- Email: [email protected]
Valve replacement for appetite suppressant–induced valvular heart disease
CURRENT REVIEW
Valve Replacement for Appetite Suppressant–Induced Valvular Heart Disease Shankha S. Biswas, MD, Carolyn L. Donovan, MD, Joseph M. Forbess, MD, Stephen H. Royal, MD, and Kevin P. Landolfo, MD Divisions of Thoracic and Cardiovascular Surgery and Cardiology, Duke University Medical Center, Durham, North Carolina
Valvular heart disease associated with the use of appetite-suppressant medication is a recently described clinical entity. Although the mechanism of valvular injury remains elusive pathologically, the valvular abnormalities resemble those observed in carcinoid syndrome. The incidence of clinically evident valvular heart disease is low with short-term (less than 3 months) exposure to appetite-suppressant drugs. Prolonged exposure to
higher doses in addition to combination drug therapy confers an excess risk for valvular pathologic changes. We report the case of a patient with severe mitral regurgitation who had short-term exposure (3 weeks) to the combination of fenfluramine (20 mg) and phenteramine (15 mg). (Ann Thorac Surg 1999;67:1819 –22) © 1999 by The Society of Thoracic Surgeons
A
Case Report
ppetite-suppressant medications have long been a standard therapy for obesity. Phentermine hydrochloride was approved for use in 1959 as a single-agent appetite suppressant for short-term use. Fenfluramine hydrochloride was approved in 1973. Dexfenfluramine, the dextrorotatory isomer of fenfluramine, is an agent that was approved in 1996 for 1-year treatment in markedly obese patients [1]. Both dexfenfluramine and fenfluramine act by releasing serotonin and inhibiting its uptake. Although each drug was approved for singleagent use only, fenfluramine-phentermine (“fen-phen”) gained popularity as combination therapy in 1992 because of its synergistic efficacy, fewer side effects, and improved patient tolerance. The Centers for Disease Control estimated that up to 4.7 million Americans had taken the “fen-phen” combination [2, 3]. The use of appetite-suppressant medication declined abruptly in 1997 after the publication of a study [3] suggesting the association of serious valvular heart disease resulting from these medications. Connolly and co-workers [3] reported a landmark series of 24 patients in whom valvular heart disease had developed in conjunction with combination fenfluramine and phentermine use, 5 of whom required surgical intervention. The US Department of Health and Human Services [2] identified a series of 113 patients with cardiac valvular heart disease related to use of fenfluramine or dexfenfluramine. Among these 113 patients, 27 required cardiac valve replacement. The potential severity of this valvular pathologic response prompted withdrawal of dexfenfluramine and fenfluramine from the market on September 15, 1997 [4]. In our patient, severe mitral regurgitation developed after short-term exposure to and low doses of fenfluramine-phentermine.
Address reprint requests to Dr Landolfo, Division of Thoracic and Cardiovascular Surgery, Duke University Medical Center, Box 3857, Durham, NC 27710; e-mail: [email protected].
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
A 32-year-old white woman with no history of heart problems was prescribed appetite-suppressant medication in 1996 for obesity. The drug regimen combined fenfluramine, 20 mg, and phentermine, 15 mg, daily for 3 weeks. From 1996 to early 1998, she remained asymptomatic. In the postpartum period after the delivery of twins in May 1998, dyspnea developed. Workup included a transesophageal echocardiogram, which demonstrated severe mitral regurgitation with thickened mitral leaflets. She was also found to have moderate tricuspid regurgitation, left atrial enlargement, and normal left ventricular function with an ejection fraction of 0.60. The congestive heart failure was treated medically early with diuretics, digitalis, and vasodilators. Right heart catheterization showed a pulmonary artery pressure of 33/13 mm Hg and a mean pulmonary capillary wedge pressure of 11 mm Hg with V waves to 17 mm Hg. Left ventriculography demonstrated an ejection fraction of 0.55 with 3-41 mitral regurgitation. Coronary arteries were normal. In June 1998, the patient was referred to Duke University Medical Center for evaluation. Transesophageal echocardiography revealed marked dilatation of the mitral annulus with severe mitral regurgitation. The mitral valve leaflets were mildly thickened with moderate restriction of the posterior leaflet and mild anterior leaflet restriction but no stenosis (Fig 1). There was mild dilatation of the tricuspid valve annulus with mild regurgitation. Mild to moderate aortic insufficiency was also present. The left ventricle was dilated with preserved function. On June 17, 1998, the patient underwent mitral valve replacement with a 29-mm St. Jude Medical prosthesis. Gross inspection of the valve revealed two glistening white leaflets with focal thickening and minimal calcification. Microscopic evaluation revealed leaflet thickening and chordal encasement by fibroproliferative surface 0003-4975/99/$20.00 PII S0003-4975(99)00328-8
1820
REVIEW BISWAS ET AL APPETITE SUPPRESSANT–INDUCED VALVULOPATHY
Ann Thorac Surg 1999;67:1819 –22
Fig 1. Transesophageal echocardiogram demonstrating (A) marked mitral annulus dilatation with moderate restriction of the posterior mitral valve leaflet and (B) resultant severe mitral regurgitation. (AMVL 5 anterior mitral valve leaflet; LA 5 left atrium; LV 5 left ventricle; PMVL 5 posterior mitral valve leaflet.)
