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Background: Carcinoid heart disease (CHD) can develop in patients with carcinoid syndrome (CS), itself caused by overproduction of hormones and other products from some neuroendocrine tumours. The most common hormone is serotonin, detected as high 5-hydroxyindoleacetic acid (5-HIAA). This systematic literature review summarises current literature on the impact of CHD on survival, and the relationship between 5-HIAA levels and CHD development, progression, and mortality., Methods: MEDLINE, Embase, Cochrane databases, and grey literature were searched using terms for CHD, 5-HIAA, disease progression, and mortality/survival. Eligible articles were non-interventional and included patients with CS and predefined CHD and 5-HIAA outcomes., Results: Publications reporting on 31 studies were included. The number and disease states of patients varied between studies. Estimates of CHD prevalence and incidence among patients with a diagnosis/symptoms indicative of CS were 3-65% and 3-42%, respectively. Most studies evaluating survival found significantly higher mortality rates among patients with versus without CHD. Patients with CHD reportedly had higher 5-HIAA levels; median urinary levels in patients with versus without CHD were 266-1,381 versus 67.5-575 µmol/24 h. Higher 5-HIAA levels were also found to correlate with disease progression (median progression/worsening-associated levels: 791-2,247 µmol/24 h) and increased odds of death (7% with every 100 nmol/L increase)., Conclusions: Despite the heterogeneity of studies, the data indicate that CHD reduces survival, and higher 5-HIAA levels are associated with CHD development, disease progression, and increased risk of mortality; 5-HIAA levels should be carefully managed in these patients., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Carcinoids are rare tumors originating from neuroendocrine cells. A large proportion of these tumors produce serotonin and other biologically active hormones which may produce carcinoid syndrome characterized by flushing, diarrhoea and bronchospasm. Carcinoid heart disease, a rare complication of carcinoid syndrome, may itself have a great impact on life expectancy of patients with carcinoid syndrome. The authors present a case history of a patients with carcinoid heart disease and they review the symptoms, diagnosis and therapeutic options of this rare complication of carcinoid syndrome.

Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting., (Copyright © 2011. Published by Elsevier Inc.)

The carcinoid syndrome is usually evident when enterochromaffin (EC) cell-derived neuroendocrine tumors (carcinoids) metastasize to the liver. In addition to carcinoid symptomatology, about 40% of patients exhibit carcinoid heart disease (CHD) with fibrotic endocardial plaques and associated heart valve dysfunction. The mechanism behind CHD development is not fully understood, but serotonin (5-HT) is considered to be a major initiator of the fibrotic process. Most patients present with right-sided heart valve dysfunction since pulmonary and tricuspid valves lesions are the most common (>95%) cardiac pathology. Left-sided valvular involvement, and angina associated with coronary vasospasm occur in ~10% of subjects with CHD. Pathognomonic echocardiograpic features include immobility of valve leaflets and thickening and retraction of the cusps most commonly resulting in tricuspid valve regurgitation and pulmonary stenosis. Therapeutic options include cardioactive pharmacotherapy for heart failure and, in selected individuals, cardiac valve replacement. Previously valve replacement was reserved for advanced disease due to a perioperative mortality of >20% however in the last decade, technical advances as well as an earlier diagnosis have decreased surgical mortality to <10% and valve replacements are undertaken more frequently. A recent analysis of 200 cases demonstrated an increase in median survival from 1.5 years to 4.4 years in the last two decades. Although the improved prognosis might also reflect the increased use of surgical cytoreduction, hepatic metastatic ablative therapies and somatostatin analogs a robust correlation between diminution of circulating tumor products and an increased long-term survival in CHD has not been rigorously demonstrated.

