Circ J. 2012;76(6):1354-62.
Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-β1.
제1저자 최의근 · 교신저자 Peng-Sheng Chen
소속 (1)
- Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Abstract
BACKGROUND Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca(i)) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1).
METHODS AND RESULTS MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Ca(i)transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca(i) transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca(2+)-ATPase 2a.
CONCLUSIONS Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca(i) transient, EAD and triggered activity. Inhibition of Ca(2+) release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.
그 밖의 정보
- 출판 형태
- Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- 저널
- Circulation journal : official journal of the Japanese Circulation Society · eISSN 1347-4820
- 전자 출판
- 2012-03-22
- MeSH
- Action Potentials · Animals · Atrial Fibrillation / etiology / genetics / metabolism / pathology / physiopathology / prevention & control · Atrial Function* / drug effects · Blotting, Western · Calcium Signaling* / drug effects · Cardiac Pacing, Artificial · Disease Models, Animal · Electrophysiologic Techniques, Cardiac · Enzyme Inhibitors / pharmacology · Fibrosis · Heart Atria / metabolism / pathology / physiopathology · Heart Conduction System / drug effects / metabolism / pathology / physiopathology · Mice · Mice, Transgenic · Ryanodine / pharmacology · Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors / metabolism · Thapsigargin / pharmacology · Time Factors · Transforming Growth Factor beta1 / genetics / metabolism · Up-Regulation
- Substances
- Enzyme Inhibitors · Transforming Growth Factor beta1 · Ryanodine · Thapsigargin · Sarcoplasmic Reticulum Calcium-Transporting ATPases · Atp2a2 protein, mouse
- 연구비
- NHLBI NIH HHS R01 HL109205 · NHLBI NIH HHS R21 HL091189 · NHLBI NIH HHS P01 HL078931 · NHLBI NIH HHS R01 HL83126 · NHLBI NIH HHS R01 HL75165 · NHLBI NIH HHS R01 HL078932 · NHLBI NIH HHS P01 HL85098 · NHLBI NIH HHS R01 HL071140 · NHLBI NIH HHS P01 HL78931 · NHLBI NIH HHS R01 HL78932 · NHLBI NIH HHS P01 HL085098 · NHLBI NIH HHS R01 HL083126 · NHLBI NIH HHS R01 HL075165 · NHLBI NIH HHS R01 HL71140
- 참고문헌
- 30편