lesions. In some areas, there was cellular proliferation within a rich myxoid matrix as well as hypocellular surface lesions with a dense fibroelastic extracellular matrix. There was minimal neovascularization, and neither calcification nor inflammatory infiltrates were identified (Fig 2). Given the patient’s prior exposure to the
fenfluramine-phentermine combination, intraoperative findings, and histologic evaluation, the final pathologic diagnosis was consistent with valve disease caused by “fen-phen” exposure. Postoperatively, the patient had an unremarkable course with resolution of symptoms.
Comment
Fig 2. Low-power magnification of the mitral valve demonstrating leaflet thickening and chordal encasement (dark red) by fibroproliferative surface lesions. (Lawson elastic–van Gieson; 34 before % reduction.)
Recent reports [2, 3] of appetite suppressant–induced cardiac valvulopathy have generated concern about the prevalence and mechanism of these disorders. Both fenfluramine and dexfenfluramine have mechanisms of action related to serotonin release. Fenfluramine promotes the rapid release of serotonin and inhibits its uptake in the ventromedial nucleus of the hypothalamus [5]. Both of these medications may have receptor-agonist activity [6]. Prolonged exposure to combination therapy with fenfluramine and phentermine has been shown to increase neuronal serotonin levels [1]. The reported incidence of mitral valve disease associated with use of appetite suppressants is less than that of aortic valve disease. Three recently published studies [4, 7, 8] used transthoracic echocardiography to evaluate valvular heart disease in patients with prior fenflura-
Ann Thorac Surg 1999;67:1819 –22
mine, dexfenfluramine, or phentermine use. Weissman and co-workers [4] prospectively identified 1,072 obese patients who were randomly assigned to dexfenfluramine (n 5 366), sustained-release dexfenfluramine (n 5 352), or placebo (n 5 354). The average duration of appetite-suppressant use was 71 days. Transthoracic echocardiography was performed within a median duration of 1 month after discontinuation of treatment. Mitral regurgitation of moderate severity occurred in 1.7%, 1.8%, 1.8%, and 1.2% of patients in the dexfenfluramine group, the sustained-release dexfenfluramine group, the two active-treatment groups combined, and the placebo group, respectively. Aortic regurgitation of mild or greater severity occurred in 5.0%, 5.8%, 5.4%, and 3.6% of patients in the treatment groups, respectively [4]. Jick and colleagues [7] reported 11 cases of valvular disease diagnosed by transthoracic echocardiography among 2,371 patients who received fenfluramine and 862 patients who received phentermine. Of the 11 patients, 2 had mitral regurgitation, 6 had aortic regurgitation, and 3 had both aortic and mitral regurgitation. None of these patients underwent valve operations. Khan and associates [8] examined the prevalence of valvular heart disease among patients adhering to three different appetite-suppressant drug regimens and compared the results with those in a control group of agematched obese subjects who had never taken these medications. The prevalence of valvular regurgitation meeting the Food and Drug Administration definition (greater than mild aortic regurgitation and greater than moderate mitral regurgitation) was higher in patients with a history of appetite-suppressant drug use (1.3% in the control group, 13% in the dexfenfluramine group, 23% in the dexfenfluramine-phentermine group, and 25% in the “fen-phen” group). The valvular disease in the patient described here warrants attention in that the duration of medical treatment was relatively short and the dosages administered were half of the standard treatment. Furthermore, although patients who manifest valvular heart disease typically have development of symptoms within months of exposure, symptoms