Citations

Background— K201 (JTV519) is a newly developed 1,4-benzothiazepine drug with antiarrhythmic and cardioprotective properties. It functions via stabilization of the ryanodine receptor–calcium release channel in the heart (RyR2). This receptor has been identified in the kidney, and in vitro studies suggest a role in the control of renal hemodynamics. To date, the in vivo function of this receptor is undefined. We hypothesized that this new drug, which is being developed for the treatment of heart failure for its myocardial actions, also possesses renal hemodynamic enhancing and excretory properties. We also used immunohistochemistry to identify RyR2 in the normal canine kidney. Methods and Results— We investigated the renal actions of K201 during intrarenal infusion in normal anesthetized dogs. K201 was infused after baseline measurements at 2 doses (0.1 and 0.5 mg · kg −1 · min −1 ). Immunohistochemistry was used to identify RyR2 presence in the kidney not exposed to K201. K201 was potently natriuretic and diuretic, with glomerular filtration rate– and renal blood flow–enhancing actions. The excretory responses to K201 administration were associated with decreases in distal tubular reabsorption of sodium despite a mild decrease in mean arterial pressure, which returned to baseline levels after K201 discontinuation. Immunohistochemistry of the normal canine kidney revealed the presence of RyR2 in the medullary collecting duct cells. Conclusions— We report for the first time that the newly developed cardioprotective drug K201 possesses natriuretic, diuretic, glomerular filtration rate–enhancing, and vasodilating properties that go beyond myocardial actions and may support its therapeutic role in treatment of heart failure.

Background— Cardiac resynchronization therapy (CRT) is an effective therapy for patients with moderate to severe heart failure and prolonged QRS duration. The purpose of this study was to determine whether reverse left ventricular (LV) remodeling and symptomatic benefit from CRT were sustained at 12 months, and if so, in what proportion of patients this occurred. Methods and Results— Serial Doppler echocardiograms were obtained at baseline and 6 and 12 months after CRT in 228 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Measurements were made of LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E wave) and late (A wave) diastolic filling, and myocardial performance index. At both 6 and 12 months, respectively, CRT was associated with reduced LV EDV ( P <0.0001 and P =0.007) and LV ESV ( P <0.0001 and P <0.0001), improved ejection fraction ( P <0.0001 and P <0.0001), regression of LV mass ( P =0.012 and P <0.0001), and reduced MR ( P <0.0001 and P <0.0001). LV filling time, transmitral E/A ratio, and myocardial performance index all improved at 12 months compared with baseline ( P <0.001, P =0.031, and P <0.0001). Reverse LV remodeling with CRT occurred in more patients at 6 than at 12 months (74% versus 60%, respectively; P <0.05) and was greater in patients with a nonischemic than an ischemic etiology. Conclusions— Reverse LV remodeling and symptom benefit with CRT are sustained at 12 months in patients with New York Heart Association class III/IV heart failure but occur to a lesser degree in patients with an ischemic versus a nonischemic etiology, most likely owing to the inexorable progression of ischemic disease.

Abstract Context: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which might offer the potential to treat breast cancer with radioiodine. Objective: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS expression and therapeutic efficacy of 131-I in MCF-7 cells. Design: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern and Western blot analysis after incubation with Dex (10−9 to 10−7m) in the presence of atRA (10−6m) as well as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro clonogenic assay. Results: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of 131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-7 cells treated with Dex in the presence of atRA. Conclusion: Treatment with Dex in the presence of atRA significantly increases functional NIS expression levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7 breast cancer cells.

Purpose Currently, there is little information available concerning the results of shoulder synovectomy in patients with rheumatoid arthritis. Furthermore, it remains difficult to assess the success of shoulder synovectomy because of a high association of rotator cuff tears in rheumatoid patients. We hypothesized that synovectomy in patients with a functionally intact rotator cuff would provide durable pain relief. Type of Study Case series. Methods Sixteen shoulders in 13 patients with rheumatoid arthritis were treated with arthroscopic shoulder synovectomy from 1988 to 2002 with a mean follow‐up of 5.5 years. Patients with full‐thickness rotator cuff tears or partial tears that required repair were excluded. Two of the 13 patients had been diagnosed with juvenile rheumatoid arthritis and 11 had adult‐onset disease. The medical records of the patients were reviewed and patients were assessed clinically and by questionnaire to assess pain, satisfaction, range of motion, radiographic outcomes, and occurrence of complications. Results There was an improvement in pain at long‐term follow‐up in 13 of 16 patients ( P < .001). Active shoulder elevation improved from a median of 145° to 160° but was not significant ( P = .14). External rotation improved significantly ( P = .01) from a median of 45° (range, 0° to 90°) to 60° (range, 0° to 100°). According to the Neer rating system, there were 5 excellent, 8 satisfactory, and 3 unsatisfactory results. Seven of 8 shoulders followed‐up radiographically for more than 1 year showed radiographic progression of disease. All 3 patients reporting pain that was no better or worse than before surgery had radiographic arthrosis at last follow‐up with advancing periarticular erosions and reduction of glenoid articular space. Conclusions Arthroscopic synovectomy of the shoulder in patients with rheumatoid arthritis with an intact rotator cuff offers a reliable decrease in pain with less predictable improvements in range of motion. Limitations in predicting final results based on preoperative radiographs should be discussed with patients; those with more advanced radiographic changes may not benefit from the procedure. Level of Evidence Level IV, therapeutic study, case series, no control group.