Leukocyte profiles across the cardiovascular disease continuum: A population-based cohort study☆

https://doi.org/10.1016/j.yjmcc.2019.11.156Get rights and content

Highlights

  • •

    Overall leukocyte count increase across the cardiovascular disease (CVD) continuum.

  • •

    This increase mainly depends on the increase in neutrophil count.

  • •

    High leukocyte levels are predictive for the development of coronary artery disease.

  • •

    Women have a greater lymphocyte increase across the CVD continuum compared to men.

Abstract

Introduction

Inflammation plays a pivotal role across all stadia of the cardiovascular disease (CVD) continuum, i.e. non-obstructive coronary artery disease (CAD), myocardial infarction (MI), and ischemic heart failure (iHF). However, inflammation across CVD continuum has not been studied yet within one population. Therefore, we mapped leukocyte profiles across the continuum within the UK Biobank.

Methods

The UK Biobank cohort study includes >500,000 participants aged 40 to 70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. A total of 333,218 individuals with available laboratory measurements at baseline were included in this study. These consisted of controls and individuals who had progression of CVD during follow-up (i.e. who developed CAD, MI, or iHF during follow-up). We investigated whether leukocytes and subtypes of leukocytes at baseline differed among the CVD continuum. Furthermore, we studied the possible interactions between sex and CVD on leukocytes.

Results

Of 333,218 individuals, 325,054 (97.5%) individuals were categorized as controls, and 8164 (2.5%) individuals had progression of CVD during follow-up. Of those 8164 individuals, 4552 (1.4%) developed CAD during follow-up, 2839 (0.9%) MI, and 773 (0.2%) in iHF. Compared to controls, mean leukocyte levels at baseline increased across the CVD continuum from 6.8·109 cells/L (SD 1.7·109 cells/L) to 7.7·109 cells/L (SD 1.9·109 cells/L) (Ptrend = 2.19·10−132) in individuals who developed iHF. This increase mainly depended on an increase in neutrophils. Furthermore, controls with leukocyte levels in the highest quartile at baseline had a 1.44 higher chance of being diagnosed with CAD during follow-up compared with individuals with leukocyte levels in lower quartiles (OR 1.44, 95% CI 1.34–1.56 P = 9.63·10−21). A similar increased change was observed for neutrophils, lymphocytes, monocytes, and eosinophils. There was a significant interaction between sex and CVD continuum on lymphocytes (P = 8.49·10−5).

Conclusion

Overall leukocyte count increased across the CVD continuum, which mainly depended on the increase in neutrophil count. High leukocytes in individuals not having CAD at baseline were predictive for the development of CAD during follow-up. Women had a greater increase of lymphocytes across the CVD continuum compared to men. Understanding which cells are key players in which stadium, could serve as a starting point for the identification of new potential therapeutic targets in CVD.

Introduction

It is generally appreciated that inflammation plays a pivotal role in the pathophysiology of atherosclerosis and cardiovascular disease (CVD). This has been shown on genetic, biologic, epidemiologic and clinical trial level [1,2]. Nevertheless, these supporting data contrast with neutral clinical trials studying the effect on anti-inflammatory agents on (a composite of) major cardiovascular events, emphasizing the complexity of the human immune system and the need for more studies unravelling this complex mechanism [3]. Recently, the CANTOS trial showed improved CVD outcomes using the anti-interleukin-1β antibody canakinumab, although CVD mortality did not improve and there was an increase in the rate of infections. Therefore, optimization of immunotherapy for CVD is required (i.e. identification of novel drug targets that block inflammatory pathways, but do not exhibit immune-suppressive side effects). In order to achieve this optimization it is of value to first obtain an overview of the immune response in CVD patients. This has been done in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) study, which studied differential white blood cell count in approximately sixteen thousand apparently healthy individuals [4,5]. They observed associations between increased leukocytes and the risk for CVD. However, leukocyte profiles in different conditions of CVD (i.e. coronary artery disease (CAD), myocardial infarction (MI), and ischemic heart failure (iHF)), also known as the cardiovascular disease continuum (CVD continuum) [6], within one population have not been studied yet. In combination with an increased sample size, information on the different components of granulocytes (i.e. neutrophils, eosinophils, and basophils), and further exploration of potential sex differences, this might be of additive value to the existing data from the EPIC-Norfolk study. Understanding which immune cells are present in particular stadia of the continuum may aid in increasing our knowledge of the underlying pathophysiologic process and expanding our efforts of optimising therapies. Therefore, we aimed to study leukocyte profiles in different stadia of the CVD continuum and to provide a broader overview of associations between leukocytes and CVD in individuals participating in the UK Biobank.

