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Monaldi Arch Chest Dis2013; 80: 133-136 A case of iatrogenic severe mitral regurgitation
Un caso di insufficienza mitralica severa iatrogena
Antonio D'Aloia, Barbara Piovanelli, Riccardo Rovetta, Ivano Bonadei, Enrico Vizzardi, Antonio Curnis, Marco Metra ABSTRACT: A case of iatrogenic severe mitral regurgitation.
diac valve disease. Here we present a case of iatrogenic
A. D'Aloia, B. Piovanelli, R. Rovetta, I. Bonadei, E. Vizzardi,
symptomatic severe mitral regurgitation due to these drugs.
A. Curnis, M. Metra.
Keywords: valve disease, cabergoline, severe mitral re-
Bromocriptine and cabergoline, ergot derived dopamine re-
ceptor agonists used to treat Parkinson's disease and pro-
lactinomas, have been associated with increased risk of car-
Monaldi Arch Chest Dis 2013; 80: 133-136.
Deparment of medical and surgical, radiological sciences and public health specialty, Section of Cardiovascular Diseases,University of Study of Brescia. Corresponding author: Riccardo Rovetta; Piazzale Spedali civili 1, I-25100 Brescia, Italy; Tel.: +39 030 399575, Fax: +39 030 3995018,E-mail address: [email protected] and a 2/6 pan systolic murmur radiating to the axillawere noted. The blood pressure was 110/70 mmHg, Bromocriptine (Br) and Cabergoline (Cb), ergot heart rate was regular with 120 bpm, and tempera- derived dopamine receptor agonists used to treat ture was 39° C. ECG showed sinus tachycardia, Parkinson's disease and prolactinoma, have been as- without significant alterations of ventricular repolar- sociated with increased risk of cardiac valve disease.
ization. Blood tests showed elevated C-reactive pro- The mechanism behind this association is believed tein (355 ng/mL), high values of D-Dimer (2532 to be linked to the agonism of these drugs to the ng/mL) and elevated NTpro BNP (2030 pg/ml). A serotonin receptor 5-HT present at the level of the fi- chest radiograph showed mild cardiomegaly and broblasts of the heart valves and that the stimulation signs of acute pulmonary edema and bilateral of these receptors leads to this adverse effect of pro- pleural effusions. The chest CT was negative for liferation of fibroblasts and deposition of cells on pulmonary embolism. The pleural fluid was then the surface of valves causing retraction and fibrosis drained by thoracentesis and the cytological exami- [1]. These fibrotic changes cause thickening, retrac- nation had documented reactive inflammatory liq- tion and stiffening of the valves with consequent in- uid. During the hospitalization, sudden worsening of complete leaflet closure and relevant regurgitation.
hemodynamic compensation occurred with hyper- Here we present a case of Br and Cb induced symp- capnic respiratory acidosis (pH 7.2, pCO2 60 tomatic severe mitral regurgitation.
mmHg). The patient was urgently transferred to theintensive care unit for ventilatory and cardiovascu- Case Report
lar support needed for a cardiogenic shock setting.
Transthoracic echocardiography showed a not di- A 56-year-old man was admitted to our depart- lated left ventricle with normal global systolic func- ment for acute heart failure. From the medical his- tion and a mild dilated and hypokinetic right ventri- tory emerged a prolactin-secreting pituitary ade- cle with pulmonary arterial hypertension. Mild noma, treated surgically several times and followed valve tricuspid valve regurgitation and venous con- by radiotherapy with recidivism, hypoadrenocorti- gestion. Severe mitral regurgitation has been re- cism withdrawal of replacement therapy in pan hy- vealed through thickened, retracted mitral leaflets popituitarism, with recent hospitalizations for pleu- with incomplete coaptation (Fig. 1, Fig. 2). The ex- ropneumonia, pericardial effusion and bilateral cursion of the mitral leaflets was severely impaired.
pleural effusions. Treatment consisted of Br 5 mg Since there was no commissural or chordal fusion, a twice daily for 12 years and then the dosage was re- rheumatic cause was unlikely. The patient has un- duced to 2,5 mg three times a day for 11 years; then dergone to coronary angiography demonstrating it has been replaced by Cb 0,5 mg once daily for 6 normal coronary arteries and a Intra Aortic Balloon months. At the hospitalization, the patient presented Pump was started. In view of the worsening clinical with dyspnea at rest and orthopnea (NYHA class condition, the patient was undergone to a brain com- IV). The physical examination was notable for in- puted tomography scan that was negative for bleed- creased jugular venous pressure, bilateral rales, and ing lesions, and showed the presence of 2 hyper edema in both legs. On auscultation, a gallop rhythm dense nodules related to the known residual macro A. D'ALOIA ET AL.
adenoma. Given the persistence of heartfailure, despite pharmacological andmechanical therapy and the persistenceof severe mitral valve regurgitation, thepatient underwent a valve replacementwith mechanical prostheses. The macro-scopic examination of the valve re-placed documented the presence of mul-tiple areas of valve atherosclerosis withmicro calcifications. After surgery thepatient's condition improved and he wasasymptomatic at discharge in good he-modynamic compensation. Echocardio-graphic control after surgery excludedthe presence of pericardial effusion,while mild pleural effusion persisted bi-laterally. During the hospitalization Cbhas been stopped. Given the absence ofother possible causes, this drug is mostlikely due to the development of valvedisease in this patient. In the nextmonths the patients remained healthyand was treated with steroid and anti-in-flammatory non steroidal agents.
Br, a dopamine receptor-2 agonist used to treat prolactinomas, has been as-sociated with cases of cardiopulmonaryfibrosis [2] and valve diseases [1] in pa-tients with Parkinson's disease. Re-cently the use of this drug was ques-tioned, after the evidence of increasedrisk of valve regurgitation [1, 3]. Ergot-derived dopamine agonist, and espe-cially Cb, are efficacious and well-toler-ated drugs in the treatment of prolactin-oma by reducing both hyperprolactine-mia and pituitary adenoma volume. BRand CAB are used in different settings at Figure 1. - Transesophageal echocardiography in four chambers views show severe different doses. In patients with Parkin- son's disease, the usual daily doseranges from 2 to 6 mg, whereas in hy- perprolactinemia, the weekly doseranges from 0.25 to 3.5 mg. So far, fi-brotic reactions and valve heart diseasedue to the use of ergot dopamine ago-nists have been reported almost exclu-sively in patients with Parkinson's dis-ease and thus could be related to age,dosage, or both. Our patient was treatedinitially with 10 mg of Br daily for 12years, followed by 7,5 mg daily for 11years and only in the last six months hadtaken Cb 0,5 mg daily. Given the timecourse and the absence of any other of-fending agent, we conclude that Br andCb were most likely responsible for thedevelopment of valve heart disease inthis patient.
The incidence of valve damage due to the cumulative dose of Br and Cb isnot well established. Boguszewski et al.,comparing the effects of Cb and Br, have Figure 2. - Transesophageal ecocardiographic zoom on lack of coaptation of thethickened mitral leaflets.
documented that both drugs showed A CASE OF IATROGENIC SEVERE MITRAL REGURGITATION higher prevalence of trace and mild tricuspid or mi- tral regurgitation, but these findings were not clini-cally significant [4]. Also, Gu et al. have stated that This case shows severe valve pathology, proba- long-term, low-dose dopamine agonist therapy rarely bly as a result of long term and high exposure to BR causes cardiac valve disease [5]. Studies conducted and then to CAB. Agonists of 5-HT2B serotonin re- by Tan et al. demonstrated that Br use was associated ceptors produce structural changes in heart valves with an increased risk of developing valve heart dis- that result in regurgitation. Prescribers need to be ease, which occurred in a cumulative dose-depen- aware of the risk of cardiac valve diseases associ- dent manner [6]. Horvath et al. reported pluri valve ated with the use of ergot-derived dopamine ago- regurgitation in a patient taking Cb for 20 months, nists and young patients receiving low-dose of BR with stepwise increases in the dosage from 2 mg to 4 or CAB therapy for hyperprolactinemia should be mg per day [7]. Pinero described another patient was aware of the potential risk of fibrotic side effects.
treated initially with 2 mg of CAB daily; he subse- Patients being treated with these drugs should be quently received an additional 2 mg daily, starting at carefully examined with echocardiography to pre- the beginning of the second month. The serious ad- vent the progression of early changes and they verse effect has been observed at the end of the should be warned about the potential adverse events.
fourth month of treatment [8]. Delgrado et al. de- Furthermore, there is a need for larger studies and scribed how the long-term therapy with dopamine with longer duration of follow up with echocardio- agonists in patients with prolactinoma is associated graphic assessment to establish how heart-valve with an increased prevalence of valve calcifications.
changes progress and if they are reversible when pa- However, these structural changes were not accom- tients are switched to a non-ergot agonist.
