Several drugs have been associated with an increased risk of heart valve disease. Numerous reports have shown an unquestionable association between fibrotic valve disease and the following drugs: rye ergot alkaloids, such as methysergide (sold as Desernil ® in France) and ergotamine (Gynergene ® ), used as migraine drugs ; appetite suppressants, such as fenfluramine (Ponderal ® ) and dexfenfluramine (Isomeride ® ) , also known for their link with precapillary pulmonary hypertension (PPH) ; and ergotic dopaminergic agonists , such as pergolide (Celance ® ) and cabergoline (Dostinex ® ). The so-called ‘recreational’ drug 3,4-methylene-dioxy-methylamphetamine (better known as ‘ecstasy’ ) has also been potentially associated with fibrotic valvular disease. Benfluorex was withdrawn from sale in France in November 2009 and from the European market in June 2010 following reports strongly suggesting an increased risk of valvular disease and PPH in patients with previous exposure to this drug. In France, benfluorex was prescribed as an adjuvant to an appropriate diet in overweight diabetics; its indication as an adjuvant to an appropriate diet in patients with hypertriglyceridaemia was withdrawn in 2007, following assessment of a very poor efficacy in this setting. Benfluorex had also been widely prescribed in France as an appetite suppressant.
In France, about 2.9 million people have been exposed for more than 3 months to benfluorex since its market launch in 1976. At the time of its market withdrawal, over 300,000 patients were still taking the drug. French healthcare authorities recommend that patients who have taken benfluorex should consult their primary care physician for a clinical examination, including an interview and cardiac auscultation. If there is the slightest suspicion of heart valve disease or if the patient requests it, the performance of a clinical examination and transthoracic echocardiography by a cardiologist is further recommended.
Recent literature reports have established that benfluorex can cause restrictive leaky valve damage. All four valves can be affected but aortic and/or mitral regurgitation predominates . Aortic regurgitation seems more frequent than mitral regurgitation. Dual restrictive mitroaortic regurgitation is suggestive of drug-induced valvular disease . The precise prevalence of this type of regurgitation is not yet known. Severe regurgitation seems to be rare, estimated at less than one case per 1000 exposed patient-years , whereas mild valve disease appears to be more frequent. Drug-induced fibrotic valve disease is generally not responsible for severe valve stenosis.
Echocardiography is the key examination for screening and grading iatrogenic valve disease . The echocardiographic features are similar for all drug-induced valve diseases. This type of valve regurgitation can be discovered late on, if echocardiography has not been performed since the withdrawal of the drug. The echocardiographic signs of this type of damage are not often described in the literature and thus are not always well known. It is possible that confusion between unrecognized drug-induced valve disease and supposedly rheumatic valve disease has contributed to the delay in recognizing this specific pathology in France. Moreover, it can be difficult to attribute a causal relationship between a specific drug and valve damage because, in the vast majority of cases, pretreatment echocardiographic data are not available. In fact, mere detection of regurgitation does not provide information about aetiology. Restricted valve motion, which is responsible for the regurgitation, is the most characteristic feature of drug-induced valve disease. Hence, diagnosis-using echocardiography is mainly based on studying the texture and motion of the valves, and analysing the subvalvular apparatus. Typically, one can see generally mild or moderate valve thickening in the absence of calcification or marked commissural fusion (in contrast with rheumatic valve disease). Nevertheless, drug-induced valve disease can probably develop in pre-existing valve lesions. Conversely, calcification might subsequently occur in drug-induced valve lesions.
In mitral valve regurgitation, leaflet thickening is often minimal and is generally associated with thickening and shortening of the chordae tendineae ( Fig. 1 ). The leaflets become retracted and less flexible, which reduces valve mobility. In severe cases, leaflets may have a typical drumstick appearance with abnormal valve coaptation in systole causing the leak. The restriction generally affects both mitral leaflets but often predominates at the posterior leaflet. 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. 2 ). Using two-dimensional echocardiography, a small central triangular valve hiatus during diastole is observed in the short-axis view, sometimes associated in the long-axis view with a subtle dome-like aspect of the aortic valve during systole. Aortic regurgitation visualized with colour Doppler is generally central ( Fig. 2 ). Tricuspid and pulmonary regurgitations are less common but are similar to mitral/aortic lesions.
