Aging and Protein Kinase Activation
Is It the Missing Link Between Age and Atrial Fibrillation?
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Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with substantial morbidity and mortality.1 Age is a key determinant of AF risk: <2% for individuals <60 years of age, increasing exponentially to >14% by 85 years of age.1 Whereas older age makes AF more likely, younger age seems protective: congenital heart disease patients with enormous, extensively remodeled atria develop atrial tachyarrhythmias, but AF remains the least common form until 50 years of age.2
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Studies of Mechanisms Underlying Age-Dependent AF Susceptibility
The Table summarizes the principal studies in the literature that address mechanisms underlying aging-related AF. Atrial muscle bundles from humans <14 years of age show smooth conduction, whereas older individuals (40–60 years old) have impaired transverse-impulse propagation because of increased interstitial collagen, leading to zigzag conduction.3 Optical mapping in beagle hearts confirmed transverse conduction changes in 6- to 10-year-old dogs (equivalent to 40–56-year-old humans), with associated decreases in transverse connexin 43 expression.4 Atrial electrogram fragmentation and refractoriness prolongation occur in older patients, indicating disturbances in both conduction and repolarization.5 Electroanatomic studies show slowed conduction and reduced electrogram voltage (consistent with fibrosis) in humans >50 years of age versus younger individuals.6,7 A potential molecular basis for aging-related conduction disturbances was provided by studies showing increased phosphorylated (active) JNK (C-jun N-terminal kinase) and decreased connexin 43 expression with aging in humans, mice, and rabbits.8 Conduction slowing and increased AF vulnerability in aged mouse hearts were reversed by a JNK inhibitor that reduced JNK phosphorylation and restored connexin 43 expression.8 Pharmacological and genetic JNK activation downregulated atrial connexin 43 and slowed conduction. Aging has also been associated with action potential prolongation in dogs9 and enhanced triggered activity/AF because of spontaneous intracellular calcium releases …