Phosphodiesterase-4 activity: a critical modulator of atrial contractility and arrhythmogenesis.

Abstract

Atrial excitation-contraction coupling (ECC) and pacemaker activity are both dependent on intracellular calcium (Ca²⁺) cycling, and alterations in Ca²⁺ cycling are strongly implicated in the pathophysiology of atrial fibrillation (AF). Depolarization of cardiac myocytes promotes Ca²⁺ influx via L-type calcium channels (LTCCs), which then releases a larger quantity of Ca²⁺ from intracellular stores. For ECC, elevated Ca²⁺ interacts with troponin C, promoting cross bridge interaction and myocyte contraction. Relaxation during diastole requires intracellular Ca²⁺ levels to return to baseline levels, either via reuptake of Ca²⁺ into the sarcoplasmic reticulum or extrusion from the cell by the sodium calcium exchanger. In pacemaking cells, Ca²⁺ influx via the LTCC underlies the upstroke of the action potential; Ca²⁺ (and sodium) influx via HCN (hyperpolarization-activated cyclic nucleotide-gated) channels regulates the rate of diastolic depolarization.