From the discussion in the above article:


The study reported here examined the interaction of 9 medications that are associated with VHD (positive controls) and 5 medications that are not associated with VHD (negative controls) at 11 cloned 5-HT receptors. We sought to identify a mitogenic 5-HT receptor that would be activated by the positive but not the negative controls. We hypothesized that this CASR mediates fenfluramine-associated VHD. Among the receptors assayed, the 5-HT2B receptor has 5 characteristics consistent with its being the CASR: (1) it is located on both mitral and aortic valves10 ; (2) it mediates mitogenisis27 ; (3) the norfenfluramines have high affinity and efficacy at the 5-HT2B receptor; (4) ergotamine and methylergonovine, the active metabolite of methysergide, are high-affinity partial agonists for the 5-HT2B receptor; and (5) with the exception of mCPP (see below), the negative control drugs (fluoxetine, norfluoxetine, phentermine) have very low affinity for this site and lack agonist effects at this receptor. The 5-HT2C receptor is ruled out as the CASR, primarily because few of these receptors are expressed in heart valves.10

There are several observations that, at first glance, are difficult to reconcile with the hypothesis that the 5-HT2B receptor mediates the valvulopathy associated with administration of fenfluramine, ergotamine, and methysergide. First, whereas (+)-fenfluramine produces primarily aortic regurgitation,4 7 ergotamine and methysergide produce primarily mitral regurgitation.16 Given that 5-HT2B receptors are found on both valves,10 the mechanism underlying the anatomic specificity of the valvulopathy associated with these 2 classes of drugs is enigmatic. Second, methysergide appears to produce a more severe form of VHD than fenfluramine. Patients with fenfluramine-associated VHD are clinically asymptomatic and typically do not have audible heart murmurs.2 The best estimate of the incidence of clinically significant fenfluramine-associated VHD is 0.07% per year.7 In contrast, patients treated with methysergide developed clinically significant VHD, including new heart murmurs,16 with an incidence of 3%.16 Thus, although methylergonovine is a less effective agonist at the 5-HT2B receptor than norfenfluramine, it produces a more severe form of VHD in a greater number of patients. Third, methysergide administration is associated with fibrosis of other anatomic sites in addition to heart valves.28 In contrast, fenfluramine-associated fibrosis appears to be localized to heart valves.

Fourth, the finding that mCPP has activity at 5-HT2B receptors must be reconciled with observations that trazodone, from which it is metabolically derived, is not associated with VHD. Therapeutic doses of trazodone generate plasma levels of mCPP from 150 to 550 nmol/L,29 which are in the range needed to activate 5-HT2B receptors. However, trazodone is a potent 5-HT2B receptor antagonist, and its plasma levels are {approx}5-fold higher than that of mCPP.29 Thus, trazodone would act to block activation of 5-HT2B receptors by mCPP.

Thus, a possible explanation for the differing degrees of VHD prevalence seen among the 5-HT2B agonists is the degree of 5-HT2B antagonism produced by either parent drug or metabolites. Methysergide, as a very-low-efficacy 5-HT2B agonist, would act to antagonize the agonist effects of methylergonovine (Table 2Up). However, methysergide is rapidly metabolized to methylergonovine, is more rapidly eliminated, and achieves blood levels 10-fold lower than methyergonovine.15 Because the agonist actions of methylergonovine are most likely not significantly blocked by its parent drug, methysergide administration would probably cause a higher prevalence of VHD. In the case of fenfluramine, (+)-fenfluramine and (-)-fenfluramine have lower efficacy ({approx}40%) at the 5-HT2B receptor than (+)-norfenfluramine (75%) and achieve blood levels twice that of norfenfluramine.8 This indicates that the parent drugs would partially antagonize activation of 5-HT2B receptors by (+)-norfenfluramine. This may explain why the fenfluramines appear to produce a less severe form of VHD than methysergide (see above).

Taken at face value, the 5-HT2B hypothesis predicts that elevations of plasma 5-HT should produce valvulopathy in both the aortic and mitral valves. Indeed, 5-HT is the most potent and efficacious agonist at the 5-HT2B receptor. Medications such as lithium and monoamine oxidase inhibitors produce sustained 2-fold increases in plasma 5-HT and are not associated with VHD.30 31 This suggests that modest elevations of plasma 5-HT are unlikely to produce this adverse effect. Patients with carcinoid syndrome develop extremely high levels of plasma 5-HT (>500 nmol/L32 ), and fibrotic valve lesions occur exclusively on the right side of the heart. Although some attribute the lack of left-sided VHD in carcinoid syndrome to the almost complete removal of plasma 5-HT by the lung before the blood empties into the left atrium,12 this hypothesis fails to take into account the fact that the blood samples taken for analysis of 5-HT are withdrawn from the antecubital vein in the arm, the blood of which is derived most directly from the left side of the heart. Although the right side of the heart is undoubtedly bathed in higher concentrations of 5-HT than the left side, the left side is clearly exposed to 5-HT concentrations well in excess of that necessary to completely activate the 5-HT2B receptor. Thus, it is not clear why carcinoid syndrome produces fibrotic lesions on the valves of the right side of the heart, whereas fenfluramine, methysergide and ergotamine affect primarily the valves of the left side.

Viewed collectively, these considerations suggest that activation of 5-HT2B receptors may be necessary to produce VHD. Clearly, other factors also determine the susceptibility of an individual to develop the lesion, its anatomic location, and its severity. Despite our lack of knowledge of what these factors might be, these data suggest that serotonergic medications, which do not activate 5-HT2B receptors, are unlikely to produce VHD. These findings further suggest that the simplest pathogenic mechanism to explain anorexigen-associated VHD is a direct activation of 5-HT2B receptors by norfenfluramine. This mechanism does not necessitate the formulation of unlikely synergistic mechanisms between phentermine and fenfluramine33 or a role for plasma 5-HT to explain the occurrence of VHD. Finally, on the basis of these results and those recently reported by Fitzgerald et al,10 we suggest that all clinically available medications with serotonergic activity and their metabolites should be screened for agonist activity at 5-HT2B receptors.

Note Added in Proof
Dr Roth’s laboratory has begun to measure the efficacies of clinically used serotonergic compounds at the h5-HT2B receptor and have not yet found any that are agonists.