Preoperative soluble VCAM‐1 contributes to predict late mortality after coronary artery surgery

Abstract Background Soluble vascular cell adhesion molecule‐1 has been associated with long‐term cardiovascular mortality in patients with stable coronary artery disease and to the development of new atrial fibrillation in subjects with cardiovascular risk factors but no evidence of cardiac disease. Hypothesis Preoperative soluble vascular cell adhesion molecule‐1 predicts the risk of future all‐cause death and cardiovascular death among patients submitted to elective coronary artery bypass surgery. Methods From a cohort of 312 patients who underwent elective coronary artery bypass surgery prospectively followed for a median of 6.7 years, we evaluated the prognostic role of preoperative soluble vascular cell adhesion molecule‐1, inflammatory markers, CHA2DS2‐VASc score and development of postoperative atrial fibrillation (POAF). Univariable and multivariable Cox regression analyses were performed to establish an association of these parameters with long term all‐cause death and cardiovascular death. Results During 2112 person‐years of follow‐up, we observed 41 deaths, 10 were cardiovascular deaths. Independently increased levels of preoperative soluble vascular cell adhesion molecule‐1, POAF, and CHA2DS2‐VASc score were associated with all‐cause mortality. After multivariate adjustment, elevated preoperative soluble vascular cell adhesion molecule‐1 and POAF were the only independent predictors of all‐cause death. Also, preoperative soluble vascular cell adhesion molecule‐1, POAF, and CHA2DS2‐VASc score resulted in being independent predictors of cardiovascular mortality. Conclusions Increased circulating levels of preoperative soluble vascular cell adhesion molecule‐1, together with POAF and CHA2DS2‐VASc score, were significantly associated with future all‐cause death and cardiovascular death among patients submitted to coronary artery bypass surgery.


| INTRODUCTION
VCAM-1 is a membrane protein belonging to the superfamily of immunoglobulins and is mainly expressed in the endothelium. The primary role of VCAM-1 is related to adhesion and transmigration of inflammatory cells (macrophages and dendritic cells) through the endothelium. Thus, VCAM-1 is considered a biomarker for inflammation and endothelial activation. 1 Soluble VCAM-1 (sVCAM-1) is generated by cleavage of the VCAM-1 molecule by tumor necrosis factor-alpha-converting enzyme (TACE or ADAM 17) in response to cytokines. sVCAM-1 has also been associated with all-cause and cardiovascular mortality in patients with diabetes and advanced chronic kidney disease. 2,3 sVCAM-1, a biomarker of endothelial dysfunction, has also been associated with the extension of atherosclerosis, 4 long-term cardiovascular mortality in patients with stable coronary artery disease and the development of new atrial fibrillation in subjects with cardiovascular risk factors but no evidence of baseline cardiac disease. [5][6][7] Increased levels of sVCAM-1 have been reported as predictors of postoperative atrial fibrillation (POAF) in patients undergoing onpump elective cardiac surgery. 8,9 This arrhythmia is linked to a higher risk of late adverse cardiac events in patients submitted to cardiac surgery. [10][11][12] The prognostic role of CHA 2 DS 2− VASc score that incorporates age and most cardiovascular risk factors is associated with a higher risk of POAF and stroke after cardiac surgery. 13

| Clinical, biochemical, and echocardiographic characteristics
The following preoperative variables were included: age, gender, associated comorbidities including hypertension, diabetes mellitus, and chronic obstructive pulmonary disease (COPD), previous cerebrovascular accident (CVA), heart failure, valvular heart disease, the severity of the coronary artery disease (Syntax score I), standard additive Euroscore, logistic Euroscore, CHA 2 DS 2 -VASc score, and two-D echocardiogram cardiac dimensions. Systolic left ventricular function was considered normal when left ventricular (LV) ejection fraction (EF) was higher than 50%, moderate to reduced when it was 40% to 50%, and decreased when EF was less than 40%. Clinical variables were defined using standard operational definitions.
POAF was defined as any new episode of AF lasting more than 15 minutes during the first 72 hours after surgery. Patients were monitored continuously with a telemetry system with automated arrhythmia detection (IntelliVue MP70, Phillips Healthcare, Andover, Massachusetts). In every patient with a suspected arrhythmic event, a standard 12-lead Electrocardiogram (EKG) was performed and reviewed by a trained cardiologist. Management of POAF comprised oral anticoagulants and antiarrhythmic agents, which was recommended for 6 weeks; after that, this was left to treating physicians.
Biochemical variables: white blood cell (WBC), neutrophil count, and usCRP were utilized as inflammatory markers. WBC and neutrophil count were performed with an automated cell detector, and usCRP was evaluated using a high sensitivity immunoreagent (Dade Behring, Deerfield, Illinois). Soluble adhesion molecule VCAM (sVCAM-1) was determined using a commercial A method to measure circulating biomarkers (Elisa) kit (R&D Systems Inc, Minneapolis, MM, USA).
Cardiac surgery: The surgical procedure consisted of an on-pump aortocoronary bypass using a Terumo Sarns 8000 (Terumo Corporation, Tokyo, Japan) system and a standard cardiotomy suction setup.
No aprotinin was used during or after surgery. Preoperative medications were collected as well as the following intraoperative variables: cardiopulmonary bypass time and aortic cross-clamp time.

