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(Circulation. 1995;92:790-795.)
© 1995 American Heart Association, Inc.

Articles

Carcinoid Heart Disease

Correlation of High Serotonin Levels With Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography

Paul A. Robiolio, MD; Vera H. Rigolin, MD; John S. Wilson, MD; J. Kevin Harrison, MD; Linda L. Sanders, MPH; Thomas M. Bashore, MD; Jerome M. Feldman, MD

From the Divisions of Cardiology, Duke University Medical Center, Durham, NC, and the Division of Internal Medicine, Durham (NC) VA Medical Center.

Correspondence to Thomas M. Bashore, MD, Duke University Medical Center, PO Box 3012, Durham, NC 27710.

	Abstract

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Background Although serotonin has been postulated as an etiologic agent in the development of carcinoid heart disease, no direct evidence for different ambient serotonin levels in cardiac and noncardiac patients has been reported to date.

Methods and Results The present study reviews our experience with 604 patients in the Duke Carcinoid Database. Nineteen patients with proven carcinoid heart disease (by cardiac catheterization and/or echocardiogram) were compared with the remaining 585 noncardiac patients in the database with regard to circulating serotonin and its principal metabolite, 5-hydroxyindole acetic acid (5-HIAA). No significant demographic differences existed between the cardiac and noncardiac groups; however, typical carcinoid syndrome symptoms (ie, flushing and diarrhea) were almost threefold more common in the cardiac group (P<.001). Compared with the noncardiac group, heart disease patients demonstrated strikingly higher (P<.0001) mean serum serotonin (9750 versus 4350 pmol/mL), plasma serotonin (1130 versus 426 pmol/mL), platelet serotonin (6240 versus 2700 pmol/mg protein), and urine 5-HIAA (219 versus 55.3 mg/24 h) levels. The spectrum of heart disease among the 19 patients showed a strong right-sided valvular predominance, with tricuspid regurgitation being the most common valvular dysfunction (92% by cardiac catheterization; 100% by echocardiogram).

Conclusions These data suggest that serotonin plays a major role in the pathogenesis of the cardiac plaque formation observed in carcinoid patients.

Key Words: serotonin • heart diseases • valves

	Introduction

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Carcinoid tumors are rare malignancies that arise from enterochromaffin cells and characteristically secrete a variety of humoral factors, the most notable of which is serotonin.¹ Carcinoid syndrome classically manifests a triad of cutaneous vasomotor flushing, diarrhea, and endocardial plaquing. Within the group of carcinoid patients, the literature suggests a prevalence of carcinoid heart disease ranging from 57% to 77% on the basis of selected series of patients with relatively advanced tumors.^{2 3 4} Efforts to elucidate the biochemical basis for heart disease have been based on indirect means (ie, urinary 5-hydroxyindole acetic acid [5-HIAA]) to assess ambient serotonin exposure. This method has been shown to be less accurate than direct measures of circulating serotonin.⁵

In the present report, we review our experience with carcinoid heart disease at a tertiary referral medical center. Cardiac catheterization and/or echocardiography were used to define a subgroup with heart disease within a large carcinoid cohort that included patients with localized and metastatic tumors (Duke Carcinoid Database). In addition to urinary 5-HIAA, circulating serotonin levels were systematically measured on all patients.

	Methods

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Patient Selection
The Duke Carcinoid Database was prospectively amassed during 1972 through 1994 and contains information on demographics, symptoms, laboratory results (including urine 5-HIAA or circulating serotonin in our research laboratory), and clinical courses of 604 patients with carcinoid tumors referred to one of us (J.M.F.).

Carcinoid patients underwent screening histories and physical examinations at the time of entry into the database; 37 patients with possible carcinoid heart disease were identified in this fashion. The medical records of these 37 patients were later retrospectively reviewed, and reports of cardiac catheterization and echocardiogram were noted. These diagnostic examinations were obtained for clinical indications and not as part of the study. Records pertaining to cardiac surgical interventions and, when relevant, death notes or autopsy results also were reviewed.

Inclusion in the subgroup with carcinoid heart disease required evidence of valvular heart disease (stenosis or regurgitation) by echocardiogram or cardiac catheterization, excluding both trivial or mild tricuspid regurgitation and mitral or aortic valve disease if explained on the basis of another etiology (eg, rheumatic or ischemic). Of the 37 patients, 19 met these criteria and were included in the carcinoid heart disease subgroup. (Of these 19 patients, 13 had undergone cardiac catheterization, and 16 had undergone echocardiography. The mean time between studies for those who had both was 39 days.) For purposes of comparison, this cardiac subgroup was contrasted with the remaining 585 patients in the carcinoid database without known carcinoid heart disease as defined above.

Endocrine Laboratory
Tumor secretory products were prospectively assayed in all 604 patients in our research laboratory. Virtually all (>98%) measurements were made at the time of first presentation to our medical center. Twenty-four-hour urine samples were routinely collected, maintained at 3°C, and quantitatively evaluated for 5-HIAA by spectrophotometric assay (normal, 2 to 8 mg/24 h).⁶ Blood samples were fractionated, and serotonin levels were measured in the serum (normal, 200 to 1500 pmol/mL), plasma (normal, 5 to 100 pmol/mL), and platelets (normal, 300 to 2200 pmol/mg protein) by a radioenzymatic method.^{7 8} After 1988, urine, serum, and platelet levels were measured by high-pressure liquid chromatography (HPLC).⁹ Normal ranges for all parameters are the same by HPLC and the radioenzymatic method.