occurred in this patient 2 years after discontinuation of the medications, which later led to mitral valve replacement. In the original case series of 24 patients from the Mayo Clinic [3], the mean exposure to “fen-phen” averaged 12 months. The median duration of exposure reported in the 1997 FDA series [2] was 9 months (range, 1 to 39 months). The case-control study by Jick and associates [7] suggested that valvulopathy associated with less than 3 months’ exposure to appetitesuppressant drug use occurs infrequently. Several hypotheses have been proposed to explain the mechanism of appetite suppressant drug–related valvular heart disease. Recent epidemiologic studies [9 –11] have determined that obesity alone is not the cause of the observed valvular regurgitation. The fibrotic endocardial changes seen in the surgical specimens of these patients are identical to those observed in ergotamine-induced and carcinoid valve disease [12]. The “serotonin hypothesis” has evolved to explain the mechanism of appetite
REVIEW BISWAS ET AL APPETITE SUPPRESSANT–INDUCED VALVULOPATHY
1821
suppressant drug–related heart disease. Both dexfenfluramine and fenfluramine are known to inhibit uptake of serotonin as well as to promote its release in the brain. Phentermine interference with serotonin clearance in the lungs has been postulated as a mechanism for the development of primary pulmonary hypertension [13]. Classically, the valvular lesions associated with malignant carcinoid syndrome and high levels of circulating serotonin are characterized by fibroplasia mostly involving the tricuspid and pulmonary (right-sided) valves [14, 15]. Left-sided valvular lesions would require a source of serotonin distal to the pulmonary circulation. Platelet granules have the largest supply of serotonin in plasma and have been the postulated source of serotonin release by appetite-suppressant medications [16]. This released serotonin would be rapidly metabolized and excreted, which may account for the normal and reduced blood serotonin levels in patients on a regimen of fenfluramine and phentermine [17]. High shear forces imposed on platelets against valve endothelium may enhance local release of serotonin on the surface of the valve [18]. Accordingly, quiescent fibroblasts within the valve leaflet may be induced to proliferate and migrate across the valve endothelium and secrete an extracellular matrix to consolidate the plaquelike lesion [1]. However, these theories remain speculative because of the lack of prospective data in experimental models of appetite suppressant–induced valve disease. Recommendations are being developed for patients with a history of appetite-suppressant treatment. Patients with a heart murmur or symptoms suggestive of valvular disease or those with greater than 3 months’ or high-dose exposure should undergo transthoracic echocardiography. The case of our patient suggests that patients with a history of short-term and low-dose usage of these medications may also be at risk for valvular disease. Consideration should be given to early echocardiography. Other recommendations include prophylaxis against endocarditis for patients with a heart murmur, “silent” moderate or severe regurgitation on echocardiogram, and mild regurgitation associated with defined structural valvular lesions [19]. We thank William H. Edwards, MD, of Rochester, MN, for his expert analysis of the pathology in this patient.
References 1. Wong J, Reddy SSK, Klein AL. Anorectic drugs and valvular heart disease: a biologic and clinical perspective. Cleve Clin J Med 1998;65:35– 41. 2. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services interim public health recommendations, November 1997. JAMA 1997;278:1729–31. 3. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581– 8. 4. Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine,
1822
5. 6. 7.
8.
9. 10.
11.
