Correspondence
Dopamine Agonists and Valvular Heart Disease
N Engl J Med 2007; 356:1676-1680April 19, 2007
- Article
To the Editor:
Schade et al. (Jan. 4 issue)1 report an adjusted incidence-rate ratio of 4.9 for valvular regurgitation among patients taking the dopamine agonist cabergoline, especially at a daily dose above 3 mg and a duration of use of 6 months or more. The authors also report an incidence-rate ratio of 2.6 for cabergoline at a dose of 3 mg or less, adjusted for the cumulative duration of use. In the same issue, Zanettini et al.2 report a relative risk of moderate or severe valvular regurgitation of 4.6 to 7.3 among patients taking cabergoline. They also describe a dose effect on the severity of valvular dysfunction. Of note, Zanettini et al. do not report the prevalence of left ventricular dilatation and remodeling, which weakens their assertion that the tenting area of the mitral valve is solely an index of “stiffening of the leaflets.”
Cabergoline is a first-line therapy in prolactin-secreting pituitary tumors. The usual dose is 0.25 to 2.0 mg weekly (maximum, 4.5 mg). Young patients with hyperprolactinemia often receive therapy for life. Have the authors examined the prevalence of valvular dysfunction at lower doses of cabergoline in their studies? Further work with rigorous quantitative echocardiography is required to study the effect of lower doses of cabergoline administered over a long period in patients with hyperprolactinemia.
2 ReferencesJeffrey W. Stephens, M.B., B.S., Ph.D.
David E. Price, M.D., F.R.C.P.
Adrian Ionescu, M.D., M.R.C.P.
Morriston Hospital, Swansea SA6 6NL, United Kingdom
j.w. stephens@swansea. ac. uk 1
Schade R ,Anderson F ,Suissa S ,Haverkamp W ,Garde E . Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007;356:29-38
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Zanettini R ,Antonini A ,Gatto G ,Gentile R ,Tesei S ,Pezzoli G . Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007;356:39-46
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To the Editor:
Schade et al. and Zanettini et al. report a high incidence of significant valvular regurgitation in patients taking the ergot-derived dopamine agonist pergolide for the treatment of Parkinson's disease. Zanettini et al. report that severe regurgitation was associated with a high mean cumulative dose of pergolide (i.e., 6498 mg). In another study,1 patients who took a high daily dose of pergolide (more than 5 mg) had a slightly higher prevalence of restrictive valvular disease than did patients who took lower doses.
We studied 90 patients with Parkinson's disease (mean age, 61 years, of whom 24% were women) who were taking pergolide and 42 healthy matched controls. The average daily dose of pergolide was 2.93 mg, the average cumulative dose was 4541 mg, and the median duration of treatment was 51 months. None of the patients had restrictive valvular morphology or severe valvular regurgitation. The prevalence of moderate valvular regurgitation was 4.4% in the pergolide group and 2.4% in the control group, a difference that was not significant. Discrete leaflet thickening of left-sided valves without restricted motion was found in 11.1% of patients in the pergolide group, as compared with none in the control group. These findings corroborate previous reports1 that low daily and cumulative doses of pergolide do not appear to be associated with clinical valvular disease.
1 ReferencesHana Linkova, M.D.
Evzen Ruzicka, D.Sc.
Martin Penicka, Ph.D.
Charles University, 10000 Prague, Czech Republic
penicka@fnkv.cz 1
Van Camp G ,Flamez A ,Cosyns B , et al. Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004;363:1179-1183
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To the Editor:
Schade et al. and Zanettini et al. report that the ergot-derived dopamine agonists pergolide and cabergoline are associated with a significant risk of heart-valve regurgitation, a risk not associated with dopamine agonists that are not derived from ergot. In these articles and the accompanying Perspective article by Roth,1 the suggested explanation for this difference is mitogenesis caused by ergot-derived products binding to serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 5-HT2B. Roth notes that other 5-HT2B agonists, such as fenfluramine, ergotamine, and methysergide, can also cause valvular heart disease.
Methysergide is a well-known cause of retroperitoneal fibrosis. Agonists at 5-HT receptors have been associated not only with hyperplasia in cardiac valves but also with liver fibrosis.2 These observations suggest that retroperitoneal fibrosis that is associated with methysergide and possibly with other drugs may be due to agonism at 5-HT receptors.