Cardiac Catheterization
Regurgitant valvular heart disease was assessed by power injection of a radiocontrast agent into the relevant distal chamber (eg, right ventricle in the case of tricuspid regurgitation) and cineangiographic viewing of the proximal chamber (eg, right atrium in the case of tricuspid regurgitation).¹⁰ Severity of regurgitation was graded mild (opacification less intense in the proximal chamber than in the distal chamber), moderate (opacification equal between the two chambers), or severe (opacification more intense in the proximal chamber than in the distal chamber).

The severity of stenotic mitral and aortic valvular disease was graded on the basis of valve areas calculated by the modified Gorlin equation.¹¹ For mitral stenosis, classification was mild (1.6 to 2.5 cm²), moderate (1.0 to 1.5 cm²), or severe (<1.0 cm²). For aortic stenosis, classification was mild (1.1 to 2.0 cm²), moderate (0.7 to 1.0 cm²), or severe (<0.7 cm²). Directly measured pressure gradients were used to assess stenotic grade across the tricuspid and pulmonic valves. For tricuspid stenosis, classification was based on mean gradient in diastole: mild (1 to 4 mm Hg), moderate (5 to 10 mm Hg), and severe (>10 mm Hg). For pulmonic stenosis, classification was based on the peak-to-peak gradient in systole: mild (3 to 10 mm Hg), moderate (11 to 30 mm Hg), or severe (>30 mm Hg).

Echocardiography
Semiquantitative grades (mild, moderate, or severe) for the severity of valvular dysfunction were assigned by the attending echocardiographer at the time of the examination on the basis of integration of the available data from two-dimensional, continuous- and pulsed-wave Doppler, and color flow Doppler recordings. In general, regurgitant lesions were graded on the basis of Doppler visualization of the extent of filling of the proximal chamber.¹²

Statistics
Statistical analyses were performed with the SAS statistical package for the Microsoft Windows environment. Data are expressed as mean±SD unless otherwise specified. Comparisons between the cardiac and noncardiac groups were made by use of a two-sample Student's t test (if the variable was normally distributed) or the Wilcoxon rank-sum test (if the variable was not normally distributed) for continuous variables, with ² analysis for equality of proportions or Fisher's exact test for categorical variables. Values of P<.05 (two-tailed) were considered statistically significant. Concordance between valvular severity grades by echocardiogram and cardiac catheterization was defined as percent agreement to within one grade on a 0 (none), 1 (mild), 2 (moderate), or 3 (severe) scale. Survival analysis was performed by use of the product-limit survival estimate with 95% confidence intervals.¹³

	Results

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No significant differences between the cardiac (n=19) and noncardiac groups (n=585) were seen with respect to race, sex, age at onset of carcinoid tumor symptoms, and age at diagnosis of carcinoid tumor (Table 1). Symptoms of flushing and diarrhea were almost threefold more common in the cardiac group (Table 1). Fig 1 shows the locations of primary carcinoid tumors. Although the noncardiac group had a wide distribution of primary tumor sites, the cardiac group exhibited a heavy preponderance of small-intestine tumors (47%) and tumors of unknown primary location (48%).

View this table: [in this window] [in a new window]   Table 1. Demographics and Symptoms of Carcinoid Syndrome

View larger version (46K): [in this window] [in a new window]   Figure 1. Pie charts showing the locations of primary carcinoid tumors within the groups with heart disease and no heart disease. Misc includes Ampulla of Vater, breast, central nervous system, gall bladder, esophagus, Meckel's diverticulum, ovary, and thymus.

The principal finding in the present study is that circulating serotonin levels were more than twofold higher in the cardiac group compared with the noncardiac group. (Fig 2). Specifically, cardiac patients demonstrated higher (P<.0001) levels of serum serotonin (9750±4130 versus 4350±6460 pmol/mL), plasma serotonin (1130±1210 versus 426±1130 pmol/mL), and platelet serotonin (6240±4030 versus 2700±2880 pmol/mg protein). Urine levels of the serotonin metabolite 5-HIAA were almost fourfold higher (P<.0001) in the heart disease patients compared with the noncardiac group (219±124 versus 55.3±141 mg/24 h).

View larger version (30K): [in this window] [in a new window]   Figure 2. Bar graphs comparing cardiac and noncardiac patients. Cardiac patients demonstrated higher (P<.0001) mean levels of urine 5-hydroxyindole acetic acid (5-HIAA; 219±124 vs 55.3±141 mg/24 h), serum serotonin (9750±4130 vs 4350±6460 pmol/mL), plasma serotonin (1130±1210 vs 426±1130 pmol/mL), and platelet serotonin (6240±4030 vs 2700±2880 pmol/mg protein). Stippled box indicates no heart disease; solid box, heart disease.

Elevated serum serotonin (above the upper limit of normal range, ie, >1500 pmol/mL) was 100% sensitive but only 46% specific for carcinoid heart disease. Furthermore, there was no clear cutoff point in serotonin level that delineated the two groups.

