Drug-induced Valvular Heart Disease Research Articles

Cardiac valvular surgery and history of anorectic drug intake: A retrospective study of a large population of benfluorex-exposed patients

Anorectic drugs are overlooked as a cause of valvular heart disease (VHD). To describe the characteristics of a large population of patients with severe VHD who underwent cardiac surgery and had a history of benfluorex intake. Retrospective observational and cross-sectional study of patients from a large French database (Office National d'Indemnisation des Accidents Médicaux). Clinical, echocardiographic, surgical and pathology findings were comprehensively collected from medical files. From a chart review of 9584 subjects, 1031 patients with VHD underwent cardiac surgery; 453 surgical patients were excluded because of VHD obviously unrelated to benfluorex exposure, six because of missing data and eight declined to participate. The final study population comprised 564 patients who had surgery between 1987 and 2019. Median age was 58 (interquartile range 50-65) years; 85% were female. Median duration of preoperative benfluorex exposure was 5.8 (3.3-10) years. Most patients had aortic and mitral valve disease. Pure or predominant aortic and/or mitral regurgitation were found in 84% of patients (n=471), and aortic or mitral stenosis (pure or combined with regurgitation) in 12% (n=67) and 15% (n=84), respectively. Overall, 403 aortic, 402 mitral and 64 tricuspid valve surgical procedures were collected. Aortic and mitral valves were found to be thickened, rigid and/or restrictive in most cases; restrictive tricuspid valve disease was seldom documented. Pathology was available in half of the population (276 patients); valvular fibrosis suggestive of drug-induced VHD was found in 222 patients, including 146 with expert examination. Mixed VHD aetiologies were discussed in 107 patients, including 54 with available pathology. Drug-induced VHD features are miscellaneous, including well-known restrictive valvular regurgitation, but also stenosis or combined regurgitation and stenosis. Besides a history of drug taking, thorough echocardiography and comprehensive surgical reports, pathology is key in the diagnostic procedure.

Regulatory Forum Review*: Utility of in Vitro Secondary Pharmacology Data to Assess Risk of Drug-induced Valvular Heart Disease in Humans: Regulatory Considerations.

Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC50, Ki) or cellular functional activity (EC50) are often compared to maximum therapeutic free plasma drug levels ( fCmax) from which safety margins (SMs) can be derived. However, there is no clear consensus on what constitutes an appropriate SM under various therapeutic conditions of use. The strengths and limitations of SM determinations and current risk assessment methodology are reviewed and evaluated. It is concluded that the use of SMs based on Ki values, or those relative to serotonin (5-HT), appears to be a better predictor than the use of EC50 or EC50/human fCmax values for determining whether known 5-HT2B agonists have resulted in VHD. It is hoped that such a discussion will improve efforts to reduce this preventable serious drug-induced toxicity from occurring and lead to more informed risk assessment strategies.

Drug-induced aortic valve stenosis: An under recognized entity

BackgroundWe have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS. MethodsHerein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient >15mmHg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria. ResultsTwenty-five (19 females, mean age 62years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/−13mmHg. Aortic regurgitation was ≥ mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD. ConclusionThe association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS.

Acute pergolide exposure stiffens engineered valve interstitial cell tissues and reduces contractility in vitro.

Medications based on ergoline-derived dopamine and serotonin agonists are associated with off-target toxicities that include valvular heart disease (VHD). Reports of drug-induced VHD resulted in the withdrawal of appetite suppressants containing fenfluramine and phentermine from the US market in 1997 and pergolide, a Parkinson's disease medication, in 2007. Recent evidence suggests that serotonin receptor activity affected by these medications modulates cardiac valve interstitial cell activation and subsequent valvular remodeling, which can lead to cardiac valve fibrosis and dysfunction similar to that seen in carcinoid heart disease. Failure to identify these risks prior to market and continued use of similar drugs reaffirm the need to improve preclinical evaluation of drug-induced VHD. Here, we present two complimentary assays to measure stiffness and contractile stresses generated by engineered valvular tissues in vitro. As a case study, we measured the effects of acute (24 h) pergolide exposure to engineered porcine aortic valve interstitial cell (AVIC) tissues. Pergolide exposure led to increased tissue stiffness, but it decreased both basal and active contractile tone stresses generated by AVIC tissues. Pergolide exposure also disrupted AVIC tissue organization (i.e., tissue anisotropy), suggesting that the mechanical properties and contractile functionality of these tissues are governed by their ability to maintain their structure. We expect further use of these assays to identify off-target drug effects that alter the phenotypic balance of AVICs, disrupt their ability to maintain mechanical homeostasis, and lead to VHD.

