Purkinje Cells as Sources of Arrhythmias in Long QT Syndrome Type 3.
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.
Department of Pharmacology, Columbia University Medical Center, New York, NY.
Vivek
V
Iyer
Department of Pharmacology, Columbia University Medical Center, New York, NY.
Danilo
D
Roman-Campos
Department of Pharmacology, Columbia University Medical Center, New York, NY.
Kevin J
KJ
Sampson
Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
Guoxin
G
Kang
Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
Glenn I
GI
Fishman
Department of Pharmacology, Columbia University Medical Center, New York, NY.
Robert S
RS
Kass
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D000075224:Cardiac Conduction System Disease; D006352:Heart Ventricles / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008133:Long QT Syndrome / Q000473:pathology* / Q000503:physiopathology; D008801:Mexiletine / Q000494:pharmacology; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D062554:NAV1.5 Voltage-Gated Sodium Channel; D008801:Mexiletine; D002118:Calcium