EXPERIMENTAL STUDY
Autoimmunity against the second extracellular loop of beta1-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits
Yukiko Fukuda, MD*,*,
Shunichiro Miyoshi, MD, PhD*,
Kojiro Tanimoto, MD*,
Kenichi Oota, MD*,
Kana Fujikura, MD*,
Michikado Iwata, MD*,
Akiyasu Baba, MD*,
Yoko Hagiwara, MD*,
Tsutomu Yoshikawa, MD, PhD*,
Hideo Mitamura, MD, PhD* and
Satoshi Ogawa, MD, PhD*
* Cardiopulmonary Division of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Manuscript received July 1, 2003;
revised manuscript received August 8, 2003,
accepted September 15, 2003.
* Reprint requests and correspondence: Dr. Yukiko Fukuda, Cardiopulmonary Division of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
yukikof{at}cpnet.med.keio.ac.jp
smiyoshi{at}cpnet.med.keio.ac.jp
OBJECTIVES: We sought to define the electrophysiologic property of the rabbit heart associated with autoimmunity against the second extracellular loop of the beta1-adrenergic receptor.
BACKGROUND: Sudden death of patients with cardiomyopathy, probably due to lethal ventricular arrhythmias, can be predicted by the presence of autoantibodies against the second extracellular loop of the beta1-adrenergic receptor.
METHODS: Rabbits were immunized by repetitive subcutaneous administration of a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta group; n = 30) for a mean of 4.2 months. Control rabbits received only vehicle (control group; n = 30).
RESULTS: One of the rabbits in the beta group died suddenly during the observation period, but none of the control animals died. The prevalence of sustained ventricular tachycardia was significantly higher in the beta group (beta: 4 of 27 vs. control: 0 of 30), and a standard microelectrode experiment revealed prolongation of the action potential duration (APD) in the right ventricular papillary muscle (beta: 156 ± 5 ms vs. control: 131 ± 4 ms; p < 0.05). Early afterdepolarization (EAD) was observed in one rabbit in the beta group (1 of 26), but not in any animals in the control group (0 of 17). A dose of 100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the control group, except for one rabbit (1 of 10). The whole-cell, patch-clamp experiment on left ventricular M cells showed significant decreases in transient outward current (Ito1) (–43%) and slowly activated delayed rectifier current (IKs) densities (–33%), whereas the inward-rectifying K current (IK1) and rapidly activated delayed rectifier current (IKr) densities remained unchanged.
CONCLUSIONS: Long-term immunization against the second extracellular loop of the beta1-adrenergic receptor caused EAD and APD prolongation and decreased the K-channel density, suggesting that an arrhythmic substrate via autoimmune mechanisms is present in cardiomyopathic patients who have autoantibodies directed against the receptors.
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Abbreviations and Acronyms
| | APD | = action potential duration | | BSA | = bovine serum albumin | | EAD | = early after depolarization | | ECG | = electrocardiogram/electrocardiograph/ electrocardiographic | | ICaL | = L-type calcium current | | If | = hyperpolarization-dependent current | | IK1 | = inward-rectifying K current | | IKr | = rapidly activated delayed rectifier current | | IKs | = slowly activated delayed rectifier current | | Ito | = transient outward current | | PCL | = pacing cycle length | | SVT | = sustained ventricular tachycardia | | VT | = ventricular tachycardia |
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