Section snippets

UK Biobank participants

The UK Biobank study design and population have been described in detail elsewhere [7]. In brief, UK Biobank is a large community-based prospective study in the United Kingdom that recruited >500,000 participants aged 40 to 69 years old with the aim of improving prevention, diagnosis, and treatment of a plethora of illnesses including cancer, diabetes mellitus, stroke, and heart diseases. All participants gave informed consent for the study. UK Biobank has approval from the relevant

Population characteristics

From the 502,559 individuals, we included a total of 333,218 individuals for the present analyses (Fig. 1). Overall, 153,043 (46%) were male. Mean age was 57 years (SD 8 years) and median follow-up of 6 years (interquartile range [IQR] 5–7). Baseline characteristics, including cardiovascular risk factors and medical history of coronary heart diseases are provided in Table 1.

Leukocytes increase across the CVD continuum

Of 333,218 individuals, 325,054 (97.5%) individuals were categorized as controls and 8164 (2.5%) individuals had

Discussion

In this large community-based population of >330,000 individuals, we mapped leukocyte profiles across the different stadia of the CVD continuum (CAD, MI, and iHF). First, overall leukocyte count increased across the continuum, which mainly depended on the increase in neutrophil count. Second, high levels of leukocytes at baseline were predictive for the progression of CVD during follow-up. Third, women showed overall higher leukocyte levels and there was an interaction between CVD continuum and

Conclusions

Our study provided an overview of the different leukocyte profiles across different stadia of the CVD continuum. Overall leukocyte count increased across the continuum, which mainly depended on the increase in neutrophil count. Furthermore, high levels of leukocytes at baseline were predictive for the progression of CVD during follow-up. Last, women showed overall higher leukocyte levels and there was an interaction between CVD continuum and sex on lymphocytes, suggesting a sex specific

Explanation of the role of funder/sponsor

The funding agencies had no role in the study design, analysis, or interpretation of data; the writing of the manuscript; or in the decision to submit the article for publication.

Data statement

The data, analytical methods, and study materials will be made available to other researchers for purposes of reproducing the results or replicating the procedure (contact the corresponding author).

Declaration of Competing Interest

All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Acknowledgement

We would like to thank the Centre for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high-performance computing cluster. We thank Ruben N. Eppinga, MD, Tom Hendriks, MD, M. Abdullah Said, BSc, Yordi J. van de Vegte, BSc, M. Yldau van der Ende, BSc, Yanick Hagemeijer, MSc, and Jan-Walter Benjamins, BEng (Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands), for their

References (27)

  • C. Sudlow et al.

    UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age

    PLoS Med.

    (2015)
  • M. Abdullah Said et al.

    Relationship of arterial stiffness index and pulse pressure with cardiovascular disease and mortality

    J. Am. Heart Assoc.

    (2018)
  • A. Stang et al.

    Algorithms for converting random-zero to automated oscillometric blood pressure values, and vice versa

    Am. J. Epidemiol.

    (2006 Jul)

    • Cited by (0)

    ☆

    All authors take full responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

    View full text
    © 2019 Published by Elsevier Ltd.