Valvular heart disease induced by drugs

INTRODUCTION — Drug-induced valvular heart disease refers to morphological and functional abnormalities of valve leaflets secondary to exposure to various medications. This topic will review the causes, prevention, and management of drug-induced valvular heart disease.

Diagnosis and evaluation of valve disease is discussed in separate topics, including:

●(See "Echocardiographic evaluation of the mitral valve" and "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

●(See "Echocardiographic evaluation of the aortic valve" and "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults".)

●(See "Echocardiographic evaluation of the tricuspid valve" and "Etiology, clinical features, and evaluation of tricuspid regurgitation".)

CAUSES — The following drugs have been linked to valve disease [1]:

●Amphetamine derivatives

•Fenfluramine (a racemic mixture of levofenfluramine and dexfenfluramine), dexfenfluramine, and benfluorex. (See 'Appetite suppressants' below.)

•3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy). (See 'MDMA (ecstasy)' below.)

●Ergot alkaloids – Ergotamine and methysergide were the first drugs linked to valvulopathy. (See 'Ergot alkaloids' below.)

●Ergot-derived dopamine agonists – These include the drugs pergolide and cabergoline. (See 'For Parkinson disease' below and 'For hyperprolactinemia and other uses' below.)

PATHOGENESIS — The echocardiographic and pathologic features of drug-induced valve disease are similar to those occurring in carcinoid heart valve disease [2]. Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter that is elevated in serum and plasma of most patients with carcinoid heart valve disease. (See "Carcinoid heart disease".)

While it was previously postulated that drug-induced valve disease was caused by elevations in plasma serotonin, laboratory data suggest that drug-induced valvulopathy is caused by activation of 5-HT_2B receptors on heart valves by drug or drug metabolite [1,3-5]. Activation of 5-HT_2B receptors may also play a role in drug-induced pulmonary arterial hypertension [6]. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins'.)

Support for a role for 5-HT_2B receptors comes from studies finding that drugs associated with valvular heart disease, including ergot derivatives (ergotamine [7] and methysergide [8]), dopamine agonists (cabergoline and pergolide) [5,9-12], fenfluramine, dexfenfluramine, and 3,4-methylenedioxymethamphetamine (MDMA), or their metabolites have high affinity for and are partial to full agonists at the 5-HT_2B receptor [5,9,10]. Stimulation of 5-HT_2B receptors on heart valve cells induces mitogenesis leading to excessive growth and valvulopathy [10].

Dexfenfluramine not only activates 5-HT_2B receptors but also increases serotonin signaling by inhibiting the serotonin transporter solute carrier family 6 member 4 (SLC6A4), known as SERT. A preliminary study suggested that decreased SERT activity may contribute to progressive mitral valve disease [13]. Decreased SERT activity may be caused by genetic variants in the SERT region or by drug exposure, such as a higher than average concentration of selective serotonin reuptake inhibitor (SSRI). However, an association between SSRI and valve disease has not been established. (See 'Association not established for SSRIs' below.)

ECHOCARDIOGRAPHIC FEATURES

Characteristic features — Drug-induced valve disease is most commonly detected by echocardiography. The mitral, aortic, and tricuspid valves are most commonly affected [14,15]. Most affected patients have valve regurgitation. A minority of patients have some degree of mitral or aortic valve stenosis (with or without regurgitation) [15].

●Mitral valve

•Leaflet thickening (generally mild to moderate)

•Diastolic doming of the anterior mitral leaflets with relative immobility of the posterior leaflets

•Prominent subvalvular disease with thickening and shortening of the chordae tendineae

•Leaflet tethering and malcoaptation contribute to the mitral regurgitation

●Aortic valve

•Leaflet thickening (generally mild and may be absent even with aortic regurgitation)

•Leaflet retraction (variable) causing malcoaptation resulting in aortic regurgitation (generally central)

●Tricuspid valve – Although not included in the US Food and Drug Administration (FDA) case definition, rates of significant (greater than mild) tricuspid regurgitation may approach those for significant mitral regurgitation [16,17]. Tricuspid leaflets may be thickened with restricted mobility.

●Pulmonic valve – Pulmonic valve disease is uncommonly reported. Features may be similar to those for aortic valve disease.