Of the 16 cardiac patients who had echocardiograms performed, 13 (81%) had evidence of right atrial and right ventricular enlargement by echocardiogram; 9 (56%) had evidence of a thickened or immobile tricuspid valve. Table 2 details the valvular abnormalities in this subgroup. The results for the 13 patients who underwent cardiac catheterization are similar and also are shown in Table 2. Tricuspid valve disease (especially regurgitation) was most prevalent. Left-sided valve lesions tended to be less common and of milder severity than their right-sided counterparts. Cardiac catheterization and echocardiography had an overall concordance of 91% on the basis of valvular lesions assessed by both methods.

View this table: [in this window] [in a new window]   Table 2. Number of Patients With Valvular Disease Stratified by Severity

Further review of the subgroup of cardiac patients who underwent catheterization showed that 12 (92%) had New York Heart Association class III or IV symptoms of congestive heart failure, and 1 (8%) had class II symptoms. Table 3 gives the hemodynamic profile of the group. Right-sided filling pressures tended to be mildly to moderately elevated (mean right atrial pressure >10 mm Hg in 8 patients and >20 mm Hg in 3 of these), whereas left-sided filling pressures were generally normal (mean pulmonary capillary wedge pressure >10 mm Hg in 3 patients and >20 mm Hg in 0 patients). This is consistent with the greater prevalence and severity of tricuspid and pulmonic valve diseases compared with mitral and aortic valve diseases.

View this table: [in this window] [in a new window]   Table 3. Hemodynamic Findings in the Subgroup of Cardiac Patients Undergoing Cardiac Catheterization

Significant coronary artery disease (defined as at least 75% diameter stenosis in at least one major coronary artery or first-order branch) was noted in 5 of the 13 patients who underwent catheterization: 3 had single-vessel disease, 1 had two-vessel disease, and 1 had three-vessel disease.

Survival was measured from each of two different starting points: from the onset of the first carcinoid tumor symptom (ie, symptom of local tumor growth, metastatic disease, or carcinoid syndrome) and from diagnosis of carcinoid tumor. Regardless of which starting point was used, survival between the cardiac and noncardiac groups was not statistically different (Table 4). Furthermore, there was not even a clear trend because survival from onset of symptoms and survival from diagnosis of carcinoid tumor showed disparate trends.

View this table: [in this window] [in a new window]   Table 4. Survival Estimates by the Product-Limit Method

	Discussion

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While the ultrastructural details of the carcinoid plaque have been understood for almost two decades,¹⁴ insights into the biochemical basis of carcinoid heart disease have been elusive. Carcinoid tumors secrete a variety of agents, including kallikrein, histamine, prostaglandins, ACTH, gastrin, calcitonin, and growth hormone¹⁵ ; however, serotonin has received the most attention in hypotheses concerning the genesis of heart disease.¹⁶ Attempts to demonstrate higher levels of tumor secretory products in cardiac patients and thus deduce a potential etiologic role for these products initially showed no statistically significant difference in urinary 5-HIAA levels between cardiac and noncardiac patients.^{17 18} However, within the past decade, three studies have shown higher levels of urinary 5-HIAA in cardiac patients.^{3 19 20} Lundin et a³ also showed higher levels of neuropeptide K and substance P in patients with heart disease.

Elevated urinary 5-HIAA is a less-than-ideal serotonin surrogate because it misses 10% of patients with true elevated circulating serotonin levels.⁵ These patients can be identified by direct measurement of circulating serotonin in the blood or plasma; however, because the majority of circulating serotonin is taken up and carried in the dense granules of platelets, platelet serotonin level is perhaps the most useful measure of the circulating hormone. The present study includes three different measurements of circulating serotonin (serum, plasma, and platelets); it is the first to directly demonstrate elevations of circulating serotonin in cardiac patients relative to patients without heart disease. Indeed, the twofold to fourfold higher levels of serotonin and 5-HIAA in the cardiac group may be an underestimation of the difference. Our stringent definition of heart disease may have resulted in the inclusion of some undocumented heart disease patients in the "noncardiac" group, a misclassification that would be expected to bias toward the null hypothesis.

Although this novel finding is consistent with a causal role for serotonin in the pathogenesis of heart disease, it is not proof. The high sensitivity (100%) and low specificity (46%) of elevated serum serotonin level as a marker for heart disease suggest that elevated circulating serotonin is a necessary but not a sufficient component in the development of heart disease. Some other factor (eg, duration of high levels, cofactor, or genetic predisposition) may play a role in determining who will get heart disease. It is possible, for example, that the same tumors that secrete high quantities of serotonin also secrete high quantities of other agents that are causative or synergistic with serotonin in producing the characteristic fibrotic damage of the heart. Such a scenario would explain the absence of heart disease in some carcinoid patients with high circulating serotonin.

In addition to numerous case reports, the literature on carcinoid heart disease includes several autopsy,^{17 18 21 22} echocardiography,^{2 3 4 19 20 23} and surgical series.^{24 25} Table 5 summarizes the larger series pertinent to the spectrum of valvular disease.

