Heart failure is characterized by unfavorable prognosis [
Endocan is a novel biomarker, which has been closely associated with endothelial dysfunction and low-grade inflammation [
The aim of the present study was to describe baseline values of endocan in individuals with chronic HF and to evaluate the potential prognostic impact of the novel biomarker on morbidity and mortality in ambulatory HF patients.
One hundred and twenty consecutive chronic HF patients from the RESPOND Heart Failure Registry at the University Medical Centre Ljubljana were recruited for the study (Figure
Patient flow diagram.
Patients were included if they met the following criteria: (1) signs/symptoms of HF at inclusion, (2) echocardiographic evidence of left ventricular dysfunction with reduced LVEF (≤49%) or preserved LVEF (>50%) with either an
At inclusion, patients underwent thorough clinical examination, comprehensive echocardiographic assessment, and 6-minute walking test (6MWT) and completed the Minnesota Living with Heart Failure (MLHF) Questionnaire. Coronary artery disease (CAD) was defined as an angiographically proven obstructive atherosclerotic
Endocan plasma levels were determined in an independent laboratory blinded to the patient clinical data on stored plasma specimens using a commercially available, sandwich-based enzyme-linked immunosorbent assay (ELISA; Lunginnov® Systems, Lille, France) following the manufacturers’ instructions. This assay quantitatively measures the concentration of endocan in EDTA plasma and has been shown to have high sensitivity with a lower detection limit of 0.2 ng/mL, linearity between 0.4 and 10.0 ng/mL, no cross-reactivity with other human proteoglycans, and no known interference by commonly used heart failure medications.
All patients were followed on the outpatient basis at the Heart Failure Clinic and evaluated by a dedicated cardiologist for a minimum of 18 months at regular 3-month interval visits. If the patient missed a follow-up appointment, a telephone contact with him/herself or his/her relatives or the general practitioner was carried out and all relevant medical records examined in order to assess any changes in patient’s health status. The primary outcome in our study was the composite of HF-related death (pump failure or sudden cardiac death) and/or unplanned hospitalization for management of HF deterioration requiring intravenous inotropic support. In all events, the observed composite endpoint was reconfirmed by two additional independent cardiologists, blinded for baseline measurements.
Baseline characteristics are expressed as
A total of 120 patients were enrolled and data from all included individuals was utilized in the final analysis. In our study cohort, the mean age was
Baseline clinical and laboratorial characteristics of patients included in the study.
All patients |
Event |
Event-free |
||
---|---|---|---|---|
Age (years) ( |
0.745 | |||
Gender (male), |
77 (64) | 37 (74) | 43 (61) | 0.172 |
HF etiology, | ||||
Ischemic | 61 (51) | 31 (62) | 31 (44) | 0.018 |
Nonischemic | 59 (49) | 19 (38) | 39 (56) | |
LVEF (%) ( |
<0.001 | |||
NYHA class, | ||||
II | 77 (64) | 23 (46) | 53 (76) | 0.001 |
III | 43 (36) | 27 (54) | 17 (24) | |
6 MWT (m) ( |
0.002 | |||
MLHF (pt) ( |
0.203 | |||
KI (%) | 52 (43) | 25 (50) | 27 (39) | 0.182 |
DM (%) | 48 (40) | 23 (46) | 25 (36) | 0.128 |
AH (%) | 84 (70) | 36 (72) | 48 (69) | 0.746 |
PAD (%) | 22 (18) | 8 (16) | 14 (20) | 0.517 |
HLP (%) | 70 (58) | 27 (54) | 43 (61) | 0.479 |
Therapy, | ||||
RAAS inhibitors | 120 (100) | 50 (100) | 70 (100) | N/A |
MRA | 83 (69) | 36 (72) | 44 (63) | 0.573 |
|
109 (91) | 43 (86) | 66 (94) | 0.124 |
Diuretics | 80 (67) | 45 (90) | 38 (54) | 0.004 |
Antithrombotic | 83 (69) | 38 (76) | 47 (67) | 0.377 |
Statins | 46 (38) | 18 (36) | 27 (38) | 0.757 |
NT-proBNP (pg/mL) (median (IQR)) | 1967 (731-4352) | 3595 (1817-7436) | 1539 (602-3308) | <0.001 |
Endocan (ng/mL) (median (IQR)) | 3.38 (2.46-4.81) | 4.26 (3.16-6.13) | 3.21 (2.25-4.45) | <0.001 |
HF: heart failure; LVEF: left ventricle ejection fraction; NYHA class: New York Heart Association class; 6MWT: 6-minute walking test; MLHF: Minnesota Living with Heart Failure Questionnaire; KI: kidney insufficiency; DM: diabetes mellitus; AH: arterial hypertension; HLP: hyperlipidemia; RAAS inhibitors: renin-angiotensin-aldosterone system inhibitors; MRA: mineralocorticoid-receptor antagonists;
Median plasma endocan levels in our patient cohort was 3.38 (2.46-4.81) ng/mL (Table
Endocan levels in chronic HF patients in regard to patient’s comorbidities.
