Elsevier

American Heart Journal

Volume 253, November 2022, Pages 39-47
American Heart Journal

Clinical Investigations
Inflammation biomarkers and incident coronary heart disease: the Reasons for Geographic And Racial Differences in Stroke Study

https://doi.org/10.1016/j.ahj.2022.07.001Get rights and content

Abstract

Background

Individual inflammation biomarkers are associated with incident coronary heart disease (CHD) events. However, there is limited research on whether the risk for incident CHD is progressively higher with a higher number of inflammation biomarkers in abnormal levels.

Methods

We used data from 15,758 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants aged ≥45 years without a history of CHD at baseline in 2003-2007. Abnormal levels of baseline high-sensitivity C-reactive protein, leukocyte count and serum albumin were defined as ≥3.8 mg/L (3rd tertile), ≥6.3 x 109 cells/L (3rd tertile), and <4.0 g/dL (1st tertile), respectively. The outcome was a composite of incident myocardial infarction or CHD death.

Results

Overall, 38.9% (n = 6,123) had 0, 36.6% (n = 5,774) had 1, 19.8% (n = 3,113) had 2 and 4.7% (n = 748) had 3 biomarkers of inflammation in abnormal levels. Over a median follow-up of 11.4 years, 954 (6.1%) participants had incident CHD. The rate of incident CHD per 1000 person-years for individuals with 0, 1, 2, and 3 biomarkers of inflammation in abnormal levels was 4.4 (95% confidence interval [CI]: 3.9-5.0), 6.3 (95% CI: 5.6-6.9), 8.8 (95% CI: 7.8-9.9), and 10.6 (95% CI: 8.1-13.1), respectively. Multi-variable adjusted hazard ratios for incident CHD associated with 1, 2 and 3 versus no inflammation biomarker in abnormal levels were 1.26 (95% CI: 1.07-1.49), 1.72 (95% CI: 1.43-2.07), and 1.84 (95% CI: 1.37-2.47), respectively (P-trend < .001).

Conclusions

The number of inflammation markers in abnormal levels was associated with increased risk of incident CHD after multi-variable adjustment.

Section snippets

Methods

The REGARDS study enrolled a cohort of 30,239 Black and White adults aged ≥45 years from all 48 contiguous US states and the District of Columbia between 2003 and 2007.11 The REGARDS-myocardial infarction (MI) is an ancillary study investigating reasons for Black-White disparities in the risk for CHD events. The REGARDS study was approved by the Institutional Review Boards at the participating institutions and all participants provided written informed consent.

We restricted the current analysis

Baseline assessment

A computer-assisted telephone interview was administered by trained research staff to collect self-reported information on participant's age, sex, race, smoking status, and medical history, including a prior coronary revascularization and prior diagnosis of diabetes or MI. A subsequent in-home examination was conducted where measurements including height, weight, blood pressure (BP), and electrocardiography (ECG) were performed. Body mass index (BMI) was defined as weight (kg) divided by height

Exposure variable (baseline inflammation biomarkers)

hsCRP, leukocyte count and serum albumin were measured using blood samples collected at baseline. hsCRP was measured using high sensitivity particle enhanced immunonephelometric assay on the BNII nephelometer, Dade Behring Incorporated, Deerfield, Illinois; interassay coefficients of variation of 2.1%-5.7%.13 Leukocyte count was measured using automated cell counting (Beckman Coulter, Inc., Fullerton, CA).12 Serum albumin was measured using colorimetric reflectance spectrophotometry (Johnson &

Incident CHD

Participants were telephoned every 6 months to ascertain events of potential MIs, which were adjudicated by 2 experts following published guidelines, with disagreements resolved by a committee.15,16 MI was defined based on signs, symptoms, ECG and troponin levels.17 Microsize MI was defined as an MI with peak troponin level <0.5 ng/mL.18 For fatal events, interview with next of kin and the national death index were used to identify deaths. Medical records, death certificates and interviews with

Statistical analyses

Restrictive cubic splines were used to graph hazard ratios (HRs) of incident CHD associated with hsCRP, leukocyte count and serum albumin, separately (Supplementary Figure 1). Based on the spline, tertile cutpoints were used to define abnormally elevated levels of hsCRP (≥3.8 mg/L), leukocyte count (≥6.3 × 109 cells/L) and abnormal low levels of serum albumin (≤4.0 g/dL). We derived 4 mutually exclusive groups corresponding to having 0, 1, 2, or 3 markers of inflammation in abnormal levels,

Participants’ characteristics

Out of the 15,758 participants included in the current analysis, 38.9% (n = 6,123) had 0, 36.6% (n = 5,774) had 1, 19.8% (n = 3,113) had 2 and 4.7% (n = 748) had 3 markers of inflammation. Participants with a higher count of markers of inflammation were more likely to be older, Black, current smoker, be obese, have higher systolic BP, history of diabetes, and antihypertensive medication use and less likely to be male and never smoker (Table I). Also, participants with a higher count of markers

Discussion

In this large contemporary cohort of adults without a history of CHD, we observed a graded association between the number of biomarkers of inflammation and incident CHD after adjusting for traditional risk factors. There was no evidence of interaction in the association of the number of markers of inflammation and incident CHD by sex or race. Also, participants with more biomarkers of inflammation had higher risk for incident non-fatal MI, fatal incident CHD, sudden cardiac death and incident

Strengths and limitations

Our study's strengths include the use of a contemporary, large, national, biracial sample with rigorously collected data and expert adjudicated events. We analyzed the association between inflammation biomarkers and incident non-fatal MI, fatal CHD, sudden cardiac death and CHD excluding microsize MI, separately. Our study also had some limitations. The REGARDS study enrolled only non-Hispanic White and Black participants, therefore, our findings may not be generalizable to other race/ethnic

Conclusions

In conclusion, the number of markers of inflammation was associated with a graded risk for incident CHD independent of traditional risk factors. Our findings suggest that a simple count of inflammation biomarkers including hsCRP, leukocyte count and serum albumin in abnormal levels may help identify individuals at increased risk for incident CHD.

Funding

The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. Additional funding was provided by R01 HL80477 from the National Heart Lung and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not

Conflict of interest

Dr. Akinyelure reports grants from the American Heart Association unrelated to the study. Drs. Colantonio and Safford report research support from Amgen unrelated to the study. Other authors report no relevant disclosures.

Acknowledgments

We would like to gratefully acknowledge Mr. Amit Patki for his contribution toward the data analysis of this study.

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