FDA case definition — The 1997 FDA case definition for valve disease associated with use of fenfluramine or dexfenfluramine required documented at least mild aortic regurgitation or at least moderate mitral regurgitation [18]. Minor degrees of regurgitation (trace or mild mitral regurgitation or trace aortic regurgitation) are relatively common in the general population and may occur without valvular disease [19]. Therefore, these lesser degrees of regurgitation were excluded from the FDA case definition.

Course — Echocardiography has been used to monitor the course of valvular heart disease associated with appetite suppressant drugs. The valvular lesions tend to be stable or improve in the great majority of patients after the cessation of these drugs [20-23].

●One of the trials described above randomly assigned over 1000 patients to dexfenfluramine, sustained-release dexfenfluramine, or placebo for an average of only 71 days [24]. Echocardiograms were obtained one month and one year after discontinuation in 914 patients [20]. The major finding was greater regression of aortic regurgitation compared with the placebo group but no change in mitral regurgitation.

●Similar findings were noted in a second report of 50 patients with previous exposure to fenfluramines who had at least mild mitral (76 percent) and/or aortic regurgitation (86 percent) [22]. An initial echocardiogram was obtained a mean of 190 days after drug cessation and repeat echocardiography performed approximately one year later. Among the 38 patients with mitral regurgitation, 17 improved, 19 experienced no change, and 2 worsened by at least one grade. Among the 43 patients with aortic regurgitation, 19 improved, 22 were stable, and two worsened by at least one grade.

PATHOLOGY — The gross pathologic features of drug-induced valve disease include fibrous thickening of the valve leaflets and chordae, with a glistening white appearance [15,25]. The mitral and aortic valves are most frequently affected. The chordae tendineae are thickened and shortened. Tricuspid valve involvement is less commonly seen. Chordal fusion may occur. These features may be similar to those seen in rheumatic heart disease.

The histopathologic picture is one of intact leaflet architecture with a plaque-like encasement of the leaflets; proliferative myofibroblasts are surrounded by an abundant extracellular matrix. Gross and histologic valve findings are similar to carcinoid heart disease, except drug-induced valve disease involves predominantly the aortic and mitral valves, and less commonly the tricuspid valve. Valves exposed to anorexic drugs have a larger number of onlays (plaques) per valve than rheumatic or normal valves, while rheumatic valves showed the greatest average onlay size and thickness [26]. The valve onlays from anorexic agent-exposed valves contained a higher percentage of glycosaminoglycans compared with normal and rheumatic valves.

AMPHETAMINE DERIVATIVES

Appetite suppressants — Certain anorectic amphetamine derivatives (fenfluramine, dexfenfluramine, and benfluorex) have been implicated in the pathogenesis of valvular heart disease and were withdrawn from the market.

One of these drugs, fenfluramine, is a currently approved treatment of seizures in patients with Dravet syndrome or Lennox-Gastaut syndrome. (See 'Prevention and management' below.)

Fenfluramine and dexfenfluramine

●Pharmacology – Fenfluramine (previously Pondimin, currently licensed as Fintepla) is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine. These are sympathomimetic amines that promote the release of serotonin and block its neuronal uptake. The ensuing increase in serotonergic activity has an anorectic effect. Dexfenfluramine was previously also marketed separately as Redux. Norfenfluramine (a metabolite of dexfenfluramine) has high affinity for 5-hydroxytryptamine 2B (5-HT_2B) receptors. Levonorfenfluramine (a metabolite of levofenfluramine) is also a 5-HT_2B receptor agonist.

●Risk of valve disease – Estimates of risk of valve disease associated with exposure to fenfluramine or dexfenfluramine have varied widely [24,27-31], in part because long-term longitudinal echocardiographic data prior to and following exposure are generally not available and some estimates have not accounted for short durations of exposure [32].

A meta-analysis of eight echocardiographic studies among individuals exposed to fenfluramine or dexfenfluramine corrected for background prevalence, estimated incidence rates in unexposed individuals, and performed an analysis based on duration of exposure [32]. This analysis found that the appearance of new aortic regurgitation was strongly related to the duration of exposure to fenfluramine or dexfenfluramine. For mild or greater aortic regurgitation during the summary duration of 8.78 months, there were 220.8 estimated incident cases associated with exposure, compared with 14.01 expected cases (relative risk [RR] 19.6, 95% CI 16.3-23.5). For moderate or greater mitral regurgitation, during the summary duration of 8.89 months, there were 38.5 estimated incident cases associated with exposure, compared with 5.7 expected cases (RR 5.9, 95% CI 4.0-8.6).

