TY - JOUR
T1 - Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents
AU - Wongcharoen, Wanwarang
AU - Chen, Yao Chang
AU - Chen, Yi Jen
AU - Chen, Szu Ying
AU - Yeh, Huang I.
AU - Lin, Cheng I.
AU - Chen, Shih Ann
N1 - Funding Information:
This study was supported by the Topnotch Stroke Research Center Grant, Ministry of Education, and Grants NSC 94-2314-B-075-093, NSC 94-2314-B-010-056, NSC-94-2314-B-010-053, NSC 95-2314-B-016-015, NSC 95-2314-B-038-026, VGH-94-204, VGH-94-005, VGH-94-206, VGH-94-009, V95A-008, and SKH-TMU-94-01 from Shih Kong Wu Ho-Su Memorial Hospital.
PY - 2007/10
Y1 - 2007/10
N2 - Background: Aging and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Abnormal Ca2+ regulation and ryanodine receptors are known to contribute to PV arrhythmogenesis. Objective: The purpose of this study was to investigate whether aging alters PV electrophysiology, Ca2+ regulation proteins, and responses to rapamycin, FK-506, ryanodine, and ouabain. Methods: Conventional microelectrodes were used to record action potential and contractility in isolated PV tissue samples in 15 young (age 3 months) and 16 aged (age 3 years) rabbits before and after drug administration. Expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), ryanodine receptor, and Na+/Ca2+ exchanger was evaluated by western blot. Results: Aged PVs had larger amplitude of delayed afterdepolarizations, greater depolarized resting membrane potential, longer action potential duration, and higher incidence of action potential alternans and contractile alternans with increased expression of Na+/Ca2+ exchanger and ryanodine receptor and decreased expression of SERCA2a. Rapamycin (1,10,100 nM), FK-506 (0.01, 0.1, 1 μM), ryanodine (0.1, 1 μM), and ouabain (0.1, 1 μM) concentration-dependently increased PV spontaneous rates and the incidence of delayed afterdepolarizations in young and aged PVs. Compared with results in young PVs, rapamycin and FK-506 in aged PVs increased PV spontaneous rates to a greater extent and exhibited a larger delayed afterdepolarization amplitude. In PVs without spontaneous activity, rapamycin and FK-506 induced spontaneous activity only in aged PVs, but ryanodine and ouabain induced spontaneous activity in both young and aged PVs. Conclusion: Aging increases PV arrhythmogenesis via abnormal Ca2+ regulation. These findings support the concept that ryanodine receptor dysfunction may result in high PV arrhythmogenesis and aging-related arrhythmogenic vulnerability.
AB - Background: Aging and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Abnormal Ca2+ regulation and ryanodine receptors are known to contribute to PV arrhythmogenesis. Objective: The purpose of this study was to investigate whether aging alters PV electrophysiology, Ca2+ regulation proteins, and responses to rapamycin, FK-506, ryanodine, and ouabain. Methods: Conventional microelectrodes were used to record action potential and contractility in isolated PV tissue samples in 15 young (age 3 months) and 16 aged (age 3 years) rabbits before and after drug administration. Expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), ryanodine receptor, and Na+/Ca2+ exchanger was evaluated by western blot. Results: Aged PVs had larger amplitude of delayed afterdepolarizations, greater depolarized resting membrane potential, longer action potential duration, and higher incidence of action potential alternans and contractile alternans with increased expression of Na+/Ca2+ exchanger and ryanodine receptor and decreased expression of SERCA2a. Rapamycin (1,10,100 nM), FK-506 (0.01, 0.1, 1 μM), ryanodine (0.1, 1 μM), and ouabain (0.1, 1 μM) concentration-dependently increased PV spontaneous rates and the incidence of delayed afterdepolarizations in young and aged PVs. Compared with results in young PVs, rapamycin and FK-506 in aged PVs increased PV spontaneous rates to a greater extent and exhibited a larger delayed afterdepolarization amplitude. In PVs without spontaneous activity, rapamycin and FK-506 induced spontaneous activity only in aged PVs, but ryanodine and ouabain induced spontaneous activity in both young and aged PVs. Conclusion: Aging increases PV arrhythmogenesis via abnormal Ca2+ regulation. These findings support the concept that ryanodine receptor dysfunction may result in high PV arrhythmogenesis and aging-related arrhythmogenic vulnerability.
KW - Aging
KW - Atrial fibrillation
KW - Calcium
KW - Pulmonary Veins
KW - Ryanodine
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U2 - 10.1016/j.hrthm.2007.06.023
DO - 10.1016/j.hrthm.2007.06.023
M3 - Article
C2 - 17905341
AN - SCOPUS:34848918916
SN - 1547-5271
VL - 4
SP - 1338
EP - 1349
JO - Heart Rhythm
JF - Heart Rhythm
IS - 10
ER -