The aim of this study was to evaluate the prognostic value of tissue Doppler imaging (TDI) in carcinoid heart disease (CHD). We prospectively enrolled 56 consecutive patients with proved digestive endocrine tumor and carcinoid syndrome. All patients underwent serial conventional, contrast, and TDI echocardiographic studies. The end point was all-cause mortality. Mean follow-up was 34 ± 21 months. At the end of follow-up, 30 patients (54%) presented right CHD and 13 patients (23%) left CHD. A progression of CHD was documented in 23 patients (41%). Twenty-two patients (39%) died during follow-up. According to mortality receiver operating characteristic curves, ratio of early transmitral flow velocity to early diastolic mitral annulus velocity (E/e′ ratio) associated with an optimal sensitivity of 80% and specificity of 90% was 8. Mortality rate was significantly higher when the E/e′ ratio was ≥8 (94% vs 10% when E/e′ ratio was <8, p <0.0001). Using univariate analysis, the following factors were associated with death: left-sided CHD (p = 0.07) and E/e′ ratio ≥8 (p <0.0001). The only independent marker of death detected by multivariate analysis was an E/e′ ratio ≥8 (odds ratio 6.2, 95% confidence interval 1.95 to 19.7, p = 0.002). In conclusion, TDI used during routine transthoracic echocardiography can be helpful to identify high-risk patients with CHD.
Carcinoid heart disease (CHD), which is mainly defined as a valvular heart disease, may occur in patients presenting with digestive endocrine tumor and carcinoid syndrome. In recent years, prognosis of CHD has been significantly improved, suggesting the utility of efficient cardiac surgery. However, the detection of patients with CHD and better prognosis is still unclear and may help in selecting patients who will benefit from cardiac surgery. Tissue Doppler imaging (TDI) is a recent echocardiographic Doppler tool for determination of left ventricular filling pressure and previous studies have demonstrated its prognostic value in different clinical settings. The main echocardiographic criterion derived from mitral TDI is the ratio of early transmitral flow velocity to early diastolic mitral annulus velocity (E/e′ ratio) and is currently measured during routine examinations. The aim of this study was to evaluate the prognostic value of TDI in CHD.
Methods
From January 1998 to December 2005, we prospectively studied patients presenting with digestive endocrine tumor and carcinoid syndrome. Entry criteria included age >18 years, histologically proved digestive endocrine tumor, carcinoid syndrome defined by the presence of ≥1 of the following criteria (flushing, secretory diarrhea, or wheezing), and ≥12-month follow-up. Patients with previous heart disease (n = 3) or requiring urgent valvular surgery (n = 2) were excluded. Presence of carcinoid syndrome was assessed by 2 experienced investigators (EM and PR). According to guidelines, we investigated digestive endocrine tumor using multiple imaging techniques (ultrasound studies, computed tomography, magnetic resonance imaging, and colonoscopy) and laboratory carcinoid markers (urinary 5-hydroxyindoleacetic acid [5-HIAA], normal value <40 mg/24 hour; and chromogranin A, normal value <100 ng/ml). Treatment and management of patients were left to the discretion of the physician.
CHD was systematically assessed using conventional transthoracic echocardiography, once the diagnosis of carcinoid syndrome was made. All patients had ≥2 echocardiographic examinations (echocardiographic follow-up ≥12 months) and echocardiographic examinations were systematically performed yearly. Right-sided CHD was defined as tricuspid or pulmonary valvular injury (thickening, retraction, or decreased valvular mobility) associated with tricuspid or pulmonary regurgitation or stenosis ( Figure 1 ) and left-sided CHD was defined as significant mitral or aortic regurgitation associated with a decrease of mitral or aortic valvular mobility. CHD progression was assessed using a previous validated scoring system.
During transthoracic echocardiography, we systematically assessed mitral inflow in an apical 4-chamber view, the sample volume of pulse-wave Doppler being placed at the mitral valve tips. Peak Doppler velocities of mitral inflow (E wave and A wave) and mitral E-wave deceleration time were measured. With the pulse-wave TDI program, a sample volume was placed at the lateral corner of the mitral annulus in the 4-chamber view. Analysis was performed for the early diastolic peak velocity (E′ wave). The E/e′ ratio was thus calculated.
Contrast transthoracic echocardiography was performed at the end of conventional transthoracic echocardiography, searching for a right-to-left atrial shunt through a patent foramen ovale. A minimum of 3 injections of stirred 5% glucose solution (10 ml) through an upper extremity vein was performed and patent foramen ovale was affirmed when >8 microcavitations passed from the right to left atrium within the first 3 cardiac cycles after contrast appearance in the right atrium, at rest, and after a Valsalva maneuver and/or a cough test.
Follow-up was performed in collaboration with physicians of our institution or was established by telephone contact with the patients or their families. The primary end point was all-cause mortality.
Continuous variables are presented as mean ± SD and ranges, unless otherwise specified. Categorical data are presented as absolute values and percentages. Continuous and categorical variables were compared with chi-square test, paired t tests, unpaired t tests, or Fisher’s exact test, as appropriate. Investigation for a prognostic cutoff of the E/e′ ratio was based on receiver operating characteristic curves. The cut-off value of the E/e′ ratio was calculated according to the results of sensitivity and specificity. Survival curves were established by the Kaplan-Meier method. Comparisons of death rates were tested with log-rank test. Prognostic factors of CHD were identified by univariate analysis (age, urinary 5-HIAA level, plasma chromogranin A level, right-sided CHD, left-sided CHD, progression of CHD, patent foramen ovale, mitral E wave deceleration time, and E/e′ ratio) and significant markers of prognosis (p <0.20) were evaluated in multivariate analysis (logistic regression). A p value <0.05 was considered to indicate statistical significance. All analyses were performed using STATA 8.0 (STATA Corp., College Station, Texas).