Complications cardiaques des médicaments

Thanks to science advances, cancer is no longer synonymous with death. Life expectancy improvement reveals a new problem: cancer treatment toxicity, including cardiovascular complications, responsible for significant morbidity and mortality. Media scandal of drug-induced valvular heart disease did revise the risk-benefit balance of drugs used (often off-label) as anorectics. Today's society uses drugs heavily but does not accept their side effects. Knowledge and information of these complications is essential. Coronary toxicity of some treatments or drugs commonly used must be known.

High-dose oral intake of serotonin induces valvular heart disease in rabbits

Carcinoid tumors are rare neuroendocrine malignancies, often originating from enterochromaffin cells in the gastrointestinal tract. They can secrete serotonin (5-hydroxytryptamine, 5-HT), which is largely inactivated by the liver [ [1] Lundin L. Norheim I. Landelius J. Oberg K. Theodorsson-Norheim E. Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation. 1988; 77: 264-269 Crossref PubMed Scopus (207) Google Scholar ]. Carcinoid heart disease occurs when tumor cells metastasize to the liver, as the vasoactive substances produced are able to reach the systemic circulation via the hepatic vein, causing deposition of fibrous tissue on the endocardial surfaces of the heart [ [2] Ferrans V.J. Roberts W.C. The carcinoid endocardial plaque: an ultrastructural study. Hum. Pathol. 1976; 7: 387-409 Abstract Full Text PDF PubMed Scopus (81) Google Scholar ]. It is predominantly manifested by right-sided valvular heart disease (VHD). Scavenging enzymes in the pulmonary endothelium may explain why left-sided cardiac involvement is unusual [ [3] Chaowalit N. Connolly H.M. Schaff H.V. Webb M.J. Pellikka P.A. Carcinoid heart disease associated with primary ovarian carcinoid tumour. Am. J. Cardiol. 2004; 93: 1314-1315 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar ]. The severity of cardiac damage is correlated with the plasmatic levels of serotonin, but the low specificity of serotonin for cardiac damage suggests that serotonin may be necessary but not sufficient to induce cardiac lesions [ [4] Robiolio P.A. Rigolin V.H. Wilson J.S. et al. Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation. 1995; 92: 790-795 Crossref PubMed Scopus (283) Google Scholar ]. Therefore, other factors combined with serotonin might be required to induce VHD. However, recent animal studies confirmed the development of carcinoid-like valvular deposits in rats after 3 months of daily subcutaneous/intraperitoneal serotonin injections to avoid the liver first-pass clearance [ 5 Gustafsson B. Tommeras K. Nordrum I. et al. Long-term serotonin administration induces heart valve disease in rats. Circulation. 2005; 111: 1517-1522 Crossref PubMed Scopus (198) Google Scholar , 6 Droogmans S. Franken P.R. Garbar C. et al. In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology. Eur. Heart J. 2007; 28: 2156-2162 Crossref PubMed Scopus (58) Google Scholar ]. Whether oral administration of serotonin can also induce VHD is unknown. We hypothesized that long-term oral serotonin overload in rabbits can lead to VHD, mimicking serotonin-induced lesions of carcinoid heart disease.

0562: Long term outcome of patients with benfluorex-induced mitral regurgitation and first episode of heart failure

Benfluorex’s imputability in drug-induced valvular heart disease (DIVHD) is now well established. However no data about long term clinical and echocardiographic follow-up of patients suffering from benfluorexrelated DIVHD are available. The present study was conducted to address this issue. Between January 2003 and June 2012, after an exhaustive analysis of our database, 20 patients (55±9 years, 90% women, body mass index: 32.9±9 kg/m²) hospitalized for heart failure were retrospectively identified with benfluorex induced moderate or severe mitral regurgitation (MR). Initially 70% of them presented NYHA class III or IV. MR was quantified as moderate in 11, moderate to severe in 8 and severe in one patient. Aortic regurgitation (AR) was also present in 17 patients (85%): mild in 5, moderate in 9 and moderate to severe in 3 patients. During a median follow-up of 7 years, heart failure episodes led to 53388 Valve replacements. Two patients died, one in the surgical group and one in the medical group. Among survivors, NYHA class improved in 6 patients in the surgical group but only in 4 in the medical group. After withdrawal of benfluorex, MR decreased in 7 patients and AR decreased in 5 patients. MR was stable in 3 patients and AR in 4 patients. A worsening of MR was not observed and AR worsened in 2 patients. After an hospitalization for a first episode of heart failure related to benfluorex-induced MR, patients are exposed to a large number of cardiac events including repeated hospitalizations and death.

