Drug-induced VHD shows clinical, histopathological and pathophysiological similarities with the carcinoid syndrome [5, 7]. The latter occurs in only 10 % of patients with carcinoid tumours when hormonally vasoactive tumour products exceeding the hepatic capacity for degradation (in case of hepatic metastasis) reach the systemic venous circulation. Serotonin is a key element that induces right-sided VHD in 40 % of these patients [12–14]. The presence of left heart disease is less frequent as serotonin is normally degraded by monoamine oxidase in the lungs (except in pulmonary metastasis or patent foramen ovale) [7, 15]. In contrast, drug-induced VHD affects even more importantly the aortic and mitral valves [16].

Superficial plaque-like thickening of the valvular leaflets and subvalvular apparatus composed of fibromyxoid tissue can be observed. Usually, no signs of calcification are present. Macroscopically, valves and tendinous cords are thickened, shortened and may have a pearly white appearance [17, 18].

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 (Chap.​ 55).

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. Using two-dimensional echocardiography, a small central triangular valve hiatus during diastole is observed in the short-axis view, sometimes associated with a subtle ‘domelike’ aspect of the aortic valve during systole. Aortic regurgitation visualized with colour Doppler is generally central (Chap.​ 57).

Tricuspid and pulmonary drug-induced VHD is less common; echocardiographic findings seem similar to those observed in mitral and aortic damage.

In younger patients (<50 years), the background prevalence of aortic regurgitation (AR) and mitral regurgitation (MR) in normal subjects is low or even absent [19]. Therefore, the FDA applied criteria for the diagnosis of drug-induced VHD. These were at least light to moderate AR and/or moderate to severe MR [20].

However, in older patients, e.g. with Parkinson’s disease, underlying valvular sclerosis and calcification might be present with AR or MR. For this reason, the FDA criteria cannot be used in this subgroup of patients. A scoring system had been used [18] in which restrictive tricuspid valve leaflet involvement was considered more important in defining ergot-like abnormalities compared to restrictive mitral and aortic valve motion (score 1–4: from very likely to unlikely):

Another potential approach to quantify the restrictive tricuspid and/or mitral valve motion is to determine the tenting area and tethering distance as described in ischaemic heart disease [21].

Before the diagnosis of drug-induced VHD can be made, other causes of restrictive VHD need to be excluded: remodelling of the left ventricle (i.e. ischaemic MR), rheumatic heart and other interstitial diseases, carcinoid syndrome, cardiac mass (e.g. atrial myxoma), infectious endocarditis (i.e. intravenous drug use) and congenital abnormalities. In rheumatic heart disease, valvular damage and thickening are usually more pronounced and, to a certain extent, commissural fusion of valvular leaflets occurs leading to valvular stenosis, which is not a typical feature of drug-induced VHD. As usual, blood pressure should be a part of the echocardiographic examination since it might influence the severity of MR and AR (Chap.​ 54).

Ergotamine and methysergide were the first drugs described to be associated with VHD since 1966 [22]. Until the early nineties, only sporadic cases were reported [23–25]. With the routine use of two-dimensional echocardiography and later on second harmonic imaging, valvular morphology and function were easier to evaluate. This led to a better echocardiographic and pathological correlation and an increased awareness and reports of toxic valvulopathy [26]. Ergotamine and methysergide are still used in some countries for the prophylactic treatment of vascular headache. Before 1990, toxic valvulopathy remained mostly undiscovered until symptoms such as fatigue, dyspnoea, chest pain, palpitations and a new heart murmur become apparent [27]. At that point, valvular damage was already pronounced so that valvular replacement seemed the only therapeutic option. There are no reports of case–control series of ergotamine or methysergide-induced VHD, and no dose-dependent relation has been described.

In 1997, Connolly reported a series of case reports of young women that developed VHD several months after treatment with the anorectic agents (dex)fenfluramine and the combination Fen-Phen [17]. Echocardiographically and histopathologically, these valves showed a striking resemblance to carcinoid valvular heart disease, which occurs in about 10 % of carcinoid syndrome. Based on this study and other case reports, the FDA reported that toxic valvulopathy was identified in 113 young women (mean age 44 years) that took slimming drugs and that valve replacement was needed in 24 % of patients. These findings led to the rapid withdrawal of fenfluramine from the market in 1997 [28]. Later on, several retrospective case–control and follow-up studies were published confirming the association between (dex)fenfluramine use and VHD [29–34].