Use of fenfluramine or dexfenfluramine is also associated with risk of pulmonary arterial hypertension [33]. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins'.)

●Approval status – Fenfluramine was originally approved by the US Food and Drug Administration (FDA) in 1973 for single-drug, short-term use as an appetite suppressant. Patients who developed valvular heart disease were commonly treated with an off-label combination of fenfluramine with phentermine (called "fen-phen") [34,35]. There were approximately 18 million prescriptions for either fenfluramine or phentermine in 1996 [36]. However, phentermine given alone has not been implicated in the pathogenesis of valvular heart disease or pulmonary arterial hypertension. Phentermine (Adipex-P, Lomaira) is a noradrenergic central nervous system stimulant that was approved by the FDA as an appetite suppressant in 1959.

In 1996, the FDA approved dexfenfluramine as a single-drug appetite suppressant for longer-term use in individuals with marked obesity. There were over 2 million prescriptions for dexfenfluramine during the first six months of its availability [36].

In 1997 the FDA, acting on evidence that fenfluramine or dexfenfluramine use was associated with valve disease, asked the manufacturers to voluntarily withdraw these drugs from the market. Use of fenfluramine or dexfenfluramine is also associated with risk of pulmonary arterial hypertension [33]. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins'.)

In 2020, the FDA approved use of fenfluramine for the treatment of seizures associated with Dravet syndrome in patients age 2 and older. In 2022, the FDA approved use of fenfluramine for treatment of seizures associated with Lennox-Gastaut syndrome. FDA-approved labeling for fenfluramine includes a boxed warning for valvular heart disease and pulmonary arterial hypertension. (See "Dravet syndrome: Management and prognosis" and "Lennox-Gastaut syndrome", section on 'Antiseizure medications'.)

Benfluorex — Benflourex is an amphetamine derivative related to fenfluramine and dexfenfluramine. Benfluorex was used as an add-on treatment in patients with diabetes mellitus (DM) who were overweight. Benfluorex was marketed in Europe from 1976 to 2009. It was withdrawn from the European markets in 2010 following several reports linking it to valve disease [37]. Norfenfluramine (a metabolite of benfluorex and dexfenfluramine) has high affinity for 5-HT_2B receptors.

The risk of valve disease associated with benfluorex use is illustrated by the following studies:

●A study of data from two French national linked databases included 1,048,173 patients aged 40 to 69 years old with DM, of which 43,044 (4.1 percent) were exposed to benfluorex in 2006 [38]. The risk of hospitalization in 2007 and 2008 for any cardiac valve regurgitation was higher with benfluorex exposure (76 versus 27 per 100,000 person years; adjusted RR 3.1, 95% CI 2.4-4.0). Exposure to benfluorex was associated with an elevated risk of requiring valve replacement surgery (28 versus 8 per 100,000 person years; adjusted RR 3.9, 95% CI 2.6-6.1).

●A double-blind trial randomly assigned 846 patients with type 2 diabetes to one year of treatment with benfluorex (150 to 450 mg/day) or pioglitazone (30 to 40 mg/day) [39]. There was a larger decline in hemoglobin A1C in the pioglitazone group. Among 615 patients with assessable paired echocardiograms, 310 were treated with benfluorex and 305 were treated with pioglitazone. New morphological valve abnormalities occurred in eight patients with benfluorex and four with pioglitazone. New or worsening valve regurgitation occurred more frequently in the benfluorex group (27 percent versus 11 percent; odds ratio [OR] 2.97, 95% CI 1.91-4.63) and were mainly trace.

●A prospective echocardiographic reader-blinded study in 10 centers in France in 2010 and 2011 included 293 individuals with DM who were previously exposed to benfluorex and 293 propensity-matched diabetic control subjects [40]. In the matched sample, the frequency of mild or greater left-sided valve regurgitation was significantly higher in benfluorex-exposed patients compared with control subjects: 19.8 versus 4.7 percent (OR 5.29, 95% CI 2.46-11.4) for aortic regurgitation and 19.4 versus 9.6 percent (OR 2.38, 95% CI 1.27-4.45) for mitral regurgitation.

