Fenfluramine: riddle or Rosetta stone?

I diopathic pulmonary arterial hypertension (IPAH) used to be called primary pulmonary hypertension. Both terms indicate that we do not yet fully understand the aetiology of the disease. A clue to the underlying mechanisms lies in the observation that the appetite-suppressant drugs aminorex [1, 2] and fenfluramine [3] were both associated with a marked increase in the incidence of pulmonary arterial hypertension (PAH) while they were available in Europe. Although they are no longer prescribed, it is important to study them to gain an understanding of IPAH and to ensure that new drugs do not have the potential to cause pulmonary hypertension. In general, there is no clinical or pathological way to distinguish PAH associated with these anorectic agents from IPAH independent of them. This point is clearly made in a study by SOUZA et al. [4] in the present issue of the European Respiratory Journal. SOUZA et al. [4] describe the follow-up of 109 patients diagnosed with PAH in association with exposure to fenfluramine between 1986 and 2004. In virtually every respect, the presentation and clinical course of these patients was the same as that of patients with IPAH who were diagnosed over the same period. Interestingly, 18% of the fenfluramine PAH patients had a bone morphogenic protein receptor 2 (BMPR2) gene mutation, a very similar incidence to that observed in sporadic IPAH [5]. This suggests the likelihood of underlying genetic susceptibility that renders both groups vulnerable, perhaps to a similar second hit. FENFLURAMINE-INDUCED VALVE DISEASE There is one marked difference in the spectrum of disease caused by fenfluramine and that seen in IPAH. Although fenfluramine was recognised to cause PAH it was actually withdrawn from the market in 1997 because of an associated cardiac valvulopathy [6]. The valvulopathy does not occur in IPAH but resembles that seen in clinical carcinoid heart disease, where high levels of 5-hydroxytryptamine (5-HT) are primarily responsible. Indeed, chronic systemic administration of 5-HT in rats has been demonstrated to cause valvulopathy and myofibroblast proliferation [7]. The fenfluramine-related valvulopathy is thought to be caused by stimulation of the 5-HT2B receptor by the metabolite norfenfluramine [8]. 5-HT acts on cells not only by binding to receptors on the cell surface but also by being taken up into the cell through the 5-HT transporter (5-HTT). Genetically induced deficiency of the 5-HTT in mice also leads to valvulopathy and fibrosis [9]. Fenfluramine inhibits the 5-HTT, in addition to …