Furthermore, atypical antipsychotic medications, such as risperidone and ziprasidone, are potent 5-HT–receptor antagonists.3 If a medication that is a 5-HT2B agonist must be used, then an atypical antipsychotic agent might be started as well to provide prophylaxis against mitogenic effects.
3 ReferencesRichard E. Kast, M.D.
University of Vermont, Burlington, VT 05401Eric L. Altschuler, M.D., Ph.D.
University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
eric.altschuler@umdnj. edu 1
Roth BL . Drugs and valvular heart disease. N Engl J Med 2007;356:6-9
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Ruddell RG ,Oakley F ,Hussain Z , et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol 2006;169:861-876
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Richelson E ,Souder T . Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29-39
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To the Editor:
The Perspective article by Roth brings to mind endomyocardial fibrosis, a restrictive cardiomyopathy linked to carcinoid and hypereosinophilic syndromes. Originally described by Davies in Uganda,1 endomyocardial fibrosis is endemic in sub-Saharan Africa and is characterized by thickening of the valve leaflets and fibrosis of the outflow tracts that progress to regurgitant heart failure. Endomyocardial fibrosis is linked to poverty and eosinophilia,2 but its cause is unknown.3
Is there a link between endomyocardial fibrosis and the 5-HT2B receptor? Agonists of 5-HT2B do not universally cause valvulopathy, and a dose response is evident. Genetic polymorphisms in receptor genes may influence receptor activation and downstream pathological responses. Dietary exposure to 5-HT2B agonists might be implicated in endomyocardial fibrosis in Africa. Serotonin interacts with eotaxin to promote eosinophilia.4
Thus, we are curious whether any of the affected patients described by Schade et al. and Zanettini et al. had eosinophilia, as compared with controls. If 5-HT2B is an important etiologic factor in the development of endomyocardial fibrosis, an interaction among 5-HT2B polymorphisms, eosinophilia, and environmental exposure (e.g., dietary tryptophan) could be explored.
4 ReferencesJohn L. Ziegler, M.D.
University of California, San Francisco, San Francisco, CA 94143
john.ziegler@ucsf. edu Gene Y. Bukhman, M.D., Ph.D.
Brigham and Women's Hospital, Boston, MA 021151
Davies JNP . Endomyocardial fibrosis: a heart disease of obscure etiology in Africans. East Afr Med J 1948;5:10-142
Rutakingirwa M ,Ziegler JL ,Newton R ,Freers J . Poverty and eosinophilia are risk factors for endomyocardial fibrosis (EMF) in Uganda. Trop Med Int Health 1999;4:229-235
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Sliwa K ,Damasceno A ,Mayosi BM . Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005;112:3577-3583
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Boehme SA ,Lio FM ,Sikora L , et al. Cutting edge: serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin. J Immunol 2004;173:3599-3603
Web of Science | Medline
To the Editor:
Schade et al. and Zanettini et al. report a causal association between 5-HT2B agonism and valvular heart disease. The accompanying commentary by Roth suggests that the valvulopathy could be due to valve-cell overgrowth stimulated by 5-HT2B–receptor agonists. Valvular remodeling has also been ascribed to an embryonic proliferative expansion process, based on transdifferentiation of precursors to a myofibroblast-like phenotype.1
Along these lines, we suggest a mechanism that may involve recruitment and differentiation of circulating or cardiac stem cells induced by 5-HT2B–receptor activation. Our recent unpublished data from studies of embryonic stem cells show a role of 5-HT2B receptors in cardiac differentiation. Myocytes derived from embryonic stem cells express 5-HT2B receptors during development (Figure 1Figure 1
Expression of 5-HT2B in Murine Embryonic Stem Cells and Differentiating Embryoid Bodies.). Serotonin stimulation promotes cell differentiation through a process sensitive to selective 5-HT2B–receptor blockers. It is possible that such a pathway is involved in the differentiation process of adult stem cells. Since adult stem cells can differentiate into valvular interstitial cells,2 one could speculate that 5-HT2B receptors are implicated in this process.2 ReferencesLaura Sartiani, Ph.D.
Elisabetta Cerbai, Ph.D.
Alessandro Mugelli, M.D.
