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(Circulation. 2005;111:1517-1522.)
© 2005 American Heart Association, Inc.

Valvular Heart Disease

Long-Term Serotonin Administration Induces Heart Valve Disease in Rats

Björn I. Gustafsson, MD; Karin Tømmerås, PhD; Ivar Nordrum, MD, PhD; Jan P. Loennechen, MD, PhD; Anders Brunsvik, BA; Erik Solligård, MD; Reidar Fossmark, MD, PhD; Ingunn Bakke, PhD; Unni Syversen, MD, PhD; Helge Waldum, MD, PhD

From the Departments of Internal Medicine (B.I.G., J.P.L., U.S., H.W.), Clinical Pharmacology (A.B.), and Anesthesiology and Intensive Care (E.S.), St Olavs Hospital HF, Trondheim University Hospital, and Departments of Laboratory Medicine, Children’s and Women’s Health (I.N.) and Cancer Research and Molecular Medicine (B.I.G., K.T., J.P.L., R.F., I.B., U.S., H.W.), Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

Correspondence to Dr Björn Gustafsson, Medisinsk avd, Gastroseksjon, St Olavs Hospital HF, N-7006 Trondheim, Norway. E-mail bjorn.gustafsson{at}medisin.ntnu.no

Received June 12, 2004; revision received November 12, 2004; accepted November 15, 2004.

Background— The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease.

Methods and Results— Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a >10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT_1A, 5-HT_2A, and 5-HT_2B and the serotonin transporter 5-HTT.

Conclusions— For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.

Key Words: carcinoid heart disease • receptors • serotonin • valves

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