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Valvular heart disease in patients with Parkinson’s disease treated with pergolide, levodopa or both
Available online at www.sciencedirect.com
Journal of Clinical Neuroscience 16 (2009) 83–87 www.elsevier.com/locate/jocn
Clinical Study
Valvular heart disease in patients with Parkinson’s disease treated with pergolide, levodopa or both Feriha Ozer a,*, Raziye Tiras b, Sibel Cetin b, Oya Ozturk b, Tuba Aydemir b, Serkan Ozben b, Hasan Meral b, Sibel Kizkin c, Halit Bader d, Beste Ozben e a
Movement Disorders Outpatient Clinic, Department of Neurology, Haseki Educational and Research Hospital, Atako¨y 9. kisim A 14/B Daire, _ 138 Istanbul, Turkey b Department of Neurology, Haseki Educational and Research Hospital, Istanbul, Turkey c Department of Neurology, Inonu University, Faculty of Medicine, Malatya, Turkey d Department of Cardiology, Eminonu Kizilay Medical Center, Istanbul, Turkey e Department of Cardiology, Marmara University Faculty of Medicine, Istanbul, Turkey Received 20 September 2007; accepted 2 February 2008
Abstract Cardiac valvulopathy has been reported in patients with Parkinson’s disease treated with pergolide. The aim of this study was to clarify the frequency and severity of valvular heart disease (VHD) in patients treated with pergolide, levodopa or both. We evaluated VHD by transthoracic echocardiography in 25 patients who were taking pergolide, 29 patients taking levodopa and 20 patients taking both levodopa and pergolide. All groups were compared with two separate age-matched control groups. There was no increase in the frequency of any type of echocardiographically-significant valvulopathy in the pergolide groups. Echocardiographically significant aortic regurgitation was found in 8% of the patients in the pergolide group and in 37.9% of the patients in the levodopa group. There was no correlation between VHD and pergolide dose, cumulative dose or duration of therapy. The mean pergolide dose was 2.6 ± 1.4 mg/day in the pergolide monotherapy group. We did not find any unequivocal evidence that pergolide causes significant valvular regurgitation. However, the mean pergolide dosage in our study was lower than in previous studies. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Levodopa; Parkinson’s disease; Pergolide; Valvulopathy
1. Introduction Ergot derivatives have been shown to cause retroperitoneal, pleural and pericardial fibrosis.1 Recently, cardiac valvulopathy has been reported in Parkinson’s disease (PD) patients treated with pergolide.2–6 The valvular lesions identified in these patients receiving pergolide were strikingly similar to those seen in patients receiving ergot derivates such as methysergide and ergotamine, or the ano-
*
Corresponding author. Tel./fax: +90 212 5295356. E-mail address: ff[email protected] (F. Ozer).
0967-5868/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.02.005
rectic drugs fenfluramine and dexfluramine, and in patients with carcinoid heart disease.7–10 The underlying mechanisms that lead to valvulopathies remain unclear. These drugs stimulate the 5-hydroxytryptamine 2B (5-HT2B) receptors, which are notably expressed in heart valves and induce fibroblast mitogenesis. This may partly explain how 5-HT2B receptor agonists cause valvular lesions.11 Pergolide has an agonistic effect on serotonergic receptors, and the cardiac side effects are claimed to be due to the activation of these serotonergic receptors. The stimulation of the 5-HT2B receptors in the cardiac valves may increase the risk of cardiac valvular fibrosis due to the trophic effect on fibromyoblasts.12
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F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
The aim of our study was to clarify the frequency and severity of valvular heart disease (VHD) in patients treated with pergolide and to compare them with patients using levodopa or both levodopa and pergolide. 2. Patients and methods The study was approved by the local ethics committee. All patients gave written informed consent. The patients and control subjects were included in the study as five groups: Group 1, PD patients treated with only pergolide (n = 25); Group 2, PD patients treated with only levodopa (n = 29); Group 3, PD patients treated with both pergolide and levodopa (n = 20); Group 4 (control 1), age-matched control group for Groups 2 and 3 (n = 31); and Group 5 (control 2), age-matched control group for Group 1 (n = 26). Patients with previous rheumatic VHD and those with coronary heart disease prior to or during antiparkinsonian therapy were excluded from the study, as were patients with hypertension and angina pectoris. All patients were carefully examined and evaluated according to clinical features, Unified Parkinson’s Disease Rating Scale (UPDRS) scores13 and Hoehn-Yahr stage14 during the on phase. All patients underwent echocardiographic examination to assess valvular structures. The patients were examined for valvular regurgitation, restrictive valvular disease and pulmonary hypertension. Clinical and demographic features of the groups are presented in Table 1. 2.1. Cardiac assessment A cardiologist, blind to the patients’ diseases and therapies, carried out the cardiac assessments (including physical
examination and echocardiography). Transthoracic echocardiography was performed using the Wingmed Vivid 3 echocardiography device (GE Wingmed Ultrasound, Horten, Norway) with 2.5-MHz multiphase images. Parasternal long-axis and parasternal short-axis, apical 4-cavity, apical 5-cavity, apical 2-cavity and subcostal standard imaging methods were used for echocardiographic assessments. Color Doppler, pulsed wave and continuous wave Doppler echocardiography were used to detect and evaluate the severity of valvular regurgitation. The severity of valvular (mitral, aortic, tricuspid and pulmonary) regurgitation was assessed using the indexes of the American Society of Echocardiography.15,16 The severity of regurgitation was classified as mild, moderate or severe. Moderate or severe regurgitation for mitral and tricuspid valves and mild, moderate or severe regurgitation for aortic and pulmonary valves were regarded as echocardiographically significant. The thickness and mobility of cardiac valves were also assessed; and patients with valves thicker than the internationally accepted 5 mm and limited valvular motion were regarded as having restrictive valvular cardiac disease. Similarly, stenosis was classified as mild, moderate or severe. Pulmonary arterial systolic pressure was calculated from tricuspid regurgitation flow velocity using the Bernoulli equation, and adding right atrial pressure (assumed to be 5 mmHg). Pulmonary arterial pressure was considered normal (630 mmHg), or classified as mild (30–45 mmHg), moderate (45–60 mmHg) or severe (>60 mmHg).17 Patients with valvular lesions possibly resulting from other pathologies (eg rheumatic VHD, valvular calcification, valvular disorders accompanied by left ventricular wall motion disorders, valvular prolapsus, annular dilatation, or congenital valvular abnormalities) were excluded from the study.