University Center of Molecular Medicine, 50139 Florence, Italy1
Shworak NW . Angiogenic modulators in valve development and disease: does valvular disease recapitulate developmental signaling pathways? Curr Opin Cardiol 2004;19:140-146
CrossRef | Web of Science | Medline2
Sutherland FW ,Perry TE ,Yu Y , et al. From stem cells to viable autologous semilunar heart valve. Circulation 2005;111:2783-2791
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Author/Editor Response
Stephens et al. and Linkova et al. focus on the potential association of low-dose pergolide or cabergoline therapy with valvular heart disease. In our study, the incidence-rate ratio for newly diagnosed cardiac-valve regurgitation was 5.1 (95% confidence interval [CI], 1.3 to 20.4) with 3 mg or less of pergolide and 2.6 (95% CI, 0.5 to 12.8) with 3 mg or less of cabergoline. Further substratification (e.g., for doses of 1 mg or less) was not possible because of the small number of exposed patients. Systematic echocardiographic studies are required to investigate the effect of treatment with low-dose pergolide or cabergoline over a period of several years.
Ziegler and Bukhman discuss the potential role of eosinophilia in endemic endomyocardial fibrosis in Uganda. In our study, none of the patients with newly diagnosed heart-valve regurgitation had a recorded finding of eosinophilia during the study period.
Kast and Altschuler suggest that mitogenic effects of 5-HT2B agonists may be antagonized by atypical antipsychotic agents such as risperidone and ziprasidone. From the pharmacologic point of view, this is an interesting hypothesis. However, treatment with atypical antipsychotic agents may cause additional adverse reactions. Antipsychotic agents such as risperidone and ziprasidone may interfere with the efficacy of dopaminergic treatment and may aggravate parkinsonism. In addition, there is a concern that atypical antipsychotic agents are associated with an increased risk of death in elderly patients with dementia.1 Thus, routine coadministration of atypical antipsychotic agents seems to be problematic from the clinical point of view, especially considering the availability of dopamine agonists without 5-HT2B agonism (e.g., non–ergot-derived dopamine agonists or ergot-derived lisuride, which is a potent 5-HT2B antagonist2,3).
3 ReferencesRené Schade, M.D.
Frank Andersohn, M.D.
Edeltraut Garbe, M.D., Ph.D.
Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany
edeltraut.garbe@charite. de 1
Schneider LS ,Dagerman KS ,Insel P . Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934-1943
CrossRef | Web of Science | Medline2
Millan MJ ,Maiofiss L ,Cussac D ,Audinot V ,Boutin JA ,Newman-Tancredi A . Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 2002;303:791-804
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Jahnichen S ,Horowski R ,Pertz HH . Agonism at 5-HT2B receptors is not a class effect of the ergolines. Eur J Pharmacol 2005;513:225-228
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Author/Editor Response
In response to the question about endomyocardial fibrosis posed by Ziegler and Bukhman: we have the complete blood counts of approximately 80% of our patients for the past 12 months and have not seen any cases of eosinophilia. Our nutritionist reports that their diet was low in tryptophan. Since tryptophan is a neutral, large amino acid that competes with levodopa for absorption, patients with Parkinson's disease are told to avoid tryptophan-rich foods.
The proposal by Kast and Altschuler to use risperidone or ziprasidone as an atypical antipsychotic agent and 5-HT–receptor antagonist in patients with Parkinson's disease is theoretically correct. However, in clinical practice, the antidopaminergic effects of these drugs are fairly powerful, and they have a major negative effect on motor function, which would prevent us from using them routinely.
The data cited by Linkova et al. are consistent with ours, since the subgroup of our patients who were exposed to a mean cumulative dose of pergolide of 4566 mg (close to the cumulative dose of 4541 mg that they cite) did not have moderate-to-severe regurgitation. However, Linkova et al. did record discrete leaflet thickening in 11.1% of their patients, as compared with none in healthy volunteers. The phenomenon appears to depend on the cumulative dose, but we are unable to set a safety threshold.
The hypothesis that the mitral tenting area could be used as an early marker of leaflet stiffness is based mainly on the finding that the area was significantly greater in the ergot group without valvular disorders (grade 0 or 1) than in controls (2.68 vs. 2.37 cm2, P=0.02).
