Ann Thorac Surg 2007;83:1541-1543
© 2007 The Society of Thoracic Surgeons
Case Reports
Valvular Heart Disease Associated With Fenfluramine Detected 7 Years After Discontinuation of Treatment
Guillaume Greffe, MDa,
Lara Chalabreysse, MDb,
Carine Mouly-Bertin, MDc,
Pierre Lantelme, MD, PhDd,
Françoise Thivolet, MDb,
Gilles Aulagner, MDc,
Jean-François Obadia, MD, PhDa,*
a Department of Cardiothoracic Surgery, Louis Pradel Hospital, Lyon, France
b Department of Cytopathology, Louis Pradel Hospital, Lyon, France
c Department of Pharmacy, Louis Pradel Hospital, Lyon, France
d Department of Cardiology, Croix-Rousse Hospital, Lyon, France
Accepted for publication November 9, 2006.
* Address correspondence to Dr Obadia, Hôpital Cardiothoracique Louis Pradel, 28 Avenue du Doyen Lépine, Lyon-Bron, 69677 France (Email: jf.o{at}chu-lyon.fr).
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Abstract
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We report the case of a patient referred to us for mitral and aortic valvular disease with a rheumatic appearance. The unusual macroscopic appearance on valve resection was not compatible with a rheumatic cause. A detailed review of this patient’s clinical history (ie, a history of treatment with fenfluramine) suggested an iatrogenic cause, which was confirmed by histology. For the first time, a case of valvular heart disease that deteriorated was discovered 7 years after treatment with fenfluramine, whereas this iatrogenic disease classically resolves after discontinuation of treatment. This case illustrates the need for continuing heart valve surveillance of patients who have used these anorectics.
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Introduction
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Fenfluramine, a serotonergic anorectic, was marketed in 1973 and then later withdrawn from the market on September 15, 1997 due to the risk of development of primary pulmonary hypertension or valvular heart disease. The authors report the first case of fenfluramine-associated valvular heart disease discovered 7 years after discontinuation of treatment and requiring double valve replacement 2 years later.
A 39-year-old woman was hospitalized for management of pneumonia. A systolodiastolic murmur detected at the age of 25 years was re-evaluated. She reported increasing breathlessness on exertion over the previous 2 years. Echocardiography showed grade III mitral incompetence (surface = 1.5 cm2) and grade II/III aortic incompetence with retractile lesions and a rheumatic appearance. These findings were confirmed by cardiac catheterization. This patient did not present any risk factors or any history of rheumatic disease.
Therefore the patient was operated on for a double mechanical valve replacement. The macroscopic appearance was very unusual, with a pearly white and retractile appearance of the mitral and aortic cusps (Figs 1, 2),
with no commissural symphysis or calcification. The mitral subvalvular apparatus was thickened and retractile.
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Fig 1. Macroscopic appearance: two thickened and fibrous aortic cusps with a pearly appearance without symphysis or calcifications.
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Fig 2. Macroscopic appearance: anterior leaflet of the mitral valve with thickened and retractile insertion of the chordae tendineae.
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A detailed review of this patient’s clinical history revealed anorexia nervosa after a first pregnancy at the age of 19 (106 kg postpartum). No heart murmur was detected at that time. She then started intermittent treatment with serotoninergic anorectics for a period of 10 years (with a complete first year and then 2 months per year for a cumulative total of 34 months of fenfluramine [60 mg/day] and 3 months of dexfenfluramine [45 mg/day]). The patient’s murmur was discovered at the age of 25 years (ie, 6 years after she was started on anorectics) by an occupational health physician, and the patient remained moderate during a second pregnancy without any problems at the age of 27 years.
Histologic examination did not show any vessels with thickened walls as observed in rheumatic lesions. The aortic valve was thickened with proliferation of spindle-shaped cells (Fig 3), corresponding to myofibroblasts expressing smooth muscle 
-actin (Fig 4). The valve surface was intact with no vegetations and no signs of myxoid degeneration or calcification.
