Yuko Miki

Expression, Transcription, and Possible Antagonistic Interaction of the Human Nedd4L Gene Variant Implications for Essential Hypertension

Net sodium balances in humans are maintained through various ion transporters expressed along the entire nephron. Among these ion transporters, epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. This is supported by analyses of inherited hypertensive disorders, showing that genes encoding ENaC and other modulatory proteins cause hereditary hypertension, such as Liddle syndrome. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH2 terminus of the protein for subsequent degradation. Both evolutionarily conserved and evolutionarily new C2 domains of human Nedd4L, a cryptic splice variant resulting in a disrupted isoform product formed by a frame-shift mutation, were reported previously. We focused on one of the isoforms, isoform I, generated by SNP (rs4149601), and studied its expression and interactions with other isoforms by molecular biological, immunohistochemical, and electrophysiological methods. We found that isoform I may interact with other human isoforms in a dominant-negative fashion. Such interactions might abnormally increase sodium reabsorption. Taken together, our analyses suggest that the human Nedd4L gene, especially the evolutionarily new isoform I, is a candidate gene for hypertension.

Optimal observation time after completion of circumferential pulmonary vein isolation for atrial fibrillation to prevent chronic pulmonary vein reconnections

PURPOSEnTo identify predictors of chronic pulmonary vein (PV) reconnection (CPVR) after successful circumferential PV isolation (CPVI) for atrial fibrillation (AF).nnnMATERIALS AND METHODSnA total of 718 PVs from 181 consecutive AF patients (141 males, median age 61 years, 92 paroxysmal AF) who underwent a second ablation procedure for recurrent AF were retrospectively analyzed.nnnRESULTSnDuring the second procedure, a CPVR was observed in 477 PVs (66.4%) among 169 patients. In a multiple logistic regression analysis, the observation time after the final completion of the PVI (OT-final) was a significant negative predictor (odds ratio 0.980; P<0.001). A receiver operating characteristic analysis demonstrated that the greatest area under the curve was for the OT-final (0.670). At an optimal cutoff of 35 min, the sensitivity and specificity for predicting a CPVR were 66.9% and 60.6%, respectively. By Kaplan Meier analysis, CPVR was more frequent in PVs with an OT-final of <35 min than ≥35 min (log-rank test, P=0.018). In a vessel-by-vessel analysis, the OT-final at all PV sites was a significant negative predictor, while male gender in the right PVs and left-inferior PV, number of RF applications for the ipsilateral CPVI in the right PVs and left-superior PV, and major PV diameter in the left-superior PV were significant positive predictors of a CPVR (all P<0.05).nnnCONCLUSIONSnAn optimal observation time (≥35 min in this study) to determine whether PVI is successfully completed during the initial CPVI for AF may be needed to prevent a CPVR and subsequent AF recurrence thereafter.

Optimal Programming of the Atrioventricular Delay Using the Phonocardiogram

Purpose: To predict the optimal atrioventricular (AV) delay using the phonocardiogram (PCG).