A subsequent meta-analysis conducted by Sachdev et al. in 2002 showed that (dex)fenfluramine-induced VHD was less common than initially reported but still present in one out of eight patients treated for more than 90 days [35]. In another meta-analysis by Hopkins and colleagues, a much higher relative risk for aortic (RR 19,6) and mitral (RR 5,9) valvulopathy after (dex)fenfluramine exposure was found compared to previous reports when they corrected for several bias factors [36]. The same group recently published the largest single centre observational study in 5,743 patients that had taken fenfluramine before. In this study, the prevalence of FDA criteria-positive AR or MR was 19.6 % in women and 11.8 % in men [1]. Valve surgery was performed on 38 patients (0.66 %), 25 (0.44 %) with clear evidence of fenfluramine-related aetiology.

In 2002, Pritchett reported the association between pergolide and VHD [37] for the first time. This relation was confirmed in 2004 by Van Camp and colleagues in a cross-sectional case–control study of 78 patients with Parkinson’s disease treated with high-dose pergolide [18]. Restrictive VHD with MR, AR and tricuspid regurgitation was found in 33 % of patients treated with pergolide. Besides increased prevalence of valvular regurgitation, an increase in mitral tenting areas and distances was also found in the pergolide group compared to controls. Pergolide and also cabergoline are ergot-derived dopamine agonists with an ergolinic structure and 5-HT_2B agonist activity.

Recent population-based studies have more clearly defined the relative risk associated with the use of different agonists in patients with Parkinson’s disease. From these studies, a clearly increased risk for the development of toxic valvulopathy with pergolide and cabergoline use [18, 38–43] was found. In a recent review, Antonini calculated from these studies a prevalence of 22 and 34 % of moderate to severe regurgitation in at least one heart valve in patients with Parkinson’s disease treated with pergolide and cabergoline, respectively [44]. All these studies were conducted in patients from Europe or North America.

Similar to these studies, a Japanese study of Yamamoto et al. reported an increased risk of valvular regurgitation in patients taking cabergoline [40]. However, this Japanese and a Korean study were excluded from this analysis because the average daily pergolide dose was 1.40 and 1.13 mg, respectively, compared to 3.0 mg in the other studies [40, 45]. The low dose of pergolide used in Asian patients could explain why no increased rates of regurgitation were found. A recent meta-analysis and observational study by Corvol et al. found a similar prevalence of 22 % of moderate to severe valvulopathy in pergolide-treated patients compared to 7.1 % in the control group [46]. In another meta-analysis by Simonis et al. including seven cross-sectional studies with 477 patients treated with ergot-derived dopamine agonists pergolide or cabergoline, a prevalence of 26 % of moderate to severe VHD was found compared to 10 % in non-ergot-derived dopamine agonists and 10 % in controls [47].

Cabergoline is also used for the treatment of prolactinoma. In contrast to Parkinson’s disease, this population is younger with a more female predominance, and most importantly, the cumulative dose is about ten times less. Until now, seven cross-sectional studies have been published of which six did not find an association with clinically relevant regurgitation, as reported by Kars et al. [48]. However, one study shows a significant increase in moderate tricuspid regurgitation, and two studies show a mild increase in tricuspid regurgitation [49–51]. The clinical relevance of these findings is therefore still uncertain.

One recent cross-sectional case–control study from Singapore found an increased risk of valvular regurgitation in Parkinson’s patients treated with bromocriptine compared to controls [52]. However, another study in Korea did not find increased frequencies of valvular regurgitation in patients treated with bromocriptine [45]. This might be due to a lower cumulative dose in the latter study. Bromocriptine is a weak partial 5-HT_2B receptor agonist and was not thought to be associated with toxic valvulopathy. More studies are needed to confirm this possible relation between bromocriptine and toxic valvulopathy.

Besides the above-mentioned drugs, MDMA also is a potent 5-HT_2B receptor agonist and induces fenfluramine-like proliferations of human valvular interstitial cells in vitro [53]. Until now, only one cross-sectional case–control study has been published, suggesting an association between MDMA abuse and toxic valvulopathy [54]. An increased incidence of mild AR and MR was found in patients younger than 30 years old taking MDMA on a regular and recreational basis compared to age- and sex-matched controls. MDMA is not only used for recreational purposes but is currently under investigation for the treatment of post-traumatic stress syndrome. By consequence, these findings may have important health implications but need to be confirmed by larger trials.

Benfluorex is the most recent drug found to be involved in inducing VHD. This drug is structurally related to amphetamines and is partially metabolized to norfenfluramine. It was initially indicated in patients with hypertriglyceridaemia or for diabetes mellitus in overweight patients in combination with dietetic recommendations. In France, following reassessment of the benefit–risk balance in patients with hypertriglyceridaemia, the Medicines Drug Agency decided in April 2007 to limit benfluorex use to its other indication, diabetes mellitus in overweight patients (BMI ≥25 kg/m²) in association with an appropriate diet. Benfluorex had also been widely prescribed in France as an appetite suppressant.