MDMA (ecstasy) — The drug 3,4-Methylenedioxymethamphetamine (MDMA; known as ecstasy) is an amphetamine derivative. MDMA was first synthesized in 1912 [41]. Use of MDMA as an adjunct to psychotherapy began in the 1970s. Recognition of MDMA's potential for abuse led to its categorization as a Schedule I drug in 1985. (See "MDMA (ecstasy) intoxication".)

Limited data suggest that use of MDMA may cause valve disease. An in vitro study found that MDMA and its N-demethylated metabolite norfenfluramine activated the 5-HT_2B serotonin receptor and elicited a prolonged mitogenic response in human valvular interstitial cells similar to that induced by fenfluramine [42].

A preliminary report of 29 current or former users of MDMA and 29 sex- and age-matched controls found that 8 of 29 MDMA users had abnormal echocardiographic results compared with none in the control group (using the FDA case definition for valvulopathy due to appetite suppressant drugs [18]) (see 'FDA case definition' above) [43]. Among MDMA users, 13 had greater than mild tricuspid regurgitation and six had valvular strands; neither of these findings was present in any of the control subjects.

Other cardiovascular effects of MDMA are discussed separately. (See "MDMA (ecstasy) intoxication".)

ERGOT ALKALOIDS — The ergot derivatives ergotamine and methysergide have limited utility for treatment and prophylaxis of migraines largely due to uncertain efficacy and adverse effects. Methysergide is no longer available in the United States and Canada, and its use is restricted in Europe. The efficacy of ergotamine in the treatment of migraine is uncertain. (See "Acute treatment of migraine in adults" and "Preventive treatment of episodic migraine in adults" and "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Medications to avoid'.)

Adverse effects of ergotamine and methysergide include rare induction of mitral, aortic, and/or tricuspid valvular disease with daily use [7,8,44-48]. Some patients treated with methysergide developed retroperitoneal fibrosis and valve disease [44]. Valve thickening has been rarely reported with long-term continuous use of ergotamine and caffeine [49]. Although most reported cases of valve disease with ergot alkaloid drugs have been asymptomatic (and some valve disease regressed with discontinuation of the ergot alkaloid), some patients have developed symptoms and required valve replacement.

Injectable dihydroergotamine (DHE) mesylate is one of the therapies used for acute migraine. Rare cases of valvular fibrosis have been reported with use of injectable DHE but in these cases the patients also received drugs with known association with valvular fibrosis [50]. (See "Acute treatment of migraine in adults".)

ERGOT-DERIVED DOPAMINE AGONISTS

For Parkinson disease — Ergot-derived dopamine agonists pergolide and cabergoline were previously used to treat Parkinson disease. These drugs are no longer used to treat Parkinson disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 due to the potential risk of valve disease [51]. In the United States, cabergoline is not approved to treat Parkinson disease.

Use of pergolide or cabergoline is associated with risk of valvular heart disease, with lesions similar to those associated with carcinoid, fenfluramine use, and other ergot-induced valvular disease [9,11,12,52-56]. As with anorectic drugs, the mechanism appears to be pergolide or cabergoline activation of 5-hydroxytryptamine 2B-type receptors expressed on heart valves, which in turn leads to valvular overgrowth [10]. (See 'Pathogenesis' above.)

●Cabergoline – A meta-analysis of six studies included 495 patients exposed to cabergoline treatment and 479 patients who were not exposed. Valve disease was identified in 17 percent of patients exposed to cabergoline compared with 6 percent of those not exposed (odds ratio [OR] 4.62, 95% CI 1.93-11.09) [57].

●Pergolide – A meta-analysis of six studies included 475 patients exposed to pergolide and 306 patients who were not exposed. Valve disease was identified in 28 percent in those exposed to pergolide and 19 percent of those not exposed (OR 2.34, 95% CI 1.29-4.25) [57].

●Effect of cumulative dose – The risk of valvular disease appears to be related to the cumulative dose of pergolide or cabergoline, as illustrated by the following study. In a nested case-control study from the United Kingdom involving a cohort of 11,417 patients taking antiparkinsonian drugs, 31 patients with newly diagnosed cardiac valve regurgitation were compared with 664 controls; six were taking pergolide and six were taking cabergoline [11]. The risk of valve regurgitation was significantly increased with current use of pergolide (incidence-rate ratio [IRR] 7.1, 95% CI 2.3-22.3) and cabergoline (IRR 4.9, 95% CI 1.5-15.6) but not with other dopamine agonists. The risk of valve regurgitation was increased only for patients taking pergolide or cabergoline for six months or longer and was particularly increased for either medication at doses higher than 3 mg daily.