REVIEW BISWAS ET AL APPETITE SUPPRESSANT–INDUCED VALVULOPATHY
or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med 1998;339:725–32. Pinder RM, Brogden RN, Sawyer PR, Speight TM, Avery GS. Fenfluramine: a review of the pharmacological properties and therapeutic efficacy in obesity. Drugs 1975;10:241–323. Mitchell P, Smythe G. Hormonal responses to fenfluramine in depressed and control subjects. J Affective Disord 1990;19: 43–51. 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;339:719–24. Khan MA, Herzog CA, St. Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetitesuppressant drugs. N Engl J Med 1998;339:713– 8. Singh JP, Evans JC, Levy D, et al. Prevalence of valvular regurgitation in a population-based cohort. Circulation 1997; 96(Suppl 1):541. Lebowitz NE, Bella JN, Roman MJ, et al. Prevalence and correlates of aortic regurgitation in American Indians: the Strong Heart Study [Abstract]. J Am Soc Echocardiogr 1998; 11:559. Jones EC, Devereux RB, Roman MJ, et al. Prevalence and correlates of mitral regurgitation in the general population: the Strong Heart Study [Abstract]. J Am Soc Echocardiogr 1998;11:500.
Ann Thorac Surg 1999;67:1819 –22
12. Redfield MM, Nicholson WJ, Edwards WD, Tajik AJ. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med 1992; 117:50–2. 13. Morita T, Mehendale H. Effects of chlorphenterimine and phenterimine on the pulmonary disposition of 5-hydroxytryptamine in the rat in vivo. Am Rev Respir Dis 1983;127: 747–50. 14. Thorson AH. Endocardial sclerosis and other heart lesions in the carcinoid disease. Acta Med Scand [Suppl] 1958;334:99 – 119. 15. Robiolio PA, Rioglin VH, Wilson JS, et al. Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995;92:790–5. 16. Robertson JI. Serotonergic type-2 (5-HT2) antagonists: a novel class of cardiovascular drugs. J Cardiovasc Pharmacol 1991;17(Suppl 5):S48 –53. 17. Redmon B, Raatz S, Bantle JP. Valvular heart disease associated with fenfluramine-phentermine [Letter]. N Engl J Med 1997;337:1773– 4. 18. Chesebro JH, Lam JY, Badimon L, Fuster V. Restenosis after arterial angioplasty: a hemorrheologic response to injury. Am J Cardiol 1987;60:10B– 6B. 19. Devereux RB. Appetite suppressants and valvular heart disease. N Engl J Med 1998;339:765–7.
Valve Replacement for Appetite Suppressant–Induced Valvular Heart Disease Shankha S. Biswas, MD, Carolyn L. Donovan, MD, Joseph M. Forbess, MD, Stephen H. Royal, MD, and Kevin P. Landolfo, MD Divisions of Thoracic and Cardiovascular Surgery and Cardiology, Duke University Medical Center, Durham, North Carolina
Valvular heart disease associated with the use of appetite-suppressant medication is a recently described clinical entity. Although the mechanism of valvular injury remains elusive pathologically, the valvular abnormalities resemble those observed in carcinoid syndrome. The incidence of clinically evident valvular heart disease is low with short-term (less than 3 months) exposure to appetite-suppressant drugs. Prolonged exposure to
higher doses in addition to combination drug therapy confers an excess risk for valvular pathologic changes. We report the case of a patient with severe mitral regurgitation who had short-term exposure (3 weeks) to the combination of fenfluramine (20 mg) and phenteramine (15 mg). (Ann Thorac Surg 1999;67:1819 –22) © 1999 by The Society of Thoracic Surgeons
A
Case Report
ppetite-suppressant medications have long been a standard therapy for obesity. Phentermine hydrochloride was approved for use in 1959 as a single-agent appetite suppressant for short-term use. Fenfluramine hydrochloride was approved in 1973. Dexfenfluramine, the dextrorotatory isomer of fenfluramine, is an agent that was approved in 1996 for 1-year treatment in markedly obese patients [1]. Both dexfenfluramine and fenfluramine act by releasing serotonin and inhibiting its uptake. Although each drug was approved for singleagent use only, fenfluramine-phentermine (“fen-phen”) gained popularity as combination therapy in 1992 because of its synergistic efficacy, fewer side effects, and improved patient tolerance. The Centers for Disease Control estimated that up to 4.7 million Americans had taken the “fen-phen” combination [2, 3]. The use of appetite-suppressant medication declined abruptly in 1997 after the publication of a study [3] suggesting the association of serious valvular heart disease resulting from these medications. Connolly and co-workers [3] reported a landmark series of 24 patients in whom valvular heart disease had developed in conjunction with combination fenfluramine and phentermine use, 5 of whom required surgical intervention. The US Department of Health and Human Services [2] identified a series of 113 patients with cardiac valvular heart disease related to use of fenfluramine or dexfenfluramine. Among these 113 patients, 27 required cardiac valve replacement. The potential severity of this valvular pathologic response prompted withdrawal of dexfenfluramine and fenfluramine from the market on September 15, 1997 [4]. In our patient, severe mitral regurgitation developed after short-term exposure to and low doses of fenfluramine-phentermine.
