Cardiotrophin-1 (21. Cardiotrophin-1 in Circulation)

Cardiotrophin-1 as a stable analyte

CT-1 is stable in specimens of whole blood treated with EDTA and aprotinin and stored for up to 48 hours at room temperature or on ice, hence permitting its development in the routine clinical investigation ^Ref .

Heart is also a source of cardiotrophin-1 in circulation

There was a significant increase in the plasma CT-1 concentration from the aorta and coronary sinus, which clearly indicates that the heart secretes CT-1 via the coronary sinus into the peripheral circulation ^Ref .

Heart failure

Significant elevation of plasma CT-1 in patients with heart failure was reported ^Ref .
In patients with left ventricular systolic dysfunction (LVSD) [median wall motion index 0.6 (range 0.3–1.4)], CT-1 was elevated [median 110.4 fmol/ ml (range 33–516 fmol/ml)] compared with controls [wall motion index 2 in all cases; median CT-1 level 34.2 fmol/ml (range 6.9–54.1 fmol/ml); P<0.0001]. Log CT-1 was correlated with log wall motion index (r=-0.76, P<0.0001), log left ventricular end-systolic volume (r=0.54, P<0.05), stroke volume (r=-0.60, P=0.007) and log fractional shortening (r=-0.70, P=0.001). In a multivariate model of the predictors of log wall motion index, the only significant predictor was log CT-1 (R(2)=56%, p=0.006). This demonstrates that CT-1 is elevated in heart failure in relation to the severity of LVSD ^Ref . The plasma CT-1 level was increased in dilated cardiomyopathy (DCM) patients with the severity of congestive heart failure (CHF) and was significantly higher in the large left ventricular (LV) mass group than in the small LV mass group, despite the absence of a difference in LV ejection fraction between the two groups. In addition, there was a significant positive correlation between the plasma CT-1 level and the LV mass index (r = 0.627, P < 0.0001). According to stepwise multivariate analyses among hemodynamic and neurohumoral factors, a high plasma CT-1 level showed an independent and significant positive relationship with a large LV mass index in patients with DCM. These results indicate that the plasma CT-1 level is increased in patients with DCM and is significantly correlated with the LV mass index, suggesting that CT-1 plays an important role in structural LV remodeling in patients with DCM ^Ref . Using a novel non-competitive assay measurements of CT-1 levels in patients with heart failure (median 166.5 fmol/ml; range 49.5–2788 fmol/ml) revealed very significantly elevated levels compared with those in normal controls (median 43.5 fmol/ml; range 11.2–258.6 fmol/ml; P<0.0001 by Mann-Whitney test). At a CT-1 concentration of 68 fmol/ml, sensitivity and specificity were 95% and 82.5% respectively. Thus this new non-competitive immunochemilu­minometric assay for CT-1 could successfully detect full-length recombinant CT-1 in unextracted plasma, and demonstrated that plasma levels of CT-1 were significantly elevated in patients with heart failure ^Ref . A comparison between patients with cfronique kidney disease having left ventricular hypertrophy (LVH) with those without LVH showed significant differences in plasma levels CT-1 (P < 0.002) ^Ref .

Prognosis of chronique heart failure

Prognostic significance was assessed using the measurement the plasma levels of CT-1, brain natriuretic peptide (BNP), and IL-6 in 125 patients with chronique heart failure (CHF). Patients were monitored for a mean follow-up period of 2.9 years.plasma levels of CT-1 increased with severity of CHF.there was a significant negative correlation between plasma CT-1 and left ventricular ejection fraction. There was a significant correlation between plasma CT-1 and log IL-6. During the follow-up period, 37 patients died. High plasma levels of CT-1, BNP, and IL-6 were independent predictors of mortality on stepwise multivariate analysis. The hazard ratio for mortality in patients with plasma BNP>170 pg/mL and CT-1>658 fmol/mL was 2.48 (95% confidence interval, 1.217–5.060) compared to those with plasma BNP>170 pg/mL and CT-1<658 fmol/mL (p=0.0124). These findings indicate that plasma CT-1 measurement provides additional prognostic information and that combined levels of CT-1 and BNP are more accurate at predicting mortality in patients with CHF than either marker alone ^Ref .

