Long-Term Serotonin Administration Induces Heart Valve Disease in Rats

Abstract

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 Ͼ10-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.

Connective tissue growth factor expression in endocrine tumors is associated with high stromal expression of α-smooth muscle actin

“…Serotonin-independent mechanisms for CTGF production must, therefore, exist. Serotonin administration induces carcinoid heart disease in rats through a TGFB-mediated mechanism (2), and the presence of serotonin and perhaps other specific hormones likely modulate CTGF function.…”

“…The mechanism behind carcinoid-associated fibrosis is not established; yet, the list of factors that have been implicated is long. Carcinoid-produced hormones, serotonin (2) and tachykinins (3)(4)(5), have been shown to be related to fibroblast growth and fibrotic changes in the heart valves. Growth factors produced in ileal carcinoids such as platelet-derived growth factor, insulin-like growth factors 1 and 2 (IGF1 and 2), epidermal growth factor (EGF), and transforming growth factors a and b (TGFA and TGFB) and their receptors have also been postulated as potential mediators in the context of carcinoid fibrosis (6)(7)(8)(9).…”

Carcinoid heart disease: two clinical cases and a review

“…18 Additionally, rats injected with high doses of daily serotonin for three months, developed increased cardiac mass, cardiac fibrosis and valvulopathy. 22 Concomitant use of a serotonin receptor antagonist inhibited these changes. 23 Whether treatment with serotonin antagonists can prevent cardiac progression in humans is not known.…”

Consensus Recommendations for the Diagnosis and Management of Well-Differentiated Gastroenterohepatic Neuroendocrine Tumours: A Revised Statement from a Canadian National Expert Group

“…Only patients with elevated 5-hiaa levels develop this complication [39][40][41][42] ; serotonin receptors have been identified in the heart [85][86][87][88] ; experimentally, stimulation of these receptors causes cardiac cell proliferation [89][90][91] ; and two drugs, fen-phen and methysergide, can cause identical cardiac pathology (both have chemical structures analogous to serotonin, and both can be shown to bind to heart serotonin receptors) 92 .…”