Comorbidity | Endocan levels (median (IQR)) | |||
---|---|---|---|---|
CAD | Yes | 57 (47) | 3.37 (2.39-4.76) | 0.976 |
No | 63 (53) | 3.38 (2.48-4.85) | ||
PAD | Yes | 22 (18) | 3.61 (2.32-4.97) | 0.218 |
No | 98 (82) | 3.38 (2.48-4.85) | ||
DM | Yes | 48 (40) | 3.51 (2.55-4.50) | 0.776 |
No | 72 (60) | 3.25 (2.40-4.89) | ||
AH | Yes | 84 (70) | 3.30 (2.34-4.75) | 0.292 |
No | 36 (30) | 3.66 (2.82-5.01) | ||
HLP | Yes | 70 (58) | 3.25 (2.28-4.28) | 0.401 |
No | 50 (42) | 3.92 (2.58-5.31) | ||
KI | Yes | 52 (43) | 3.55 (2.44-4.97) | 0.309 |
No | 68 (57) | 3.26 (2.39-4.47) |
CAD: coronary artery disease; PAD: peripheral artery disease; DM: diabetes mellitus; AH: arterial hypertension; HLP: hyperlipidemia; KI: kidney insufficiency.
Cumulative HF event-free survival curves according to baseline endocan levels expressed in quartile cut-offs.
An adjusted Cox proportional hazard model was built to test endocan values as a predictor of HF related death and/or unplanned hospitalization for management of HF deterioration requiring intravenous inotropic support (HR, 1.518 CI 95% 1.269-1.816,
Univariate and multivariate predictors of HF-related mortality and hospitalization requiring inotropic support.
Univariate HR (95% CI) | Multivariate HR (95% CI) | |||
---|---|---|---|---|
Age (per 1 year increase) | 0.979 (0.842-1.012) | 0.289 | 0.993 (0.949-1.039) | 0.761 |
Gender (male vs. female) | 1.462 (0.710-3.012) | 0.303 | 1.184 (0.478-2.936) | 0.715 |
Etiology (ischemic vs. nonischemic) | 1.615 (1.094-2.387) | 0.016 | 1.445 (0.955-2.189) | 0.082 |
LVEF(per 1% increase) | 1.032 (1.001-1.062) | 0.040 | 1.011 (0.978-1.045) | 0.506 |
NYHA class | 3.419 (1.877-6.231) | 0.001 | 2.825 (1.299-6.144) | 0.009 |
Log NT-proBNP | 5.016 (2.587-9.725) | <0.001 | 2.207 (1.002-4.861) | 0.049 |
6 MW (per 1 meter increase) | 0.997 (0.995-0.999) | 0.001 | 0.997 (0.995-1.000) | 0.032 |
Endocan levels (per 1 ng/mL increase) | 1.518 (1.269-1.816) | <0.001 | 1.471 (1.183-1.829) | 0.001 |
HR: hazard ratio; CI: confidence interval; LVEF: left ventricle ejection fraction; NYHA class: New York Heart Association class; 6MWT: 6-minute walking test; log NT-proBNP: logarithmic value of N-terminal pro-b-type natriuretic peptide.
The main findings of our study are that (i) plasma levels of endocan—a novel marker of endothelial dysfunction—are markedly elevated in patients with chronic HF as compared to previously reported values in healthy subjects or patients with CAD; (ii) endocan levels are increased irrespective of comorbidities, such as CAD, PAD, AH, DM, KI, or HLP; and (iii) plasma endocan levels are an independent predictor of HF-related morbidity and mortality. Our findings suggest that the extent of endothelial dysfunction—as determined by endocan levels—could potentially assist in prognostic assessment and risk stratification of HF patients and thus may potentially help identify patients who would mostly benefit from intensified medical treatment, stringent follow-up, and/or advanced heart failure management options.
Chronic HF is becoming one of the most prominent public health problems affecting around 2% of general and over 10% of elderly populations and rising in prevalence each year [
Over the last two decades, a vast amount of evidence has accumulated that endothelial dysfunction plays a pivotal role in the development and deterioration of HF with various endothelial functions, including vasomotor, hemostatic, antioxidant, and inflammatory activity being affected [
At present, a considerable number of chronic HF patients continue to have a very poor quality of life and an unacceptable high risk of 1-year mortality, indicating that currently available treatment regimens remain inadequate in this fragile patient population [
Although our study has identified increased levels of endocan as independent predictors of chronic HF prognosis, some limitations to our work should be addressed. Firstly, only optimally managed chronic HF patients were included in the study; thus, our results cannot be generalized to all individuals suffering from various other stages of HF. Secondly, in our multivariate model, endocan was assessed only against most known and clinically established predictors of HF prognosis and not against other possible cofounders due to a relative small number of included patients. This is particularly important in terms of exercise capacity which was assessed with the 6MWT. Although 6MWT has been validated as an important prognostic factor in patients with HF [
In conclusion, our study is the first to address the expression of endocan in the ambulatory chronic HF population. We have shown that endocan is markedly elevated and associated with disease severity as well as long-term prognosis in patients with HF. Endocan emerged as an independent prognostic marker of HF-related mortality and hospitalization requiring inotropic support in chronic HF individuals, even after allowing for clinically established predictors of HF-related events. Our results suggest that endocan may serve as a simple marker for better risk stratification in the chronic HF population.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors report no conflict of interest.