Lipoprotein Subclasses Associated With High‐Risk Coronary Atherosclerotic Plaque: Insights From the PROMISE Clinical Trial

BACKGROUND: More than half of major adverse cardiovascular events (MACE) occur in the absence of obstructive coronary artery disease and are often attributed to the rupture of high‐risk coronary atherosclerotic plaque (HRP). Blood‐based biomarkers that associate with imaging‐defined HRP and predict MACE are lacking. METHODS AND RESULTS: Nuclear magnetic resonance–based lipoprotein particle profiling was performed in the biomarker substudy of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial (N=4019) in participants who had stable symptoms suspicious for coronary artery disease. Principal components analysis was used to reduce the number of correlated lipoproteins into uncorrelated lipoprotein factors. The association of lipoprotein factors and individual lipoproteins of significantly associated factors with core laboratory determined coronary computed tomographic angiography features of HRP was determined using logistic regression models. The association of HRP‐associated lipoproteins with MACE was assessed in the PROMISE trial and validated in an independent coronary angiography biorepository (CATHGEN [Catheterization Genetics]) using Cox proportional hazards models. Lipoprotein factors composed of high‐density lipoprotein (HDL) subclasses were associated with HRP. In these factors, large HDL (odds ratio [OR], 0.70 [95% CI, 0.56–0.85]; P<0.001) and medium HDL (OR, 0.84 [95% CI, 0.72–0.98]; P=0.028) and HDL size (OR, 0.82 [95% CI, 0.69–0.96]; P=0.018) were associated with HRP in multivariable models. Medium HDL was associated with MACE in PROMISE (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P=0.004), which was validated in the CATHGEN biorepository (HR, 0.91 [95% CI, 0.88–0.94]; P<0.001). CONCLUSIONS: Large and medium HDL subclasses and HDL size inversely associate with HRP features, and medium HDL subclasses inversely associate with MACE in PROMISE trial participants. These findings may aid in the risk stratification of individuals with chest pain and provide insight into the pathobiology of HRP. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT01174550