Address reprint requests to Dr Landolfo, Division of Thoracic and Cardiovascular Surgery, Duke University Medical Center, Box 3857, Durham, NC 27710; e-mail: [email protected].
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
A 32-year-old white woman with no history of heart problems was prescribed appetite-suppressant medication in 1996 for obesity. The drug regimen combined fenfluramine, 20 mg, and phentermine, 15 mg, daily for 3 weeks. From 1996 to early 1998, she remained asymptomatic. In the postpartum period after the delivery of twins in May 1998, dyspnea developed. Workup included a transesophageal echocardiogram, which demonstrated severe mitral regurgitation with thickened mitral leaflets. She was also found to have moderate tricuspid regurgitation, left atrial enlargement, and normal left ventricular function with an ejection fraction of 0.60. The congestive heart failure was treated medically early with diuretics, digitalis, and vasodilators. Right heart catheterization showed a pulmonary artery pressure of 33/13 mm Hg and a mean pulmonary capillary wedge pressure of 11 mm Hg with V waves to 17 mm Hg. Left ventriculography demonstrated an ejection fraction of 0.55 with 3-41 mitral regurgitation. Coronary arteries were normal. In June 1998, the patient was referred to Duke University Medical Center for evaluation. Transesophageal echocardiography revealed marked dilatation of the mitral annulus with severe mitral regurgitation. The mitral valve leaflets were mildly thickened with moderate restriction of the posterior leaflet and mild anterior leaflet restriction but no stenosis (Fig 1). There was mild dilatation of the tricuspid valve annulus with mild regurgitation. Mild to moderate aortic insufficiency was also present. The left ventricle was dilated with preserved function. On June 17, 1998, the patient underwent mitral valve replacement with a 29-mm St. Jude Medical prosthesis. Gross inspection of the valve revealed two glistening white leaflets with focal thickening and minimal calcification. Microscopic evaluation revealed leaflet thickening and chordal encasement by fibroproliferative surface 0003-4975/99/$20.00 PII S0003-4975(99)00328-8
1820
REVIEW BISWAS ET AL APPETITE SUPPRESSANT–INDUCED VALVULOPATHY
Ann Thorac Surg 1999;67:1819 –22
Fig 1. Transesophageal echocardiogram demonstrating (A) marked mitral annulus dilatation with moderate restriction of the posterior mitral valve leaflet and (B) resultant severe mitral regurgitation. (AMVL 5 anterior mitral valve leaflet; LA 5 left atrium; LV 5 left ventricle; PMVL 5 posterior mitral valve leaflet.)
lesions. In some areas, there was cellular proliferation within a rich myxoid matrix as well as hypocellular surface lesions with a dense fibroelastic extracellular matrix. There was minimal neovascularization, and neither calcification nor inflammatory infiltrates were identified (Fig 2). Given the patient’s prior exposure to the
fenfluramine-phentermine combination, intraoperative findings, and histologic evaluation, the final pathologic diagnosis was consistent with valve disease caused by “fen-phen” exposure. Postoperatively, the patient had an unremarkable course with resolution of symptoms.
Comment
Fig 2. Low-power magnification of the mitral valve demonstrating leaflet thickening and chordal encasement (dark red) by fibroproliferative surface lesions. (Lawson elastic–van Gieson; 34 before % reduction.)
