Background: Acute ischemic stroke (AIS) and coronary heart disease (CHD) share many of the underlying pathophysiologic causes of atherosclerotic disease. Patients with CHD also have an elevated risk for AIS. Secondary preventive measures are aimed at modulating the shared clinical risk factors. Finding novel biomarkers predicting AIS, may provide tools for mechanistic understanding and improved secondary prevention.
Purpose: To assess potential associations between 155 biomarkers and subsequent AIS in a prospective cohort of patients with stable CHD on optimal secondary prevention, in addition to established biomarkers and clinical risk factors.
Methods: In the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial, 15,828 patients with stable CHD and at least one clinical risk factor were included. During a median follow-up time of 3.7 years, 258 patients suffered from AIS. Baseline plasma samples from cases with AIS and 2,886 randomly selected control cases from the same cohort, underwent analysis for normalized protein expression (NPX) levels with proximity extension assay (PEA) technology. An unbiased selection of variables with AIS association (proteins and clinical risk factors) was performed with random forest analysis. Confirmation of variable importance for AIS was determined by Boruta analysis. Independent associations between variables and AIS were evaluated by weighted multivariate Cox regression analysis adjusted for baseline characteristic and established cardiorenal biomarkers: cystatin C, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and high sensitivity troponin T (hs-TnT). Cox regression analysis used NPX levels modeled as continuous by standard deviation and because of multiple testing, threshold of significance was Bonferroni adjusted (p<0.00038).
Results: Median age was 68 years for cases and 65 years for controls. At baseline 92% and 97% were treated with acetylsalicylic acid and statin, respectively. Out of 155 analyzed proteins, 24 differed in NPX levels when comparing cases and controls (p<0.0001). After selection of variables associated with AIS, variable importance was confirmed for 10 proteins. Further, 2 of them passed the threshold of significance with independent associations (hazard ratio, 95% confidence interval) with AIS in adjusted models comparing cases with controls: NT-proBNP 1.39 (1.18–1.64) and hs-TnT 1.29 (1.11–1.49).
Conclusions: In this well-managed patient cohort with stable CHD and high cardiovascular risk, the established cardiac risk markers NT-proBNP and hs-TnT were independently associated with AIS. No other novel biomarker passed the statistical threshold. This might be explained by the heterogeneous group of causes accounting for AIS events or a statistically underpowered analysis. The potential protein biomarkers associated with outcome before adjustment for established cardiorenal biomarkers, need further evaluation.