Background

The possibility that the intake of drugs might be responsible for the onset of valvular heart disease (VHD) was first proposed in the mid-1960s for ergot alkaloids used for migraine prophylaxis – initially methysergide (Desernil ^® ) and then ergotamine (Gynergene ^® ). In 1997 to 1998, drug-related VHD was reported for two appetite suppressants – fenfluramine (Ponderal ^® ) and dexfenfluramine (Isomeride ^® ) – that had previously been recognized as being associated with the occurrence of pulmonary arterial hypertension. These findings led to the withdrawal from the market of these two drugs. More recently, similar findings of drug-related VHD with ergot-derived dopamine agonists were reported in patients treated with pergolide (Celance ^® ) for Parkinson’s disease and cabergoline (Dostinex ^® ) for hyperprolactinaemic disorders. Subsequently, similar drug-related VHD was reported with prolonged use of the recreational drug ecstasy (3,4-methylenedioxymethamphetamine; MDMA) and with a drug indicated for diabetes in overweight patients (benfluorex; Mediator ^® ). The diagnosis of such drug-related VHD is based on echocardiography.

All of these drugs that have been shown to be capable of inducing VHD were found to have a common pharmacological action on a specific serotonin receptor – the 5HT _2B receptor. Indeed, these drugs have an agonistic action, with a high affinity for these receptors (which are highly present in valvular tissue), leading to valvular alterations similar to those observed previously in carcinoid heart disease, a neuroendocrine malignancy linked to enterochromaffin cells, which produce great quantities of serotonin. The various drug-induced VHDs have similar morphological and histological features, characterized by tissue thickening and an abundant extracellular matrix of glycosaminoglycans and collagen, with proliferation of myofibroblasts and smooth muscle cells, few calcifications and no pronounced inflammation. The underlying valve structure is usually unchanged.

Echocardiographic features

Echocardiography is the key examination for screening and grading iatrogenic valve disease . The echocardiographic features are common for all drug-induced VHDs. Variable degrees of valve regurgitation are observed. Drug-induced valve disease is generally not responsible for severe valve stenosis. It can be difficult to attribute a causal relationship between a specific drug and valve damage because pretreatment echocardiographic data are not available in the majority of cases. Moreover, mere detection of regurgitation does not provide information on the aetiology. Actually, diagnosis using two-dimensional echocardiography is based, above all, on studying the texture and motion of the valves and analysing the subvalvular apparatus for mitral and tricuspid VHD. Typically, one can generally see mild or moderate valve thickening in the absence of calcification or marked commissural fusion (in contrast with rheumatic valve disease). Restricted valve motion, which is responsible for the regurgitation, is the most characteristic feature of drug-induced valve disease. In mitral valve regurgitation, the restriction generally affects both mitral leaflets but often predominates at the posterior leaflet. Leaflet thickening is often minimal but is generally associated with unequivocal thickening and shortening of the chordae tendineae ( Figs. 1 and 2 ). In aortic regurgitation, valve thickening is often mild (and may not be present). Variable degrees of leaflet retraction are observed, responsible for malcoaptation and regurgitation during diastole ( Fig. 1 ). Using two-dimensional echocardiography, a small central triangular valve hiatus during diastole is observed in the short-axis view, sometimes associated with a subtle ‘dome-like’ aspect of the aortic valve during systole. Aortic regurgitation visualized with colour Doppler is generally central. Tricuspid and pulmonary drug-induced VHD is less common; echocardiographic findings seem similar to those observed in mitral and aortic damage.

Patient with toxic aortic and mitral valvulopathy due to benfluorex. On this apical four-chamber view using two-dimensional echocardiography, the mitral leaflets have lost their flexibility. Note the marked remodelling of the mitral subvalvular apparatus, with slight thickening of both leaflets.

Same patient as in Fig. 1 : the aortic cusps are slightly thickened, restrictive and fibrous-looking, with defective central coaptation.