Table 1 Clinical and demographic features of the study groups
Age (years) Gender (male/female) Age of onset (years) Duration of disease (years) Dosage of pergolide (mg/day) Duration of pergolide usage (years) Dosage of levodopa (mg/day) Duration of levodopa usage (years) UPDRS total UPDRS motor UPDRS daily life
Group 1 pergolide (n = 25)
Group 2 levodopa (n = 29)
Group 3 pergolide + levodopa (n = 20)
Group 4 control 1 (n = 31)
Group 5 control 2 (n = 26)
p
58.3 ± 9.1 (34–75) 11/14 50.5 ± 9.5 7.8 ± 3.7
71.6 ± 6.6 (55–84) 15/14 66.2 ± 5.8 5.4 ± 3.5
66.8 ± 9.2 (49–78) 15/5 56.4 ± 10.5 10.4 ± 3.9
66.6 ± 6.9 (50–80) 22/9 – –
57.5 ± 11.1 (35–74) 16/10 – –
< 0.001a,b,c,d
2.6 ± 1.4 (0.75–5.50)
–
2.3 ± 0.9 (0.75–4.00)
–
–
0.360
4.6 ± 2.1 (1–8)
–
6.0 ± 2.4 (1–10)
–
–
0.048a
–
556.5 ± 196.8 (250–900)
–
–
0.105
–
445.7 ± 251.3 (150–1200) 3.8 ± 3.1 (1–16)
7.9 ± 2.9 (2–14)
–
–
23.2 ± 15.4 13.5 ± 9.0 7.2 ± 6.3
35.5 ± 16.1 23.9 ± 10.6 8.8 ± 5.3
37.0 ± 19.4 22.6 ± 14.1 11.1 ± 6.1
– – –
– – –
< 0.001b,e < 0.001e
< 0.001e 0.010a,b 0.002a,b 0.102
Post hoc analysis: a statistically significant difference between Groups 1 and 3; b statistically significant difference between Groups 1 and 2; c statistically significant difference between Groups 1 and 4; d no significant difference between Groups 1 and 5; e statistically significant difference between Groups 2 and 3. UPDRS = Unified Parkinson’s Disease Rating Scale.
F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
2.2. Statistical analysis Statistical analysis of data was performed using the Statistical Package for the Social Sciences v. 13.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables were expressed as the mean ± standard deviation (SD) while categorical variables were expressed as ratios. Valvular lesions were individually evaluated, and all groups were compared in terms of the incidence of valvular regurgitation, stenosis, and pulmonary hypertension using the chi-square test. The clinical and demographic differences among the groups, and the differences between drug doses and duration of treatment in groups with and without valvular lesions were compared by the analysis of variance (ANOVA) test. For a post hoc analysis, a Bonferroni correction was performed when appropriate. A logistic regression analysis was performed to define the independent determinants of VHD (echocardiographically significant). p < 0.05 was accepted as the level of significance. 3. Results The clinical and demographic features of groups are shown in Table 1, while the echocardiographic assessments of the patients are shown in Tables 2 and 3. Multiple abnormal valvulopathy was present in Groups 2 and 3. There was no echocardiographically significant tricuspid regurgitation in any group (Table 3). Echocardiographically significant aortic valvular regurgitation was observed in 2 patients (8%) in Group 1, 11
85
patients (37.9%) in Group 2, 6 patients (30%) in Group 3, 4 patients (12.9%) in Group 4 and 1 patient (3.8%) in Group 5 (Table 3). Both of the patients in the pergolide group (Group 1) had mild aortic regurgitation and they had been taking pergolide at doses of 5.0 and 5.5 mg/day for 4.5 years. Restrictive VHD was detected in only two patients in the levodopa group (Group 2) and both patients had moderate aortic stenosis. Moderate pulmonary hypertension was present in one patient in the pergolide group, one patient in the levodopa group and one subject in control 1. In Group 3 (levodopa + pergolide), 3 patients had mild while 2 patients had moderate pulmonary hypertension. When the study group was divided into two according to the use of pergolide (Groups 1 and 3 vs. Group 2), the frequency of significant valvular regurgitation was not significantly different between the patients using pergolide (Groups 1 and 3) and patients not using pergolide (Group 2) (p = 0.85). Similarly, the pergolide cumulative dose (dose/day multiplied by years of pergolide use) was not associated with significant valvular regurgitation (p = 0.21). When the study group was divided into two according to the use of levodopa (Groups 2 and 3 vs. Group 1), significant valvular regurgitation was higher in patients using levodopa (Groups 2 and 3) compared to those not using levodopa (Group 1) (36.73% vs. 8.54%, p < 0.001). We modelled a logistic regression analysis to define the independent determinants of VHD. Both levodopa treatment (p = 0.03, 95% CI 1.115–9.241) and age (p = 0.003, 95% CI 1.039–1.201) were independently associated with echocardiographically significant valvular regurgitation,
Table 2 The frequency of valvular regurgitation of any type and severity among the study groups*
Mitral regurgitation Aortic regurgitation Tricuspid regurgitation Total
Group 1 pergolide (n = 25)
Group 2 levodopa (n = 29)
Group 3 pergolide + levodopa (n = 20)
Group 4 control 1 (n = 31)
Group 5 control 2 (n = 26)
5 2 1 6
5 (17.2%) 11 (37.9%) 1 (3.4%) 13 (44.8%)
9 (45%) 7 (35%) 3 (15%) 13 (65%)
2 (6.5%) 4 (12.9%) – 5 (16.2%)
5 4 4 8
(20%) (8%) (4%) (24%)
(19.2%) (15.4%) (15.4%) (30.8%)
* More than one type of valvular regurgitation was present in some patients. In Group 1, one patient had both mitral and aortic regurgitation and one patient had both mitral and tricuspid regurgitation. In Group 2, two patients had mitral and aortic regurgitation and two patients had mitral, aortic and tricuspid regurgitation. In Group 3, two patients had mitral and aortic regurgitation, two patients had mitral and tricuspid regurgitation and one patient had mitral, aortic and tricuspid regurgitation. In Group 4, one patient had mitral and aortic regurgitation. In Group 5, two patients had mitral and aortic regurgitation, one patient had aortic and tricuspid regurgitation and one patient had mitral, aortic and tricuspid regurgitation.
