Prediction of cardioembolic, arterial, and lacunar causes of cryptogenic stroke by gene expression and infarct location

Abstract

Background and purpose: The cause of ischemic stroke remains unclear, or cryptogenic, in as many as 35% of patients with stroke. Not knowing the cause of stroke restricts optimal implementation of prevention therapy and limits stroke research. We demonstrate how gene expression profiles in blood can be used in conjunction with a measure of infarct location on neuroimaging to predict a probable cause in cryptogenic stroke.

Methods: The cause of cryptogenic stroke was predicted using previously described profiles of differentially expressed genes characteristic of patients with cardioembolic, arterial, and lacunar stroke. RNA was isolated from peripheral blood of 131 cryptogenic strokes and compared with profiles derived from 149 strokes of known cause. Each sample was run on Affymetrix U133 Plus 2.0 microarrays. Cause of cryptogenic stroke was predicted using gene expression in blood and infarct location.

Results: Cryptogenic strokes were predicted to be 58% cardioembolic, 18% arterial, 12% lacunar, and 12% unclear etiology. Cryptogenic stroke of predicted cardioembolic etiology had more prior myocardial infarction and higher CHA(2)DS(2)-VASc scores compared with stroke of predicted arterial etiology. Predicted lacunar strokes had higher systolic and diastolic blood pressures and lower National Institutes of Health Stroke Scale compared with predicted arterial and cardioembolic strokes. Cryptogenic strokes of unclear predicted etiology were less likely to have a prior transient ischemic attack or ischemic stroke.

Conclusions: Gene expression in conjunction with a measure of infarct location can predict a probable cause in cryptogenic strokes. Predicted groups require further evaluation to determine whether relevant clinical, imaging, or therapeutic differences exist for each group.

Figures

Figure 1

Flow diagram for the prediction of cryptogenic stroke by infarct location and gene expression profiles. Cryptogenic strokes were divided into small deep infarcts (SDI) and non-SDI by location of infarct on neuroimaging. Cryptogenic SDI were predicted to be lacunar or non-lacunar stroke using a 41 gene profile. SDI of predicted non-lacunar stroke were then predicted to be arterial or cardioembolic stroke using a 40 gene profile. Cryptogenic non-SDI were predicted to be arterial or cardioembolic stroke using the 40 gene profile.

Figure 2

Principal components analysis (PCA) of cryptogenic strokes using the genes predictive of stroke cause. A. PCA of non-SDI cryptogenic strokes predicted to be arterial or cardioembolic stroke using the 40 gene profile. B. PCA of SDI cryptogenic strokes predicted to be lacunar or non-lacunar stroke using the 41 gene profile. C. PCA of the cryptogenic SDI predicted to be non-lacunar stroke in B, predicted to be arterial or cardioembolic stroke using the 40 gene profile.