Food and Drug Administration criteria for the diagnosis of drug-induced valvular heart disease in patients previously exposed to benfluorex: a prospective multicentre study.

The Food and Drug Administration (FDA) criteria for diagnosis of drug-induced valvular heart disease (DIVHD) are only based on the observation of aortic regurgitation ≥ mild and/or mitral regurgitation ≥ moderate. We sought to evaluate the diagnostic value of FDA criteria in a cohort of control patients and in a cohort of patients exposed to a drug (benfluorex) known to induce VHD. This prospective, multicentre study included 376 diabetic control patients not exposed to valvulopathic drugs and 1000 subjects previously exposed to benfluorex. Diagnosis of mitral or aortic DIVHD was based on a combined functional and morphological echocardiographic analysis of cardiac valves. Patients were classified according to the FDA criteria [mitral or aortic-FDA(+) and mitral or aortic-FDA(-)]. Among the 376 control patients, 2 were wrongly classified as mitral-FDA(+) and 17 as aortic-FDA(+) (0.53 and 4.5% of false positives, respectively). Of those exposed to benfluorex, 48 of 58 with a diagnosis of mitral DIVHD (83%) were classified as mitral-FDA(-), and 901 of the 910 patients (99%) without a diagnosis of the mitral DIVHD group were classified as mitral-FDA(-). All 40 patients with a diagnosis of aortic DIVHD were classified as aortic-FDA(+), and 105 of the 910 patients without a diagnosis of aortic DIVHD (12%) were classified aortic-FDA(+). Older age and lower BMI were independent predictors of disagreement between FDA criteria and the diagnosis of DIVHD in patients exposed to benfluorex (both P ≤ 0.001). FDA criteria solely based on the Doppler detection of cardiac valve regurgitation underestimate for the mitral valve and overestimate for the aortic valve the frequency of DIVHD. Therefore, the diagnosis of DIVHD must be based on a combined echocardiographic and Doppler morphological and functional analysis of cardiac valves.

Adverse effects of benfluorex on heart valves and pulmonary circulation.

Benfluorex is responsible for the development of restrictive valvular regurgitation due to one of its metabolites, norfenfluramine. The 5-HT2B receptor, expressed on heart valves, acts as culprit receptor for drug-induced valvular heart disease (VHD). Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways. Valve lesions essentially involve the mitral and/or aortic valves. The randomised prospective REGULATE trial shows a threefold increase in the incidence of valvular regurgitation in patients exposed to benfluorex. A cross-sectional trial shows that about 7% of patients without a history of VHD previously exposed to benfluorex present echocardiographic features of drug-induced VHD. The excess risks of hospitalisation for cardiac valvular insufficiency and of valvular replacement surgery were respectively estimated to 0.5 per 1000 and 0.2 per 1000 exposed patients per year. Recent data strongly suggest an aetiological link between benfluorex exposure and pulmonary arterial hypertension (PAH). The PAH development may be explained by serotonin, which creates a pulmonary vasoconstriction through potassium-channel blockade. Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects.

Drug-induced valve disease and considerations of benefit versus risk

This editorial refers to ‘Frequency of drug-induced valvular heart disease in patients previously exposed to benfluorex: a multicentre prospective study’[†][1], by C. Tribouilloy et al. , on page 3580 Data from epidemiological studies, and a single randomized trial, have plausibly suggested that a variety of amphetamine-related molecules can cause valvular morphological lesions and variable degrees of valvular dysfunction.1–10 Though a causal relationship has not been unequivocally proven, cellular mechanisms have been defined that may account for such a relationship.11,12 However, early in the experience with the phentermine–fenfluoramine combination that sensitized the medical community to such problems,1 the frequency of valve involvement probably was markedly overstated. Indeed, at the height of the concern, when several very small series suggested that the majority of exposed patients developed valve disease, five patients (as large as some of the published series) were referred to me after moderately long exposure to seek evidence of valve disease; none was apparent in any. Importantly, the involved drugs all were approved for specific benefits, e.g. weight reduction for morbidly obese persons who might suffer from orthopaedic, psychological, cardiovascular, and other debilities in part because of their body weight, and diabetes control for patients in whom glucose metabolic abnormalities could have several unwanted and potentially preventable consequences. In all such situations, the appropriateness of the therapies must be determined on the basis of a judgement of putative benefits vs. putative risks. Since the benefits and the risks of the amphetamine-related therapies are intrinsically different, the relationship between benefit and risk is impossible to quantify rigorously and must be based on the judgement of experienced observers. Therefore, it is essential to quantify, as precisely as possible, the benefits and the risks. Benefits often are reasonably quantified by randomized, appropriately controlled trials enabling comparison of … [1]: #fn-2