View this table: [in this window] [in a new window]   Table 5. Summary of the Literature

Within the heart disease group, the relative proportions of valvular pathologies are of interest. Classically, tricuspid regurgitation and pulmonic stenosis have been reported as the most common valvular lesions, often on the basis of a physical examination or autopsy.^{19 26} Because pulmonic stenosis and tricuspid regurgitation are easier to appreciate on physical examinations than pulmonic regurgitation and tricuspid stenosis and because pathological tissue can be artifactually altered, studies that look at the functioning valves in situ would be expected to be more accurate. In our cardiac group, tricuspid regurgitation was almost universal at 92% to 100%, followed by tricuspid stenosis (38% to 44%), pulmonic regurgitation (31% to 38%), and pulmonic stenosis (25% to 31%). These frequencies are in reasonable agreement with the previously reported series summarized in Table 5.

Left-sided heart disease caused by carcinoid tumor is a more controversial issue. There are case reports of left-sided heart disease (eg, intestinal primaries with intracardiac shunts²⁷ and bronchial carcinoids^{28 29} ) and even nonvalvular pathology.³⁰ The larger series summarized in Table 5 suggest a prevalence of left-sided disease between 0% and 39%, most of it mild. In the three autopsy series from Roberts and colleagues,^{17 18 22} no left-sided involvement was felt to be of functional significance. Given the relatively high frequency of mitral and aortic valve diseases (ischemic, rheumatic, etc), some have proposed that left-sided lesions observed in carcinoid patients are coincidental. For example, Lundin et al³ reported that patients with advanced right-sided cardiac abnormalities had a lower frequency of left-sided disease than did their counterparts with mild right-sided abnormalities. These authors concluded that a carcinoid etiology was unlikely for the left-sided disease. Our series confirms the low frequency of left-sided valvular disease.

As for primary tumor location, tumors arising from the small intestine account for 31% to 80% of all carcinoids.^{31 32} In four series of carcinoid patients with heart disease, however, small-intestine primaries accounted for 87% to 100% of cases.^{17 18 20 22} Our cardiac group included 47% with ileal or jejunal primaries compared with only 26% in the noncardiac group. This apparent association of heart disease and midgut tumors may be a reflection of the high tendency of these malignancies to metastasize to the liver and spill high amounts of serotonin into the right side of the heart. The small heart disease series reported by Callahan et al²³ included only 20% with small-intestine tumors; an additional 60% were of unknown primary.²³ Our cardiac group also included a high proportion (48%) of tumors of unknown primary. The significance of this finding is uncertain, but perhaps these patients represent a group with more aggressively disseminated tumors that obscure the primary location.

Although multiple case reports on the findings of carcinoid heart disease at cardiac catheterization have been published,^{33 34 35} the only series available is that of Himelman and Schiller¹⁹ of 7 patients.¹⁹ Hemodynamic findings included a mean right atrial pressure of 15 mm Hg, with a v wave of 22 mm Hg and a right ventricular pressure of 39/10 mm Hg; these numbers are in close agreement with our own findings in 13 patients (Table 3).

Coronary disease was seen in a substantial minority (26%) of cardiac patients in the present report. Although coronary fibrosis has been propounded as a potential mechanism of coronary insufficiency in carcinoid patients, it is more likely that our finding is due to superimposition of a common disease (coronary atherosclerosis) on an uncommon one (carcinoid heart disease). Consistent with this is the observation that, at the time of catheterization, the mean age of the cardiac patients was 62.4 years; indeed, 4 of the 5 coronary artery disease patients were over the age of 65. Western epidemiological studies suggest an overall prevalence of coronary artery disease of about 25% in the elderly.³⁶

Two reports have purported a survival disadvantage of cardiac disease in the setting of carcinoid syndrome.^{19 20} In both instances, survival was measured from the time of echocardiography. At least in the study by Pellikka et al,²⁰ some echocardiograms were performed because of the clinical suspicion of heart disease; others were baseline screening tests. It might be argued that cardiac patients tended to have more advanced tumors and thus be subject to mortality on that basis. The present study did not demonstrate a survival difference between the cardiac and noncardiac groups regardless of whether survival was measured from the time of onset of first carcinoid symptom or from the time of diagnosis of carcinoid tumor. Given the small number of cardiac patients in this study, however, a true survival difference may have been undetected because of insufficient power.

Conclusions
Although serotonin has been indirectly linked to carcinoid heart disease, no direct evidence for different ambient serotonin levels in carcinoid cardiac and noncardiac patients has previously been reported. This study demonstrates that carcinoid patients with heart disease exhibit higher circulating serotonin levels than do their counterparts without heart disease. This finding supports the contention that serotonin plays a role in the pathogenesis of carcinoid heart disease.

	Acknowledgments

 
We wish to acknowledge Debbie Riley for her assistance in the preparation of this manuscript.

Received January 11, 1995; accepted February 21, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Feldman JM. Carcinoid tumors and syndrome. Semin Oncol. 1987;14:237-246. [Medline] [Order article via Infotrieve]

2. Howard RJ, Drobac M, Rider WD, Keane TJ, Finlayson J, Silver MD, Wigle ED, Rakowski H. Carcinoid heart disease: diagnosis by two-dimensional echocardiography. Circulation. 1982;66:1059-1065. [Abstract/Free Full Text]

3. Lundin L, Norheim I, Landelius J, Oberg K, Thoedorsson-Norheim E. Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation. 1988;77:264-269. [Abstract/Free Full Text]

4. Lundin L, Landelius J, Andren B, Oberg K. Transesophageal echocardiography improves the diagnostic value of cardiac ultrasound in patients with carcinoid heart disease. Br Heart J. 1990;64:190-194. [Abstract/Free Full Text]

5. Feldman JM. The carcinoid syndrome. Endocrinologist. 1993;3:129-135.

6. Udenfriend S, Titus E, Weissbach H. The identification of 5-hydroxyindoleacetic acid in normal urine and a method for its assay. J Biol Chem. 1955;216:499-505. [Free Full Text]

7. Feldman JM, Davis JA. Radioenzymatic assay of platelet serotonin, dopamine, and norepinephrine in subjects with normal and increased serotonin production. Clin Chim Acta. 1981;9:275-283.

