Serotonin Transporter Mechanisms and Cardiac Disease

erotonin (5-HT)-related mechanisms have been ex- plored extensively for pharmaceutical development, especially with regard to antidepressants and appetite suppressants. However, pharmacological agents acting through 5-HT-related pathways have been associated with a number of significant cardiovascular adverse effects, includ- ing pulmonary hypertension,1,2 cardiac arrhythmias,2 and cardiac valve abnormalities.1-4 Evidence for a 5-HT valvu- lopathy has arisen from a variety of observations, including clinical,3,4 animal model,5 and cell culture investigations.6,7 Patients with carcinoid syndrome tumors,4 others treated with the diet drug combination fenfluramine-phentermine (Fen/ Phen),3 and individuals treated with ergot derivatives8 have been observed to develop what is most likely a 5-HT valvulopathy with comparable heart valve pathology between these different clinical groupings. In patients with carcinoid syndrome tumors, high 5-HT levels were observed to be associated with fibrodysplasia affecting predominantly the right-side cardiac valves3; a comparable pattern of valve disease was observed in a number of reported patients treated with ergot derivatives.8 The reason for this right-side valvu- lopathy distribution (tricuspid and pulmonary valves) has been hypothetically attributed to pulmonary monoamine ox- idase clearance of 5-HT, thereby resulting in left-side cardiac valves being exposed to relatively lower 5-HT levels1,4 despite elevated systemic 5-HT. However, a recent animal study involving daily injection of 5-HT in rats demonstrated both elevated 5-HT levels and right- and left-side valve abnormalities.5 Article p 81 The Fen/Phen valvulopathy has been reported to affect both right- and left-side cardiac valves,3 and this was hypoth- esized to be due in part to pulmonary monoamine oxidase inhibition by Phen, resulting in increased 5-HT exposure for left-side cardiac valves.1 However, the mechanisms respon- sible for the pathogenesis of the cardiac effects of 5-HT are likely linked to interactions involving both 5-HT receptors and the 5-HT transmembrane transporter (5-HTT). This issue of Circulation contains an important study9 of 5-HTT-