Valvular heart disease associated with migraine drugs

Methysergide and ergotamine are old drugs used to prevent or treat migraine. These drugs were the first to be recognized as being associated potentially with the occurrence of valvular regurgitation. Methysergide – already known to induce fibrotic tissue alterations, which may explain pulmonary arterial hypertension as well as retroperitoneal fibrosis – was the first drug to be implicated. In 1967, Graham et al. associated the development of valvular abnormalities with the use of this drug. Indeed, they published a series of 36 patients treated on a long-term basis with methysergide, who developed cardiac murmurs linked to mitral and/or aortic regurgitation (generally without clinical symptoms), with regression or disappearance of the murmurs after drug discontinuation in more than one third of patients. Some years later, a frequently-associated involvement of the tricuspid valves was highlighted . Then, in 1974, ergotamine – another ergot alkaloid structurally related to methysergide – was also shown to be associated with left-sided VHD for the first time, with other cases reported thereafter. From 1974, the fibrotic nature of the valvular lesions was recognized, with an emphasis on these lesions being morphologically similar to those described in carcinoid heart disease . These drugs are still on the market but are used only for short-term treatment and very rarely induce VHD.

Valvular heart disease associated with fenfluramine and dexfenfluramine

VHDs have been observed with fenfluramine and dexfenfluramine, which were used largely as anti-obesity drugs. A short time after the withdrawal of these drugs from the market in France, due to the demonstration that they may induce pulmonary arterial hypertension , the first 24 cases of valvular insufficiencies were reported in the USA with the fenfluramine-phentermine association, in women aged 44 ± 8 years . These patients were known to have no past cardiovascular history and took this drug combination for a mean duration of 12 months; they presented with cardiac failure symptoms or a heart murmur. Echocardiograms performed on these patients demonstrated an unusual valvular morphology, with varying degrees of valvular regurgitation involving both left- and right-sided valves. The involved valves exhibited leaflet thickening, with retraction of the chordae tendineae leading to malcoaptation of the valves and regurgitation. Five of the patients subsequently underwent cardiac surgery for valve replacement. The histopathological features of the valves excised were nearly identical to those seen in patients with carcinoid syndrome and those previously described with ergot alkaloid-related antimigraine drugs (plaques of proliferative myofibroblasts in an abundant extracellular myxoid or collagen matrix). After this first publication, the Food and Drug Administration (FDA) indicated that a significant number of VHD notifications had been received in association with the intake of phentermine in combination with fenfluramine as well as with dexfenfluramine (approved for use in the USA in 1996). Thirty-three cases were indeed retrieved by notifications.

Other studies were published some months later, showing that duration of drug exposure played a significant role in the development of VHD. Thus, in the study performed by Khan et al. , it was found that prolonged intake of fenfluramine or dexfenfluramine led to a multiplication of the risk of VHD by 22. Data other than from the USA were published with concordant results. Thus, Jick et al. retrospectively analysed the UK General Practice Research Database (GPRD) and extracted symptomatic cases of VHD confirmed by echocardiography and associated with the intake of fenfluramine or dexfenfluramine (duration of treatment 21 ± 12 months) but no cases associated with phentermine alone or obese patients who did not take appetite suppressants. This was an important consideration, as a hypothesis regarding a specific potential role for obesity itself in the development of VHD had been advanced. The 5-year cumulative incidence of valvular regurgitation was found to be 7.1 per 10,000 patient-years when fenfluramine or dexfenfluramine was taken for less than 3 months and 35 per 10,000 patient-years for a treatment duration of 4 months or more.

Studies performed later also took into account the potentially confounding factor of obesity itself and the fact that unexplained valvular regurgitations may occur spontaneously. Taking into account these possible biases, all the studies confirmed the potential of fenfluramine and dexfenfluramine to induce valvular regurgitations when administered on a long-term basis. A meta-analysis of nine published case-control pharmacoepidemiological studies by Sachdev et al. compared 3769 patients with 5009 matched controls (mean age 46 years; 85% of women with a mean body mass index [BMI] of 36; mean duration of treatment 397 days). When the drug intake duration was greater than 90 days, 12% of patients presented VHDs when taking fenfluramine-type appetite suppressants compared with 5% of obese patients who were not taking these drugs (odds ratio [OR] 2.2; 95% confidence interval [CI] 1.7–2.7). Thus, one in eight patients receiving these drugs for greater than 90 days was found to have VHD, with aortic regurgitations occurring three times more frequently than mitral regurgitations.

So, much data reported in the literature support the point that fenfluramine-type appetite suppressants may induce VHD – mainly aortic regurgitation but also, although with a lower incidence, mitral restrictive regurgitation, essentially when the duration of drug intake was greater than 3 to 6 months , whereas pulmonary arterial hypertension may appear after a shorter treatment time. It has been reported that withdrawal of the drugs decreases the severity of regurgitation or stabilizes the valvular lesions in some of the patients involved . However, several cases of fenfluramine-associated valvular disease have been reported up to 7 years after drug withdrawal .