8. Hussain MN, Sole MJ. A simple, specific, radioenzymatic assay for picogram quantities of serotonin or acetylserotonin in biological fluids or tissues. Anal Biochem. 1981;11:105-110.

9. Taqari PC, Boullin DJ, Davies CL. Simplified determination of serotonin in plasma by liquid chromatography with electrochemical detection. Clin Chem. 1984;30:131-135. [Abstract/Free Full Text]

10. Kisslo KB, Bashore TM. Common disease states. In: Bashore TM, ed. Invasive Cardiology: Principles and Techniques. Toronto, Ontario, Canada: BC Decker Inc; 1990:255-278.

11. Carabello BA, Grossman W. Calculation of stenotic valve orifice area. In: Grossman W, Baim DS, eds. Cardiac Catheterization, Angiography and Intervention. 4th ed. Philadelphia, Pa: Lea & Febiger; 1991:152-165.

12. Mark DB, Robertson JH, Adams D, Kisslo, J. Doppler evaluation of valvular regurgitation. In: Kisslo J, Adams D, Mark DB, eds. Basic Doppler Echocardiography. New York, NY: Churchill Livingstone Inc; 1986:91-122.

13. Lee ET. Statistical Methods for Survival Data Analysis. New York, NY: John Wiley & Sons Inc; 1992:67-128.

14. Ferrans VJ, Roberts WC. The carcinoid endocardial plaque: an ultrastructural study. Hum Pathol. 1976;7:387-409. [Medline] [Order article via Infotrieve]

15. Kaplan EL. The carcinoid syndromes. In: Friesen SR, Bolinger RE, eds. Surgical Endocrinology: Clinical Syndromes. Philadelphia, Pa: JB Lippincott Co; 1978:120-147.

16. Feldman JM. Carcinoid tumors. In: Mazzaferri EL, Samaan NA, eds. Endocrine Tumors. Boston, Mass: Blackwell Scientific Publications; 1993:700-722.

17. Roberts WC, Sjoerdsma A. The cardiac disease associated with the carcinoid syndrome. Am J Med. 1964;36:5-26. [Medline] [Order article via Infotrieve]

18. Ross EM, Roberts WC. The carcinoid syndrome: comparison of 21 necropsy subjects with carcinoid heart disease to 15 necropsy subjects without carcinoid heart disease. Am J Med. 1985;339-354.

19. Himelman RB, Schiller NB. Clinical and echocardiographic comparison of patients with the carcinoid syndrome with and without carcinoid heart disease. Am J Cardiol. 1989;63:347-352. [Medline] [Order article via Infotrieve]

20. Pellikka PA, Tajik J, Khandheria BK, Seward JB, Callahan JA, Pitot HC, Kvols LK. Carcinoid heart disease: clinical and echocardiographic spectrum in 74 patients. Circulation. 1993;87:1188-1196. [Abstract/Free Full Text]

21. Thorson AH. Studies on carcinoid disease. Acta Med Scand. 1958;334(suppl):99-119.

22. Roberts WC, Dangel JC, Bulkley BH. Nonrheumatic valvular cardiac disease: a clinicopathologic survey of 27 different conditions causing valvular dysfunction. Cardiovasc Clin. 1973;5:352-359.

23. Callahan JA, Wroblewski EM, Reeder GS, Edwards WD, Seward JB, Tajik AJ. Echocardiographic features of carcinoid heart disease. Am J Cardiol. 1982;50:762-768. [Medline] [Order article via Infotrieve]

24. Knott-Craig CJ, Schaff HV, Mullany CJ, Kvols LK, Moertel CG, Edwards WD, Danielson GK. Carcinoid disease of the heart: surgical management of ten patients. J Thorac Cardiovasc Surg. 1992;104:475-481. [Abstract]

25. Lundin L, Hansson HE, Landelius J, Oberg K. Surgical treatment of carcinoid heart disease. J Thorac Cardiovasc Surg. 1990;100:552-561. [Abstract]

26. Lundin L. Carcinoid heart disease: a cardiologist's viewpoint. Acta Oncol. 1991;30:499-502. [Medline] [Order article via Infotrieve]

27. Millward MJ, Hung J, Blake MP, Gibson P, Byrne MJ. Left heart involvement with cardiac shunt complicating carcinoid heart disease. Aust N Z J Med. 1989;19:716-717. [Medline] [Order article via Infotrieve]

28. Greminger P, Hess OM, Muller AE, von Segesser L, Schneider J, Sutsch G, Siegenthaler W, Heitz, PU. Bronchial neuroendocrine (carcinoid) tumor causing unilateral left-sided carcinoid heart disease. Klin Wochenschr. 1991;69:128-133. [Medline] [Order article via Infotrieve]

