Neutrophil Counts and Initial Presentation of 12 Cardiovascular Diseases: A CALIBER Cohort Study

Abstract

Background: Neutrophil counts are a ubiquitous measure of inflammation, but previous studies on their association with cardiovascular disease (CVD) were limited by small numbers of patients or a narrow range of endpoints.

Objectives: This study investigated associations of clinically recorded neutrophil counts with initial presentation for a range of CVDs.

Methods: We used linked primary care, hospitalization, disease registry, and mortality data in England. We included people 30 years or older with complete blood counts performed in usual clinical care and no history of CVD. We used Cox models to estimate cause-specific hazard ratios (HRs) for 12 CVDs, adjusted for cardiovascular risk factors and acute conditions affecting neutrophil counts (such as infections and cancer).

Results: Among 775,231 individuals in the cohort, 154,179 had complete blood counts performed under acute conditions and 621,052 when they were stable. Over a median 3.8 years of follow-up, 55,004 individuals developed CVD. Adjusted HRs comparing neutrophil counts 6 to 7 versus 2 to 3 × 10⁹/l (both within the 'normal' range) showed strong associations with heart failure (HR: 2.04; 95% confidence interval [CI]: 1.82 to 2.29), peripheral arterial disease (HR: 1.95; 95% CI: 1.72 to 2.21), unheralded coronary death (HR: 1.78; 95% CI: 1.51 to 2.10), abdominal aortic aneurysm (HR: 1.72; 95% CI: 1.34 to 2.21), and nonfatal myocardial infarction (HR: 1.58; 95% CI: 1.42 to 1.76). These associations were linear, with greater risk even among individuals with neutrophil counts of 3 to 4 versus 2 to 3 × 10⁹/l. There was a weak association with ischemic stroke (HR: 1.36; 95% CI: 1.17 to 1.57), but no association with stable angina or intracerebral hemorrhage.

Conclusions: Neutrophil counts were strongly associated with the incidence of some CVDs, but not others, even within the normal range, consistent with underlying disease mechanisms differing across CVDs. (White Blood Cell Counts and Onset of Cardiovascular Diseases: a CALIBER Study [CALIBER]; NCT02014610).

Keywords: disease mechanisms; electronic health records; epidemiology; incidence; inflammation.

Graphical abstract

Figure 1

Cumulative Incidence Curves For cardiovascular presentations among people without prior cardiovascular disease (CVD), crude cumulative incidence curves are shown for the highest and lowest categories of neutrophil count within the normal range. An artefact of imprecise coding rather than a clinical diagnosis, ‘nonspecific coronary disease’ was combined with unstable angina. Similarly, nonspecific stroke was combined with ischemic stroke. The plots show that, for myocardial infarction, heart failure, ischemic stroke, peripheral arterial disease (PAD), and abdominal aortic aneurysm, the incidence was greater among people with higher neutrophil counts.

Figure 2

Association of Neutrophil Count With Initial CVD Presentation Neutrophil count categories influenced cause-specific adjusted hazard ratios for cardiovascular presentations among people without prior cardiovascular disease (CVD). Hazard ratios were adjusted for age, sex, deprivation, ethnicity, smoking, diabetes, systolic blood pressure (SBP), blood pressure medication, body mass index (BMI), total cholesterol, high-density lipoprotein cholesterol (HDL-C), statin use, estimated glomerular filtration rate (eGFR), atrial fibrillation (AF), autoimmune conditions, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), cancer, and acute conditions at the time of blood testing. Shaded = normal range. *p < 0.05; **p < 0.0036; ***p < 0.0001. CI = confidence interval; other abbreviations as in Figure 1.

Figure 3

CVD and Neutrophil Counts by Clinical State at Blood Sampling Hazard ratios for initial presentation of CVDs by neutrophil count varied by clinical state at the time of blood sampling. ‘Mean of 2 stable’ refers to the mean of 2 consecutive neutrophil counts performed in a stable clinical state. Hazard ratios are adjusted for age, sex, socioeconomic deprivation, ethnicity, smoking, diabetes, SBP, blood pressure medication, BMI, total cholesterol, HDL-C, statin use, eGFR, AF, autoimmune conditions, IBD, COPD, and cancer. *p < 0.05; **p < 0.0036; ***p < 0.0001. Abbreviations as in Figures 1 and 2.

Central Illustration

Neutrophil Counts and CVDs Potential causal pathways are depicted linking chronic inflammation, neutrophil counts, and onset of cardiovascular diseases (CVD). Environmental and behavioral risk factors such as smoking, air pollution, and physical inactivity contribute to chronic inflammation. An inflammatory state results in a higher neutrophil count, which may be causally linked with increased risk of certain cardiovascular conditions.