RESUMEN
The novel antiarrhythmic drug K201 (4-[3-{1-(4-benzyl)piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride) is currently in development for treatment of atrial fibrillation. K201 not only controls intracellular calcium release by the ryanodine receptors, but also possesses a ventricular action that might predispose to torsade de pointes arrhythmias. The anti- and proarrhythmic effects of K201 were investigated in the anesthetized canine chronic atrioventricular block model. Two doses of K201 (0.1 and 0.3mg/kg/2 min followed by 0.01 and 0.03 mg/kg/30 min i.v.) were tested in 4 serial experiments in dogs with normally conducted sinus rhythm (n=10) and in torsade de pointes-susceptible dogs with chronic atrioventricular block. Susceptibility was assessed with dofetilide (0.025 mg/kg/5 min i.v.). Beat-to-beat variability of repolarization was quantified as short-term variability of left ventricular monophasic action potential duration. In dogs with normally conducted sinus rhythm, both doses of K201 prolonged ventricular repolarization whereas only the higher dose prolonged atrial repolarization. At chronic atrioventricular block, dofetilide induced torsade de pointes in 9 of 10 dogs. K201 did neither suppress nor prevent dofetilide-induced torsade de pointes. K201 dose-dependently prolonged ventricular repolarization. In contrary to the lower dose, the higher dose did increase beat-to-beat variability of repolarization (from 1.2 ± 0.3 to 2.9 ± 0.8 ms, P<0.05) and resulted in spontaneous, repetitive torsade de pointes arrhythmias in 1 of 7 dogs; Programmed electrical stimulation resulted in torsade de pointes in 2 more dogs. In conclusion, both doses of K201 showed a class III effect. No relevant antiarrhythmic effects against dofetilide-induced torsade de pointes were seen. Only at the higher dose a proarrhythmic signal was observed.
Asunto(s)
Anestesia , Antiarrítmicos/farmacología , Bloqueo Atrioventricular/patología , Potenciales de la Membrana/efectos de los fármacos , Fenetilaminas/efectos adversos , Sulfonamidas/efectos adversos , Tiazepinas/farmacología , Torsades de Pointes/inducido químicamente , Animales , Bloqueo Atrioventricular/fisiopatología , Enfermedad Crónica , Susceptibilidad a Enfermedades , Perros , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Factores de Tiempo , Torsades de Pointes/patología , Torsades de Pointes/fisiopatología , Torsades de Pointes/prevención & controlRESUMEN
Excessive collagen deposition is a major hallmark of cardiac disease. Fibrosis reduces cardiac function and plays a major role in cardiac arrhythmogeneity. Despite the clinical importance, there is no non-invasive technique for direct detection of myocardial fibrosis yet. Ultra short echo time (UTE) MRI has been shown to detect tissues with a fast T(2)* signal decay. Collagen has a fast T(2)* signal decay compared to myocardium and should therefore be detectable with UTE MRI. This study aims to investigate the use of UTE MRI to detect fibrosis after myocardial infarction without using exogenous contrast. In 7 male Lewis rats either myocardial infarction was created (n=5) or sham surgery was performed (n=2). Six weeks after surgery, hearts were isolated and visualized by MRI. Images were acquired with UTE (TE 0.15ms), to detect tissue with a fast T(2)* decay. Acquired conventional images (TE=6.0ms) were subtracted from UTE images to maintain only 'short living signal' (SLS): tissue with a fast decay. In infarcted hearts, SLS was observed in subtracted images, whereas in control hearts hardly any SLS was detected. Subtracted images were cross-referenced with histology and showed that the SLS area observed with UTE MRI corresponded to the collagen-rich areas observed in histology. Normalized SLS areas correlated well with the normalized collagen-rich areas; r=0.7, p=0.002. We show for the first time that UTE MRI technology can be used for direct detection of post-infarcted fibrosis without the use of contrast agents.