29. Tanaka M, Matsubara O, Takemura T, Watanabe S, Suzuki K, Okano T, Kawaoi A, Kasuga T. Cardiovascular lesion of carcinoid syndrome: an autopsy case of bronchial carcinoid. Acta Pathol Jpn. 1984;34:201-213. [Medline] [Order article via Infotrieve]

30. Lachter JH, Lavy A, Eidelman S. Right heart failure as the sole presentation of carcinoid syndrome. Int J Cardiol. 1989;25:129-130. [Medline] [Order article via Infotrieve]

31. Cheek RC, Wilson H. Carcinoid tumors. Curr Probl Surg. 1970;11:4-31.

32. Kaplan LM. Endocrine disorders of the GI tract and pancreas. In: Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, Root RK, eds. Harrison's Principles of Internal Medicine. 12th ed. New York, NY: McGraw-Hill Publishing Co; 1991:1386-1393.

33. Stephan E, deWit J. Carcinoid heart disease from primary carcinoid tumour of the ovary: haemodynamic and cine coronary angiographic study after operation. Br Heart J. 1974;36:613-616. [Free Full Text]

34. Levine RJ, Folse R. Hemodynamic observations in a case of carcinoid heart disease associated with an atrial right-to-left shunt. Am Heart J. 1961;62:830-834. [Medline] [Order article via Infotrieve]

35. Charms BL, Kohn P, Applebaum HI, Geller J. Hemodynamic studies in a case of carcinoid cardiovascular syndrome. Circulation. 1959;20:208-214. [Abstract/Free Full Text]

36. Tervahauta M, Pekkanen J, Kivinen P, Stengard J, Jauhiainen M, Ehnholm C, Nissinen A. Prevalence of coronary heart disease and associated risk factors among elderly Finnish men in the Seven Countries Study. Atherosclerosis. 1993;104:47-59.[Medline] [Order article via Infotrieve]

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				R. O. Bonow, B. A. Carabello, K. Chatterjee, A. C. de Leon Jr, D. P. Faxon, M. D. Freed, W. H. Gaasch, B. W. Lytle, R. A. Nishimura, P. T. O'Gara, et al. 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons J. Am. Coll. Cardiol., September 23, 2008; 52(13): e1 - e142. [Full Text] [PDF]

				M. Kars, V. Delgado, E. R. Holman, R. A. Feelders, J. W. A. Smit, J. A. Romijn, J. J. Bax, and A. M. Pereira Aortic Valve Calcification and Mild Tricuspid Regurgitation But No Clinical Heart Disease after 8 Years of Dopamine Agonist Therapy for Prolactinoma J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3348 - 3356. [Abstract] [Full Text] [PDF]

				T. A. Townsend, J. L. Wrana, G. E. Davis, and J. V. Barnett Transforming Growth Factor-{beta}-stimulated Endocardial Cell Transformation Is Dependent on Par6c Regulation of RhoA J. Biol. Chem., May 16, 2008; 283(20): 13834 - 13841. [Abstract] [Full Text] [PDF]

				D. Zolkowska, M. H. Baumann, and R. B. Rothman Chronic Fenfluramine Administration Increases Plasma Serotonin (5-Hydroxytryptamine) to Nontoxic Levels J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 791 - 797. [Abstract] [Full Text] [PDF]

				A. M. Bernheim, H. M. Connolly, J. Rubin, J. E. Moller, C. G. Scott, D. M. Nagorney, and P. A. Pellikka Role of Hepatic Resection for Patients With Carcinoid Heart Disease Mayo Clin. Proc., February 1, 2008; 83(2): 143 - 150. [Abstract] [Full Text] [PDF]

				S. Bhattacharyya, J. Davar, G. Dreyfus, and M. E. Caplin Carcinoid Heart Disease Circulation, December 11, 2007; 116(24): 2860 - 2865. [Full Text] [PDF]

				Y.-J. Liang, L.-P. Lai, B.-W. Wang, S.-J. Juang, C.-M. Chang, J.-G. Leu, and K.-G. Shyu Mechanical stress enhances serotonin 2B receptor modulating brain natriuretic peptide through nuclear factor-{kappa}B in cardiomyocytes Cardiovasc Res, November 1, 2006; 72(2): 303 - 312. [Abstract] [Full Text] [PDF]

				R. O. Bonow, B. A. Carabello, K. Chatterjee, A. C. de Leon Jr, D. P. Faxon, M. D. Freed, W. H. Gaasch, B. W. Lytle, R. A. Nishimura, P. T. O'Gara, et al. ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Developed in Collaboration With the Society of Cardiovascular Anesthesiologists Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons J. Am. Coll. Cardiol., August 1, 2006; 48(3): e1 - e148. [Full Text] [PDF]

				D. Zolkowska, R. B. Rothman, and M. H. Baumann Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 604 - 610. [Abstract] [Full Text] [PDF]

				P. Poirier, T. D. Giles, G. A. Bray, Y. Hong, J. S. Stern, F. X. Pi-Sunyer, and R. H. Eckel Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss: An Update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease From the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism Circulation, February 14, 2006; 113(6): 898 - 918. [Abstract] [Full Text] [PDF]

