Stress-induced myocardial perfusion defects found in dipyridamole–thallium-201 single-photon emission computed tomography imaging may indicate vascular perfusion abnormalities and risk of obstructive or nonobstructive coronary heart disease. Besides nuclear imaging and subsequent coronary angiography (CAG), no blood test can indicate whether dysregulated homeostasis is associated with stress-induced myocardial perfusion defects. This study investigated the expression signature of long noncoding RNAs (lncRNAs) and genes involved in vascular inflammation and stress response in the blood of patients with stress-induced myocardial perfusion abnormalities (n= 27). The results revealed an expression signature consisting of the upregulation ofRMRP(p< 0.01) and downregulations ofTHRIL(p< 0.01) andHIF1A(p< 0.01) among patients with a positive thallium stress test and no significant coronary artery stenosis within 6 months after baseline treatment. We developed a scoring system based on the expression signatures ofRMRP,MIAT,NTT,MALAT1,HSPA1A, andNLRP3to predict the need for further CAG among patients with moderate-to-significant stress-induced myocardial perfusion defects (area under the receiver operating characteristic curve = 0.963). Therefore, we identified a dysregulated expression profile of lncRNA-based genes in the blood that could be valuable for the early detection of vascular homeostasis imbalance and personalized therapy.