Abstract Body (Do not enter title and authors here): Background: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of a constitutively expressed β subunit (HIF-1β) and an oxygen-dependent α subunit (HIF-1α). HIF-1α has an important protective effect on the pathophysiology underlying coronary artery disease (CAD). However, the association between serum HIF-1α levels and mortality in patients with suspected or known CAD is unknown.
Methods and Results: Serum levels of HIF-1α were measured in 2,418 patients with suspected or known CAD using a commercially available enzyme-linked immunosorbent assay kit (sensitivity, 30 pg/mL). The outcomes were all-cause death, cardiovascular (CV) death, and non-CV death. Patients were divided into 5 groups according to HIF-1α levels; below the sensitivity (Q0, <30 pg/mL) and quartiles of measurable HIF-1α levels (Q1, 31-127; Q2, 128-303; Q3, 307-765; Q4, 774-4131 pg/mL). Patients were followed up over a 6-year period. During the follow-up, 536 (22.2%) deaths occurred, including 166 (6.9%) CV deaths, 326 (13.5%) non-CV deaths, and 44 (1.8%) undetermined deaths. At baseline, HIF-1α levels were significantly and inversely associated with the rate of current smoker (P<0.001), and showed significant U-shaped associations with age (P=0.016) and high-sensitivity C-reactive protein levels (P<0.001). Interestingly, HIF-1α levels exhibited U-shaped associations with incidence of all-cause, CV death, and non-CV death (Figure 1). Since the rates of incident outcomes were similar among Q1-Q3, we combined these 3 groups into the reference group for Cox proportional hazard analyses thereafter. After adjustment for potential clinical confounders and established CV biomarkers, the low HIF-1α level (Q0) was significantly associated with all-cause death (adjusted hazard ratio [aHR], 1.38; 95% confidence interval [CI], 1.02–1.91), but not with CV death (aHR, 1.12; 95% CI, 0.68–1.97) or non-CV death (aHR, 1.45; 95% CI, 0.98–2.23), while the high HIF-1α level (Q4) was not significantly associated with all-cause death (aHR, 1.12; 95% CI, 0.66–1.86), CV death (aHR, 0.76; 95% CI, 0.28–1.86), or non-CV death (aHR, 1.17; 95% CI, 0.58–2.25).
Conclusions: We first demonstrated that serum HIF-1α levels exhibited a reverse J-shaped association with the risk of all-cause mortality in patients with suspected or known CAD.