Recent reports [2, 3] of appetite suppressant–induced cardiac valvulopathy have generated concern about the prevalence and mechanism of these disorders. Both fenfluramine and dexfenfluramine have mechanisms of action related to serotonin release. Fenfluramine promotes the rapid release of serotonin and inhibits its uptake in the ventromedial nucleus of the hypothalamus [5]. Both of these medications may have receptor-agonist activity [6]. Prolonged exposure to combination therapy with fenfluramine and phentermine has been shown to increase neuronal serotonin levels [1]. The reported incidence of mitral valve disease associated with use of appetite suppressants is less than that of aortic valve disease. Three recently published studies [4, 7, 8] used transthoracic echocardiography to evaluate valvular heart disease in patients with prior fenflura-
Ann Thorac Surg 1999;67:1819 –22
mine, dexfenfluramine, or phentermine use. Weissman and co-workers [4] prospectively identified 1,072 obese patients who were randomly assigned to dexfenfluramine (n 5 366), sustained-release dexfenfluramine (n 5 352), or placebo (n 5 354). The average duration of appetite-suppressant use was 71 days. Transthoracic echocardiography was performed within a median duration of 1 month after discontinuation of treatment. Mitral regurgitation of moderate severity occurred in 1.7%, 1.8%, 1.8%, and 1.2% of patients in the dexfenfluramine group, the sustained-release dexfenfluramine group, the two active-treatment groups combined, and the placebo group, respectively. Aortic regurgitation of mild or greater severity occurred in 5.0%, 5.8%, 5.4%, and 3.6% of patients in the treatment groups, respectively [4]. Jick and colleagues [7] reported 11 cases of valvular disease diagnosed by transthoracic echocardiography among 2,371 patients who received fenfluramine and 862 patients who received phentermine. Of the 11 patients, 2 had mitral regurgitation, 6 had aortic regurgitation, and 3 had both aortic and mitral regurgitation. None of these patients underwent valve operations. Khan and associates [8] examined the prevalence of valvular heart disease among patients adhering to three different appetite-suppressant drug regimens and compared the results with those in a control group of agematched obese subjects who had never taken these medications. The prevalence of valvular regurgitation meeting the Food and Drug Administration definition (greater than mild aortic regurgitation and greater than moderate mitral regurgitation) was higher in patients with a history of appetite-suppressant drug use (1.3% in the control group, 13% in the dexfenfluramine group, 23% in the dexfenfluramine-phentermine group, and 25% in the “fen-phen” group). The valvular disease in the patient described here warrants attention in that the duration of medical treatment was relatively short and the dosages administered were half of the standard treatment. Furthermore, although patients who manifest valvular heart disease typically have development of symptoms within months of exposure, symptoms occurred in this patient 2 years after discontinuation of the medications, which later led to mitral valve replacement. In the original case series of 24 patients from the Mayo Clinic [3], the mean exposure to “fen-phen” averaged 12 months. The median duration of exposure reported in the 1997 FDA series [2] was 9 months (range, 1 to 39 months). The case-control study by Jick and associates [7] suggested that valvulopathy associated with less than 3 months’ exposure to appetitesuppressant drug use occurs infrequently. Several hypotheses have been proposed to explain the mechanism of appetite suppressant drug–related valvular heart disease. Recent epidemiologic studies [9 –11] have determined that obesity alone is not the cause of the observed valvular regurgitation. The fibrotic endocardial changes seen in the surgical specimens of these patients are identical to those observed in ergotamine-induced and carcinoid valve disease [12]. The “serotonin hypothesis” has evolved to explain the mechanism of appetite
REVIEW BISWAS ET AL APPETITE SUPPRESSANT–INDUCED VALVULOPATHY
1821
suppressant drug–related heart disease. Both dexfenfluramine and fenfluramine are known to inhibit uptake of serotonin as well as to promote its release in the brain. Phentermine interference with serotonin clearance in the lungs has been postulated as a mechanism for the development of primary pulmonary hypertension [13]. Classically, the valvular lesions associated with malignant carcinoid syndrome and high levels of circulating serotonin are characterized by fibroplasia mostly involving the tricuspid and pulmonary (right-sided) valves [14, 15]. Left-sided valvular lesions would require a source of serotonin distal to the pulmonary circulation. Platelet granules have the largest supply of serotonin in plasma and have been the postulated source of serotonin release by appetite-suppressant medications [16]. This released serotonin would be rapidly metabolized and excreted, which may account for the normal and reduced blood serotonin levels in patients on a regimen of fenfluramine and phentermine [17]. High shear forces imposed on platelets against valve endothelium may enhance local release of serotonin on the surface of the valve [18]. Accordingly, quiescent fibroblasts within the valve leaflet may be induced to proliferate and migrate across the valve endothelium and secrete an extracellular matrix to consolidate the plaquelike lesion [1]. However, these theories remain speculative because of the lack of prospective data in experimental models of appetite suppressant–induced valve disease. Recommendations are being developed for patients with a history of appetite-suppressant treatment. Patients with a heart murmur or symptoms suggestive of valvular disease or those with greater than 3 months’ or high-dose exposure should undergo transthoracic echocardiography. The case of our patient suggests that patients with a history of short-term and low-dose usage of these medications may also be at risk for valvular disease. Consideration should be given to early echocardiography. Other recommendations include prophylaxis against endocarditis for patients with a heart murmur, “silent” moderate or severe regurgitation on echocardiogram, and mild regurgitation associated with defined structural valvular lesions [19]. We thank William H. Edwards, MD, of Rochester, MN, for his expert analysis of the pathology in this patient.
