Abstract
Introduction: Inflammation plays a key role in ischemic cardiovascular disease. The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive marker for inflammation and correlates with outcomes in critical limb ischemia (CLI). Previous studies have suffered from low power due to low event rates, and show only limited adjustment for confounders. We examined in a prospective cohort whether the peripheral blood (PB) NLR predicts amputation-free-survival (AFS) and has additional predictive power over established risk factors. We also studied bone-marrow (BM) composition and plasma cytokines to elucidate the etiology of NLR alterations. Methods and Results: Data from CLI patients in the JUVENTAS Trial and ATHERO-EXPRESS registry were pooled (N=351). Median follow-up was 3.16 years during which 128 events (amputation or death) occurred. In patients that experienced an event, the PB NLR was elevated (Event: 4.2 (SD 2.8) vs No event: 3.0 (SD 1.9) p=<0.001), the neutrophil count was higher (6.3 (SD 2.5) vs 5.5 (SD2.3) p=0.0003), and the lymphocyte count was lower (1.7 (SD 0.8) vs 2.1 (SD 0.8) p<0.001). Cox regression showed that the hazard ratio (HR) for AFS was 1.6 (CI: 1.4-1.9), p=2*10 -8 . In a model adjusting for age, sex, diabetes mellitus, BMI, smoking, and GFR the NLR significantly predicted AFS, HR 1.4 (CI 1.2-1.7) p=0.0003. In a sub study in the JUVENTAS cohort, the PB NLR correlated with the BM NLR, but the BM NLR did not correlate with AFS. Additionally, the NLR correlated strongly with the inflammatory cytokines IL-6, IL-8, and CRP. Discussion and Conclusion: These results show that the NLR is an independent predictor of AFS in CLI. While most studies analyzed the NLR as a binary value, here we show a continuous correlation between the NLR and AFS, even when corrected for major confounders. We show that blood NLR is reflected in BM and correlates with inflammatory cytokines, indicating that our incidental measurements may reflect chronic inflammation-driven alterations in BM.
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