Results
Fifty-six consecutive patients (27 men, 29 women) were enrolled and patient characteristics are presented in Table 1 . Mean age of the population was 59 ± 11 years (range 36 to 83). No included patients had hypertension or other heart disease. One hundred forty-one transthoracic echocardiographic examinations were completed ( Table 2 ). All patients had ≥2 echocardiographic examinations. At the end of echocardiographic follow-up (mean duration 29 months, range 12 to 60), a progression of CHD was documented in 23 patients (41%). The incidence of left-sided CHD was increased during follow-up (p = 0.04). Left ventricular ejection fraction was not significantly different in patients with or without CHD (p = 0.45; Table 2 ). Mean urinary 5-HIAA and mean chromogranin A were significantly higher in patients with CHD (p = 0.02 and p = 0.04, respectively).
| Characteristics | All Patients (n = 56) | Patients With CHD (n = 30) | Patients Without CHD (n = 26) | p Value ⁎ |
|---|---|---|---|---|
| Age (years) | 59 ± 11 | 60 ± 10 | 59 ± 12 | 0.82 |
| Women | 29 (52%) | 15 (50%) | 14 (54%) | 0.77 |
| Primary site of tumor | ||||
| Foregut | 7 (12%) | 4 (13%) | 3 (12%) | 0.99 |
| Stomach | 4 (7%) | 2 (7%) | 2 (8%) | — |
| Pancreas | 3 (5%) | 2 (7%) | 1 (4%) | — |
| Midgut | 44 (79%) | 24 (80%) | 20 (77%) | 0.99 |
| Ileo-jejunum | 42 (75%) | 23 (77%) | 19 (73%) | 0.77 |
| Proximal colon | 2 (4%) | 1 (3%) | 1 (4%) | — |
| Hindgut | 5 (9%) | 2 (7%) | 3 (12%) | 0.65 |
| Distal colon | 3 (5%) | 1 (3%) | 2 (8%) | — |
| Rectum | 2 (4%) | 1 (3%) | 1 (4%) | — |
| Metastases | 56 (100%) | 30 (100%) | 26 (100%) | — |
| Treatment (during follow-up) | ||||
| Somastatin analog | 43 (77%) | 23 (77%) | 20 (77%) | 0.98 |
| Hepatic artery embolization | 22 (39%) | 10 (33%) | 12 (46%) | 0.33 |
| Chemotherapy | 27 (48%) | 13 (43%) | 14 (54%) | 0.43 |
| Highest value of urinary 5-hydroxyindoleacetic acid level (mg/24 hours) | ||||
| Median | 251 ± 330 | 358 ± 407 | 123 ± 119 | 0.02 |
| Range | 22–1,776 | 22–1,776 | 23–500 | |
| Highest value of plasmatic chromogranin A level (ng/ml) | ||||
| Median | 250 ± 1,278 | 958 ± 1,506 | 400 ± 871 | 0.04 |
| Range | 43–5,777 | 44–5,777 | 43–4,430 |
| Baseline | Follow-up | |||
|---|---|---|---|---|
| Patients With CHD (n = 21) | Patients Without CHD (n = 35) | Patients With CHD (n = 30) | Patients Without CHD (n = 26) | |
| Right-sided carcinoid heart disease | 21 (100%) | 0 (0%) | 30 (100%) | 0 (0%) |
| Tricuspid injury | 18 (86%) | 0 (0%) | 29 (97%) | 0 (0%) |
| Pulmonary injury | 14 (67%) | 0 (0%) | 24 (80%) | 0 (0%) |
| Left-sided carcinoid heart disease | 5 (24%) | 0 (0%) | 13 (43%) | 0 (0%) |
| Mitral regurgitation (moderate or severe) | 3 (14%) | 0 (0%) | 11 (37%) | 0 (0%) |
| Aortic regurgitation (moderate or severe) | 4 (19%) | 0 (0%) | 7 (23%) | 0 (0%) |
| Patent foramen ovale | 5 (24%) | 7 (20%) | 17 (57%) | 5 (19%) |
| Mitral E-wave velocity (m/s) | 0.56 ± 0.29 | 0.53 ± 0.2 | 0.62 ± 0.3 | 0.57 ± 0.22 |
| Mitral A-wave velocity (m/s) | 0.53 ± 0.26 | 0.58 ± 0.35 | 0.56 ± 0.32 | 0.61 ± 0.3 |
| Mitral e′-wave velocity (m/s) | 0.10 ± 0.08 | 0.11 ± 0.03 | 0.09 ± 0.06 | 0.11 ± 0.04 |
| E/e′ ratio | 6.7 ± 3.9 | 6.6 ± 1.9 | 7.8 ± 4.2 | 7 ± 2.6 |
| Left atrial diameter (mm) | 39.9 ± 3.5 | 37.8 ± 3.3 | 41.3 ± 4.1 | 38.1 ± 3.6 |
| Left ventricular ejection fraction (%) | 68 ± 5 | 67 ± 3 | 66 ± 6 | 67 ± 4 |
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