Search

Background: The calcium-dependent signaling molecules calcineurin and calcium/calmodulin–dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels. Objective: The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype. Methods: AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide-induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4). Results: Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca2+]i and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. Conclusion: The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K+ currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB). Background: Ranolazine inhibits the late Na+ current (INaL) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current. Methods: Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR). In single ventricular myocytes, effects of ranolazine were studied on INaL, action potential duration, and dofetilide-induced BVR and early afterdepolarizations. Results: After dofetilide, ranolazine reduced the number of TdP episodes from 10 ± 3 to 3 ± 1 (p < 0.05) and partially reversed the increase of BVR with no abbreviation of the dofetilide-induced QT prolongation. Likewise, pre-treatment with ranolazine, or using lidocaine as a specific Na+ channel blocker, attenuated TdP, but failed to prevent dofetilide-induced increases in QT, BVR, and ectopic activity. In cAVB myocytes, ranolazine suppressed dofetilide-induced early afterdepolarizations in 25% of cells at 5 μmol/l, in 75% at 10 μmol/l, and in 100% at 15 μmol/l. At 5 μmol/l, ranolazine blocked 26 ± 3% of tetrodotoxin-sensitive INaL, and 49 ± 3% at 15 μmol/l. Despite a 54% reduction of INaL amplitude in cAVB compared with control cells, INaL inhibition by 5 μmol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations. Conclusions: Despite down-regulation of INaL in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR. [Copyright &y& Elsevier]

The anesthetized chronic AV-blocked dog (cAVB) and methoxamine-sensitized rabbit model are widely used to determine pro-arrhythmic properties of drugs. In general, both models show similar results. However, conflicting data have also been reported; K201 and AZD1305 induced Torsade de Pointes (TdP) exclusively in cAVB dogs. Vernakalant, an antiarrhythmic drug that blocks several ion channels has been approved only in Europe. Its propensity to induce repolarization-dependent TdP arrhythmias has been evaluated solely in the methoxamine-sensitized rabbits. We therefore assessed the proarrhythmic potential of vernakalant in the cAVB dog model. Vernakalant was evaluated in 10 mongrel dogs (sinus rhythm (SR) 2mg/kg; chronic AV block (cAVB) 2+3mg/kg). The same dogs were challenged with dofetilide (25μg/kg) to evaluate TdP inducibility. During the serial experiments the animals were paced from the right ventricular apex (60beats/min). Short-term variability of repolarization (STV) was quantified for proarrhythmic risk. In SR (n=8) vernakalant prolonged QT (265±11 to 311±18ms P<0.01⁎⁎) but not PQ or QRS. In cAVB (n=8), 2mg/kg vernakalant prolonged QT (391±43 to 519±73ms⁎⁎) and QRS (103±24 to 108±23ms⁎⁎). After a 30min lag-time, 3mg/kg vernakalant (n=4) increased QT to a lesser extent (413±34 to 454±27ms⁎⁎) while maintaining QRS prolongation (114±18 to 122±20ms⁎⁎). Neither dose increased STV or caused arrhythmias. Dofetilide prolonged QT (398±51 to 615±71ms⁎⁎), increased STV (1.0±0.4 to 2.2±1.0ms P<0.05⁎) and induced TdP arrhythmias in 6/8⁎ cAVB dogs. Vernakalant did not induce arrhythmias in the cAVB dog model. Higher dosages (3mg/kg) did not prolong repolarization further whereas negative inotropic effects were starting to become apparent precluding further increases in dose. [ABSTRACT FROM AUTHOR]