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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 ≤ -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 ≥ 77 μg/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).</p> <p>Conclusions</p> <p>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.</p

942-39 Carcinoid Heart Disease: Correlation of High Serotonin Levels with Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography

BackgroundAlthough seratonin 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 ResultsThe present study reviews the experience with 604 patients in the Duke Carcinoid Database. Nineteen patients with proven carcinoid heart disease (by cardiac catheterization and/or echocardiography) were compared with the remaining 585 noncardiac patients in the database with regard to circulating serotonin and its principle metabolite. 5-hydroxyindoleacetic acid (5-HIAA). No significant demographic differences existed between the cardiac and noncardiac groups; however, typical carcinoid syndrome symptoms (i.e. flushing and diarrhea) were almost threefold more common in the cardiac group (p&lt;0.001). 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% byechocardiography). No survival differences were found between the cardiac and noncardiac groups. Compared with the noncardiac group, heart disease patients demonstrated strikingly higher (p&lt;0.0001) mean serum serotonin (9750 vs 4350 pmoles/ml), plasma serotonin (1130 vs 426 pmoles/ml), platelet serotonin (6240 vs 2700 pmoles/mg protein), and urine 5-HIAA (219 vs 55.3 mg/24 hr).ConclusionsThese data suggest that serotonin plays a major role in the pathogenesis of the cardiac plaque formation observed in carcinoid patients

994-97 Quantitating Pulmonary Capillary Volume Using Digital Parametric Angiographic Analysis

Assessment of the distal pulmonary vasculature in patients with pulmonary hypertension has been limited to qualitative description of pulmonary arteriograms. Digital parametric imaging, using contrast density and transit time, has been used to qualitative blood volume and flow in the coronary and renal vascular beds. This study was performed to determine whether digital parametric imaging can quantitate vascular volume in the distal pulmonary capillary bed with pulmonary flow intact.Two digital angiograms of the pulmonary vasculature were acquired in 11 patients with varying degrees of pulmonary hypertension. A balloon flotation catheter was advanced distally into the pulmonary artery. The first angiogram (static image) was performed with blood flow occluded by inflation of the catheter balloon. Non-ionic contrast was then hand injected to completely fill the vasculature beyond the balloon occlusion. The second angiogram (flow image) was performed with the balloon deflated and blood flow preserved. A hand injection of a rapid bolus of contrast, 1–2 cc, was given. Digital subtraction image data were obtained at 15 frames/sec at end expiration for both angiograms. Contrast density measurements of the distal pulmonary vasculature were determined from the static images in various 2×2mm areas using digital parametric imaging. The maximum density in these same areas was similarly determined from the flow images.The correlation of the density measurements between the static and the flow images in 64 regions of interest was excellent (R=0.92, regression slope=0.98). This correlation was similar to that observed for repeated injections using the same technique (flow image) (R=0.97, regression slope=0.97).ConclusionDigital parametric measurements of pulmonary capillary volume obtained with blood flow preserved are the same as those obtained with flow occluded and the entire bed replaced by contrast. This method allows quantitation of pulmonary vascular volume and flow using a simple, single contrast injection in the distal pulmonary artery

978-120 Exercise Performance in Moderate Mitral Stenosis is Limited by Cardiac Output Reserve Rather than Maximal Pulmonary Capillary Wedge Pressure

To assess the hemodynamic limitations of exercise in patients with mitral stenosis (MS), 29 patients with MS (mean age 49, mean valve area 1.4 cm2) and 29 age matched controls underwent symptom limited upright bicycle exercise with simultaneous expired gas analysis, right heart catheterization and radionuclide angiography. Supine rest hemodynamics and left ventricular volumes were abnormal in MS patients compared to control. Despite maximal (MAX) exercise effort, MS patients achieved a lower MAX heart rate (HR) and oxygen consumption (VO2/kg) compared to control. With exercise. other intergroup differences were accentuated, especially for MAX cardiac index (CI), pulmonary capillary wedge pressure (PCWP), and end-diastolic volume index (EDVI)Rest and Exercise HemodynamicsVO2kgHRPCWPCIEDVIRESTMS2.675.819.12.451.5Control3.468.48.23.476.6MAXMS10.4131.029.14.043.1Control23.5162.38.47.865.2Mean values shown (p≤0.05 MS vs Control for all values)For the MS group, MAX VO2/kg was predicted by MAX CI (r=0.6) but not by MAX PCWP. Exercise was limited by fatigue rather than shortness of breath in 18/29 patients in the MS group, suggesting a low output state as a reason for exercise termination. No difference was seen in MAX PCWP between patients stopping due to fatigue and those stopping due to shortness of breath (27.3 vs 32.0mmHg, p=0.4).ConclusionExercise tolerance in patients with moderate mitral stenosis is not limited by MAX PCWP but by failure to augment cardiac output due to abnormal left ventricular diastolic filling and to chronotropic incompetence