Key result
Purkinje cells carrying the ΔKPQ mutation exhibited significantly prolonged action potential duration (193.0 ms vs 104.3 ms in wild-type) and frequent early afterdepolarizations.
Why the study?
Do Purkinje cells exhibit unique pro-arrhythmic electrophysiological properties in a murine model of Long QT Syndrome Type 3?
Do Purkinje cells exhibit unique pro-arrhythmic electrophysiological properties in a murine model of Long QT Syndrome Type 3?
Absolute Event Rate: 193% vs 104.3%
p-value: p=<0.01
Purkinje cells are uniquely sensitive to the LQT3 ΔKPQ mutation, displaying severe repolarization abnormalities and early afterdepolarizations that may serve as the primary source of arrhythmias in this syndrome.
May implicate Purkinje cells as arrhythmia triggers in LQT3; hypothesis-generating in murine model, requires validation.
Long QT syndrome (LQTS) is characterized by ventricular arrhythmias and sudden cardiac death. Purkinje cells (PC) within the specialized cardiac conduction system have unique electrophysiological properties that we hypothesize may produce the primary sources of arrhythmia in heritable LQTS. LQTS type 3 (LQT3) transgenic mice harboring the ΔKPQ(+/-) mutation were crossed with Contactin2-EGFP BAC transgenic mice, which express a fluorescent reporter gene within the Purkinje fiber network. Isolated ventricular myocytes (VMs) (EGFP(-)) and PCs (EGFP(+)) from wild type and ΔKPQ mutant hearts were compared using the whole-cell patch clamp technique and microfluorimetry of calcium transients. Increased late sodium current was seen in ΔKPQ-PCs and ΔKPQ-VMs, with larger density in ΔKPQ-PCs. Marked prolongation of action potential duration of ΔKPQ-PCs was seen compared to ΔKPQ-VMs. ΔKPQ-PCs, but not ΔKPQ-VMs, exhibited frequent early afterdepolarizations, which corresponded to repetitive oscillations of intracellular calcium. Abnormalities in cell repolarization were reversed with exposure to mexiletine. We present the first direct experimental evidence that PCs are uniquely sensitive to LQT3 mutations, displaying electrophysiological behavior that is highly pro-arrhythmic.
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Iyer et al. (2015) studied Long QT Syndrome Type 3. ΔKPQ mutation (LQT3) vs. Wild-type was evaluated on Action potential duration at 90% repolarization (APD90) (p=<0.01). Purkinje cells carrying the ΔKPQ mutation exhibited significantly prolonged action potential duration (193.0 ms vs 104.3 ms in wild-type) and frequent early afterdepolarizations.
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