For hyperprolactinemia and other uses — Cabergoline is a treatment for hyperprolactinemia, and is used off-label to treat acromegaly, Cushing disease, and to inhibit lactation.

Cabergoline-associated valvular disease has only rarely been reported in patients treated with cabergoline for hyperprolactinemia. The higher risk of valve disease seen in patients previously taking cabergoline for Parkinson disease compared with those taking cabergoline for hyperprolactinemia is likely dose-related. Patients taking cabergoline for Parkinson disease often take doses more than 10 times higher than the doses taken for hyperprolactinemia. In the United Kingdom study cited above, only one of the 31 patients with valve disease were being treated for hyperprolactinemia compared with 29 for Parkinson disease [11]. As noted above, the risk of valve disease is particularly increased at doses higher than 3 mg/day [11]; in comparison, the recommended cabergoline dose for hyperprolactinemia is only 0.5 to 2 mg per week. (See "Management of hyperprolactinemia", section on 'Initial therapy'.)

ASSOCIATION NOT ESTABLISHED FOR SSRIS — An association between selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitor (SNRIs) and valve disease has not been established [58], as reflected by the following studies:

A retrospective study compared 292 patients with prior SSRI exposure with 5145 patients without SSRI exposure [59]. The prevalence of mitral or aortic regurgitation meeting US Food and Drug Administration criteria (at least moderate mitral regurgitation or mild aortic regurgitation) was similar in patients with SSRI exposure compared with controls (26.7 versus 30.4 percent). The association remained negative when comparing SSRI-treated patients with controls with similar characteristics.

In contrast, a retrospective study found that among 206 patients with valve regurgitation, 11.6 percent had been exposed to SSRI or SNRI agents compared with 4.1 percent in the 195 control patients (odds ratio 3.08, 95% CI 1.35-7.04) [60].

PREVENTION AND MANAGEMENT

For withdrawn drugs — As described above, most drugs known to cause valvular heart disease are no longer approved and/or marketed. For patients previously exposed to withdrawn drugs linked to valve disease, echocardiography is indicated if there is a murmur or symptoms of valve disease.

For approved drugs — For the drugs linked to valve disease that are still approved and marketed, measures to minimize the risk of valve disease include using safe and effective alternatives when available. When a drug linked to valve disease is required, the lowest effective dose is used with clinical monitoring including baseline and follow-up echocardiography when drug dose and expected duration of therapy is within a range associated with risk of valve disease, as discussed below.

Drugs linked to valve disease that are currently available include:

●Fenfluramine – This drug is available through a restricted program in the United States to treat seizures in patients with Dravet or Lennox-Gastaut syndrome. The US Food and Drug Administration (FDA)-approved label for fenfluramine includes a black box warning for valve disease and pulmonary hypertension. Echocardiography to evaluate for valve disease and pulmonary hypertension is required prior to, every six months during, and once three to six months after the final dose of treatment [61]. (See "Dravet syndrome: Management and prognosis", section on 'Fenfluramine' and "Lennox-Gastaut syndrome", section on 'Fenfluramine'.)

No cases of development of valve disease or pulmonary arterial hypertension were identified in randomized trials comparing fenfluramine with placebo in patients with Dravet or Lennox-Gastaut syndrome treated with fenfluramine [62-64].

●Cabergoline – This drug is used in low doses to treat hyperprolactinemia (see 'For hyperprolactinemia and other uses' above), and is used off-label to treat acromegaly, to inhibit lactation, and to treat Cushing disease. (See "Treatment of acromegaly", section on 'Role of primary medical therapy' and "Overview of the treatment of Cushing syndrome", section on 'Medical therapy' and "Overview of the postpartum period: Normal physiology and routine maternal care", section on 'Lactation suppression'.)

•Hyperprolactinemia – The dose of cabergoline to treat hyperprolactinemia is generally much lower than the dose that was previously used to treat Parkinson disease, and the risk of valve disease is likely to be lower with lower cabergoline doses. Management of the risk of valve disease in patients treated with cabergoline for hyperprolactinemia is discussed separately. This includes baseline and periodic echocardiographic monitoring for patients taking larger than typical doses of cabergoline (eg, >2 g/week). (See "Management of hyperprolactinemia", section on 'Valvular heart disease'.)