Two studies have compared patients selected as having ‘unexplained’ mitral regurgitation with age- and sex-matched patients who had mitral regurgitation with aetiological or functional explanations [55]; the latter patients were used as the control group. In the first study, performed by Frachon et al. [55], 27 patients with unexplained mitral regurgitation were compared with 54 controls. The use of benfluorex was documented in 19 patients in the first group and in three in the second group, with an odds ratio of 17.1 (3.5–83) after adjustment for BMI, diabetes and dexfenfluramine intake.

In a second study confirming these results, 22 patients with unexplained mitral regurgitation were compared with 22 of 156 patients who underwent surgery for dystrophic MR, matched for age, body weight and diabetes [56]. Eight of the 22 patients (36.4 %) in the first group but only one (4.5 %) in the group with dystrophic valvulopathy had a history of benfluorex use. The total duration of benfluorex treatment associated with unexplained MR was 63 (12–175) months; the duration of benfluorex treatment was 56 months at the time of valvular disease diagnosis.

More recently, 40 cases identified retrospectively in the cardiology departments in eight hospitals in France have been reported and analysed [57]. Owing to hospital recruitment of symptomatic patients, the observations collected represent the most severe presentation of these VHDs. The cases analysed in this multicentre registry had quite a homogeneous presentation: patients were middle aged and mainly women, with obesity and/or diabetes mellitus and exposure to benfluorex for a mean duration of 72 ± 53 months. Most patients had symptomatic heart failure. Multiple fibrotic valve diseases were present in more than 75 % of patients, displaying predominantly an association of aortic and mitral regurgitations (72.5 %) and leading to combined valve surgery in 11 cases (27.5 %). These morphological and histological features (valvular tissue thickening and an abundant extracellular matrix of glycosaminoglycans and collagen with proliferation of myofibroblasts and smooth muscle cells) were similar to those previously reported after exposure to other appetite suppressants and ergot alkaloids.

A cohort study using two large French national databases, with patients aged 40–69 years with reimbursements for antidiabetic drugs in 2006, was recently analysed [58]. The risk of hospitalization for valvular regurgitation in the following 2 years was found to be 2.5 times higher when taking benfluorex for MR, 4.4 times higher for AR and 3.9 times higher for valvular replacement surgery. The estimated number of hospitalizations for a diagnosis of VHD was found to be 5 per 10,000 patient-years. The re-evaluation of the benefit–risk balance of benfluorex in the light of these data led to the suspension of the marketing authorization of the drug in France and then in Europe, in November and December 2009, respectively [58].

More recently, the randomized prospective REGULATE trial [59], whose results were published in 2012, included 847 patients with type II diabetes (mean age, 59 years) randomized to 1 year of treatment with a combination of either benfluorex–sulphonylurea (n = 423) or pioglitazone–sulphonylurea (n = 424). Emergence (appearance or deterioration) of valvular regurgitation was observed more frequently (27 % vs 11 %; P < 0.0001) in the group treated with benfluorex (OR 2.97 [1.91–4.63]).

Last, an echocardiography-based multicentre study [60] compared the frequency of left heart valve regurgitation in diabetic patients exposed to benfluorex for at least 3 months and in diabetic controls never exposed to the drug: 293 patients and 293 controls were matched for age, gender, body mass index, smoking, dyslipidaemia, hypertension and coronary artery disease. The frequency and relative risk (OR) of mild or more severe left heart valve regurgitation were significantly increased in benfluorex-exposed patients compared with controls: 31.0 % vs 12.9 % (OR 3.55 [2.03–6.21]) for aortic and/or mitral regurgitation, 19.8 % vs 4.7 % (OR 5.29 [2.46–11.4]) for aortic regurgitation, and 19.4 % vs 9.6 % (OR 2.38 [1.27–4.45]) for mitral regurgitation. This study, therefore, confirmed that the use of benfluorex is associated with a significant increase in the frequency of left heart valve regurgitation in diabetic patients. Estimates of the number of benfluorex-associated deaths in France have been proposed as probably being higher than 500 [61] and were more recently calculated to be around 1,300 due to VHD in these patients; this number is regarded as possibly underestimated [62].

New drugs such as lorcaserin have been released to treat obesity and even approved by the FDA. Recent publications have provided reassuring data regarding the absence of VHD in the group of patients treated by this drug [63]. Interestingly, the methodology used was the FDA valvulopathy criteria that may be inappropriate as mentioned above. On the other hand, a recent paper is dealing with the unacceptable risk represented by lorcaserin in treated obese patients [64]. Knowing that lorcaserin has an effect on 5-HT_2B receptors, even with a low affinity for 5-HT_2B receptors compared to 5-HT_2C receptor, a close follow-up of the patients receiving this drug is mandatory.