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In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established.<\/jats:p><jats:p><jats:italic>Methods<\/jats:italic>We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%,<jats:italic>P<\/jats:italic>=.02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (<jats:italic>P<\/jats:italic>=.007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block.<\/jats:p><jats:p><jats:italic>Conclusions<\/jats:italic>Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.<\/jats:p>","DOI":"10.1161\/01.cir.92.5.1300","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:34:42Z","timestamp":1339461282000},"page":"1300-1311","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Determinants and Mechanisms of Flecainide-Induced Promotion of Ventricular Tachycardia in Anesthetized Dogs"],"prefix":"10.1161","volume":"92","author":[{"given":"Suzanne","family":"Ranger","sequence":"first","affiliation":[{"name":"From the Department of Medicine (S.N.), Montreal Heart Institute and the University of Montreal, and Department of Pharmacology and Therapeutics (S.R., S.N.), McGill University, Montreal, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Nattel","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (S.N.), Montreal Heart Institute and the University of Montreal, and Department of Pharmacology and Therapeutics (S.R., S.N.), McGill University, Montreal, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199141050-00002"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(87)90204-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198908103210629"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(92)90267-Q"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(90)90972-4"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.82.4.2144796"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(92)90003-6"},{"key":"e_1_3_2_8_2","first-page":"391","volume":"5","year":"1985","unstructured":"Zimmerman JM, Bigger JT Jr, Coromilas J. 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