Valvular disease

Regurgitation

Anothert study involved patients with mitral (MR),tricuspidal (TR) and aortic (AR) regurgitation. Sixty-three subjects had no significant valvular lesion, seven had moderate/severe MR, nine had moderate/severe TR and four had moderate/severe AR. These subjects had CT-1 concentrations of 53. 3+/23.2, 90.5+/-44.4, 72.6+/-43.8 and 48.4+/-24.4, respectively (P=0.02, ANOVA). Mean log CT-1 was higher in those with moderate/severe MR when compared to those without a significant regurgitant valvular lesion (p<0.03). The only predictor of moderate/severe MR was log CT-1 (P=0.004). It was concluded that these results suggest that plasma CT-1 is raised in those patients with moderate/severe MR in the presence of normal left ventricular systolic function. This secretion of CT-1 could potentially be the cause of ventricular dilatation and subsequent loss of contractile function in these patients. It also offers the intriguing possibility that plasma CT-1 could be used to monitor progression of mitral regurgitation biochemically ^Ref .

Stenosis

Another study compared plasma NT proBNP and CT-1 in 15 aortic stenosis (AS) patients [five males, mean age 79 years [range 60–94], mean trans-valvular pressure gradient (TPVG) 39.3 mmhg (20–100)] with 10 controls (five male, mean age 68 years [56–79]). Results are expressed as mean [ranges] and comparisons were by the Mann-Whitney test. NT proBNP levels were elevated in AS patients [252.9 fmol/ml (79.2–541.8)] when compared with the controls (157.2 fmol/ml [104.7–236.9], P<0.005). Also CT-1 levels were elevated in AS patients (57.3 fmol/ml [33–86.3] when compared with the controls [28.3 fmol/ml (6.9–48.3), P<0.0005]. Both NT proBNP and CT-1 levels were correlated to the TVPG (r=0.53 and r=0.65, P<0.05 and P=0.009, respectively). On best subset analysis the strongest correlate with TVPG was CT-1 (r2=38%). The addition of NT proBNP did not improve diagnostic accuracy (r2=39%). These results suggest NT proBNP and CT-1 levels increase in proportion to the TVPG and could potentially be used to monitor progression of disease non-invasively. These markers may also be useful to identify the optimum time for surgery in AS ^Ref .

Hypertension

Plasma levels of CT-1 in patients with untreated hypertension (UTH, 606+/18 pmol/L, n=24) were significantly higher than those in age-and BMI-matched normotensive volunteers (nt, 546+/-12 pmol/L, n=31, p<0.01 vs. UTH). CT-1 levels in matched patients with treated hypertension (tht, 618+/10 pmol/L, n=35) were similar to those in UTH patients, but higher than in nt controls (p<0.01). Plasma CT-1 demonstrated a weak but significant correlation with systolic blood pressure in all patients (r=0.241, p<0.05, n=90) ^Ref . Another study was performed in 118 patients with never-treated hypertension and without prevalent cardiac disease. The left ventricular mass prediction from stroke work (systolic blood pressure x doppler stroke volume), sex, and height (in meters (2.7)) was derived. An observed left ventricular mass/predicted left ventricular mass value >128% defined inappropriate left ventricular mass. Plasma cardiotrophin-1 was measured by an enzyme-linked immunosorbent assay. The studies were repeated in a group of 45 patients after 1 year of antihypertensive treatment. At baseline 67 and 51 patients presented with appropriate and inappropriate left ventricular mass, respectively. Plasma cardiotrophin-1 was higher (P<0.001) in patients with inappropriate mass than in patients with appropriate mass and normotensive controls. A direct correlation was found between cardiotrophin-1 and observed left ventricular mass/predicted left ventricular mass ratio (r=0.330, P<0.001) in all hypertensive patients. After treatment, plasma cardiotrophin1 decreased and increased in patients in which inappropriate left ventricular mass regressed and persisted, respectively, despite a similar reduction of blood pressure in the 2 subgroups of patients. Albeit descriptive in nature, these results suggest the hypothesis that an excess of cardiotrophin-1 may contribute to inappropriate left ventricular growth in hypertensive patients ^Ref . The left ventricular mass index (LVMI) was normalized in 23 patients (49%) and persisted at an abnormally increased level in 24 patients (51%) after 1 year of treatment, whereas the reduction in clinic and home blood pressure was similar in the two groups: CT-1 decreased (-48%, P < 0.005) and increased (+35%, P < 0.05) in patients in whom left ventricular hypertrophy (LVH) regressed and LVH persisted, respectively. Final values of CT-1 were inversely correlated (r = 0.534, P < 0.001) with the decrease in LVMI after treatment in all patients.a significant association (chi2 = 16.87,P < 0.001) was found between normalization of CT-1 and regression of LVH with treatment.a cut-off value of 41 fmol/ml for CT-1 provided a relative risk of 43.13 (95% confidence interval, 4.88–380.48) for detecting LVH regression. These results show an association between treatment-induced decrease of plasma CT-1 and LVH regression in essential hypertension. Although preliminary, these findings suggest that the determination of plasma CT-1 may be useful for the follow-up of hypertensive heart disease in routine clinical practice ^Ref .

