ArticlesHistologic Changes in Three Explanted Native Cardiac Valves Following Use of Fenfluramines
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Background
Administration of fenfluramines, either alone or co-administered with phentermine (the combination popularized as “fen-phen”) rose sharply in the mid-1990s due to the perceived promise these agents held for controlled and sustained weight loss in patients with morbid obesity. Use of fen-phen, or of fenfluramines alone, was subsequently associated with the development of clinically significant cardiac valve disease. Affected patients characteristically develop valvular regurgitation, sometimes
Design, Materials, and Methods
We studied the macroscopic and histologic findings in native cardiac valves explanted from three patients with valvular disease clinically attributed to dexfenfluramine or fenfluramine-phentermine use. Surgical pathology files were searched to locate mitral valve tissue from three additional patients of similar demographic characteristics (women, age 26–45) with clinically identified postinflammatory mitral valve disease—two with mitral regurgitation and one with mitral stenosis were studied in
Case 1
A 37-year-old woman presented 10 months following initiation of dexfenfluramine use (15 mg po bid) with a 6-month history of progressive dyspnea (shortness of breath with minimal exertion), fatigue, and chest tightness. Prior medical history in addition to morbid obesity included hypothyroidism, treated with levothyroxine (0.125 mg po qd), and a hiatal hernia with gastroesophageal reflux, treated with omeprazole (10 mg po qd). Additional medications included enalopril (5 mg po qd) and “baby”
Pathologic Findings
Macroscopically, the resected mitral valve anterior leaflet from Patient 1 was irregularly thickened, with opaque, glistening white nodules and plaques surrounding the junction of the leaflet with groups of fused chordae tendineae (Figure 1A). White nodular plaques were concentrated along the free edge and extended onto the leaflet surfaces, but spared the most proximal (annular) portion of the leaflet, which was translucent and minimally thickened. The anterior leaflet from Patient 2 was
Discussion
Fenfluramine and phentermine were individually approved by the Food and Drug Administration (FDA) as anorexigenic agents for the treatment of morbid obesity in 1973 and 1959 respectively. Dexfenfluramine was FDA-approved as monotherapy in 1996, promising greater specificity for the central serotoninergic system and advantageous peripheral effects contributory to weight loss. The use of fenfluramine-phentermine (fen-phen) combination therapy, although not explicitly approved by the FDA,
Acknowledgements
Part of this material was presented at the United States and Canadian Academy of Pathology 88th Annual Meeting, San Francisco, California, March 1999. The authors thank Peter J. Kragel, MD, Chairman, Department of Pathology and Laboratory Medicine, East Carolina University School of Medicine, for his support of this project.
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2021, Annales d'EndocrinologieCitation Excerpt :It was previously found that the use of the anorexigenic agents such as fenfluramine and phentermine was a significant risk factor for the development of cardiac valvulopathy [6,7]. Histological examination of the valves of affected patients showed that there were changes similar to those seen in carcinoid heart disease, or in ergot alkaloid drug induced valvulopathy [8,9]. Macroscopically, there was irregular leaflet thickening with plaque-like deposits and nodules.
The Thickened Valve
2020, JACC: Case ReportsNative Cardiac Valve Pathology
2012, Surgical Pathology ClinicsCitation Excerpt :There is still some debate as to the actual risk and incidence of the valvulopathy associated with anorexogenic agents, but it is probably low.41 Grossly and microscopically the valve disease or valvulopathy associated with anorexogenic drugs has been reported to be similar morphologically to that of carcinoid valve disease.40,42 The left sided valves are predominantly affected.
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2008, Practice of Clinical Echocardiography, Thrid EditionValvular Heart Disease Associated With Fenfluramine Detected 7 Years After Discontinuation of Treatment
2007, Annals of Thoracic SurgeryCitation Excerpt :The consequences of a retracted, reorganized, and fibrous mitral subvalvular apparatus (ie, valves that remain relatively flexible and noncalcified and are essentially regurgitating) are suggestive of valvular heart disease associated with fenfluramine [6, 7]. The macroscopic appearance corresponds to that reported in valvular heart disease associated with fenfluramine [6–8] with a typical proliferative appearance of the myofibroblasts during the acute intoxication phase. This typical proliferation was observed in our patient, but to a lesser degree, probably due to the longer interval after discontinuation of treatment.