Background-The ventricular arrhythmia torsade de pointes (TdP) occurs after QT interval prolongation and is associated with sudden cardiac death. The afterdepolarizations that initiate TdP are facilitated by protein kinase A and the multifunctional Ca 2ϩ /calmodulin-dependent protein kinase II (CaM kinase). Methods and Results-In this study, we evaluated the feasibility of suppression of TdP through systemic therapy with kinase inhibitory agents in an established animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits.CaM kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose-dependent fashion (4 of 7 inducible at 25 mol/kg and 1 of 7 inducible at 50 mol/kg). Increased intracellular Ca 2ϩ has been implicated in the genesis of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP in response to the L-type Ca 2ϩ channel agonist BAY K 8644 (300 nmol/kg), suggesting that CaM kinase-independent activation of L-type Ca 2ϩ current was not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility without shortening the QT interval, increasing heart rate, or reducing the blood pressure. The protein kinase A antagonist H-8 also caused a dose-dependent reduction in TdP inducibility (5 of 6 at 1 mol/kg, 4 of 6 at 5 mol/kg, and 0 of 6 at 10 mol/kg), but unlike W-7, H-8 did so by shortening the QT interval. Conclusions-These findings show that the acute systemic application of W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may be a viable antiarrhythmic strategy. (Circulation. 1999;100:2437-2442.)
BackgroundVenous stenosis is a common complication of transvenous lead implantation, but the risk factors for venous stenosis have not been well defined to date. This study was designed to evaluate the incidence of and risk factors for venous stenosis in a large consecutive cohort.Methods and ResultsA total of 212 consecutive patients (136 male, 76 female; mean age 69 years) with existing pacing or implantable cardioverter-defibrillator systems presented for generator replacement, lead revision, or device upgrade with a mean time since implantation of 6.2 years. Venograms were performed and percentage of stenosis was determined. Variables studied included age, sex, number of leads, lead diameter, implant duration, insulation material, side of implant, and anticoagulant use. Overall, 56 of 212 patients had total occlusion of the subclavian or innominate vein (26%). There was a significant association between the number of leads implanted and percentage of venous stenosis (P =0.012). Lead diameter, as an independent variable, was not a risk factor; however, greater sum of the lead diameters implanted was a predictor of subsequent venous stenosis (P =0.009). Multiple lead implant procedures may be associated with venous stenosis (P =0.057). No other variables approached statistical significance.ConclusionsA significant association exists between venous stenosis and the number of implanted leads and also the sum of the lead diameters. When combined with multiple implant procedures, the incidence of venous stenosis is increased.
Background In 2010 the US Food and Drug Administration approved dabigatran, the first new anticoagulant for stroke prevention in non-valvular atrial fibrillation (AF) since 1954. To date there is little data that reflects the experiences and perceptions of real-world patients with dabigatran. The abundance of internet-based discussion forums and support groups related to AF or anticoagulation may provide a low-cost resource for assessing patient experiences. Objective Determine patient experiences and perceptions regarding dabigatran through qualitative thematic content analysis of comments posted on publicly accessible virtual discussion forums and internet support groups. Measurements Comments posted between January 2011 and September 2012 were downloaded from websites focusing on support of patients with AF or on anticoagulation therapy. Comments were analyzed for thematic content. Results Five broad thematic categories emerged from the posted comments: general concerns about safety and efficacy, questions about indications and contra-indications, questions about proper use and storage, questions about diet and drug restrictions, and experiences with perceived side effects. Our data revealed that a primary concern for patients taking dabigatran is the lack of antidote to reverse the effects of dabigatran if bleeding occurs. Several questions pertaining to the use of dabigatran with other medications or medical conditions were noted, and multiple patients expressed confusion about instructions for using dabigatran before and after medical procedures. An unexpected finding included several criticisms of the medication packaging, which many patients found inconvenient or difficult to open. Finally, several perceived side effects were noted, including some not reported in clinical trials. Conclusions Online communities may provide information about topics that are a concern to patients and that may not be discernible in clinical trials, such as medication side effects, proper use, and safety. Our data also highlighted potential topics that may not be a priority to researchers but are nevertheless important to patients (e.g., medication convenience or packaging). Despite the growing use of online health-related communities, very little research makes use of this low-cost resource for identifying patient interests regarding therapeutic treatments to guide patient-oriented research.
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