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CLINICAL STUDY: ELECTROPHYSIOLOGY

Up-regulation of inositol 1,4,5 trisphosphate receptor expression in atrial tissue in patients with chronic atrial fibrillation

Jutaro Yamada, MD^*, Tomoko Ohkusa, MD, PhD^*, Tomoko Nao, MD^*, Takeshi Ueyama, MD, PhD^*, Masafumi Yano, MD, PhD^*, Shigeki Kobayashi, MD, PhD^*, Kimikazu Hamano, MD, PhD, Kensuke Esato, MD, PhD and Masunori Matsuzaki, MD, PhD, FACC^*

^* Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan
First Department of Surgery, Yamaguchi University School of Medicine, Ube, Japan

Manuscript received July 10, 2000; revised manuscript received November 3, 2000, accepted December 12, 2000.

Reprint requests and correspondence: Dr. Masunori Matsuzaki, Second Department of Internal Medicine, Yamaguchi University School of Medicine, 1-1-1, Minami-kogushi, Ube, Yamaguchi 755-8505, Japan
masunori{at}po.cc.yamaguchi-u.ac.jp

OBJECTIVES

We examined whether patients with atrial fibrillation (AF) have alterations in atrial inositol 1,4,5 trisphosphate receptors (IP3 receptors).

BACKGROUND

Abnormal intracellular Ca²⁺ homeostasis occurs in chronic AF. The intracellular Ca²⁺ concentration is regulated by ryanodine and IP3 receptors. We recently reported alterations in ryanodine receptors in atrial tissue from patients in chronic AF.

METHODS

We analyzed IP3 receptor expression in the right atrial myocardium from 13 patients with mitral valvular disease (MVD) with AF (MVD/AF), five patients with MVD who had normal sinus rhythm (MVD/NSR) and eight control patients with NSR (tissue obtained during coronary artery bypass surgery). Hemodynamic and echocardiographic data were obtained preoperatively, and an immunohistochemical study was performed on atrial tissue.

RESULTS

The relative expression level of IP3 receptor protein was significantly greater in MVD/AF (0.75 ± 0.26) than it was in MVD/NSR (0.42 ± 0.13, p < 0.01), and both were significantly above control (0.14 ± 0.08). The relative expression level of IP3 receptor messenger RNA was significantly greater in the MVD/AF group (0.028 ± 0.008) than it was in the control group (0.015 ± 0.004, p < 0.01), but patients with MVD/AF did not differ from patients with MVD/NSR (0.020 ± 0.006). The relative expression levels of IP3 receptor protein and messenger RNA were higher in patients with left atrial dimension 40 mm, pulmonary capillary wedge pressure 10 mm Hg and right atrial pressure 5 mm Hg. Inositol 1,4,5 trisphosphate receptors were over-expressed in the cytosol and at the nuclear envelope of atrial myocytes in MVD.

CONCLUSIONS

Since chronic mechanical overload of the atrial myocardium increased IP3 receptor expression, especially in patients with chronic AF, up-regulation of IP3 receptors may be important in modulating intracellular Ca²⁺ homeostasis and initiating or perpetuating AF.

Abbreviations and Acronyms   AF = atrial fibrillation   cDNA = complementary DNA   GAPDH = glyceraldehyde-3-phosphate dehydrogenase   IP3 receptor = inositol 1,4,5 trisphosphate receptor   LAD = left atrial diameter   mRNA = messenger ribonucleic acid   MVD = mitral valvular disease   NSR = normal sinus rhythm   PCR = polymerase chain reaction   PCWP = pulmonary capillary wedge pressure   RAP = right atrial pressure   RT-PCR = reverse transcription-polymerase chain reaction   RyR = ryanodine receptor   SR = sarcoplasmic reticulum

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