Elsevier

Cardiovascular Pathology

Volume 8, Issue 5, September–October 1999, Pages 245-253
Cardiovascular Pathology

Articles
Histologic Changes in Three Explanted Native Cardiac Valves Following Use of Fenfluramines

https://doi.org/10.1016/S1054-8807(99)00019-8Get rights and content

Abstract

Use of fenfluramines, either alone or co-administered with phentermine (“fen-phen”) as anorexic agents in obesity, has been associated with the development of clinically significant cardiac valve disease. We present the macroscopic and histologic findings in cardiac valves explanted from three patients who presented with valvular disease after fenfluramine or fenfluramine-phentermine use and underwent single valve replacement surgery. Paraffin sections were prepared with hematoxylin and eosin, trichrome, elastic–van Gieson, and Giemsa stains, as well as immunostains using antibody to CD3 and CD20. All three patients (two females, ages 37 and 43, and a 49-year-old male) developed progressively symptomatic mitral (2 patients) or aortic (1 patient) valvular insufficiency following dexfenfluramine (2 patients) or fenfluramine-phentermine (1 patient) use. Macroscopic changes included irregular leaflet thickening, accompanied by chordal fusion in the mitral valves, but without vegetations, commissural fusion, or evidence of annular dilation. Histologically, fibromyxoid plaques and nodules just below the valve surface, superficial to a generally intact elastic fiber layer, were associated with CD3-positive lymphocytes. Valves from all three patients had central myxoid degenerative changes, which were focal/mild in one mitral valve, diffuse/moderate in one mitral valve, and diffuse/marked in one aortic valve. Focal areas of superficial fibromyxoid change or intimal thickening may also be seen in cardiac valves from patients with drug-unrelated processes leading to symptomatic or asymptomatic valvulopathy. Therefore, when valve tissue is available for histopathologic examination, valvular disease can be attributed to use of fenfluramines only if the following criteria are satisfied: (i) the macroscopic and microscopic features are consistent with fenfluramine-related valvulopathy, (ii) clinical, echocardiographic, and intraoperative findings support the diagnosis, and (iii) the history of drug exposure predates the development or exacerbation of valvular dysfunction.

Section snippets

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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