				A. Mekontso-Dessap, F. Brouri, O. Pascal, P. Lechat, N. Hanoun, L. Lanfumey, I. Seif, N. Benhaiem-Sigaux, M. Kirsch, M. Hamon, et al. Deficiency of the 5-Hydroxytryptamine Transporter Gene Leads to Cardiac Fibrosis and Valvulopathy in Mice Circulation, January 3, 2006; 113(1): 81 - 89. [Abstract] [Full Text] [PDF]

				J. E. Moller, P. A. Pellikka, A. M. Bernheim, H. V. Schaff, J. Rubin, and H. M. Connolly Prognosis of Carcinoid Heart Disease: Analysis of 200 Cases Over Two Decades Circulation, November 22, 2005; 112(21): 3320 - 3327. [Abstract] [Full Text] [PDF]

				R. Tintner, P. Manian, P. Gauthier, and J. Jankovic Pleuropulmonary Fibrosis After Long-term Treatment With the Dopamine Agonist Pergolide for Parkinson Disease Arch Neurol, August 1, 2005; 62(8): 1290 - 1295. [Abstract] [Full Text] [PDF]

				E. A. Waller, J. Kaplan, and M. G. Heckman Valvular Heart Disease in Patients Taking Pergolide Mayo Clin. Proc., August 1, 2005; 80(8): 1016 - 1020. [Abstract] [PDF]

				B. I. Gustafsson, K. Tommeras, I. Nordrum, J. P. Loennechen, A. Brunsvik, E. Solligard, R. Fossmark, I. Bakke, U. Syversen, and H. Waldum Long-Term Serotonin Administration Induces Heart Valve Disease in Rats Circulation, March 29, 2005; 111(12): 1517 - 1522. [Abstract] [Full Text] [PDF]

				J. M. Zuetenhorst and B. G. Taal Metastatic Carcinoid Tumors: A Clinical Review Oncologist, February 1, 2005; 10(2): 123 - 131. [Abstract] [Full Text] [PDF]

				D. G. Baseman, P. E. O'Suilleabhain, S. C. Reimold, S. R. Laskar, J. G. Baseman, and R. B. Dewey Jr Pergolide use in Parkinson disease is associated with cardiac valve regurgitation Neurology, July 27, 2004; 63(2): 301 - 304. [Abstract] [Full Text] [PDF]

				G. A. Kaltsas, G. M. Besser, and A. B. Grossman The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors Endocr. Rev., June 1, 2004; 25(3): 458 - 511. [Abstract] [Full Text] [PDF]

				F. Cote, E. Thevenot, C. Fligny, Y. Fromes, M. Darmon, M.-A. Ripoche, E. Bayard, N. Hanoun, F. Saurini, P. Lechat, et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function PNAS, November 11, 2003; 100(23): 13525 - 13530. [Abstract] [Full Text] [PDF]

				C. G. Nebigil and L. Maroteaux Functional Consequence of Serotonin/5-HT2B Receptor Signaling in Heart: Role of Mitochondria in Transition Between Hypertrophy and Heart Failure? Circulation, August 19, 2003; 108(7): 902 - 908. [Full Text] [PDF]

				J. E. Moller, H. M. Connolly, J. Rubin, J. B. Seward, K. Modesto, and P. A. Pellikka Factors Associated with Progression of Carcinoid Heart Disease N. Engl. J. Med., March 13, 2003; 348(11): 1005 - 1015. [Abstract] [Full Text] [PDF]

				B. Jian, J. Xu, J. Connolly, R. C. Savani, N. Narula, B. Liang, and R. J. Levy Serotonin Mechanisms in Heart Valve Disease I: Serotonin-Induced Up-Regulation of Transforming Growth Factor-{beta}1 via G-Protein Signal Transduction in Aortic Valve Interstitial Cells Am. J. Pathol., December 1, 2002; 161(6): 2111 - 2121. [Abstract] [Full Text] [PDF]

				J. Xu, B. Jian, R. Chu, Z. Lu, Q. Li, J. Dunlop, S. Rosenzweig-Lipson, P. McGonigle, R. J. Levy, and B. Liang Serotonin Mechanisms in Heart Valve Disease II: The 5-HT2 Receptor and Its Signaling Pathway in Aortic Valve Interstitial Cells Am. J. Pathol., December 1, 2002; 161(6): 2209 - 2218. [Abstract] [Full Text] [PDF]

				A. M. Pritchett, J. F. Morrison, W. D. Edwards, H. V. Schaff, H. M. Connolly, and R. E. Espinosa Valvular Heart Disease in Patients Taking Pergolide Mayo Clin. Proc., December 1, 2002; 77(12): 1280 - 1286. [Abstract] [PDF]

				H. M. Connolly, H. V. Schaff, C. J. Mullany, M. D. Abel, and P. A. Pellikka Carcinoid Heart Disease: Impact of Pulmonary Valve Replacement in Right Ventricular Function and Remodeling Circulation, September 24, 2002; 106(12_suppl_1): I-51 - I-56. [Abstract] [Full Text] [PDF]

				M. Humbert, Z. Deng, G. Simonneau, R.J. Barst, O. Sitbon, M. Wolf, N. Cuervo, K.J. Moore, S.E. Hodge, J.A. Knowles, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives Eur. Respir. J., September 1, 2002; 20(3): 518 - 523. [Abstract] [Full Text] [PDF]