Background: Carcinoid heart disease occurs in over 65% of patients with the carcinoid syndrome and is characterized by fibrous thickening of cardiac valves, leading to heart failure. Whether serotonin is directly responsible for these cardiac abnormalities is unknown. Therefore, to further understand the etiology and pathophysiology of carcinoid heart disease, we developed an animal model of the carcinoid syndrome., Materials and Methods: Seventeen nude mice underwent intrasplenic injection of human pancreatic carcinoid BON cells (10(7)) and then were euthanized 9 weeks later. Murine livers were analyzed by immunohistochemistry. Murine hearts were sectioned and the surface area of the right heart valves determined. Blood was also collected and analyzed for platelet serotonin by ELISA., Results: Sixty-five percent of the mice developed gross carcinoid liver metastases demonstrated by chromogranin-A-staining lesions within the liver. Mice with carcinoid liver metastases had elevated platelet serotonin levels (1058 +/- 529 ng/ml versus 123 +/- 52 ng/ml, P = 0.002) when compared to the controls. Animals with carcinoid liver metastases also had a trend toward greater tricuspid valvular surface areas (242 +/- 24 versus 174 +/- 25 microm, P = 0.08). On histological examination, this increase in tricuspid surface area in mice with liver metastases appeared to be due to fibrosis of the valvular tissues, consistent with the pathologic findings of carcinoid heart disease., Conclusions: Using this novel animal model of carcinoid syndrome, the tricuspid valve thickening resembling carcinoid heart disease could be due to exposure to factors such as serotonin secreted by carcinoid tumor cells.

Background: Serotonin excretion plays a role in the development of carcinoid heart disease (CHD), but the exact pathogenesis is not known. In the current study, the authors evaluated 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion, as well as plasma levels of transforming growth factor-beta (TGF-beta), fibroblast growth factor (FGF), and atrial natriuretic peptide (ANP) in patients with and without CHD determined by ultrasound examination., Methods: Urine and plasma samples were obtained for 37 patients and cardiac ultrasound was performed during follow-up in 1999 and 2000. Median 5-HIAA excretion was calculated for the period between diagnosis and ultrasound examination. CHD was defined as the thickening of the tricuspid valve with additional III-IV/IV tricuspid valve regurgitation., Results: CHD was found in 9 of 37 patients (24%). No significant differences were found for age, gender, presence, and duration of liver metastases. All CHD patients had symptoms of the carcinoid syndrome compared with 71% of the non-CHD patients (P = 0.159). Median 5-HIAA excretion was significantly higher in the CHD group compared with the non-CHD group: 576 micromol/24 hours versus 233 micromol/24 hours (P = 0.02). No difference in TGF-beta and FGF plasma levels was observed between both groups (P = 0.139 and P = 0.985, respectively), nor was there a correlation with morphology of the tricuspid valve or degree of dilatation of the right atrium/ventricle. However, the CHD group had higher median ANP levels than the non-CHD group: 48 ng/L and 25 ng/L, respectively (P = 0.026)., Conclusions: High levels of 5-HIAA excretion and plasma ANP were found to be associated with CHD. No significant relation with TGF-beta or FGF was been found., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11226)

The need for more detail regarding the clinical and morphological features of human heart valves has become evident due to recent controversy regarding anorexigen-associated valvular dysfunction. In the present study, we used quantitative digital image analysis of geometric and compositional features to compare the histopathology of cardiac valves excised from patients treated with anorexigens as compared to normal, floppy, rheumatic and carcinoid valves. Anorexigen-exposed valves had the greatest number of onlays/valve (P<.0001), while rheumatic valves showed the greatest average onlay size and thickness of the comparison groups studied (P=.01). The valve onlays from anorexigen-exposed, carcinoid and floppy valves contained a greater percentage of glycosaminoglycans (GAGs) as compared to normal and rheumatic valves (P=.01). The anorexigen-exposed valve propers contained more GAGs than any other comparison group (P=.02). Vessels were prominent in both onlay and valve proper regions of carcinoid valves, in the anorexigen-exposed valve onlays and in rheumatic valve propers. Thus, the number of onlays, their size, the degree of GAG deposition, and the presence and location of vessels and leukocytes were important features distinguishing anorexigen-exposed valves from normal valves. Discriminant analyses, based on geometry, color composition or color composition, and vessel and leukocyte counts combined, were able to separate the valves into distinguishable groups. Our findings demonstrate that specific microscopic features can be used to separate anorexigen-associated heart valve lesions from normal valves and valve lesions associated with other pathologies, and suggest that a distinctive pathological process may exist in many anorexigen-exposed valves.