Table 3 The frequency of echocardiographically significant valvular regurgitation among the study groups Group 1 pergolide (n = 25)
Group 2 levodopa (n = 29) 11 (37.9%)*
Group 3 pergolide + levodopa (n = 20) 7 (35%)*
Group 4 control (n = 31)
Group 5 (n = 26)
p
a,b,c,d Any type of abnormal 2 (8%) 4 (12.9%) 1 (3.8%) regurgitation (total) e Mitral regurgitation – 1 (3.4%) 3 (15%) – – Tricuspid regurgitation – – – – – – a,c,d Aortic regurgitation 2 (8%) 11 (37.9%)* 6 (30%) 4 (12.9%) 1 (3.8%) *Some patients had more than one type of valvular regurgitation. Level of significance was set at p < 0.05: a statistically significant difference between Groups 1 and 2; b statistically significant difference between Groups 1 and 3; c statistically significant difference between Groups 2 and 4; d no statistically significant difference between Groups 1 and 5; e no statistically significant difference between groups.
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F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
whereas pergolide treatment was not associated with valvular regurgitation (p = 0.48). 4. Discussion In our study, aortic valvular regurgitation was the most common valvular abnormality. We did not observe significant tricuspid regurgitation in any group. All types of valvular regurgitation were more severe and occurred significantly more frequently in the levodopa monotherapy group compared to the pergolide monotherapy group and the levodopa age-matched control group. We found no significant difference in the frequency of valvular regurgitation between the pergolide monotherapy group and its agematched control. However, because of the small sample size, we could not conclude that pergolide therapy did not result in valvular regurgitation. Echocardiographically significant valvular regurgitation occurred more frequently in Group 3 (levodopa + pergolide group) compared to Group 1 (pergolide monotherapy group). There was no significant difference in pergolide dose between the two groups (Groups 1 and 3); therefore difference in pergolide dose does not explain the higher presence of valvular regurgitations in Group 3. However, the duration of pergolide treatment was significantly longer in Group 3. In addition, the mean age of patients in Group 3 was higher than that in Group 1 and age might be the reason for the high prevalence of valvular regurgitation. Degenerative processes of the heart related to aging result in changes in both the aortic and mitral valves. These degenerative changes may lead to aortic stenosis or regurgitation due to aortic valve sclerosis, and mitral regurgitation resulting from myxomatous mitral valves or mitral annular calcification.18 Stewart et al. reported that age was an independent clinical factor for degenerative aortic valve disease (twofold increased risk for each 10-year increase in age).19 Although these valvular calcifications and degenerative changes are common in the elderly, they are fortunately not usually of any functional or hemodynamic significance. In both groups using levodopa (Groups 2 and 3), valvular regurgitation was more frequent when compared with the pergolide monotherapy group (Group 1). However, as far as we know, levodopa has no effect on cardiac valves. Since patients in the pergolide group were significantly younger than patients taking levodopa, increased age might explain the presence of more valvular regurgitation in patients taking levodopa. However, the frequency of valvular regurgitation was also significantly higher in the levodopa monotherapy group than among age-matched controls. We believe that this contradiction was probably a result of our small number of patients. Only two patients had aortic regurgitation in the pergolide group (Group 1) and the grade of the regurgitation was mild. The patients in the pergolide group were taking lower doses of pergolide (2.6 ± 1.4 mg/day) when compared with doses used in previous studies, in which the pergolide dos-
age was higher than 4 mg/day.2,3,5,20 The two patients who had aortic regurgitation were receiving pergolide doses of greater than 5 mg/day. Pergolide was discontinued in one patient, after which the aortic regurgitation disappeared. In the other patient, the echocardiographic findings improved when the dose was decreased from 5 mg/day to 2 mg/day. In our study, the frequency of valvular regurgitation was lower compared to other studies; only two patients had mild aortic regurgitation. Peralta et al. reported that exposure to pergolide and cabergoline was associated with higher frequencies of moderate (31%) and severe (47%) valvular regurgitation compared with age-matched controls (13%).21 Waller et al. found that 45% of patients in the pergolide group had aortic regurgitation compared with 21% of controls, while 13% had moderate to severe valvular regurgitation.20 However, Baseman et al. reported that 89% of pergolide-treated patients had some degree of valvular insufficiency.6 They showed an approximate 2-fold to 3-fold increased risk of abnormal valves in the pergolide-treated patients (odds ratio [OR] about 3) and an estimated 14-fold increased risk of concerning tricuspid regurgitation (OR = 18.4) compared to the Framingham cohort.22 Their high prevalence of valvular insufficiency might be because they included all types of valvular abnormality (irrespective of other pathological conditions), with any level of severity. This may explain the difference in the frequency of valvular regurgitation compared to our study. Alternatively, the differences may be a result of using a relatively low dose of pergolide in our study. Higher doses of pergolide (> 4 mg daily) have been found to be associated with a higher frequency of VHD.3–5,20 Waller et al.20 noticed that a low dose of pergolide (< 1 mg/day) did not seem to cause valvulopathy.22 Similarly, Kim et al. reported that 11.1% of their patients had mild aortic regurgitation, 8.3% had mild tricuspid regurgitation and 5.6% had multiple valvulopathy in the pergolide group while receiving lower doses of pergolide (mean dose 1.13 mg/day).23 After Pritchett et al. 2 reported three patients in 2002, Van Camp et al.4 reported that restrictive VHD of any type was present in 33% of their 78 patients with PD treated with pergolide, 19% of whom had severe disease. Van Camp et al. noted a significant correlation between the cumulative doses of pergolide and tenting areas of the mitral valves. Most studies, including Van Camp et al., lack echocardiographic assessment of patients prior to the initiation of therapy, which causes a major limitation in interpreting the results. Restrictive VHD was detected in only two patients in the levodopa monotherapy group in our study. Both of these patients had moderate aortic stenosis. We did not detect any mitral or tricuspid valvular thickening or stenosis. We did not detect any restrictive VHD in other therapy groups. 5. Conclusion In controlling the symptoms of PD, pergolide is useful when used alone and in combination with levodopa. We
F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
did not observe an increased frequency of valvular regurgitation in patients using pergolide when compared to agematched controls. Since the pergolide doses in our study were low and both of the patients who had valvular regurgitation were taking 5 mg/day or more, we think that a low dose of pergolide is safer. However, due to our small sample size, it is difficult to reach a definite conclusion. We believe that unusually high dosages of ergot-derived dopamine agonists should be avoided whenever possible. We recommend that all patients treated with pergolide should undergo cardiovascular examination, and whenever needed, echocardiography should be performed. Acknowledgement We would like to express our special thanks to Professor Tomris Ozben for her contribution to the writing of this article. References 1. Shaunak S, Wilkins A, Pilling JB, et al. Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999;66:79–81. 2. Pritchett AM, Morrison JF, Edwards WD, et al. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002;77: 1280–6. 3. Van Camp G, Flamez A, Cosyns B, et al. Heart valvular disease in patients with Parkinson’s disease treated with high-dose pergolide. Neurology 2003;61:859–61. 4. 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;363:1179–83. 5. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19:656–62. 6. Baseman DG, O’Suilleabhain PE, Reimold SC, et al. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology 2004;63:301–4. 7. Bana DS, MacNeal PS, LeCompte PM, et al. Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J 1974;88:640–55. 8. Redfield MM, Nicholson WJ, Edwards WD, et al. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med 1992;117:50–2. 9. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581–8.
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10. Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnmalities detected by cardiac catheterization and echocardiography. Circulation 1995;92:790–5. 11. 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;102:2836–41. 12. Millan MJ, Maiofiss L, Cussac D, et al. 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. 13. Fahn S, Elton R. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent developments in Parkinson’s disease, Vol. 1. New Jersey: MacMillan Healthcare Information; 1987. p. 153–63. 14. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427–42. 15. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777–802. 16. Quin˜ones MA, Otto CM, Stoddard M, et al. Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167–84. 17. Bonow RO, Carabello B, de Leon Jr AC, et al. Guidelines for the management of patients with valvular heart disease: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation 1998;98:1949–84. 18. VanAuker MD. Age-related changes in hemodynamics affecting valve performance. Am J Geriatr Cardiol 2006;15:277–83. 19. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630–4. 20. Waller EA, Kaplan J, Heckman MG. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2005;80:1016–20. 21. Peralta C, Wolf E, Alber H, et al. Valvular heart disease in Parkinson’s disease vs. controls: An echocardiographic study. Mov Disord 2006;21:1109–13. 22. Singh JP, Evans JC, Levy D, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999;83:897–902. 23. Kim JY, Chung EJ, Park SW, et al. Valvular heart disease in Parkinson’s disease treated with ergot derivative dopamine agonists. Mov Disord 2006;21:1261–4.
