Successful Repair of Aortic and MitralIncompetence Induced by MethylsergideMaleate: Confirmation by IntraoperativeTransesophageal EchocardiographyThomas Joseph, D.O.,* Stanley K.C. Tam, M.D.,† Brinda R. Kamat, M.D.,‡and Judy R. Mangion, M.D.*

*Division of Cardiology, North Shore University Hospital, New York UniversitySchool of Medicine, Manhasset, New York; †Division of Cardiothoracic Surgery,and ‡Division of Pathology, Mount Auburn Hospital, Harvard Medical School,Cambridge, Massachusetts

Methylsergide maleate, an effective anti-migraine medication, has a well-documented associationwith left-sided cardiac valve dysfunction. Prior reports have described cardiac valve dysfunction inpatients using methylsergide chronically for a minimum of 6 years, with surgical intervention con-sisting of valve replacement for patients with intractable congestive heart failure. We report a 51-year-old woman who developed severe mitral and aortic valvular dysfunction after taking methylsergidemaleate for migraine headaches for a period of 19 months, and who subsequently underwent aorticand mitral valve repair with excellent short-term results. (ECHOCARDIOGRAPHY, Volume 20, April2003)

methylsergide maleate, ergotamine, aortic insufficiency, mitral insufficiency, valve repair

The patient is a 51-year-old white femalewith a past medical history significant for mi-graine headaches, hypercholesterolemia, obe-sity, and significant tobacco use who was ad-mitted to the hospital with increasing dyspneaon exertion, orthopnea, paroxysmal nocturnaldyspnea, and localized left-sided chest pain.One-year prior to admission, the patient un-derwent cardiac catheterization for workup ofatypical chest pain. This revealed insignificantplaquing of a diagonal branch, mid-left anteriordescending artery and the proximal right coro-nary artery with normal left ventricular ejec-tion fraction (61%) and trace mitral regurgita-tion. At that time of catheterization, physicalexamination was unremarkable including theabsence of murmurs.

Her medications on admission to the hospitalincluded methylsergide maleate (Sansert; No-vartis Pharmaceuticals, Basel, Switzerland) ata dose of 4 mg twice a day. The patient hadbeen taking this for her migraine headaches for

Address for correspondence and reprint requests: JudyMangion, M.D., Director of Echocardiography, Division ofCardiology, North Shore University Hospital, Manhasset,NY 11030. Fax: (516) 562-2352; E-mail: mangion@aol.com

19 months, with a regimen of stopping the med-ication for 1 month every 6 months to avoid po-tential side effects.

Vital signs included blood pressure of 110/70 mmHg and pulse of 86 beats per minute andregular. Physical examination revealed an over-weight female in significant respiratory dis-tress with significant jugular venous disten-sion, bilateral rales on lung examination, anda cardiac examination demonstrating a III/VIapical holosystolic murmur and II/VI diastolicmurmur heard at the left base. Electrocardio-gram revealed normal sinus rhythm with non-specific ST-T wave changes. Serial cardiac en-zymes were negative. Chest X ray revealed thepatient to be in florid congestive heart failure.

Initial transthoracic echocardiogram re-vealed markedly thickened mitral valve leafletsand subvalvular apparatus with severe wide-open mitral regurgitation. Both leaflets wererestricted in motion, however there was noevidence of mitral stenosis. The aortic valveleaflets and proximal aortic root were alsothickened with moderate to severe aortic in-sufficiency. There was no aortic stenosis, how-ever there was reverse doming of the aorticvalve leaflets at end systole. The tricuspid valve

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appeared thickened as well, with moderate tri-cuspid regurgitation. There was severe pul-monary hypertension with pulmonary arterysystolic pressure estimated to be 70 mmHg. Leftand right ventricular size and systolic func-tion were normal, with a calculated left ven-tricular ejection fraction of 63%, in absoluteterms, however, given the severity of mitral andaortic regurgitation, one would have expectedleft ventricular systolic function to be more hy-perdynamic. Transesophageal echocardiogramconfirmed severe diffuse thickening of the mi-tral, aortic, and tricuspid valves. There wereno calcifications noted. The mitral and tricus-pid subvalvular apparatus was also markedlythickened. Both the mitral and tricuspid valveannular sizes were within normal limits. Thepulmonic valve was normal with trace regurgi-tation present by color flow mapping. The pa-tient underwent right and left heart catheriza-tion that exhibited a central venous pressure of19 mmHg with pulmonary artery systolic pres-sure of 80 mmHg. Pulmonary capillary wedgepressure was 31 mmHg with V waves as highas 40 mmHg. Left ventricular ejection fractionby ventriculography was 60%. Left ventricularend-diastolic pressure was 23 mmHg with se-vere mitral regurgitation. Moderate to severeaortic insufficiency was confirmed by aortog-raphy. Selective coronary angiography demon-strated a dominant right coronary artery withmoderate to severe stenosis of its ostium. Thepatient was initially treated medically withdiuretics, afterload reduction, and digoxin forseveral days. Her symptoms and her chestX ray improved along with her right-sidedfilling pressures.

The patient was then taken to the operatingroom, where she underwent aortic valve and mi-tral valve repair with coronary artery bypassgrafting to the right coronary artery. Intraop-eratively, the aortic valve was noted to be onlymildly thickened, especially at the leading edge.The mitral valve was approached transseptally.Both the anterior and posterior leaflets of themitral valve were thickened significantly andrestricted in motion. The subvalvular appara-tus was also thickened and shortened, with fu-sion of chordae tendineae. Notably there wasno significant calcification. The middle scal-lop of the posterior leaflet of the mitral valvewas severely fibrotic and adherent to the sub-valvular apparatus. This restricted area ap-peared to be accounting for the severe mitralregurgitation as suggested by the intraopera-tive transesophageal echocardiogram. A stan-

dard quandrangular resection of the middlescallop of the posterior leaflet was performed.The posterior annulus of the mitral valve wasthen reinforced by a 26-mm Cosgrove annulo-plasty device (Baxter Healthcare, Deefield, IL,USA). The aortic valve was repaired by placingthree pledgeted horizontal mattress sutures of#4-0 prolene at the commissures. The patientalso underwent coronary artery bypass to theright coronary artery. Of note, on inspection,the thickening of the aortic valve extended intothe root of the aorta and appeared to involve theostium of the right coronary artery causing theostial stenosis. Following the repair, intraopera-tive transesophageal echocardiogram revealedthat the aortic insufficiency had changed frommoderate-severe to mild-moderate and the mi-tral valve regurgitation was changed from se-vere to mild (Figs. 1 and 2).

Pathologic evaluation of the resected por-tion of the posterior leaflet of the mitral valveand the subvalvular apparatus revealed thatgrossly it appeared to be thickened and re-stricted. This gross appearance is indistin-guishable from that observed in patients withchronic rheumatic valve disease. However, onhistologic study with trichrome stain, the re-sected portion of the mitral valve demonstratedthat the structure of the valve was intact. Therewas a thick fibrotic layer covering the leafletand there was no evidence of destruction ofthe underlying valve leaflet. No rheumatic le-sions were seen. Calcifications were not iden-tified. Findings were consistent with valvu-lar dysfunction caused by ergot alkaloids ormethylsergide maleate (Fig. 3).

Discussion

Methylsergide maleate is a semisynthetic er-got alkaloid ergometrine derivative, commonlyused as pharmacotherapy for migraine prophy-laxis, and is a specific serotonin (5HT2) re-ceptor antagonist as well as a serotonin ago-nist (5HT1). Since the early 1970s there havebeen well-documented associations between er-got alkaloid administration and cardiac valvedysfunction, mostly resulting in left-sidedvalvular incompetence. The incidence of left-sided valvular incompetence in patients takingmethylsergide is low, and has been reported tobe approximately 3.6% in those patients whoare on a continuous regimen.1 A study from theMayo Clinic suggested that the ergot-associatedvalvular disease only occurs in patients whohad taken the medication chronically over

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6 years.2 In this study of five patients whowere treated either with ergotamine suppos-itories or methylsergide tablets, the durationof treatment ranged between 6 and 20 years.All patients underwent either aortic, mitral ortricuspid valve replacements. Three of five ofthese patients exceeded recommended doses ofergot alkaloids (4 to 8 mg/day or 5 supposito-ries/week). Our patient is unique from this setof patients because she intermittently took theappropriate dose of 4 mg tablets twice a dayof methylsergide maleate over a relatively briefduration of 19 months with skips. This sug-gests that the pathologic process is not neces-sarily dose dependent. Rarely, isolated tricuspidand pulmonic valve disease has been reported.3Although there have been no published stud-ies in the echocardiography literature confirm-ing resolution of valvular dysfunction followingthe termination of ergot therapy, one clinicalstudy reported that as many as 57% of patientsmay completely or partially resolve their car-diac murmur after the drug has been stoppedfor approximately 20 to 40 months.1

Figure 1. A. Preoperative transesophageal echocardio-gram, mid-esophageal, four-chamber view of the mitralvalve in patient with methylsergide maleate induced valvu-lar dysfunction. Note the markedly thickened mitral valveleaflets characteristic of this disease (arrows). B. Preoper-ative transesophageal echocardiogram with color Dopplerdemonstrating severe wide-open mitral insufficiency(arrows). C. Post-pump intraoperative transesophagealechocardiogram, status post quadrangular resection of themiddle scallop of the posterior leaflet. Mitral insufficiency isnow mild to moderate. Blood pressure was 110/70 mmHg.

Since 1974, 11 patients have been reported toundergo surgical intervention.1−6 All patientsunderwent aortic and/or mitral valve replace-ments. Few patients in reported cases have alsohad proximal coronary artery involvement,3presumably secondary to the underlying fi-brotic process. The true natural history of ergot-induced valvular dysfunction is unknown. Ourpatient underwent valve repair, with the viewthat methylsergide maleate-induced valve dys-function will be reversible or at least will cease.The technique for the aortic valve repair is de-signed to enhance leaflet coaptation because thetissue thickening only involved the leading edgeof the valve leaflets. Our patient will continueto require close echocardiographic follow-up todocument any potential resolution or deteriora-tion of her valvular function.

Grossly, ergot alkaloid-induced valvular dys-function is indistinguishable from chronicrheumatic valve disease, except for lack ofcalcifications seen in the former.3 Histologi-cally the changes of the resected portion of themitral valve from our case were consistent with

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Figure 2. A. Preoperative transesopahageal echocardiogram, basal view at the level of the aortic valve. Note the mildlythickened aortic valve leaflets. The pathologic process in this patient was noted to extend into the ostium of the right coronaryartery (arrow). B. Magnified preoperative longitudinal transesophageal view of the aortic valve. Note the reverse systolicdoming of the aortic valve leaflets (arrow). C. Preoperative transesophageal echocardiogram of the aortic valve with colorDoppler demonstrating moderate to severe aortic insufficiency (arrow). D. Post-pump transesophageal echocardiogram, deeptransgastric view, status post aortic valve repair. With blood pressure of 110/70 mmHg. Aortic insufficiency is now mild.

Figure 3. Histologic study of resected portions of the mitral valve with trichrome stain. Findings were consistent with valvulardysfunction caused by methylsergide maleate. A. Fibrotic layer covering the mitral valve in low power (original magnification10×). B. High power illustration revealing the proliferative changes of the mitral valve, without evidence of destruction (originalmagnification 40×).

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previous findings of ergot alkaloid-inducedvalvular dysfunction, namely fibrotic thicken-ing on the surface of what appears to be normalvalve tissue. These lesions resemble lesions ofcarcinoid valve disease and suggest direct pro-liferative stimulation of fibroblast growth byserotonin agonist effects.6 This is in contrast tochronic rheumatic heart disease, where the un-derlying valve leaflet is disrupted, with fibrosis,neovascularization, and calcification.

In conclusion, we report a case of success-ful mitral and aortic valve repair as well ascoronary revascularization in a patient withmethylsergide-induced severe multivalvulardisease with extension to the proximal rightcoronary artery. Our patient will continue torequire careful echocardiography and clinicalfollow-up to confirm the long-term feasibility ofthis approach.

References

1. Bana DS, Mac Neal PS, LeCompte PM, et al: Car-diac murmurs and endocardial fibrosis associated withmethylsergide therapy. Am Heart J 1974;88:640–655.

2. Redfield MM, Nicholson WJ, Edwards WD, et al: Valvedisease associated with ergot alkaloid use: Echocar-diographic and pathologic correlations. Ann Int Med1992;117:50–52.

3. Redfield MM: Ergot alkaloid heart disease. In HurstJW (ed): New Types of Cardiovascular Diseases: Topicsin Clinical Cardiology. New York: Igaku-Shoin Medical,1994, pp 64–76.

4. Misch KA: Development of heart valve lesions duringmethylsergide therapy. Br Med J 1974;2:365–366.

5. Hendrikx M, van Dorpe J, Flameng W, et al: Aortic andmitral valve disease induced by ergotamine therapy formigraine: A case report and review of the literature.J Heart Valve Dis 1996;5:235–237.

6. Hauck AJ, Edwards WD, Danielson GK, et al: Mi-tral and aortic valve disease associated with ergo-tamine therapy for migraine. Arch Pathol Lab Med1990;114:62–64.

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