We report a case of left ventricular (LV) myocardial uptake of a labeled somatostatin analog in a patient with a carcinoid tumor of the small bowel. The patient developed liver metastases and a carcinoid syndrome, including right carcinoid heart disease, without right-to-left shunt on contrast ultrasonography or left ventricular myocardial metastases. The basis for visualization of the LV myocardium is probable somatostatin receptor upregulation.

Carcinoid heart disease is a complication of a neuroendocrine carcinoid tumor. Morphologically, it is characterized by the formation of fibrotic plaques with deposition of extracellular matrix in the subendocardium, frequently causing heart valve dysfunction and cardiac failure. Because members of the transforming growth factor-beta (TGF-beta) family are known to stimulate fibroblasts in their production of extracellular matrix, we investigated the expression of the three isoforms of TGF-beta and the binding protein for latent TGF-beta 1 (LTBP) in carcinoid plaques of the right side of the heart, as well as from control tissue, using immunohistochemistry. Tissue specimens were obtained intraoperatively from nine consecutive patients undergoing valve replacement surgery. TGF-beta 1 and TGF-beta 3 were detected in the fibroblasts of all plaques analyzed, whereas TGF-beta 2 was only rarely expressed. The localization of LTBP was partly concordant with that of TGF-beta 1, but the positive staining for LTBP was extracellular. Sections from unaffected heart tissue contained few fibroblasts in the subendocardium, showing only weak or no immunostaining for TGF-beta 1, -beta 2, and -beta 3 and no staining for LTBP. These results suggest that TGF-beta may play a role in the proliferation of fibroblasts and their matrix production in carcinoid heart lesions.

Deficiency of tryptophan with elevated serum serotonin and liver dysfunction are the prerequisites for the experimental production of cardiac lesions in the guinea pig model of carcinoid syndrome. To apply the above principles in human subjects with carcinoid disease, various indole markers were compared in patients with or without heart involvement, to a group of normal subjects. In the present study, plasma tryptophan (T), serotonin (5HT), and urinary 5 hydroxyindoleacetic acid (5HIAA) measurements were made in 18 (group 1) patients with carcinoid syndrome and 24 normal individuals (group 2). Of the 18 patients, seven (group 1A) had valvular involvement and 11 (group 1B) had none, as determined by clinical, roentgenographic, and echocardiographic (M-mode and 2-D) techniques. Analysis of the above data shows that unlike animal models, there is no difference in serum tryptophan, serum serotonin, and urinary 5 hydroxyindoleacetic acid levels, in patients with carcinoid syndrome with or without cardiac involvement (p greater than 0.05). Furthermore, the data confirm that serum tryptophan, a substrate in carcinoid syndrome, is decreased and in serum serotonin and urinary 5 hydroxyindoleacetic acid, the metabolites are elevated.

The uptake and storage of 5-hydroxytryptamine by human platelets from normal donors and patients with the carcinoid syndrome are reported. When platelets were incubated in the presence of 3H-5-hydroxytryptamine (50 microM), an initial phase of rapid uptake was observed until 5-hydroxytryptamine levels of 1--2 microgram/10(9) cells were reached. Further accumulation occurred more slowly. Electron microscopic autoradiography of cells after 5-hydroxytryptamine uptake for 60 minutes revealed that in platelets from normal donors most of the label was localized in membranes (52%), alpha granules (27%), and cytoplasm (4%). Dense bodies were associated with 18% of the silver grains. Similar membrane (50%) and alpha-granule (27%) labeling was found with platelets from patients with carcinoid syndrome. However, more cytoplasmic labeling (10%) and less dense-body labeling (11%) were found with these cells. The results support a hypothesis of two or more sites for storage of 5-hydroxytryptamine in mammalian platelets and suggest that minimal exchange between cytoplasmic and dense-body amines occurs in carcinoid platelets.