Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability.

BACKGROUND: Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry Na(+)-channel mutations. OBJECTIVE: The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS. METHODS: In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (ΔKPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed. RESULTS: Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ΔKPQ-SCN5A hearts (all P < .05). Flecainide (1 µM) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and ΔKPQ-SCN5A but were inducible in 15 (38%) of 40 ΔKPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 (66%) of 9 ΔKPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in ΔKPQ-SCN5A mice > 5 months old without increase in fibrotic tissue. CONCLUSION: Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms.

High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience.

OBJECTIVES: To report on our 5-year results with transrectal high-intensity focused ultrasound (HIFU) in the treatment of localized prostate cancer. HIFU delivers high energy, causing rapid coagulation necrosis of tissue within the target area without damaging the surrounding tissue. METHODS: A total of 146 patients with biopsy-proven Stage T1-T2N0M0 prostate cancer have been treated using the Ablatherm device. All patients had a prostate-specific antigen (PSA) level of 15 ng/mL or less and a Gleason score of 7 or less (inclusion criteria). The mean follow-up was 22.5 months (range 4 to 62) and included PSA measurement and control sextant biopsies. RESULTS: The median PSA nadir 3 months after treatment was 0.07 ng/mL (range 0 to 5.67). The median PSA level after a follow-up of 22 months was 0.15 ng/mL (range 0 to 12.11), and 87% of the patients had a constant PSA level of less than 1 ng/mL; 93.4% of all patients had negative control biopsies. One rectourethral fistula was noted after a second HIFU treatment in a patient with a history of hemicolectomy and repetitive anal fistulas. Of all the patients, 12% underwent transurethral resection after HIFU because of obstruction, but no severe stress incontinence (grade 2 to 3) was observed. Erectile function was preserved in 47.3% of patients, and the International Prostate Symptom Score and Quality of Life Index did not change from before to after treatment. CONCLUSIONS: Our results demonstrated the efficacy and low-associated morbidity of HIFU. HIFU does not exclude other treatment options and is repeatable. HIFU seems to be a valid alternative treatment for patients who are not suitable for radical surgery.