Relative Predictive Value of Circulating Immune Markers in US Adults Without Cardiovascular Disease: Implications for Risk Reclassification

Abstract

Objective: To investigate the relative predictive value of circulating immune cell markers for cardiovascular mortality in ambulatory adults without cardiovascular disease.

Methods: We analyzed data of participants enrolled in the National Health and Nutrition Examination Survey from January 1, 1999, to December 31, 2010, with the total leukocyte count within a normal range (4000-11,000 cells/μL [to convert to cells ×10⁹/L, multiply by 0.001]) and without cardiovascular disease. The relative predictive value of circulating immune cell markers measured at enrollment-including total leukocyte count, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count, monocyte-lymphocyte ratio (MLR), neutrophil-lymphocyte ratio, and C-reactive protein-for cardiovascular mortality was evaluated. The marker with the best predictive value was added to the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to estimate net risk reclassification indices for 10-year cardiovascular mortality.

Results: Among 21,599 participants eligible for this analysis, the median age was 47 years (interquartile range, 34-63 years); 10,651 (49.2%) participants were women, and 10,713 (49.5%) were self-reported non-Hispanic white. During a median follow-up of 9.6 years (interquartile range, 6.8-13.1 years), there were 627 cardiovascular deaths. MLR had the best predictive value for cardiovascular mortality. The addition of elevated MLR (≥0.3) to the 10-year ASCVD risk score improved the classification by 2.7%±1.4% (P=.04). Elevated MLR had better predictive value than C-reactive protein and several components of the 10-year ASCVD risk score.

Conclusion: Among ambulatory US adults without preexisting cardiovascular disease, we found that MLR had the best predictive value for cardiovascular mortality among circulating immune markers. The addition of MLR to the 10-year risk score significantly improved the risk classification of participants.

Figure 1.

Flow diagram for study selection. Normal range of TLC defined as 4,000-11,000 cells/μL. Cardiovascular disease defined as self-reported coronary artery disease, heart failure, stroke or on pacemaker. CRP, C-reactive protein; HIV, Human Immunodeficiency Virus; NHANES, National Health, and Nutrition Examination Survey; TLC, Total leukocyte Count.

Figure 2:

The relative predictive value of circulating immune markers to predict CV mortality. The circulating immune markers are arranged in the decreasing order of importance. Likelihood ratio χ² using Cox Model to predict CV mortality (Panel A). Wald χ² using Cox Model to predict CV mortality (Panel B). The area under the curve (AUC) using a logistic model to predict 10-year CV mortality (Panel C). Standardized Domination Statistic using a logistic model to predict the relative importance of immune markers for 10-year CV mortality (Panel D).

Figure 3.

Risk of cardiovascular mortality stratified by monocyte-lymphocyte ratio in the Cox proportional hazards model (Panel A) and competing-risk regression model with non-cardiovascular mortality as competing risk (Panel B) adjusted for age, gender, race, hypertension, hemoglobin, diabetes mellitus, chronic obstructive pulmonary disease, current smoking, dyslipidemia, estimated glomerular filtration rate, malignancy, obesity, and NHANES cycle. MLR, monocyte-lymphocyte ratio, HR, hazards ratio, CI, confidence interval, NHANES, National Health, and Nutrition Examination Survey

Figure 4:

Dose-response relationship between monocyte-lymphocyte ratio and cardiovascular mortality. The solid red line represents the incidence rate, and the dashed red lines represent the 95% confidence interval (CI). There was a linear increase in the risk of cardiovascular mortality with increase in the monocyte-lymphocyte ratio.