Ana B Rabêlo Evangelista1, Felipe R Monteiro1, Bruce D Nearing2, Luiz Belardinelli3, Richard L Verrier4. 1. Department of Medicine, Beth Israel Deaconess Medical Center, Boston Massachusetts; Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. 2. Department of Medicine, Beth Israel Deaconess Medical Center, Boston Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. 3. InCarda Therapeutics, Inc., Newark, California. 4. Department of Medicine, Beth Israel Deaconess Medical Center, Boston Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.
Abstract
BACKGROUND: The negative inotropic effect of Class IC antiarrhythmic drugs limits their use for acute cardioversion of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine, in an intact porcine model, the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility and QRS complex width at doses that are effective in converting new-onset AF to sinus rhythm. METHODS: Flecainide (1.5 mg/kg bolus) was delivered by intratracheal administration and compared to 2.0 mg/kg 10-minute IV administration (European Society of Cardiology guideline) and to 0.5 and 1.0 mg/kg 2-minute IV doses in 40 closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in the LV to monitor QRS complex width and contractility and at the bifurcation of the main bronchi to deliver intratracheal flecainide. RESULTS: Peak flecainide plasma concentrations (Cmax) were similar, but the 30-minute area under the curve (AUC) of plasma levels was 1.4- to 2.8-fold greater for 2.0 mg/kg 10-minute IV infusion than for the lower, more rapidly delivered intratracheal and IV doses. AUC for LV contractility (ie, negative inotropic burden) was 2.2- to 3.6-fold greater for 2.0 mg/kg 10-minute IV dose than for the lower, more rapidly delivered doses. QRS complex widening by flecainide was highly correlated with the decrease in LV contractility (r2 = 0.890, P <.0001, for all IV doses; r2 = 0.812, P = .01, for intratracheal flecainide). CONCLUSION: QRS complex widening in response to flecainide is strongly correlated with decrease in LV contractility. Rapid pulmonary or IV flecainide delivery reduces the negative inotropic burden while quickly achieving Cmax levels associated with conversion of AF.
BACKGROUND: The negative inotropic effect of Class IC antiarrhythmic drugs limits their use for acute cardioversion of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine, in an intact porcine model, the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility and QRS complex width at doses that are effective in converting new-onset AF to sinus rhythm. METHODS: Flecainide (1.5 mg/kg bolus) was delivered by intratracheal administration and compared to 2.0 mg/kg 10-minute IV administration (European Society of Cardiology guideline) and to 0.5 and 1.0 mg/kg 2-minute IV doses in 40 closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in the LV to monitor QRS complex width and contractility and at the bifurcation of the main bronchi to deliver intratracheal flecainide. RESULTS: Peak flecainide plasma concentrations (Cmax) were similar, but the 30-minute area under the curve (AUC) of plasma levels was 1.4- to 2.8-fold greater for 2.0 mg/kg 10-minute IV infusion than for the lower, more rapidly delivered intratracheal and IV doses. AUC for LV contractility (ie, negative inotropic burden) was 2.2- to 3.6-fold greater for 2.0 mg/kg 10-minute IV dose than for the lower, more rapidly delivered doses. QRS complex widening by flecainide was highly correlated with the decrease in LV contractility (r2 = 0.890, P <.0001, for all IV doses; r2 = 0.812, P = .01, for intratracheal flecainide). CONCLUSION: QRS complex widening in response to flecainide is strongly correlated with decrease in LV contractility. Rapid pulmonary or IV flecainide delivery reduces the negative inotropic burden while quickly achieving Cmax levels associated with conversion of AF.