Valvular Heart Disease with the Use of Fenfluramine-Phentermine

Abstract

Exposure to the anorectic drug fenfluramine, alone or in combination with phentermine, a noradrenergic central nervous system stimulant, has been associated with unusual cardiac valvular morphology and resultant regurgitation of the left- and right-sided heart valves. The prevalence of significant valvular disease associated with the use of these anorectic drugs is reported to be as high as 23%. Herein, we report the occurrence of multivalvular disease and pulmonary hypertension associated with fenfluramine-phentermine use, discovered in an obese 59-year-old woman before expected gastric bypass surgery.

Use of the anorectic drug fenfluramine—alone or in combination with phentermine, a noradrenergic central nervous system stimulant—has been associated with unusual cardiac valve structure, resultant regurgitation of the valves on the left and right sides of the heart, and pulmonary hypertension (PH).¹ The prevalence of significant valvular heart disease associated with anorectic drug use has been reported to be as high as 23%.² Herein, we report the case of an obese woman with multivalvular disease and PH who had previously used fenfluramine-phentermine (fen-phen) for weight loss.

Case Report

A 59-year-old woman with a history of morbid obesity was referred for transthoracic echocardiography for evaluation of a heart murmur before expected gastric bypass surgery. She reported using fen-phen for approximately 6 months several years earlier. Her medical history included rheumatoid arthritis, obesity hypoventilation syndrome, obstructive sleep apnea, dyslipidemia, gastroesophageal reflux disease, and depression, but she had no history of rheumatic heart disease. Her medications included hydrochlorothiazide, oxybutynin, duloxetine, atorvastatin, zolpidem, and trazodone. She had a 30-pack-year smoking history. Her physical examination was remarkable for a soft systolic murmur at the apex and a diastolic murmur at the right upper sternal border, and her body mass index was 47.13 kg/m². Echocardiography revealed doming of the aortic valve (Fig. 1A) and restricted mitral valve leaflet motion (Fig. 1B), with mild-to-moderate aortic and mitral valve regurgitation (Figs. 1C and 1D). The tricuspid valve was also mildly thickened, with mild-to-moderate tricuspid valve regurgitation. Moderate PH was noted, with an estimated right ventricular systolic pressure of 51 mmHg and normal right ventricular function. The patient underwent gastric bypass surgery approximately 1 year after the initial echocardiography. During follow-up, her valvular heart disease remained stable and the PH resolved over 3 years.

Fig. 1 Echocardiography in parasternal long-axis view shows A) doming of the aortic valve (arrow) and B) restricted motion of the mitral valve leaflet (arrow). Color-flow Doppler echocardiography shows C) mild-to-moderate aortic valve regurgitation and D) mitral valve regurgitation (MR).

AO = aorta; LA = left atrium; LV = left ventricle

Discussion

Fen-phen use has been reported in association with valvular abnormalities, valvular regurgitation, and PH.¹ The echocardiographic features in patients using fen-phen have included decreased leaflet and cusp motility with thickened valve leaflets and shortening of the chordae tendineae, which impairs coaptation and results in valvular incompetence.² Similar echocardiographic findings can be seen in carcinoid heart disease, rheumatic valvular heart disease, and patients who have used pergolide or ergot derivates. Grossly, the affected valves have a glistening white appearance with diffusely and irregularly thickened leaflets and fused chordae.¹ Histologic examination of these valves shows adhesive plaques of proliferative myofibroblasts and intact valve architecture similar to that seen in malignant carcinoid syndrome.³ Withdrawal of fen-phen has been associated with improvement in valvular function in about half of patients with mitral and aortic valve regurgitation; only 4% to 5% of patients show disease progression.⁴ Brenot and colleagues⁵ postulated that fenfluramine may cause or accelerate the development of primary PH. However, most patients with fen-phen–induced PH have shown substantial clinical and hemodynamic improvement after discontinuation of the drug, as was observed in our patient, whose PH resolved over 3 years. The American Heart Association and American College of Cardiology Task Force has recommended cardiovascular examination for patients who have used anorectic drugs, and echocardiography for those with signs and symptoms of cardiovascular disease.⁶

Our case shows that patients with mild-to-moderate valvular heart disease who have used fen-phen can have a stable disease course after withdrawal of the drugs. It also shows that fen-phen–induced PH can resolve over time. From an imaging standpoint, our case underscores the importance of carefully evaluating valvular structures in patients who have used anorectic drugs (especially for more than 6 months), because severe valvular heart disease might have developed. Moreover, the presence of PH should also be evaluated, because it may require treatment in some patients.