Journal of Clinical Neuroscience 16 (2009) 83–87 www.elsevier.com/locate/jocn
Clinical Study
Valvular heart disease in patients with Parkinson’s disease treated with pergolide, levodopa or both Feriha Ozer a,*, Raziye Tiras b, Sibel Cetin b, Oya Ozturk b, Tuba Aydemir b, Serkan Ozben b, Hasan Meral b, Sibel Kizkin c, Halit Bader d, Beste Ozben e a
Movement Disorders Outpatient Clinic, Department of Neurology, Haseki Educational and Research Hospital, Atako¨y 9. kisim A 14/B Daire, _ 138 Istanbul, Turkey b Department of Neurology, Haseki Educational and Research Hospital, Istanbul, Turkey c Department of Neurology, Inonu University, Faculty of Medicine, Malatya, Turkey d Department of Cardiology, Eminonu Kizilay Medical Center, Istanbul, Turkey e Department of Cardiology, Marmara University Faculty of Medicine, Istanbul, Turkey Received 20 September 2007; accepted 2 February 2008
Abstract Cardiac valvulopathy has been reported in patients with Parkinson’s disease treated with pergolide. The aim of this study was to clarify the frequency and severity of valvular heart disease (VHD) in patients treated with pergolide, levodopa or both. We evaluated VHD by transthoracic echocardiography in 25 patients who were taking pergolide, 29 patients taking levodopa and 20 patients taking both levodopa and pergolide. All groups were compared with two separate age-matched control groups. There was no increase in the frequency of any type of echocardiographically-significant valvulopathy in the pergolide groups. Echocardiographically significant aortic regurgitation was found in 8% of the patients in the pergolide group and in 37.9% of the patients in the levodopa group. There was no correlation between VHD and pergolide dose, cumulative dose or duration of therapy. The mean pergolide dose was 2.6 ± 1.4 mg/day in the pergolide monotherapy group. We did not find any unequivocal evidence that pergolide causes significant valvular regurgitation. However, the mean pergolide dosage in our study was lower than in previous studies. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Levodopa; Parkinson’s disease; Pergolide; Valvulopathy
1. Introduction Ergot derivatives have been shown to cause retroperitoneal, pleural and pericardial fibrosis.1 Recently, cardiac valvulopathy has been reported in Parkinson’s disease (PD) patients treated with pergolide.2–6 The valvular lesions identified in these patients receiving pergolide were strikingly similar to those seen in patients receiving ergot derivates such as methysergide and ergotamine, or the ano-
*
Corresponding author. Tel./fax: +90 212 5295356. E-mail address: ff[email protected] (F. Ozer).
0967-5868/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.02.005
rectic drugs fenfluramine and dexfluramine, and in patients with carcinoid heart disease.7–10 The underlying mechanisms that lead to valvulopathies remain unclear. These drugs stimulate the 5-hydroxytryptamine 2B (5-HT2B) receptors, which are notably expressed in heart valves and induce fibroblast mitogenesis. This may partly explain how 5-HT2B receptor agonists cause valvular lesions.11 Pergolide has an agonistic effect on serotonergic receptors, and the cardiac side effects are claimed to be due to the activation of these serotonergic receptors. The stimulation of the 5-HT2B receptors in the cardiac valves may increase the risk of cardiac valvular fibrosis due to the trophic effect on fibromyoblasts.12
84
F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
The aim of our study was to clarify the frequency and severity of valvular heart disease (VHD) in patients treated with pergolide and to compare them with patients using levodopa or both levodopa and pergolide. 2. Patients and methods The study was approved by the local ethics committee. All patients gave written informed consent. The patients and control subjects were included in the study as five groups: Group 1, PD patients treated with only pergolide (n = 25); Group 2, PD patients treated with only levodopa (n = 29); Group 3, PD patients treated with both pergolide and levodopa (n = 20); Group 4 (control 1), age-matched control group for Groups 2 and 3 (n = 31); and Group 5 (control 2), age-matched control group for Group 1 (n = 26). Patients with previous rheumatic VHD and those with coronary heart disease prior to or during antiparkinsonian therapy were excluded from the study, as were patients with hypertension and angina pectoris. All patients were carefully examined and evaluated according to clinical features, Unified Parkinson’s Disease Rating Scale (UPDRS) scores13 and Hoehn-Yahr stage14 during the on phase. All patients underwent echocardiographic examination to assess valvular structures. The patients were examined for valvular regurgitation, restrictive valvular disease and pulmonary hypertension. Clinical and demographic features of the groups are presented in Table 1. 2.1. Cardiac assessment A cardiologist, blind to the patients’ diseases and therapies, carried out the cardiac assessments (including physical
examination and echocardiography). Transthoracic echocardiography was performed using the Wingmed Vivid 3 echocardiography device (GE Wingmed Ultrasound, Horten, Norway) with 2.5-MHz multiphase images. Parasternal long-axis and parasternal short-axis, apical 4-cavity, apical 5-cavity, apical 2-cavity and subcostal standard imaging methods were used for echocardiographic assessments. Color Doppler, pulsed wave and continuous wave Doppler echocardiography were used to detect and evaluate the severity of valvular regurgitation. The severity of valvular (mitral, aortic, tricuspid and pulmonary) regurgitation was assessed using the indexes of the American Society of Echocardiography.15,16 The severity of regurgitation was classified as mild, moderate or severe. Moderate or severe regurgitation for mitral and tricuspid valves and mild, moderate or severe regurgitation for aortic and pulmonary valves were regarded as echocardiographically significant. The thickness and mobility of cardiac valves were also assessed; and patients with valves thicker than the internationally accepted 5 mm and limited valvular motion were regarded as having restrictive valvular cardiac disease. Similarly, stenosis was classified as mild, moderate or severe. Pulmonary arterial systolic pressure was calculated from tricuspid regurgitation flow velocity using the Bernoulli equation, and adding right atrial pressure (assumed to be 5 mmHg). Pulmonary arterial pressure was considered normal (630 mmHg), or classified as mild (30–45 mmHg), moderate (45–60 mmHg) or severe (>60 mmHg).17 Patients with valvular lesions possibly resulting from other pathologies (eg rheumatic VHD, valvular calcification, valvular disorders accompanied by left ventricular wall motion disorders, valvular prolapsus, annular dilatation, or congenital valvular abnormalities) were excluded from the study.