Overall, the clinical history, the macroscopic appearance, and the histology indicated a diagnosis of fenfluramine-induced valvular heart disease.
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Comment
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Epidemiology
An estimated 70 million patients worldwide took fenfluramine between 1973 and 1997. In 1996, the total number of prescriptions of fenfluramine in the United States exceeded 18 million [1].
In industrialized countries, it has been estimated that almost 1 in 1,200 inhabitants has consumed fenfluramine for at least 3 months. The incidences of valvular heart diseases are fivefold higher when the duration of treatments exceeds 4 months [2], which was the case with our patient who took treatments for 37 months. The risks of fenfluramine were defined in 1997 as 1 of 25,000 for the development of pulmonary hypertension (20% of all cases of primary pulmonary hypertension) with disabling respiratory consequences. The risk of valvular heart disease is 20% with fenfluramine and 12.5% with dexfenfluramine, but with only minor consequences rarely leading to valve replacement. A meta-analysis concerning 1,279 patients in 2002 revealed 18% of aortic incompetence (risk ratio [RR], 2.32) and 5% of mitral incompetence (RR, 1.55) [3], essentially consisting of moderate regurgitation requiring surgery in only 9% of cases. Echocardiographic follow-up after discontinuation of fenfluramine showed stabilization or even improvement of the severity of regurgitation [4], whereas in our case the murmur and the symptoms appeared a long time after stopping treatment (Fig 5). There is a published case [5] describing a heart transplant recipient in whom the donor had taken fenfluramine. The transplant recipient had never taken any anorectics, but his pre-existing valvular heart disease nevertheless deteriorated after transplantation.
Echocardiographic Appearance
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].
Histopathologic Appearance
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. Fenfluramine appears to activate myofibroblast proliferation through a 5HT-2B receptor, which could be perpetuated by endogenous serotonin [9].
Public Health
Prophylaxis of bacterial endocarditis in patients who have taken oral anorectics is recommended [10].
In conclusion, this case suggests that severe regurgitating valvular heart disease associated with fenfluramine can occur late. This case may be exceptional as it occurred after taking high doses of anorectics for a long time. However, in view of the number of exposed patients, increased health surveillance should be recommended to more clearly determine this risk.
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References
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- Langreth R. Critics claim diet clinics misuse obesity drugs Wall Street Journal 1997:B8March 31.
- Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. 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]
- Loke YK, Derry S, Pritchard-Copley A. Appetite suppressants and valvular heart disease—a systematic review BMC Clin Pharmacol 2002;2:6.[Medline]
- Mast ST, Jollis JG, Ryan T, Anstrom KJ, Crary JL. The progression of fenfluramine-associated valvular heart disease assessed by echocardiography Ann Intern Med 2001;134:261-266.[Abstract/Free Full Text]
- Prasad A, Mehra M, Park M, Scott R, Uber PA, McFadden PM. Cardiac allograft valvulopathy: a case of donor-anorexigen-induced valvular disease Ann Thorac Surg 2001;71:397.[Medline]
- Caccitolo JA, Connolly HM, Rubenson DS, Orszulak TA, Schaff HV. Operation for anorexigen-associated valvular heart disease JTCS 2001;122:656-664.
- Connolly HM, Crary JL, McGoon, MD. Valvular heart disease associated with fenfluramine-phentermine N Engl J Med 1997;337:581-588.[Abstract/Free Full Text]
- Steffee CH, Singh HK, Chitwood WR. Histologic changes in three explanted native cardiac valves following use of fenfluramines Cardiovasc Pathol 1999;8:245-253.[Medline]
- Volmar KE, Hutchins GM. Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents Arch Pathol Lab Med 2001;125:1555-1561.[Medline]
- Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U. S. Department of Health and Human Services interim public health recommendations, November 1997 MMWR Morb Mortal Wkly Rep 1997;46:1061-1066.[Medline]
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Abstract
Introduction
