Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action.

BACKGROUND AND PURPOSE: The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca(2+) channel antagonists, flunarizine and verapamil against TdP were investigated. EXPERIMENTAL APPROACH: Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca(2+) sparks in RyR2(R4496+/+) mouse myocytes; and (iii) peak and late I(Na) in SCN5A-HEK 293 cells. KEY RESULTS: Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I(Na). Ca(2+) sparks were reduced with verapamil. CONCLUSIONS AND IMPLICATIONS: Robust anti-arrhythmic efficacy was seen with both Ca(2+) channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.

No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic-AV block.

BACKGROUND & PURPOSE: The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects. EXPERIMENTAL APPROACH & KEY RESULTS: In transfected HEK cells, the IC(50)s for I (hERG) were 45+/-6 and 856+/-259 microg ml(-1) for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg(-1) moxifloxacin (total peak-plasma concentrations 4.6+/-1.5 and 22.9+/-6.8 microg ml(-1)) prolonged the QT(c) in 6 anaesthetized dogs with chronic AV block by 7+/-3 and 21+/-19%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.4+/-1.3 and 20.8+/-4.9 microg ml(-1)) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 microg kg(-1) i.v.) caused QT(c) prolongation (29+/-15%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.8+/-0.7 to 3.8+/-1.5 ms; P<0.05). CONCLUSION & IMPLICATIONS: As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.

In vivo transluminal microvascular endothelial cell seeding on balloon injured rabbit arteries.

AIM: Seeding venous endothelial cells (EC) onto damaged vascular surfaces attenuates the development of intimal hyperplasia. Unlike venous EC, fat derived microvascular endothelial cells (MVEC) do not require a culture step to increase the yield. The authors investigated whether fat derived MVEC are suitable to reduce intimal hyperplasia after PTA. METHODS: Five rabbits were subjected to percutaneous transluminal angioplasty (PTA) of both iliac arteries. One side was seeded transluminally with autologous perirenal fat derived MVEC, using a double balloon catheter. The contralateral side was sham seeded, and served as a control. Follow-up was 4 weeks. Another rabbit was used for a feasibility experiment. This rabbit was subjected to a 1-sided seeding procedure and was sacrificed after 1 week. In a 7th rabbit, a 1-sided PTA was transformed, and autologous labelled cells were injected in the distal aorta instead of seeded, follow-up was 1 week. Histological investigation was per-formed. RESULTS: The MVEC seeded artery of the pilot experiment was patent. All sham seeded arteries (5) except for 1 were patent. The patent ones showed moderate intimal hyperplasia. MVEC seeding (5) resulted in occlusion twice. In the patent MVEC seeded arteries intimal hyperplasia was present in more extended form than in the sham seeded arteries. Both the patent MVEC- and sham-seeded arteries were covered with an EC layer. Injected labelled MVEC were not found again on the de-endothelialized artery. CONCLUSION: In this study seeding of fat derived MVEC on damaged native arteries results in an increased development of intimal hyperplasia and a decreased patency. One of the reasons may be the presence of non-EC in the seeded cell population.