Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents.
BACKGROUND
Aging and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Abnormal Ca(2+) 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, Ca(2+) 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 Ca(2+) ATPase (SERCA2a), ryanodine receptor, and Na(+)/Ca(2+) 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(+)/Ca(2+) exchanger and ryanodine receptor and decreased expression of SERCA2a. Rapamycin (1,10,100 nM), FK-506 (0.01, 0.1, 1 microM), ryanodine (0.1, 1 microM), and ouabain (0.1, 1 microM) 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.


CONCLUSIONS
Aging increases PV arrhythmogenesis via abnormal Ca(2+) regulation. These findings support the concept that ryanodine receptor dysfunction may result in high PV arrhythmogenesis and aging-related arrhythmogenic vulnerability.
Wongcharoen
Wanwarang
W
National Yang-Ming University, School of Medicine, Taipei, Taiwan.
Chen
Yao-Chang
YC
Chen
Yi-Jen
YJ
Chen
Szu-Ying
SY
Yeh
Huang-I
HI
Lin
Cheng-I
CI
Chen
Shih-Ann
SA
D000367:Age Factors; D000818:Animals; D001281:Atrial Fibrillation / Q000473:pathology / Q000503:physiopathology*; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D011667:Pulmonary Veins / Q000473:pathology / Q000503:physiopathology*; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D012815:Signal Processing, Computer-Assisted; D020123:Sirolimus / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology; D046509:Tissue Culture Techniques
D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D012433:Ryanodine; D010042:Ouabain; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus