Ann Thorac Surg 1999;68:1840-1841
© 1999 The Society of Thoracic Surgeons
Case Reports
Cardiac allograft valvulopathy: a case of donor-anorexigen-induced valvular disease
Ananth Prasad, MDa,
Mandeep Mehra, MDa,
Myung Park, MDa,
Robert Scott, MD, PhDa,
Patricia A. Uber, Pharm Da,
P. Michael McFadden, MDa
a Ochsner Cardiomyopathy and Heart Transplantation Center, Ochsner Medical Institutions, New Orleans, Louisiana, USA
Address reprint requests to Dr Mehra, Division of Cardiothoracic Surgery, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 70121;
e-mail: hrttpl{at}aol.com
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Abstract
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We report on the transplantation of a cardiac allograft from a donor with prolonged exposure to anorexigens. This event allowed us to not only examine the early pathological alterations that characterize anorexigen-induced valvular damage, but to also study the posttransplantation outcome after the donor heart had been removed from the offending milieu. A donor history of anorexigen use should be sought, and if detected, careful evaluation for underlying valvular disease should be entertained. Early valvulopathy may appear clinically mild yet pathologically significant. Our single-case experience also suggests that anorexigen-induced valvulopathy may be a progressive disorder despite removal of the heart from the causative environment.
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Introduction
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The anorexigens fenfluramine and phentermine (Fen-Phen) have been used as appetite suppressants since 1973 and 1959 respectively. An early investigation by Weintraub and colleagues [1] generated eagerness for the use of Fen-Phen in combination, but recent reports of pulmonary hypertension and valvular heart disease tempered enthusiasm for their clinical use [2–6]. The fervor against this anorexigen regimen was particularly compounded by the report by Connolly and associates [2] of 24 surgical cases of valvular heart disease associated with Fen-Phen which included three operative deaths. Since that seminal paper, several valvular heart disease case reports associated with anorectic agents have come to light [3–6]. The basic pathology of this entity bears striking similarity to the histological features of ergotamine and methysergide, or to valvular lesions found in disease states like carcinoid syndrome [7]. The central feature of all these pathological states relates to excess serotonin production and valvular exposure [2, 7]. Herein, we report on the transplantation of a cardiac allograft from a donor with prolonged exposure to anorexigens. This event allowed us to not only examine the early pathological alterations that characterize anorexigen-induced valvular damage, but to also study the posttransplantation outcome after the donor heart had been removed from the offending milieu.
A 35-year-old hypertensive woman was hospitalized for migraine headaches and seizures. A history of Fen-Phen use over the preceding 8 months (phentermine 30 mg/day and fenfluramine 60 mg/day) resulted in a 75-pound weight loss. Her other medications included oral contraceptives, prednisone, and verapamil. During her hospital course, she developed intracranial bleeding secondary to aneurysm rupture. She underwent surgical clipping of the aneurysm but suffered intracranial artery vasospasm, which lead to tentorial herniation and brain death. A transthoracic echocardiogram to assess transplant suitability revealed normal left and right ventricular size and function. There was nonspecific mitral-valve thickening with trivial mitral regurgitation and poor coaptation of mitral valve leaflets due to decreased posterior leaflet mobility. There was no evidence of any other valvular lesions. Her laboratory data and electrocardiogram were unremarkable.
The heart was harvested and examination of the donor heart during cardiac implantation revealed three discontinuous, pink-red, linear verrucous lesions measuring 1 x 2 x 2 mm, 10 x 2 x 2 mm, and 12 x 2 x 2 mm along the left atrial surface of the mitral valve annulus. A firm nodular 3 x 4 x 1 mm lesion of the annular endocardium was also present. The remainders of the heart structures, including the mitral valve leaflets and chordae tendineae, were normal. The lesions were surgically debrided to the level of endocardial surface (Fig 1). Transplantation of the heart was uneventful and an intraoperative transesophageal echocardiogram, performed after weaning from cardiopulmonary bypass, revealed trivial mitral regurgitation with excellent allograft contractility. The postoperative course was uneventful and discharge from the hospital occurred on the eighth postoperative day.
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Fig 1. Appearance of the mitral valvular apparatus during heart transplantation revealed three discontinuous, pink-red, linear verrucous lesions measuring 1 x 2 x 2 mm, 10 x 2 x 2 mm and 12 x 2 x 2 mm along the left atrial surface of the mitral valve annulus. A fourth firm nodular 3 x 4 x 1 mm lesion of the annular endocardium was also present.
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Histologic examination of the specimens revealed a glistening appearance with proliferating myofibroblasts and associated fibrinous vegetation. There was no evidence of acute or chronic inflammation. Gram stain did not reveal any bacterial or fungal elements.
A transthoracic echocardiogram 6 weeks posttransplant revealed only trivial mitral regurgitation with improved mobility of the posterior leaflet of the mitral valve. Hemodynamic data demonstrated normal allograft function. However, after 6 months of follow-up, Doppler echocardiography revealed worsening of mitral regurgitation to moderate severity, but no adverse effects of this hemodynamic load were noted and the patient has remained stable.
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Comment
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Fenfluramine is a sympathomimetic amine that has anorectic action mediated through the serotonergic pathways of the brain. When used in combination with phentermine at lower doses, it was demonstrated to be as effective as either alone, but with fewer side effects and improved patient tolerance [1]. The adverse influence of prolonged exposure to this combination of Fen-Phen was aptly demonstrated by Connolly and associates by the discovery of valve encasement with glistening white material, which on microscopy showed proliferating myofibroblasts [2]. In this series, 5 patients demonstrated moderate to severe mitral regurgitation by echocardiography and underwent valve replacement or repair. Three patients had plaques on the leaflets and 2 patients had a thickened glistening mitral valve. This visual and histological finding was similar to the cardiac allograft valvulopathy in our case. It was striking that routine transthoracic echocardiography estimated the valvular pathology as "mild," and thus underestimated the true pathological extent of valvular disease which was noted at surgery.
This case represents a case of heart transplantation with prior prolonged exposure to anorexigens. The lesions that we observed demonstrated a classical "stuck-on" appearance as described in the earlier reports [2]. In contradistinction to earlier reports, we observed no involvement of the chordal apparatus. It is therefore conceivable that the pathological changes within the valve leaflets and annulus represent the earliest sites of anorexigen-induced valvulopathy. This opportunity, to visually and histopathologically observe a case of "early" valvulopathy, offers insight into the pathogenesis and may be helpful in staging the lesions temporally.
This case allowed us to study the early clinicopathological correlation of anorexigen-induced valvulopathy and to explore the elements of reversibility of this important and rampant pathological entity. It has been previously suggested that valvular regurgitation can subside once the anorectic agents are discontinued [8]. However, in our case, despite removal of the heart from the offending milieu and surgical debridement of the endocardial plaques, the disorder continued to be progressive, as evidenced by worsening mitral regurgitation on follow-up echocardiography. The anorexigen-induced valvular architecture disturbance predisposes the donor heart to endocarditis; therefore antibiotic prophylaxis must be strictly implemented when invasive intervention is contemplated in the transplant recipient.
In conclusion, a donor history of anorexigen use should be sought, and if it is detected, careful evaluation for underlying valvular disease should be entertained. Early valvulopathy may appear clinically mild yet pathologically significant. Our single-case experience also suggests that anorexigen-induced valvulopathy may be a progressive disorder despite removal of the heart from the causative environment.
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References
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Weintraub M., Hasday J.D., Mushlin A.I., Lockwood D.H. A double blind clinical trial in weight control; use of fenfluramine and phentermine alone and in combination. Arch Intern Med 1984;144:1143-1148.[Abstract]
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Connolly H.M., Crary J.L., McGoon M.D., et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581-588.[Abstract/Free Full Text]
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SoRelle R. Fen-Phen and risk of valvular heart disease. Circulation 1997;96:1705-1706.
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Jick H., Vasilakis C., Weinrauch L.A., Meier C.R., Jick S.S., Derby L.E. A population-based study of appetite suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med 1998;339:719-724.[Abstract/Free Full Text]
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Khan M.A., Herzog C.A., St Peter J.V., et al. The prevalence of cardiac valvular insufficiency assessed by trans thoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998;339:713-718.[Abstract/Free Full Text]
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Weissman N.J., Tighe J.F., Gottdiener J.S., Gwynne J.T. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. N Engl J Med 1998;339:725-732.[Abstract/Free Full Text]
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Robiolio P.A., Rigolin V.H., Wilson J.S., et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echo-cardiography. Circulation 1995;92:790-795.[Abstract/Free Full Text]
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Cannistra L.B., Cannistra A.J. Regression of multivalvular regurgitation after cessation of fenfluramine and phentermine treatment. N Engl J Med 1998;339:771.[Free Full Text]
Accepted for publication March 31, 1999.
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Abstract
Introduction