Frequency of drug-induced valvular heart disease in patients previously exposd to benfluorex: a multicentre prospective study

The epidemiologic link between benfluorex use and an increased global frequency of left heart valve regurgitation has been well documented. However, no data linking previous drug exposure to the frequency of diagnosis of drug-induced valvular heart disease (DI-VHD) are available. The present study was conducted to address this issue. This echocardiography reader-blinded, controlled study conducted in 10 centres between February 2010 and February 2012 prospectively included 835 subjects previously exposed to benfluorex referred by primary care physicians for echocardiography. Based on blinded off-line analysis, echocardiography findings were classified as: (i) DI-VHD⁺ for patients with an echocardiographic diagnosis of DI-VHD, (ii) inconclusive, and (iii) DI-VHD⁻ for patients without signs of DI-VHD. Fifty-seven (6.8%) patients exposed to benfluorex were classified as DI-VHD⁺, 733 (87.8%) patients were classified as DI-VHD⁻, and 45 (5.4%) were classified as inconclusive. Mitral and aortic DI-VHD were reported in 43 patients (5.1%) and 30 (3.6%) patients, respectively. Longer duration of exposure, female gender, smoking, and lower BMI were independently associated with a diagnosis of DI-VHD. Good inter-observer reproducibility was observed for the echocardiography classification (Kappa = 0.83, P < 0.00001). About 7% of patients without a history of heart valve disease previously exposed to benfluorex present echocardiography features of DI-VHD. Further studies are needed to study the natural history of DI-VHD and to identify risk factors for the development of drug-induced valve lesions.

Republished: Drug-induced valvular heart disease

Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the...

Uniform pattern of immunohistochemical localization of serotonin 5-HT2 receptors in human aortic, mitral, pulmonary and tricuspid heart valves: Implication for the pathomechanism of valvular heart disease following treatment with dopamine agonists

It has been suggested that the activation of the serotonin (5-hydroxytryptamine, 5-HT) receptor family 5-HT2, in particular the subtype 5-HT2B, is a key step in the progression of drug-induced valvular heart disease (VHD). However, the localisation of 5-HT2 receptors in human valves have not been reported. Thus, the current study investigated the regional and cellular localization of 5-HT2 receptors in the tricuspid, mitral, aortic and pulmonary heart valves of six humans (n=24 samples) by immunohistochemistry post-mortem. We found that 5-HT2A and 5-HT2B receptors are present in all examined heart valves, whereas 5-HT2C receptors were either not present or scarcely found. Interestingly, we found a uniform pattern of 5-HT2B receptor numbers in all heart valves examined. Our results confirm patterns reported in echocardiographic investigations in patients with Parkinson’s disease treated with cabergoline and pergolide and suggest that the 5-HT2 receptor located in heart valves may play a role in the drug-induced VHD.

Benfluorex: the last chapter of drug-induced valvular heart disease?

This editorial refers to ‘Valvular heart disease associated with benfluorex therapy: results from the French multicenter registry’ by F.L. Ven et al ., doi:10.1093/ejechocard/jeq172 . The first case reports about drug-induced valvular heart disease (VHD) date from the 1960s with the use of ergot-derived drugs (methysergide and ergotamine) for the treatment of migraine.1 Nevertheless, public awareness about this particular entity came after the withdrawal of the appetite suppressant fenfluramine (Fen-Phen) in 1997.2 Thereafter a limited number of drugs have been added to this list such as pergolide, cabergoline, and MDMA (the main component of Ecstasy).3–5 The hallmark feature of these drugs or their metabolites is serotonin 2B (5-HT2B) receptor overstimulation, with valvular fibroblast proliferation and production of myxoid substance as a consequence.6 This leads to reduced leaflet mobility (restrictive VHD) due to superficial plaque like thickening of the valvular leaflets and subvalvular apparatus. Both …

Mechanism of subendocardial cell proliferation in the rat and relevance for understanding drug-induced valvular heart disease in humans

