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Aims There is an increasing need for translational studies identifying molecular targets contributing to atherosclerotic plaque destabilization. Local molecular plaque markers that are related to plaque vulnerability may hold predictive value to identify patients who are at increased risk to suffer from cardiovascular events. Animal studies revealed that adipocyte fatty acid binding protein (FABP4) is associated with the progression of atherosclerosis; however, FABP4 expression studies in human atherosclerotic plaques are lacking. We investigated FABP4 expression in carotid atherosclerotic lesions in relation to plaque composition and future cardiovascular events. Methods and results Atherosclerotic plaques were obtained from 561 patients undergoing carotid endarterectomy (CEA). Plaques were analysed for the presence of macrophages, lipid core, smooth-muscle cells, collagen, calcification, and intraplaque haemorrhage. Patients were followed for 3 years after CEA. The primary outcome was defined as the composite of vascular death, vascular event, and surgical or percutaneous vascular intervention. Fatty acid binding protein levels correlated with unstable plaque characteristics and symptomatic lesions. Patients with increased FABP4 plaque levels showed a two-fold increased risk \[HR = 1.99, 95% confidence interval (95% CI) (1.30–3.04)\] ( P = 0.005) to reach the primary outcome during follow-up. Increased FABP4 levels related to primary outcome, independent from general cardiovascular risk factors \[HR = 1.33, 95% CI (1.08–1.65)\] ( P = 0.008). Conclusion FABP4 levels in atherosclerotic lesions are associated with an unstable plaque phenotype and an increased risk for cardiovascular events during follow-up. Besides risk stratification for adverse future cardiovascular events, the outcome of the present study supports the relevance of exploring FABP4 antagonists as a potential pharmaceutical intervention to treat atherosclerotic disease progression.

Aim: Atherosclerotic plaque characteristics may vary among individuals, in part due to heritable factors. The genetic architecture of plaque phenotypes is largely unknown. A common variant (rs17398575-A) near PIK3CG on chromosome 7 has previously been associated with carotid plaque presence. Animal models suggest that PIK3CG may play a role in plaque formation through neovascularization. We hypothesized that the PIK3CG variant is associated with intraplaque hemorrhage and vessel density in human plaque tissue. Methods: We collected 831 patients in the Athero-Express Biobank Study, all of whom underwent carotid endarterectomy and genotyped them using Affymetrix SNP 5.0. We tested PIK3CG variants for association to intraplaque hemorrhage and vessel density using logistic and linear regression model, respectively, correcting for age, gender and principal components. We used the BiKE cohort to assess the effect of PIK3CG variants on PIK3CG expression in circulating monocytes (N=95) and in carotid plaques (N=126). Results: The reported PIK3CG variant, rs17398575 (risk allele A, frequency = 0.72), was nominally significantly associated with intraplaque hemorrhage (OR=1.40 [1.10-1.69 95% CI], p=0.0271) and vessel density (β=0.095 [0.0415 s.e.m.], p=0.0221). We also report another nearby variant, rs849429 (risk allele A, frequency=0.49), but uncorrelated to rs17398575, associated with intraplaque vessel density (β=-0.164 [0.0361 s.e.m.], p=6.70×10-6). The SNP dependent PIK3CG mRNA expression demonstrated a differential effect in the vascular wall (p=0.783 for rs17398575; p=0.0198 for rs849429) compared to circulating monocytes (p=0.0261 for rs17398575; p=0.350 for rs849429). Conclusion: To our knowledge this is the first report involving the association of common genetic variants to histological plaque phenotypes. These results require further replication in independent cohorts. Further research should focus on elucidating the underlying mechanisms leading to plaque vessel formation and intraplaque hemorrhage, as both have been demonstrated to associate with secondary cardiovascular disease.