High-dose oral intake of serotonin induces valvular heart disease in rabbits

Abstract

Carcinoid tumors are rare neuroendocrine malignancies, often originating from enterochromaffin cells in the gastrointestinal tract. They can secrete serotonin (5-hydroxytryptamine, 5-HT), which is largely inactivated by the liver [ [1] Lundin L. Norheim I. Landelius J. Oberg K. Theodorsson-Norheim E. Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation. 1988; 77: 264-269 Crossref PubMed Scopus (207) Google Scholar ]. Carcinoid heart disease occurs when tumor cells metastasize to the liver, as the vasoactive substances produced are able to reach the systemic circulation via the hepatic vein, causing deposition of fibrous tissue on the endocardial surfaces of the heart [ [2] Ferrans V.J. Roberts W.C. The carcinoid endocardial plaque: an ultrastructural study. Hum. Pathol. 1976; 7: 387-409 Abstract Full Text PDF PubMed Scopus (81) Google Scholar ]. It is predominantly manifested by right-sided valvular heart disease (VHD). Scavenging enzymes in the pulmonary endothelium may explain why left-sided cardiac involvement is unusual [ [3] Chaowalit N. Connolly H.M. Schaff H.V. Webb M.J. Pellikka P.A. Carcinoid heart disease associated with primary ovarian carcinoid tumour. Am. J. Cardiol. 2004; 93: 1314-1315 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar ]. The severity of cardiac damage is correlated with the plasmatic levels of serotonin, but the low specificity of serotonin for cardiac damage suggests that serotonin may be necessary but not sufficient to induce cardiac lesions [ [4] Robiolio P.A. Rigolin V.H. Wilson J.S. et al. Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation. 1995; 92: 790-795 Crossref PubMed Scopus (283) Google Scholar ]. Therefore, other factors combined with serotonin might be required to induce VHD. However, recent animal studies confirmed the development of carcinoid-like valvular deposits in rats after 3 months of daily subcutaneous/intraperitoneal serotonin injections to avoid the liver first-pass clearance [ 5 Gustafsson B. Tommeras K. Nordrum I. et al. Long-term serotonin administration induces heart valve disease in rats. Circulation. 2005; 111: 1517-1522 Crossref PubMed Scopus (198) Google Scholar , 6 Droogmans S. Franken P.R. Garbar C. et al. In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology. Eur. Heart J. 2007; 28: 2156-2162 Crossref PubMed Scopus (58) Google Scholar ]. Whether oral administration of serotonin can also induce VHD is unknown. We hypothesized that long-term oral serotonin overload in rabbits can lead to VHD, mimicking serotonin-induced lesions of carcinoid heart disease.