Table 1 Clinical and demographic features of the study groups
Age (years) Gender (male/female) Age of onset (years) Duration of disease (years) Dosage of pergolide (mg/day) Duration of pergolide usage (years) Dosage of levodopa (mg/day) Duration of levodopa usage (years) UPDRS total UPDRS motor UPDRS daily life
Group 1 pergolide (n = 25)
Group 2 levodopa (n = 29)
Group 3 pergolide + levodopa (n = 20)
Group 4 control 1 (n = 31)
Group 5 control 2 (n = 26)
p
58.3 ± 9.1 (34–75) 11/14 50.5 ± 9.5 7.8 ± 3.7
71.6 ± 6.6 (55–84) 15/14 66.2 ± 5.8 5.4 ± 3.5
66.8 ± 9.2 (49–78) 15/5 56.4 ± 10.5 10.4 ± 3.9
66.6 ± 6.9 (50–80) 22/9 – –
57.5 ± 11.1 (35–74) 16/10 – –
< 0.001a,b,c,d
2.6 ± 1.4 (0.75–5.50)
–
2.3 ± 0.9 (0.75–4.00)
–
–
0.360
4.6 ± 2.1 (1–8)
–
6.0 ± 2.4 (1–10)
–
–
0.048a
–
556.5 ± 196.8 (250–900)
–
–
0.105
–
445.7 ± 251.3 (150–1200) 3.8 ± 3.1 (1–16)
7.9 ± 2.9 (2–14)
–
–
23.2 ± 15.4 13.5 ± 9.0 7.2 ± 6.3
35.5 ± 16.1 23.9 ± 10.6 8.8 ± 5.3
37.0 ± 19.4 22.6 ± 14.1 11.1 ± 6.1
– – –
– – –
< 0.001b,e < 0.001e
< 0.001e 0.010a,b 0.002a,b 0.102
Post hoc analysis: a statistically significant difference between Groups 1 and 3; b statistically significant difference between Groups 1 and 2; c statistically significant difference between Groups 1 and 4; d no significant difference between Groups 1 and 5; e statistically significant difference between Groups 2 and 3. UPDRS = Unified Parkinson’s Disease Rating Scale.
F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
2.2. Statistical analysis Statistical analysis of data was performed using the Statistical Package for the Social Sciences v. 13.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables were expressed as the mean ± standard deviation (SD) while categorical variables were expressed as ratios. Valvular lesions were individually evaluated, and all groups were compared in terms of the incidence of valvular regurgitation, stenosis, and pulmonary hypertension using the chi-square test. The clinical and demographic differences among the groups, and the differences between drug doses and duration of treatment in groups with and without valvular lesions were compared by the analysis of variance (ANOVA) test. For a post hoc analysis, a Bonferroni correction was performed when appropriate. A logistic regression analysis was performed to define the independent determinants of VHD (echocardiographically significant). p < 0.05 was accepted as the level of significance. 3. Results The clinical and demographic features of groups are shown in Table 1, while the echocardiographic assessments of the patients are shown in Tables 2 and 3. Multiple abnormal valvulopathy was present in Groups 2 and 3. There was no echocardiographically significant tricuspid regurgitation in any group (Table 3). Echocardiographically significant aortic valvular regurgitation was observed in 2 patients (8%) in Group 1, 11
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patients (37.9%) in Group 2, 6 patients (30%) in Group 3, 4 patients (12.9%) in Group 4 and 1 patient (3.8%) in Group 5 (Table 3). Both of the patients in the pergolide group (Group 1) had mild aortic regurgitation and they had been taking pergolide at doses of 5.0 and 5.5 mg/day for 4.5 years. Restrictive VHD was detected in only two patients in the levodopa group (Group 2) and both patients had moderate aortic stenosis. Moderate pulmonary hypertension was present in one patient in the pergolide group, one patient in the levodopa group and one subject in control 1. In Group 3 (levodopa + pergolide), 3 patients had mild while 2 patients had moderate pulmonary hypertension. When the study group was divided into two according to the use of pergolide (Groups 1 and 3 vs. Group 2), the frequency of significant valvular regurgitation was not significantly different between the patients using pergolide (Groups 1 and 3) and patients not using pergolide (Group 2) (p = 0.85). Similarly, the pergolide cumulative dose (dose/day multiplied by years of pergolide use) was not associated with significant valvular regurgitation (p = 0.21). When the study group was divided into two according to the use of levodopa (Groups 2 and 3 vs. Group 1), significant valvular regurgitation was higher in patients using levodopa (Groups 2 and 3) compared to those not using levodopa (Group 1) (36.73% vs. 8.54%, p < 0.001). We modelled a logistic regression analysis to define the independent determinants of VHD. Both levodopa treatment (p = 0.03, 95% CI 1.115–9.241) and age (p = 0.003, 95% CI 1.039–1.201) were independently associated with echocardiographically significant valvular regurgitation,
Table 2 The frequency of valvular regurgitation of any type and severity among the study groups*
Mitral regurgitation Aortic regurgitation Tricuspid regurgitation Total
Group 1 pergolide (n = 25)
Group 2 levodopa (n = 29)
Group 3 pergolide + levodopa (n = 20)
Group 4 control 1 (n = 31)
Group 5 control 2 (n = 26)
5 2 1 6
5 (17.2%) 11 (37.9%) 1 (3.4%) 13 (44.8%)
9 (45%) 7 (35%) 3 (15%) 13 (65%)
2 (6.5%) 4 (12.9%) – 5 (16.2%)
5 4 4 8
(20%) (8%) (4%) (24%)
(19.2%) (15.4%) (15.4%) (30.8%)