				C. S. Elangbam, K. A. Colman, R. M. Lightfoot, R. D. Tyler, and H. G. Wall Endocardial Myxomatous Change in Harlan Sprague-Dawley Rats (Hsd:S--D) and CD-1 Mice: Its Microscopic Resemblance to Drug-Induced Valvulopathy in Humans Toxicol Pathol, June 1, 2002; 30(4): 483 - 491. [Abstract] [PDF]

				T. Tomita and Q. Zhao Autopsy Findings of Heart and Lungs in a Patient With Primary Pulmonary Hypertension Associated With Use of Fenfluramine and Phentermine Chest, February 1, 2002; 121(2): 649 - 652. [Abstract] [Full Text] [PDF]

				D. V. Simula, W. D. Edwards, H. D. Tazelaar, H. M. Connolly, and H. V. Schaff Surgical Pathology of Carcinoid Heart Disease: A Study of 139 Valves From 75 Patients Spanning 20 Years Mayo Clin. Proc., February 1, 2002; 77(2): 139 - 147. [Abstract] [PDF]

				H. M. Connolly, H. V. Schaff, C. J. Mullany, J. Rubin, M. D. Abel, and P. A. Pellikka Surgical Management of Left-Sided Carcinoid Heart Disease Circulation, September 18, 2001; 104 (2009): I-36 - I-40. [Abstract] [Full Text] [PDF]

				C. G. Nebigil, P. Hickel, N. Messaddeq, J.-L. Vonesch, M. P. Douchet, L. Monassier, K. Gyorgy, R. Matz, R. Andriantsitohaina, P. Manivet, et al. Ablation of Serotonin 5-HT2B Receptors in Mice Leads to Abnormal Cardiac Structure and Function Circulation, June 19, 2001; 103(24): 2973 - 2979. [Abstract] [Full Text] [PDF]

				R. B. Rothman, M. H. Baumann, J. E. Savage, L. Rauser, A. McBride, S. J. Hufeisen, and B. L. Roth Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications Circulation, December 5, 2000; 102(23): 2836 - 2841. [Abstract] [Full Text] [PDF]

				A. Prasad, M. Mehra, M. Park, R. Scott, P. A. Uber, and P. M. McFadden Cardiac allograft valvulopathy: a case of donor-anorexigen-induced valvular disease Ann. Thorac. Surg., November 1, 1999; 68(5): 1840 - 1841. [Abstract] [Full Text] [PDF]

				A. J. Burger, H. B. Sherman, M. J. Charlamb, J. Kim, L. A. Asinas, S. R. Flickner, and G. L. Blackburn Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months J. Am. Coll. Cardiol., October 1, 1999; 34(4): 1153 - 1158. [Abstract] [Full Text] [PDF]

				T. Higenbottam, H. Marriott, G. Cremona, E. Laude, and D. Bee The Acute Effects of Dexfenfluramine on Human and Porcine Pulmonary Vascular Tone and Resistance Chest, October 1, 1999; 116(4): 921 - 930. [Abstract] [Full Text] [PDF]

				S. S. Biswas, C. L. Donovan, J. M. Forbess, S. H. Royal, and K. P. Landolfo Valve replacement for appetite suppressant-induced valvular heart disease Ann. Thorac. Surg., June 1, 1999; 67(6): 1819 - 1822. [Abstract] [Full Text] [PDF]

				M. H. Kulke and R. J. Mayer Carcinoid Tumors N. Engl. J. Med., March 18, 1999; 340(11): 858 - 868. [Full Text] [PDF]

				P. Egermayer, G I. Town, and A. J Peacock Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension Thorax, February 1, 1999; 54(2): 161 - 168. [Full Text]

				A. P. Fishman Aminorex to Fen/Phen : An Epidemic Foretold Circulation, January 12, 1999; 99(1): 156 - 161. [Full Text] [PDF]

				M. A. Khan, C. A. Herzog, J. V. St. Peter, G. G. Hartley, R. Madlon-Kay, C. D. Dick, R. W. Asinger, and J. T. Vessey The Prevalence of Cardiac Valvular Insufficiency Assessed by Transthoracic Echocardiography in Obese Patients Treated with Appetite-Suppressant Drugs N. Engl. J. Med., September 10, 1998; 339(11): 713 - 718. [Abstract] [Full Text] [PDF]

				P. D. Thompson, X. Kurz, A. Van Ermen, S. Rasmussen, B. C. Corya, R. D. Glassman, B. Redmon, S. Raatz, J. P. Bantle, F. W. Wolff, et al. Valvular Heart Disease Associated with Fenfluramine-Phentermine N. Engl. J. Med., December 11, 1997; 337(24): 1772 - 1776. [Full Text]

				H. M. Connolly, J. L. Crary, M. D. McGoon, D. D. Hensrud, B. S. Edwards, W. D. Edwards, and H. V. Schaff Valvular Heart Disease Associated with Fenfluramine-Phentermine N. Engl. J. Med., August 28, 1997; 337(9): 581 - 588. [Abstract] [Full Text] [PDF]

				S. S. Kushwaha, J. T. Fallon, and V. Fuster Restrictive Cardiomyopathy N. Engl. J. Med., January 23, 1997; 336(4): 267 - 276. [Full Text] [PDF]

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