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Patel D.,University of Pittsburgh | McTiernan C.F.,University of Pittsburgh | Xiang W.,University of Pittsburgh | Yang L.,University of Pittsburgh | And 7 more authors.
Circulation Research | Year: 2013

Rationale: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy. Objective: To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR). Methods and Results: Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca2+ transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P<0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-β, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation (P<0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV (P<0.01), and reversed atrial hypertrophy (P<0.05). Independent of antifibrotic actions, RLX (0.1 μmol/L) increased Na+ current density, INa (≈2-fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P<0.01). Conclusions: RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents. © 2013 American Heart Association, Inc.

Bett G.C.L.,State University of New York at Buffalo | Bett G.C.L.,Center for Cellular and Systems Electrophysiology | Dinga-Madou I.,State University of New York at Buffalo | Dinga-Madou I.,Center for Cellular and Systems Electrophysiology | And 6 more authors.
Biophysical Journal | Year: 2011

Kv1.4 channels are Shaker-related voltage-gated potassium channels with two distinct inactivation mechanisms. Fast N-type inactivation operates by a ball-and-chain mechanism. Slower C-type inactivation is not so well defined, but involves intracellular and extracellular conformational changes of the channel. We studied the interaction between inactivation mechanisms using two-electrode voltage-clamp of Kv1.4 and Kv1.4DN (amino acids 2-146 deleted to remove N-type inactivation) heterologously expressed in Xenopus oocytes. We manipulated C-type inactivation by introducing a lysine-tyrosine point mutation (K532Y, equivalent to Shaker T449Y) that diminishes C-type inactivation. We used experimental data to develop a comprehensive computer model of Kv1.4 channels to determine the interaction between activation and N- and C-type inactivation mechanisms needed to replicate the experimental data. C-type inactivation began at lower voltage preactivated states, whereas N-type inactivation was coupled directly to the open state. A model with distinct N- and C-type inactivated states was not able to reproduce experimental data, and direct transitions between N- and C-type inactivated states were required, i.e., there is coupling between N- and C-type inactivated states. C-type inactivation is the rate-limiting step determining recovery from inactivation, so understanding C-type inactivation, and how it is coupled to N-type inactivation, is critical in understanding how channels act to repetitive stimulation. © 2011 by the Biophysical Society.

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