•Acromegaly – Cabergoline is one of the drugs used to treat acromegaly. The dose of cabergoline for this indication (0.5 to 2 mg/week) is generally much lower than the dose previously used to treat Parkinson disease and does not appear to cause valve disease. (See "Treatment of acromegaly".)

•Inhibition of lactation – As discussed separately, in selected patients with fetal demise/stillbirth who desire lactation inhibition, cabergoline is administered as a single 1 mg oral dose. The risk of inducing valve disease in this setting is likely minimal. (See "Overview of the postpartum period: Normal physiology and routine maternal care", section on 'Lactation suppression'.)

•Cushing disease – Cabergoline is one of the agents used in selected patients with Cushing disease. Principles for use of cabergoline include using the lowest effective dose and baseline and periodic echocardiography in patients receiving higher doses of chronic cabergoline therapy (eg, >2 g/week).

●Ergotamine – This drug is available as treatment to treat migraine, although limited evidence of efficacy and side effects limit its use. The FDA-approved labels for ergotamine tartrate (with or without caffeine) note the risk of fibrotic valve disease with long-term continuous use of ergotamine and caffeine and warn against chronic daily use. Alternative treatments are commonly preferred, as discussed separately. (See "Acute treatment of migraine in adults", section on 'Ergotamine'.)

When a patient develops suspected drug-induced valve disease, consideration of the risks and benefits generally results in a decision to discontinue the drug. If there is significant valve dysfunction (most commonly regurgitation) periodic clinical and echocardiographic follow-up is performed as indicated for the valve lesion and its severity. (See "Chronic primary mitral regurgitation: General management", section on 'Monitoring' and "Natural history and management of chronic aortic regurgitation in adults", section on 'Monitoring' and "Management and prognosis of tricuspid regurgitation", section on 'Follow-up'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

SUMMARY AND RECOMMENDATIONS

●Causes - Drugs linked to valvular heart disease include:

•Amphetamine derivatives

-Appetite suppressants (fenfluramine, dexfenfluramine, and benfluorex) – These drugs have been withdrawn due to evidence linking them to valve disease. (See 'Appetite suppressants' above.)

-3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy) is a Schedule I drug due to its potential for abuse. (See 'MDMA (ecstasy)' above.)

•Ergot alkaloids (ergotamine and methysergide) – Methysergide is no longer available in the United States and Canada and its use is restricted in Europe. Since ergotamine has safety issues and limited efficacy, alternative therapies are commonly preferred. (See 'Ergot alkaloids' above.)

•Ergot-derived dopamine agonists (pergolide and cabergoline) – These drugs are no longer used to treat Parkinson disease. Pergolide was withdrawn from the market due to its association with valve disease. Cabergoline is a treatment of hyperprolactinemia and is used to treat acromegaly, to inhibit lactation, and treat Cushing disease. (See 'Ergot-derived dopamine agonists' above.)

●Pathogenesis – Drug-induced valvulopathy appears to be caused by activation of 5-hydroxytryptamine 2B (5-HT_2B) receptors on heart valves by drugs or drug metabolites. Stimulation of 5-HT_2B receptors on heart valve cells induces mitogenesis leading to excessive growth and valvulopathy [10]. (See 'Pathogenesis' above.)

Activation of 5-HT_2B receptors may also play a role in drug-induced pulmonary arterial hypertension. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins'.)

●Echocardiography – Drug-induced valve disease is most commonly detected by echocardiography. The mitral, aortic, and tricuspid valves are most commonly affected. Most affected patients have valve leaflet thickening, restriction in leaflet motion, and regurgitation. (See 'Echocardiographic features' above.)

●Prevention and management – As described above, most drugs known to cause valvular heart disease are no longer approved and/or marketed. For patients previously exposed to withdrawn drugs linked to valve disease, echocardiography is indicated if there is a murmur or symptoms of valve disease. (See 'For withdrawn drugs' above and 'Echocardiographic features' above.)

For the drugs linked to valve disease that are still approved and marketed, measures to minimize the risk of valve disease include using safe and effective alternatives when available. When a drug linked to valve disease is required, the lowest effective dose is used with clinical monitoring including baseline and follow-up echocardiography when the drug dose and expected duration of use is within a range associated with valve disease. (See 'For approved drugs' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic review.

The UpToDate editorial staff acknowledges Gerard P Aurigemma, MD, who contributed to an earlier version of this topic review.