Activin A in carcinoid heart disease: a possible role in diagnosis and pathogenesis.

BACKGROUND/AIMS: Carcinoid heart disease (CHD), a complication of neuroendocrine tumors (NETs), is characterized by right heart fibrotic lesions. Though serotonin is likely involved, the pathogenesis of CHD remains unclear. Cytokines and growth factors with fibrogenic properties may play a role. We sought to examine the relationship between plasma levels of fibrogenic cytokines and growth factors and CHD, both to provide further insight into possible biomarkers of CHD as well as into the possible pathogenesis of CHD. METHODS: Plasma samples obtained from 71 patients with NETs and 18 controls were analyzed using enzyme immunoassays. All patients underwent echocardiography. RESULTS: 15 patients (21%) had CHD, all of whom had carcinoid syndrome compared to 82% of those without CHD. CHD patients were older (p = 0.01), had larger (p = 0.007) and more numerous liver metastases (p = 0.04), and had elevated 24-hour urinary 5-hydroxyindoleacetic acid (U-5HIAA) (p = 0.03) and serum chromogranin A levels (p = 0.02). CHD patients had higher plasma levels of C-reactive protein (p = 0.03), osteoprotegerin (p = 0.005), and activin A (p = 0.005) than patients without CHD. A significant direct correlation between activin A and U-5HIAA levels was observed in the total patient group (r = 0.30, p = 0.02). Activin A ≥0.34 ng/ml (odds ratio (OR) 5.35 [1.01; 28.17], p = 0.048) and age ≥69.5 (OR 6.10 [1.60; 23.24], p = 0.008) were independent predictors of CHD. Activin A levels were elevated to the same degree in both early and advanced CHD. Activin A ≥0.34 ng/ml had 87% sensitivity and 57% specificity for detecting CHD (p = 0.006). CONCLUSION: Elevated plasma activin A levels are associated with the presence of CHD.

Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors.

BACKGROUND: Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV) dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2) is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease. METHODS: Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation. RESULTS: Mean strain was -21% +/- 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% +/- 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain < or = -20%, mean -25% +/- 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 > or = 77 microg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03). CONCLUSIONS: Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.

Small intestinal neuroendocrine tumors: prognostic factors and survival.

OBJECTIVE: Small intestinal neuroendocrine tumors (SI-NETs) make up 38% of gastroenteropancreatic neuroendocrine tumors. We report our experience with SI-NETs at the National Center for Neuroendocrine Tumors in Norway, focusing on prognostic factors and survival. MATERIAL AND METHODS: The medical records of 258 patients with SI-NETs diagnosed between 1983 and 2007 were retrospectively reviewed. Demographic, clinical and tumor characteristics were registered in a database. RESULTS: Median age at diagnosis was 62 years (range 28-84); 53% of patients were men. Median survival was 9.3 years [95% confidence interval (CI) 7.6; 10.8]. Survival did not improve for patients diagnosed between 1998 and 2007 compared with those diagnosed between 1990 and 1997 (p=0.44), median survival 8.1 [7.1;9.1] versus 6.8 [4.0; 9.5] years. Overall 5-year survival was 72%, while expected 5-year survival in the general population was 92%. The corresponding relative 5-year survival for the patient group was 78%. Distant metastases, urinary 5-hydroxyindoleacetic acid ratio > or =3.7 times the upper limit of normal, chromogranin A ratio > or =6.2 times the upper limit of normal, age > or =64, male gender, carcinoid heart disease, and Ki-67 > or =5% were associated with decreased survival. Using multivariate analysis, only distant metastases (hazard ratio (HR) 1.98 [1.04;3.76], p=0.04), chromogranin A ratio > or =6.2 (HR 1.90 [1.12; 3.20], p=0.02), and age > or =64 (3.12 [1.93; 5.04], p<0.001) remained independent predictors. CONCLUSIONS: Survival did not improve over the study period. Overall and relative 5-year survival compared favorably with that in population-based studies. Distant metastases, elevated chromogranin A levels, and advanced age were the only independent predictors of poor survival.