PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function

Abstract

Background: Platelet-derived chemokines are implicated in several aspects of vascular biology. However, for the chemokine platelet factor 4 variant (PF-4var/CXCL4L1), released by platelets during thrombosis and with different properties as compared to PF-4/CXCL4, its role in heart disease is not yet studied. We evaluated the determinants and prognostic value of the platelet-derived chemokines PF-4var, PF-4 and RANTES/CCL5 in patients with stable coronary artery disease (CAD).

Methodology/principal findings: From 205 consecutive patients with stable CAD and preserved left ventricular (LV) function, blood samples were taken at inclusion and were analyzed for PF-4var, RANTES, platelet factor-4 and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were followed (median follow-up 2.5 years) for the combined endpoint of cardiac death, non-fatal acute myocardial infarction, stroke or hospitalization for heart failure. Independent determinants of PF-4var levels (median 10 ng/ml; interquartile range 8-16 ng/ml) were age, gender and circulating platelet number. Patients who experienced cardiac events (n = 20) during follow-up showed lower levels of PF-4var (8.5 [5.3-10] ng/ml versus 12 [8-16] ng/ml, p = 0.033). ROC analysis for events showed an area under the curve (AUC) of 0.82 (95% CI 0.73-0.90, p<0.001) for higher NT-proBNP levels and an AUC of 0.32 (95% CI 0.19-0.45, p = 0.009) for lower PF-4var levels. Cox proportional hazard analysis showed that PF-4var has an independent prognostic value on top of NT-proBNP.

Conclusions: We conclude that low PF-4var/CXCL4L1 levels are associated with a poor outcome in patients with stable CAD and preserved LV function. This prognostic value is independent of NT-proBNP levels, suggesting that both neurohormonal and platelet-related factors determine outcome in these patients.

Figure 1. Kaplan-Meier curves for patients with levels of NT-proBNP lower and above the median value of 164 pg/ml ( figure 1A ) and Kaplan-Meier curves for patients with levels of PF-4var lower and above the median value of 10 ng/ml ( figure 1B ).

Figure 2. Kaplan-Meier curves showing freedom from the primary outcome measure (death due to cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalization for congestive heart failure) according to 4 groups: group 1: NT-proBNP < median and PF-4var > median (n = 64); group 2: NT-proBNP < median and PF-4var < median (n = 42); group 3: NT-proBNP > median and PF-4var > median (n = 43); group 4: NT-proBNP > median and PF-4var < median (n = 56).

Figure 3. Kaplan-Meier curves showing freedom from the secondary outcome measure (death due to cardiovascular causes, non-fatal myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting or hospitalization for congestive heart failure) according to 4 groups: group 1: NT-proBNP < median and PF-4var > median (n = 64); group 2: NT-proBNP < median and PF-4var < median (n = 42); group 3: NT-proBNP > median and PF-4var > median (n = 43); group 4: NT-proBNP > median and PF-4var < median (n = 56).