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Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts.

ABSTRACT: 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.

SUBMITTER: Pezhouman A

PROVIDER: S-EPMC3963462 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts.

Pezhouman Arash A Madahian Sepideh S Stepanyan Hayk H Ghukasyan Hayk H Qu Zhilin Z Belardinelli Luiz L Karagueuzian Hrayr S HS

Heart rhythm 20131128 3

<h4>Background</h4>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.<h4>Objective</h4>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. ...[more]

PMID: 24291413

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Project description:Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (?KPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 ?M) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ?KPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 ?M) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.

Project description:BackgroundInfiltrating adipose tissue (inFAT) is a newly recognized proarrhythmic substrate for postinfarct ventricular tachycardias (VT) identifiable on contrast-enhanced computed tomography. This study presents novel digital-heart technology that incorporates inFAT from contrast-enhanced computed tomography to noninvasively predict VT ablation targets and assesses the capability of the technology by comparing its predictions with VT ablation procedure data from patients with ischemic cardiomyopathy.MethodsDigital-heart models reflecting patient-specific inFAT distributions were reconstructed from contrast-enhanced computed tomography. The digital-heart identification of fat-based ablation targeting (DIFAT) technology evaluated the rapid-pacing-induced VTs in each personalized inFAT-based substrate. DIFAT targets that render the inFAT substrate noninducible to VT, including VTs that arise postablation, were determined. DIFAT predictions were compared with corresponding clinical ablations to assess the capabilities of the technology.ResultsDIFAT was developed and applied retrospectively to 29 ischemic cardiomyopathy patients with contrast-enhanced computed tomography. DIFAT ablation volumes were significantly less than the estimated clinical ablation volumes (1.87±0.35 versus 7.05±0.88 cm3, P<0.0005). DIFAT targets overlapped with clinical ablations in 79% of patients, mostly in the apex (72%) and inferior/inferolateral (74%). In 3 patients, DIFAT targets colocalized with redo ablations delivered years after the index procedure.ConclusionsDIFAT is a novel digital-heart technology for individualized VT ablation guidance designed to eliminate VT inducibility following initial ablation. DIFAT predictions colocalized well with clinical ablation locations but provided significantly smaller lesions. DIFAT also predicted VTs targeted in redo procedures years later. As DIFAT uses widely accessible computed tomography, its integration into clinical workflows may augment therapeutic precision and reduce redo procedures.

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Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts.

Publications

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts.

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