* More than one type of valvular regurgitation was present in some patients. In Group 1, one patient had both mitral and aortic regurgitation and one patient had both mitral and tricuspid regurgitation. In Group 2, two patients had mitral and aortic regurgitation and two patients had mitral, aortic and tricuspid regurgitation. In Group 3, two patients had mitral and aortic regurgitation, two patients had mitral and tricuspid regurgitation and one patient had mitral, aortic and tricuspid regurgitation. In Group 4, one patient had mitral and aortic regurgitation. In Group 5, two patients had mitral and aortic regurgitation, one patient had aortic and tricuspid regurgitation and one patient had mitral, aortic and tricuspid regurgitation.
Table 3 The frequency of echocardiographically significant valvular regurgitation among the study groups Group 1 pergolide (n = 25)
Group 2 levodopa (n = 29) 11 (37.9%)*
Group 3 pergolide + levodopa (n = 20) 7 (35%)*
Group 4 control (n = 31)
Group 5 (n = 26)
p
a,b,c,d Any type of abnormal 2 (8%) 4 (12.9%) 1 (3.8%) regurgitation (total) e Mitral regurgitation – 1 (3.4%) 3 (15%) – – Tricuspid regurgitation – – – – – – a,c,d Aortic regurgitation 2 (8%) 11 (37.9%)* 6 (30%) 4 (12.9%) 1 (3.8%) *Some patients had more than one type of valvular regurgitation. Level of significance was set at p < 0.05: a statistically significant difference between Groups 1 and 2; b statistically significant difference between Groups 1 and 3; c statistically significant difference between Groups 2 and 4; d no statistically significant difference between Groups 1 and 5; e no statistically significant difference between groups.
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whereas pergolide treatment was not associated with valvular regurgitation (p = 0.48). 4. Discussion In our study, aortic valvular regurgitation was the most common valvular abnormality. We did not observe significant tricuspid regurgitation in any group. All types of valvular regurgitation were more severe and occurred significantly more frequently in the levodopa monotherapy group compared to the pergolide monotherapy group and the levodopa age-matched control group. We found no significant difference in the frequency of valvular regurgitation between the pergolide monotherapy group and its agematched control. However, because of the small sample size, we could not conclude that pergolide therapy did not result in valvular regurgitation. Echocardiographically significant valvular regurgitation occurred more frequently in Group 3 (levodopa + pergolide group) compared to Group 1 (pergolide monotherapy group). There was no significant difference in pergolide dose between the two groups (Groups 1 and 3); therefore difference in pergolide dose does not explain the higher presence of valvular regurgitations in Group 3. However, the duration of pergolide treatment was significantly longer in Group 3. In addition, the mean age of patients in Group 3 was higher than that in Group 1 and age might be the reason for the high prevalence of valvular regurgitation. Degenerative processes of the heart related to aging result in changes in both the aortic and mitral valves. These degenerative changes may lead to aortic stenosis or regurgitation due to aortic valve sclerosis, and mitral regurgitation resulting from myxomatous mitral valves or mitral annular calcification.18 Stewart et al. reported that age was an independent clinical factor for degenerative aortic valve disease (twofold increased risk for each 10-year increase in age).19 Although these valvular calcifications and degenerative changes are common in the elderly, they are fortunately not usually of any functional or hemodynamic significance. In both groups using levodopa (Groups 2 and 3), valvular regurgitation was more frequent when compared with the pergolide monotherapy group (Group 1). However, as far as we know, levodopa has no effect on cardiac valves. Since patients in the pergolide group were significantly younger than patients taking levodopa, increased age might explain the presence of more valvular regurgitation in patients taking levodopa. However, the frequency of valvular regurgitation was also significantly higher in the levodopa monotherapy group than among age-matched controls. We believe that this contradiction was probably a result of our small number of patients. Only two patients had aortic regurgitation in the pergolide group (Group 1) and the grade of the regurgitation was mild. The patients in the pergolide group were taking lower doses of pergolide (2.6 ± 1.4 mg/day) when compared with doses used in previous studies, in which the pergolide dos-
age was higher than 4 mg/day.2,3,5,20 The two patients who had aortic regurgitation were receiving pergolide doses of greater than 5 mg/day. Pergolide was discontinued in one patient, after which the aortic regurgitation disappeared. In the other patient, the echocardiographic findings improved when the dose was decreased from 5 mg/day to 2 mg/day. In our study, the frequency of valvular regurgitation was lower compared to other studies; only two patients had mild aortic regurgitation. Peralta et al. reported that exposure to pergolide and cabergoline was associated with higher frequencies of moderate (31%) and severe (47%) valvular regurgitation compared with age-matched controls (13%).21 Waller et al. found that 45% of patients in the pergolide group had aortic regurgitation compared with 21% of controls, while 13% had moderate to severe valvular regurgitation.20 However, Baseman et al. reported that 89% of pergolide-treated patients had some degree of valvular insufficiency.6 They showed an approximate 2-fold to 3-fold increased risk of abnormal valves in the pergolide-treated patients (odds ratio [OR] about 