Afterdepolarizations and triggered activity as a mechanism for clinical arrhythmias

Andrew L Wit
Pacing and Clinical Electrophysiology: PACE 2018 June 19
Afterdepolarizations cause triggered arrhythmias. One kind occurs after repolarization is complete, delayed afterdepolarizations (DADs). Another occurs as an interruption in repolarization, early afterdepolarizations (EADs). Afterdepolarizations initiate arrhythmias when they depolarize membrane potential to threshold potential for triggering action potentials. DADs usually occur mostly when Ca2+ in the sarcoplasmic reticulum (SR) is elevated. The SR leaks some of the Ca2+ into the myoplasm through Ca2+ release channels controlled by ryanodine receptors (RyR2) during diastole. The Na+ -Ca2+ exchanger extrudes elevated diastolic Ca2+ from the cell in exchange for Na+ (1 Ca2+ for 3 Na+ ) generating inward current causing DADs. DAD amplitude increases with decreasing cycle length, causing triggered activity during an increase in heart rate or during programmed electrical stimulation (PES). Coupling interval of the first triggered impulse is directly related to initiating cycle length. EADs are associated with an increased action potential duration (APD) causing long QT (LQT). EADs are caused by net inward currents (ICaL , INCX ) as a consequence. Hundreds of mutations can cause congenital LQT by altering repolarizing ion channels. Acquired LQT results from drug interaction with repolarizing ion channels. EAD-triggered ventricular tachycardia is polymorphic and called "torsade de pointes." Effects of PES on EAD-triggered activity is related to effects of cycle length on APD. Shortening cycle length prevents EADs by accelerating repolarization. Typical PES protocols inhibit formation of EADs which can be therapeutic.

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