panied by an increased prevalence of valve dysfunc-tion [9]. In some clinical trials, the absence of valve lesions could be due to short follow up. It is true thatthe doses of Br and Cb used in hyperprolactinemia La bromocriptina e la cabergolina, derivati del- are considerably lower than those used in Parkin- l'ergotamina, sono agonisti dei recettori dopami- son's disease [3], so it would be reasonable to as- nergici usati per curare il morbo di Parkinson e pro- sume a lower risk of valve lesions. However, higher lattinomi. Essi sono stati associati ad un aumentato doses of Br and Cb, as in our patient, similar to those rischio di patologia valvolare. Vi presentiamo un used in patients with Parkinson's disease, have been caso di insufficienza mitralica iatrogena sintoma- used in treating resistant hyperprolactinemia associ- tica di grado severo causata da questi farmaci. ated with giant prolactinomas [4]. In such cases, therisk of valve disease may be greater. These drugs have high affinity for 5-HT2B receptors located on heart valves. Surgically removed heart valves from Fitzgerald LW, Burn TC, Brown BS, et al. Possible role patents with Parkinson's disease not only show re- of valvular serotonin 5-HT (2B) receptors in the car- traction and stiffening, resulting in incomplete leaflet diopathy associated with fenfluramine. Mol Pharmacol coaptation and regurgitation, but also distinctive 2000; 57: 75-81.
histopathological changes, including fibroblast pro- Dhawan V, Medcalf P, Stegie F, et al. Retrospective eval- liferation and deposition of cellular myxoid matrix uation of cardio-pulmonary fibrotic side effects in symp- on the valve surfaces [10]. Given that all these drugs tomatic patients from a group of 234 Parkinson's disease have agonistic effects on 5-HT patients treated with cabergoline. J Neural Transm 2005 2B receptors, it is May; 112 (5): 661-8.
tempting to assume that the histopathological Schade R, Andersohn F, Suissa S, et al. Dopamine ago- changes are mediated by serotoninergic agonistic ac- nists and the risk of cardiac-valve regurgitation. N Engl J tivity on the cardiac valve 5-HT2B receptors [2, 11, Med 2007 Jan 4; 356 (1): 29-38.
12]. Some studies have evaluated the association be- Boguszewski CL, dos Santos CM, Sakamoto KS, Marini tween valve regurgitation and the use of CAB in pa- LC, de Souza AM, Azevedo M. A comparison of caber- tients with prolactinoma [13-18] and they have goline and bromocriptine on the risk of valvular heart dis- shown that clinically important valve regurgitation ease in patients with prolactinomas. Pituitary 2012 Mar; was significantly increased in patients taking ergot- 15 (1): 44-9.
derived dopamine receptor agonists, but not in pa- Gu H, Luck S, Carroll PV, et al. Cardiac valve disease tients taking non-ergot-derived dopamine agonist. In and low-dose dopamine agonist therapy: an artefact of re-porting bias? Clin Endocrinol (Oxf) 2011 May; 74 (5): contrast to CAB, evidence-based information about a possible profibrotic effect of BR in prolactinoma pa- Tan LC, Ng KK, Au WL, et al. Bromocriptine use and the tients is extremely limited. Atanaska et al. have risk of valvular heart disease. Mov Disord 2009 Feb 15; proved that long-term treatment with CAB and BR seems not to be associated with an increased risk of Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe clinically significant valve disease but possible sub- multivalvular heart disease: a new complication of the er- clinical lesions should be expected [19]. These data got derivative dopamine agonists. Mov Disord 2004; 19: should prompt more careful echocardiographic fol- low-up studies in patients with prolactinoma treated Pinero A, Marcos-Alberca P, Fortes J. Cabergoline-re- with BR and CAB or other ergot-derivative drugs.
lated severe restrictive mitral regurgitation. N Engl J Med2005; 353: 1976-1977.
Prospective follow-up studies of these patients are Delgado V, Biermasz NR, van Thiel SW, et al. Changes in underway and will establish how heart valve changes heart valve structure and function in patients treated with progress and if they are reversible when patients are dopamine agonists for prolactinomas, a 2-year follow-up switched to a non-ergot agonist.
study. Clin Endocrinol (Oxf) 2012 Jul; 77 (1): 99-105.
A. D'ALOIA ET AL.
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doses of cabergoline is not associated with increased Atanaska Elenkova, Rabhat Shabani, Krassimir Kalinov, prevalence of cardiac valve regurgitation in patients with Sabina Zacharieva. Increased prevalence of subclinical hyperprolactinaemia. Int J Clin Pract 2008; 62: 1864-9.
cardiac valve fibrosis in patients with prolactinomas on Kars M, Delgado V, Holman ER, et al. Aortic valve cal- long-term bromocriptine and cabergoline treatment. Eur J cification and mild tricuspid regurgitation, but no clinical Endocrinol 2012; 167 (1): 17-25.

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