HCM risk factors and late VA outcomes in HCM. Methods and Results Prospectively enrolled patients with HCM (n=130) with prophylactic implantable cardioverter-defibrillators underwent digital 12-lead ECG recordings during ventricular pacing (100-120 beats/min). QRSA/TWA was quantified using the spectral method. Patients were categorized as QRSA+ and/or TWA+ if sustained alternans was present in ≥2 precordial leads. The VA end point was appropriate implantable cardioverter-defibrillator therapy over 5 years of follow-up. QRSA+ and TWA+ occurred together in 28% of patients and alone in 7% and 7% of patients, respectively. QRSA magnitude increased with pacing rate (1.9±0.6 versus 6.2±2.0 µV; P=0.006). Left ventricular thickness was greater in QRSA+ than in QRSA- patients (22±7 versus 20±6 mm; P=0.035). Over 5 years follow-up, 17% of patients had VA. The annual VA rate was greater in QRSA+ versus QRSA- patients (5.8% versus 2.0%; P=0.006), with the QRSA+/TWA- subgroup having the greatest rate (13.3% versus 2.6%; P<0.001). In those with <2 risk factors, QRSA- patients had a low annual VA rate compared QRSA+ patients (0.58% versus 7.1%; P=0.001). Separate Cox models revealed QRSA+ (hazard ratio [HR], 2.9 [95% CI, 1.2-7.0]; P=0.019) and QRSA+/TWA- (HR, 7.9 [95% CI, 2.9-21.7]; P<0.001) as the most significant VA predictors. TWA and HCM risk factors did not predict VA. Conclusions In HCM, microvolt QRSA is a novel, rate-dependent phenomenon that can exist without TWA and is associated with greater left ventricular thickness. QRSA increases VA risk 3-fold in all patients, whereas the absence of QRSA confers low VA risk in patients with <2 risk factors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02560844.

Dataset Information

Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions.

Publications

Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions.

Similar Datasets

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