References 1. Wong J, Reddy SSK, Klein AL. Anorectic drugs and valvular heart disease: a biologic and clinical perspective. Cleve Clin J Med 1998;65:35– 41. 2. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services interim public health recommendations, November 1997. JAMA 1997;278:1729–31. 3. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581– 8. 4. Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine,
1822
5. 6. 7.
8.
9. 10.
11.
REVIEW BISWAS ET AL APPETITE SUPPRESSANT–INDUCED VALVULOPATHY
or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med 1998;339:725–32. Pinder RM, Brogden RN, Sawyer PR, Speight TM, Avery GS. Fenfluramine: a review of the pharmacological properties and therapeutic efficacy in obesity. Drugs 1975;10:241–323. Mitchell P, Smythe G. Hormonal responses to fenfluramine in depressed and control subjects. J Affective Disord 1990;19: 43–51. 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;339:719–24. Khan MA, Herzog CA, St. Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetitesuppressant drugs. N Engl J Med 1998;339:713– 8. Singh JP, Evans JC, Levy D, et al. Prevalence of valvular regurgitation in a population-based cohort. Circulation 1997; 96(Suppl 1):541. Lebowitz NE, Bella JN, Roman MJ, et al. Prevalence and correlates of aortic regurgitation in American Indians: the Strong Heart Study [Abstract]. J Am Soc Echocardiogr 1998; 11:559. Jones EC, Devereux RB, Roman MJ, et al. Prevalence and correlates of mitral regurgitation in the general population: the Strong Heart Study [Abstract]. J Am Soc Echocardiogr 1998;11:500.
Ann Thorac Surg 1999;67:1819 –22
12. Redfield MM, Nicholson WJ, Edwards WD, Tajik AJ. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med 1992; 117:50–2. 13. Morita T, Mehendale H. Effects of chlorphenterimine and phenterimine on the pulmonary disposition of 5-hydroxytryptamine in the rat in vivo. Am Rev Respir Dis 1983;127: 747–50. 14. Thorson AH. Endocardial sclerosis and other heart lesions in the carcinoid disease. Acta Med Scand [Suppl] 1958;334:99 – 119. 15. Robiolio PA, Rioglin VH, Wilson JS, et al. Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995;92:790–5. 16. Robertson JI. Serotonergic type-2 (5-HT2) antagonists: a novel class of cardiovascular drugs. J Cardiovasc Pharmacol 1991;17(Suppl 5):S48 –53. 17. Redmon B, Raatz S, Bantle JP. Valvular heart disease associated with fenfluramine-phentermine [Letter]. N Engl J Med 1997;337:1773– 4. 18. Chesebro JH, Lam JY, Badimon L, Fuster V. Restenosis after arterial angioplasty: a hemorrheologic response to injury. Am J Cardiol 1987;60:10B– 6B. 19. Devereux RB. Appetite suppressants and valvular heart disease. N Engl J Med 1998;339:765–7.