Neopterin as an Effect Modifier of the Cardiovascular Risk Predicted by Total Homocysteine: A Prospective 2-Cohort Study

Espen Ø Bjørnestad; Robert A Borsholm; Gard F T Svingen; Eva R Pedersen; Reinhard Seifert; Øivind Midttun; Per M Ueland; Grethe S Tell; Kaare H Bønaa; Ottar Nygård

doi:10.1161/JAHA.117.006500

Neopterin as an Effect Modifier of the Cardiovascular Risk Predicted by Total Homocysteine: A Prospective 2-Cohort Study

J Am Heart Assoc. 2017 Nov 2;6(11):e006500. doi: 10.1161/JAHA.117.006500.

Authors

Affiliations

¹ Faculty of Medicine, University of Bergen, Norway espen.bjornestad@student.uib.no robert.borsholm@student.uib.no.
² Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
³ Bevital AS, Bergen, Norway.
⁴ Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
⁵ Department of Clinical Science, University of Bergen, Norway.
⁶ Department of Global Public Health and Primary Care, University of Bergen, Norway.
⁷ Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
⁸ KG Jebsen Centre for Diabetes Research, Bergen, Norway.

Abstract

Background: Plasma total homocysteine (tHcy) is related to plasma neopterin, an indicator of interferon-γ-mediated immune activation, and both biomarkers positively predict cardiovascular risk. We examined whether the association between tHcy and subsequent risk of acute myocardial infarction (AMI) was modified by systemic concentrations of neopterin and C-reactive protein among patients with coronary heart disease.

Methods and results: By Cox modeling, we explored the association between tHcy and risk of AMI in 4164 patients with suspected stable angina pectoris. Subgroup analyses were performed according to median levels of neopterin and C-reactive protein. A replication study was performed among 3749 patients with AMI at baseline. Median follow-up was 7.3 and 8.3 years among patients with stable angina pectoris and AMI, respectively. tHcy and neopterin correlated in both cohorts (r_s=0.34 and r_s=0.30 among stable angina pectoris and AMI patients, respectively, both P<0.001). tHcy predicted AMI in both cohorts, independent of B-vitamin treatment. However, significant risk associations were confined to patients with plasma neopterin above the median (hazard ratios [95% confidence interval] per 1-SD increment of log-transformed tHcy 1.38 [1.26-1.50] and 1.18 [1.10-1.26] among stable angina pectoris and AMI patients, respectively) (P_int<0.005 in both cohorts). Further, adding information on the interaction between tHcy and neopterin improved model discrimination and reclassification. tHcy and C-reactive protein were weakly related, and no effect modification was found by C-reactive protein.

Conclusions: Among patients with coronary heart disease, tHcy predicted risk of AMI only in subjects with concomitantly elevated plasma neopterin. Our results motivate further research on the relationship between homocysteine metabolism, cellular immune activation, and atherothrombosis.

Keywords: acute myocardial infarction; biomarker; epidemiology; inflammation.

MeSH terms

Aged
Angina, Stable / blood*
Angina, Stable / diagnostic imaging
Angina, Stable / epidemiology
Biomarkers / blood
C-Reactive Protein / analysis
Coronary Angiography
Female
Homocysteine / blood*
Humans
Hyperhomocysteinemia / blood*
Hyperhomocysteinemia / diagnosis
Hyperhomocysteinemia / epidemiology
Inflammation Mediators / blood*
Kaplan-Meier Estimate
Linear Models
Logistic Models
Male
Middle Aged
Multivariate Analysis
Myocardial Infarction / blood*
Myocardial Infarction / diagnosis
Myocardial Infarction / epidemiology
Neopterin / blood*
Norway
Predictive Value of Tests
Prognosis
Proportional Hazards Models
Prospective Studies
Randomized Controlled Trials as Topic
Risk Assessment
Risk Factors
Up-Regulation

Substances

Biomarkers
Inflammation Mediators
Homocysteine
Neopterin
C-Reactive Protein