3) and an estimated 14-fold increased risk of concerning tricuspid regurgitation (OR = 18.4) compared to the Framingham cohort.22 Their high prevalence of valvular insufficiency might be because they included all types of valvular abnormality (irrespective of other pathological conditions), with any level of severity. This may explain the difference in the frequency of valvular regurgitation compared to our study. Alternatively, the differences may be a result of using a relatively low dose of pergolide in our study. Higher doses of pergolide (> 4 mg daily) have been found to be associated with a higher frequency of VHD.3–5,20 Waller et al.20 noticed that a low dose of pergolide (< 1 mg/day) did not seem to cause valvulopathy.22 Similarly, Kim et al. reported that 11.1% of their patients had mild aortic regurgitation, 8.3% had mild tricuspid regurgitation and 5.6% had multiple valvulopathy in the pergolide group while receiving lower doses of pergolide (mean dose 1.13 mg/day).23 After Pritchett et al. 2 reported three patients in 2002, Van Camp et al.4 reported that restrictive VHD of any type was present in 33% of their 78 patients with PD treated with pergolide, 19% of whom had severe disease. Van Camp et al. noted a significant correlation between the cumulative doses of pergolide and tenting areas of the mitral valves. Most studies, including Van Camp et al., lack echocardiographic assessment of patients prior to the initiation of therapy, which causes a major limitation in interpreting the results. Restrictive VHD was detected in only two patients in the levodopa monotherapy group in our study. Both of these patients had moderate aortic stenosis. We did not detect any mitral or tricuspid valvular thickening or stenosis. We did not detect any restrictive VHD in other therapy groups. 5. Conclusion In controlling the symptoms of PD, pergolide is useful when used alone and in combination with levodopa. We
F. Ozer et al. / Journal of Clinical Neuroscience 16 (2009) 83–87
did not observe an increased frequency of valvular regurgitation in patients using pergolide when compared to agematched controls. Since the pergolide doses in our study were low and both of the patients who had valvular regurgitation were taking 5 mg/day or more, we think that a low dose of pergolide is safer. However, due to our small sample size, it is difficult to reach a definite conclusion. We believe that unusually high dosages of ergot-derived dopamine agonists should be avoided whenever possible. We recommend that all patients treated with pergolide should undergo cardiovascular examination, and whenever needed, echocardiography should be performed. Acknowledgement We would like to express our special thanks to Professor Tomris Ozben for her contribution to the writing of this article. References 1. Shaunak S, Wilkins A, Pilling JB, et al. Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999;66:79–81. 2. Pritchett AM, Morrison JF, Edwards WD, et al. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002;77: 1280–6. 3. Van Camp G, Flamez A, Cosyns B, et al. Heart valvular disease in patients with Parkinson’s disease treated with high-dose pergolide. Neurology 2003;61:859–61. 4. 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;363:1179–83. 5. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19:656–62. 6. Baseman DG, O’Suilleabhain PE, Reimold SC, et al. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology 2004;63:301–4. 7. Bana DS, MacNeal PS, LeCompte PM, et al. Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J 1974;88:640–55. 8. Redfield MM, Nicholson WJ, Edwards WD, et al. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med 1992;117:50–2. 9. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581–8.
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10. Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnmalities detected by cardiac catheterization and echocardiography. Circulation 1995;92:790–5. 11. 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;102:2836–41. 12. Millan MJ, Maiofiss L, Cussac D, et al. 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. 13. Fahn S, Elton R. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent developments in Parkinson’s disease, Vol. 1. New Jersey: MacMillan Healthcare Information; 1987. p. 153–63. 14. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427–42. 15. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777–802. 16. Quin˜ones MA, Otto CM, Stoddard M, et al. Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167–84. 17. Bonow RO, Carabello B, de Leon Jr AC, et al. Guidelines for the management of patients with valvular heart disease: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation 1998;98:1949–84. 18. VanAuker MD. Age-related changes in hemodynamics affecting valve performance. Am J Geriatr Cardiol 2006;15:277–83. 19. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630–4. 20. Waller EA, Kaplan J, Heckman MG. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2005;80:1016–20. 21. Peralta C, Wolf E, Alber H, et al. Valvular heart disease in Parkinson’s disease vs. controls: An echocardiographic study. Mov Disord 2006;21:1109–13. 22. Singh JP, Evans JC, Levy D, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999;83:897–902. 23. Kim JY, Chung EJ, Park SW, et al. Valvular heart disease in Parkinson’s disease treated with ergot derivative dopamine agonists. Mov Disord 2006;21:1261–4.