Prognostic Significance of Baseline White Blood Cell Count in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome

We thank Balta et al. [1] for their interest in our article [2]. Regarding the concerns expressed in their letter, we acknowledge that our paper has some limitations including the fact that we did not address the relation between white blood cell (WBC) count and several conditions such as non-alcoholic fatty liver disease, systemic inflammatory disease, infections, medication for weight loss, and drug addiction, which may have theoretically contributed to determining the link between WBC count and cardiovascular mortality. However, in our study the WBC count was an independent predictor of long-term cardiovascular mortality, even after adjustment for several competing factors exploring the most important and recognized pathways related to outcome in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). They comprise factors associated with (1) myocardial damage (ECG abnormalities, CK-MB values, left ventricle ejection fraction, and history of previous myocardial infarction); (2) hemodynamic status (blood pressure, heart rate, and Killip class); (3) extent of coronary artery disease (age, creatinine value, ST-segment depression, ST-segment elevation in aVR, previous stroke, and diabetes mellitus), and (4) platelet reactivity (mean platelet volume). Moreover most of the suggested comorbidities are quite rare even in an unselected population of NSTE-ACS as the one included in our study. On the other hand, we acknowledge that it would have been of great interest to evaluate the association of non-alcoholic fatty liver disease with WBC count, given its emerging role as a possible factor influencing the development and progression of atherosclerosis [3]. Unfortunately, data on this condition, which refer to a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis, have not been systematically collected in our study, and therefore no conclusion on the complex relation between liver disease, systemic inflammation, and outcome in NSTE-ACS can be drawn from our study.Another controversial point highlighted in the letter by Balta et al. [1] is the relation between WBC count and C-reactive protein (CRP) as determinants of the prognosis in patients with acute coronary syndrome. However, recent data from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial [4] including 13,678 patients with NSTE-ACS showed that the WBC count was an independent predictor of mortality even after adjustment for CRP.Finally, although our study along with other epidemiologic studies consistently demonstrated that an increased baseline WBC count could predict future cardiovascular events, it was not designed to determine whether this relation is causal. Balta et al. [1] commented that WBC values could be indirectly associated with cardiovascular mortality as it is a marker of inflammation associated with atherosclerosis [5]. It is worth noting that this hypothesis is supported by few small studies using modern coronary imaging techniques such as optical coherence tomography (OCT). Interestingly, some studies have shown a correlation between WBC count and some coronary plaque characteristics. Specifically, Raffel et al. [6] showed in 43 subjects undergoing percutaneous catheterization that baseline leukocyte count correlated with plaque macrophage density (r = 0.483, p < 0.001) as assessed by OCT. Both parameters were associated with lipid-rich plaque and correlated inversely with plaque fibrous cap thickness (r = -0.547 for macrophage density and -0.423 for WBC count, p < 0.015). Plaques classified as thin-cap fibroatheromas (TCFA) had a higher median macrophage density than non-TCFA plaques (7.4 vs. 4.99, p < 0.001). Patients with TCFA had a higher WBC count compared with those without TCFA (11.0 vs. 7.9, p = 0.007). Li et al. [7] in a study with 46 subjects showed that the plasma levels of inflammatory factors and WBC count were correlated inversely with fibrous cap thickness as assessed by OCT (r = -0.775 for high-sensitivity CRP, r = -0.593 for IL-18, r = -0.60 for TNF-α, and r = -0.356 for WBC count). Patients with cap thickness of less than 65 μm (cutoff used to define TCFA) had higher plasma levels of inflammatory factors as well as WBC counts than those with thicker fibrous caps.