| Primary and secondary outcomes
The primary outcome was all-cause death in a time-to-event analysis.
Secondary time-to-event outcome was cardiovascular death. This comprised: (1) cardiac death and (2) extracardiac cardiovascular death, which included stroke, aneurysmal dissections and ruptures, and pulmonary embolism. The causes of death are incorporated in the Chilean Civil Registry.     Figure 1A. Preoperative sVCAM-1 was available in 162 patients (51.9%). Median sVCAM-1 was 777 (587-1049) ng/mL, and the histogram is presented in Figure 1B.

| All-cause death and cardiovascular death
The primary outcome all-cause death occurred in 42 patients (13.5%) in 2112 person-years of follow-up. The secondary outcome, cardiovascular death was present in 22 patients (52.4% of all death and 7% of the cohort). Among them, five patients (1.6%) had a lethal myocardial infarction, and two patients (0.6%) died due to ischemic stroke (Table S1). Noncardiovascular death occurred in 20 patients (47.6%).

| All-cause death
Hazard ratios (HR) and confidence interval (CI) corresponding to univariable Cox proportional hazard regressions are reported in After multivariable adjustment elevated sVCAM-1 (HR: 1.0012 for each ng/mL; CI: 1.0005-1.0019; P = .001) and POAF (HR: 4.14; CI: 1.4-11.8, P = .008) were the only independent predictors of all-cause death in this population (Table S3). The Forest plot of HR and 95% CI, corresponding to the multivariate Cox proportional hazard model is shown in Figure 2.
Kaplan-Meier curves of all-cause death for POAF, stratified CHA 2 DS 2 -VASc scores, and stratified sVCAM-1 are shown in Figure 3A-D. Kaplan-Meier curves for alternative stratifications of sVCAM-1 are also shown in Figures S1-4.
Also, diabetes mellitus, cerebrovascular accident, valvular heart disease, and congestive heart failure were statistically significant variables associated with all-cause death.

| Comparison with published data
Endothelial dysfunction has been associated with adverse cardiovascular events in patients with coronary artery disease. Blankenberg et al evaluated the prognostic role of multiple biomarkers in a large prospective study of patients with stable coronary artery disease and found that sVCAM-1 was a significant predictor of future death in these patients. 6  illness. 18,19 The expression of endocardial VCAM-1 increases up to double in patients with AF as well as after rapid atrial stimulation. 20 In a previous independent study, we evaluated a prospective cohort of 144 patients submitted to elective cardiac surgery with clinical and echocardiographic variables and biomarkers of inflammation, oxidative stress, and endothelial dysfunction. We found that sVCAM-1 was the only significant predictor of POAF. 8  They observed that a higher CHA 2 DS 2 -VASc score was associated with an elevated risk of ischemic stroke and late mortality. 15 Similar findings have also been reported by Peguero et al. 24 In agreement with these previous studies, our work confirmed that CHA 2 DS 2 -VASc score is a significant predictor of late mortality after cardiac surgery.
The present findings show that sVCAM-1, a biomarker of endothelial dysfunction, is an independent predictor of late all-cause mortality and cardiovascular death after coronary artery bypass surgery.
Also, POAF, and CHA 2 DS 2 -VASc score add to an adverse prognosis in these patients.

| Limitations and future investigations
Our study has several limitations. First, its relatively small sample size and consequently limited power may have obscured other subtle associations. Second, the incomplete assessment of endothelial function may have limited the estimation of HR presented here. Third, the population evaluated was a heterogeneous sample of patients with stable coronary artery disease, a few of them with heart failure, which may affect their long term prognosis. Finally, we only performed perioperative measurements without assessing the subsequent impact of the surgical act and medical therapy in the levels of sVCAM-1 during the follow-up period.
Future studies should investigate the prognostic role of sVCAM-1 in separate cohorts of patients with stable coronary artery disease submitted to elective cardiac surgery.

| CONCLUSIONS
In summary, this is the first study to identify an association between increased levels of sVCAM-1 and future death and cardiovascular death among patients submitted to elective on-pump coronary artery bypass surgery.

CONFLICT OF INTEREST
The authors declare no potential conflict of interests.