Ischemic heart disease

In another study, cardiotrophin 1 concentration was 142.5 fmol/ml (42. 2 527.4 fmol/ml) in unstable angina, 73.2 fmol/ml (41.5–102.1 fmol/ml) in stable angina (p < 0.05 v unstable angina), and 27 fmol/ml (6.9–54.1 fmol/ml) in controls (p < 0.0005 v stable angina; p < 0.0001 v unstable angina). Log cardiotrophin 1 correlated with log N-BNP in unstable angina (r = 0.93, p < 0.0001). Both circulating N-BNP and cardiotrophin 1 are raised in unstable angina,while cardiotrophin 1 alone is raised in stable angina.the role of cardiotrophin 1 and the relation between cardiotrophin 1 and N-BNP in myocardial ischaemia remain to be defined ^Ref . Serial measurements of plasma CT-1 levels were made in 60 patients at 14–48 h, 49–72 h, 73–120 h and 121–192 h following acute myocardial infarction (aMi) and at a later clinic visit. LV function was assessed using a LV wall motion index (WMi) score on admission (WMi-1) and at the clinic visit (WMi-2). Compared with values in control subjects (29.5+/-3.6 fmol/ml), the plasma CT-1 concentration was elevated in aMi patients at 14–48 h (108.1+/-15.1 fmol/ml), 49–72 h (105.2+/-19.7 fmol/ml), 73–120 h (91.2+/-14.9 fmol/ml) and 121–192 h (118.8+/-22.6 fmol/ml), and at the clinic visit (174.9+/-30.9 fmol/ml) (P<0.0001). Levels were higher following anterior compared with inferior aMi. For patients with anterior aMi, CT-1 levels were higher at the clinic visit than at earlier times. WMi-1 correlated with CT-1 at all times prior to hospital discharge (P<0.05). On best subsets analysis, the strongest correlate with WMi-1 was CT-1 level at 49–72 h (R(2)=20%, P<0.05). In conclusion, plasma levels of CT-1 are elevated soon after aMi in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after aMi is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after aMi ^Ref .

Prognosis of heart failure and death after acute myocardial infarction

In a recent study, 291 post-aMi patients were examined. There were 27 deaths and 19 readmissions with heart failure. CT-1 was raised in patients with death or heart failure compared with survivors (median [range] fmol/mL, 0.9 [0.1–392.2] vs. 0.67 [0–453.3], P = .019). Using a multivariate binary logistic model CT-1 (OR 1.8, 95% CI: 1.1–3.2, P = .031) and NT-proBNP (or 2.4, 95% CI: 1.1–5.2, P = .026) predicted death or heart failure independently of age, sex, previous aMi, serum creatinine, and Killip class. The receiver-operating curve for CT-1 yielded an area under the curve (AUC) of 0.62 (95% CI: 0.53–0.70, P = .017); for NT-proBNP the AUC was 0.77 (95% CI: 0.69–0.86, P < .001); the logistic model combining the 2 markers yielded an AUC of 0.84 (95% CI: 0.78–0.91, P < .001). After an aMi, combined levels of CT-1 and NT-proBNP are more informative at predicting death or heart failure than either marker alone ^Ref .

Metabolic syndrom

Increased CT-1 serum levels were observed in patients with metabolic syndrome (MS) compared with control subjects (127 +/- 9 vs. 106 +/- 4 ng/ml, P < 0.05). Circulating levels of CT-1 were associated with glucose levels (r = 0.2, P < 0.05). These data suggest that adipose tissue can be recognized as a source of CT-1, which could account for the high circulating levels of CT-1 in patients with MS ^Ref .

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