To exclude the possibility that left ventricular remodeling influenced this measure in patients with intermediate-grade regurgitation, we compared left ventricular end-diastolic volume, adjusted for body-surface area, in patients with grade 0 to grade 2 regurgitation who were receiving ergot with that in patients with grade 3 regurgitation of the mitral or aortic valve, and we did not find a significant difference (54.9±10.6 ml per square meter vs. 55.3±13 ml per square meter). We observed significant left ventricular remodeling only in the most severe cases: 11 patients with moderate or severe regurgitation of both mitral and aortic valves (69.3±9.9 ml per square meter vs. 55.3±13.0 ml per square meter among patients with grade 3 regurgitation, P=0.003).
We have no data on low-dose cabergoline, since we do not follow patients with prolactinomas. This is a worthwhile area of investigation.
Renzo Zanettini, M.D.
Gianni Pezzoli, M.D.
Istituti Clinici di Perfezionamento, 20126 Milan, Italy
cardriab@icp.mi. it Author/Editor Response
Kast and Altschuler propose the intriguing hypothesis that since methysergide, which is a prodrug for the potent 5-HT2B agonist methylergonovine,1,2 is associated with retroperitoneal fibrosis, the cause of this condition may be 5-HT2B agonism. This is an interesting idea, and there have been many case reports and other studies linking the use of pergolide with an increased incidence of retroperitoneal fibrosis,3 although we await definitive evidence. Kast and Altschuler also suggest that certain atypical antipsychotic drugs such as risperidone and ziprasidone might be used for prophylaxis in the rare circumstance when a drug with 5-HT2B agonism cannot be avoided. (Risperidone and ziprasidone have Ki values of 41.5 nM and 27 nM, respectively, according to the Psychoactive Drug Screening Program's Ki database, available at http://pdsp.med.unc.edu/pdsp.php.) The absolute affinities of these drugs are rather low, and atypical antipsychotic drugs are costly medications with a large number of potentially serious side effects. Instead, I would recommend cyproheptadine, which is a generic, high-affinity 5-HT2B antagonist with a Ki value of 1.4 nM, according to the above-mentioned database.
Ziegler and Bukhman wonder whether there might be some association among various 5-HT2B–receptor polymorphisms, eosinophilia, dietary tryptophan, and endomyocardial fibrosis. This is another interesting idea worthy of further study.
Sartiani et al. suggest an interesting model in which cardiac stem cells might be recruited through 5-HT2B activation. After recruitment, further 5-HT2B stimulation presumably would induce overgrowth and fibrosis. My colleagues and I have previously reported that 5-HT2B–receptor activation induces mitogenesis in human cardiac-valve interstitial cells in vitro, so there is merit to the idea that 5-HT2B–receptor activation may induce mitogenesis of cardiac-valve cells. Sartiani et al. also show that what appears to be 5-HT2B–receptor mRNA is present in embryonic stem cells, but they do not provide evidence of functioning 5-HT2B receptors in these cells. Although their hypothesis is intriguing, it will be important to demonstrate the presence of functional 5-HT2B receptors, since we have frequently found that the presence of receptor mRNA does not always indicate functional receptor protein.4
4 ReferencesBryan L. Roth, M.D., Ph.D.
University of North Carolina at Chapel Hill, Chapel Hill, NC 275991
Bredberg U ,Eyjolfsdottir GS ,Paalzow L ,Tfelt-Hansen P ,Tfelt-Hansen V . Pharmacokinetics of methysergide and its metabolite methylergometrine in man. Eur J Clin Pharmacol 1986;30:75-77
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Rothman RB ,Baumann MH ,Savage JE , et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000;102:2836-2841
Web of Science | Medline3
Kvernmo T ,Hartter S ,Burger E . A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 2006;28:1065-1078
CrossRef | Web of Science | Medline4
Bhatnagar A ,Sheffler DJ ,Kroeze WK ,Compton-Toth B ,Roth BL . Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors. J Biol Chem 2004;279:34614-34623
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- Citing Articles (3)
Citing Articles
1
Pedro Chaná. (2009) Avances en tratamiento medico de la enfermedad de Parkinson [Advances in the medical treatment of Parkinson's disease]. Parkinsonism & Related Disorders 15, S22-S25
CrossRef2
(2009) Low-dose cabergoline causing valvular heart disease in a patient treated for prolactinoma. Internal Medicine Journal 39:4, 266-267
CrossRef3
Mark Sherlock, Richard Steeds, Andy A. Toogood. (2007) Dopamine agonist therapy and cardiac valve dysfunction. Clinical Endocrinology 67:5, 643-644
CrossRef