A number of drugs and drug candidates, including fenfluramine and ergot derivatives, are associated with valvulopathy in humans; however, these responses are poorly predicted from animal studies. In vitro and in vivo evidence suggests that these compounds exert their pathological effect through activation of serotonin 2B receptor (5HT2BR) signaling. However, the variable effect of fenfluramine and other 5HT2BR agonists in rodents has cast doubt on the relevance of animal findings to predicting human risk. Herein, a candidate compound, RO3013, induced subendocardial cell proliferation in the mitral and tricuspid valves in rats after only 3 days of daily dosing. Additionally, there was a treatment-related increase in immunostaining of the proliferation marker Ki67, and phosphorylated Smad3 in the heart indicative of TGFβ signaling co-localized with 5HT2BR expression. To substantiate the hypothesis that RO3013-induced valvular proliferation is secondary to 5HT2BR activation, the compound was evaluated in vitro and found to bind to the human 5HT2BR with a K i of 3.8 μM; however, it was virtually devoid of agonist activity in a functional assay in human cells. By contrast, RO3013 bound to the rat 5HT2BR with a K i of 1.2 μM and activated the receptor with an EC50 of 0.5 μM. This agonist potency estimate is in good agreement with the free plasma concentrations of RO3013 at which valvular proliferation was observed. These results suggest that the rat may be susceptible to 5HT2BR-mediated valvular proliferation similar to humans; yet, the significant differences between binding and functional activities can be a possible explanation for the observed species-selective receptor responses.

Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2BReceptor Agonists: Implications for Drug Safety Assessment

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

Role of Serotoninergic Pathways in Drug-Induced Valvular Heart Disease and Diagnostic Features by Echocardiography

Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes, such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators or inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson's disease), can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies have suggested that both right-sided and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit, which is widely expressed in a variety of tissues, including liver, lung, heart, and coronary and pulmonary arteries; it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review, the authors discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy, with an emphasis on echocardiographic diagnosis.

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Serotonergic drugs, such as pergolide, have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (5-HT)(2B) receptor (5-HT(2B)R). Therefore, we sought to determine whether cyproheptadine, a 5-HT(2B)R antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, 50 male Wistar rats received daily intraperitoneal injections of pergolide (0.5 mg/kg, n = 14), pergolide (0.5 mg/kg) combined with cyproheptadine (10 mg/kg, n = 12), cyproheptadine (10 mg/kg, n = 12), or no injections (control, n = 12) for 20 wk. Echocardiography was performed blindly at baseline and at 10 and 20 wk followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 wk, aortic regurgitation was present in all pergolide-treated animals, whereas it was less frequently observed in the other groups (P < 0.0001). For the other valves, this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid, and exhibited more 5-HT(2B)R-positive cells in pergolide-treated animals compared with the other groups. Moreover, regurgitant aortic and mitral valves were thicker than nonregurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats, which was associated with a reduced number of 5-HT(2B)R-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.

Role of echocardiography in toxic heart valvulopathy

The notion that drugs can induce valvular heart disease (VHD) has occurred since the 1960s and has received a lot of attention in recent years. This review focuses on different aspects of this distinct valvulopathy in seven sections: (i) historical background, (ii) drug-induced VHD, is this a real entity?, (iii) its morphological and echocardiographic features, (iv) drugs associated with VHD, (v) the influence of cumulative drug dose and risk factors, (vi) the natural course of toxic valvulopathy, and (vii) practical recommendations when using potential valvulopathic drugs.

In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology

Valvular heart disease (VHD), inducing valvular regurgitation, has been described in carcinoid heart disease and recently in Parkinson's patients treated with pergolide. The aim of this study was to develop an in vivo model of drug-induced valvulopathy with pergolide in rats. Thirty male Wistar rats were given daily injections of either pergolide (0.5 mg/kg intraperitoneally) (n = 8), serotonin (20 mg/kg subcutaneously) (n = 8), or the vehicle only (n = 14) for 5 months. At 20 weeks, echocardiography demonstrated the presence of aortic regurgitation (AR) and/or mitral regurgitation (MR) in serotonin (86% AR, P = 0.0001; 57% MR, P = 0.006) and in pergolide animals (67% AR, P = 0.003; 67% MR, P = 0.003) compared with none in placebo. Pulmonary regurgitation (PR) and tricuspid regurgitation (TR) were found in the serotonin (71% PR, P = 0.19; 100% TR, P = 0.06 vs. placebo), pergolide (100% PR, P = 0.014; 83% TR, P = 0.35 vs. placebo), and placebo groups (36% PR; 57% TR). Tricuspid regurgitant area ratio (jet/atrium), however, was more severe in the serotonin [median 26.5 (range 17-42)%; P = 0.02] and pergolide animals [32 (17-39) %; P = 0.03] compared with placebo [12.5 (5-33)%]. We found a good correlation between valvular regurgitation and histologically assessed valvular thickness. Histological examination revealed the presence of diffusely thickened and myxoid aortic, mitral, and tricuspid valves in serotonin and pergolide animals as seen in VHD. We demonstrated, for the first time, that long-term pergolide administration led to VHD in rats. This small animal model will permit further in vivo investigation of drug-induced valvulopathies.