Temporal change in inflammatory biomarkers and risk of cardiovascular events: the Multi-ethnic Study of Atherosclerosis

Mahsima Shabani^{1

2}, Hooman Bakhshi^{1

3}, Mohammad R Ostovaneh^{1

4}, Xiaoyang Ma⁵, Colin O Wu⁶, Bharath Ambale-Venkatesh⁷, Michael J Blaha¹, Matthew A Allison⁸, Matthew J Budoff⁹, Mary Cushman¹⁰, Russell P Tracy¹¹, David M Herrington¹², Moyses Szklo¹³, Christopher Cox¹³, David A Bluemke¹⁴, João A C Lima¹

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD, 21287-0409, USA.
² Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
³ Inova Heart and Vascular Institute, Falls Church, VA, USA.
⁴ Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.
⁵ Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA.
⁶ Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
⁹ Department of Medicine, Los Angeles Biomedical Research Institute, Torrance, CA, USA.
¹⁰ Departments of Medicine and Pathology, University of Vermont, Burlington, VT, USA.
¹¹ Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
¹² Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁴ Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

PMID: 34240828
PMCID: PMC8497383
DOI: 10.1002/ehf2.13445

Temporal change in inflammatory biomarkers and risk of cardiovascular events: the Multi-ethnic Study of Atherosclerosis

Mahsima Shabani et al. ESC Heart Fail. 2021 Oct.

. 2021 Oct;8(5):3769-3782.

doi: 10.1002/ehf2.13445. Epub 2021 Jul 9.

Authors

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD, 21287-0409, USA.
² Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
³ Inova Heart and Vascular Institute, Falls Church, VA, USA.
⁴ Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.
⁵ Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA.
⁶ Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
⁹ Department of Medicine, Los Angeles Biomedical Research Institute, Torrance, CA, USA.
¹⁰ Departments of Medicine and Pathology, University of Vermont, Burlington, VT, USA.
¹¹ Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
¹² Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁴ Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

PMID: 34240828
PMCID: PMC8497383
DOI: 10.1002/ehf2.13445

Abstract

Aims: Little is known about the association of temporal changes in inflammatory biomarkers and the risk of death and cardiovascular diseases. We aimed to evaluate the association between temporal changes in C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and risk of heart failure (HF), cardiovascular disease (CVD), and all-cause mortality in individuals without a history of prior CVD.

Methods and results: Participants from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort with repeated measures of inflammatory biomarkers and no CVD event prior to the second measure were included. Quantitative measures, annual change, and biomarker change categories were used as main predictors in Cox proportional hazard models stratified based on sex and statin use. A total of 2258 subjects (50.6% female, mean age of 62 years) were studied over an average of 8.1 years of follow-up. The median annual decrease in CRP levels was 0.08 mg/L. Fibrinogen and IL-6 levels increased by a median of 30 mg/dL and 0.24 pg/mL annually. Temporal changes in CRP were positively associated with HF risk among females (HR: 1.18 per each standard deviation increase, P < 0.001) and other CVD in both female (HR: 1.12, P = 0.004) and male participants (HR: 1.24, P = 0.003). The association of CRP change with HF and other CVD was consistently observed in statin users (HR: 1.23 per SD increase, P = 0.001 for HF and HR: 1.19 per SD increase, P < 0.001 for other CVD). There were no significant associations between temporal changes of fibrinogen or IL-6 with HF or other CVD. Men with sustained high values of IL-6 had a 2.3-fold higher risk of all-cause mortality (P < 0.001) compared with those with sustained low values.

Conclusions: Temporal change in CRP is associated with HF only in women and statin users, and other CVD in both women and men, and statin users. Annual changes in fibrinogen and IL-6 were not predictive of cardiovascular outcomes in either sex.

Keywords: C-reactive protein; Fibrinogen; Heart failure; Interleukin; Longitudinal cohort study.

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Conflict of interest statement

Authors of this work has nothing to disclose. All authors declare that the submitted work is original and has not been published and is not under consideration for publication elsewhere. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services.

Figures

**Figure 1**
The percentage of participants with events among different categories of CRP change. (A) The percentage of participants with HF in follow‐up in different groups of change in CRP. (B) The percentage of participants with other CVD in follow‐up in different groups of change in CRP. The graphs on the left are further stratified by sex and the graphs on the right are further stratified by statin use. CRP, C‐reactive protein; HF, heart failure; CVD, cardiovascular disease.

**Figure 2**
Survival curves for time‐to‐event study. (A) The survival probability in different groups of change in CRP in women and risk of HF. (B) The survival probability of different groups of change in CRP in women (left) and men (right) and risk of other CVD. (C) The survival probability in different groups of change in IL‐6 and risk of all‐cause mortality in men. CRP, C‐reactive protein; HF, heart failure; CVD, cardiovascular disease.

See this image and copyright information in PMC

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Temporal change in inflammatory biomarkers and risk of cardiovascular events: the Multi-ethnic Study of Atherosclerosis

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Temporal change in inflammatory biomarkers and risk of cardiovascular events: the Multi-ethnic Study of Atherosclerosis

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Conflict of interest statement

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