Abstract
Background: Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations (DADs) is reproducibly inducible after anterior coronary artery occlusion. Both VT/VF and TA can be blocked by reducing reactive oxygen species (ROS). We tested the hypothesis that inhibition of NADPH oxidase and xanthine oxidase would block VT/VF. Methods: 69 dogs received apocynin (APO), 4 mg/kg intraveneously (IV), oxypurinol (OXY), 4 mg/kg IV, or both APO and OXY (BOTH) agents, or saline 3 h after coronary occlusion. Endocardium from ischemic sites (3-D mapping) was sampled for Rac1 (GTP-binding protein in membrane NADPH oxidase) activation or standard microelectrode techniques. Results (mean ± SE, * p < 0.05): VT/VF originating from ischemic zones was blocked by APO in 6/10 *, OXY in 4/9 *, BOTH in 5/8 * or saline in 1/27; 11/16 VT/VFs blocked were focal. In isolated myocardium, TA was blocked by APO (10−6 M) or OXY (10−8 M). Rac1 levels in ischemic endocardium were decreased by APO or OXY. Conclusion: APO and OXY suppressed focal VT/VF due to DADs, but the combination of the drugs was not more effective than either alone. Both drugs inhibited ischemic Rac1 with inhibition by OXY suggesting ROS-induced ROS. The inability to totally prevent VT/VF suggests that other mechanisms also contribute to ischemic VT.
Highlights
Ventricular tachycardia/ventricular fibrillation (VT/VF) due to myocardial ischemia is a major cause of cardiac arrest, a public health problem
Of the 54 dogs studied after coronary occlusion, ten were randomly treated with apocynin (APO), nine with oxypurinol (OXY), eight with APO and OXY simultaneously (BOTH) and 27 concomitantly studied with saline
Dogs without drug treatment continued to have inducibility except for one (C23) throughout the test period while drug treatment resulted in non-inducibility in of which 11 had focal mechanisms and 7 had reentry
Summary
Ventricular tachycardia/ventricular fibrillation (VT/VF) due to myocardial ischemia is a major cause of cardiac arrest, a public health problem. We have shown that oscillations in cell membrane potential termed delayed afterdepolarizations (DADs), which give rise to endocardial or Purkinje triggered activity (TA) are found more commonly at the endocardial focus of VT [1] Drugs such as lovastatin [2], whose pleiotropic effects include reduction of reactive oxygen species (ROS), prevent DADs and TA in vitro and focal VT/VF in vivo. Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations (DADs) is reproducibly inducible after anterior coronary artery occlusion. Both VT/VF and TA can be blocked by reducing reactive oxygen species (ROS).
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