High cholesteryl ester transfer protein (CETP) activity in acute phase of myocardial infarction predicts short-term mortality by inducing endothelial dysfunction and reduced microvascular perfusion

Abstract

Background: Recently, much effort has been centered on the development of cholesteryl ester transfer protein (CETP) inhibitors, based on CETP proatherogenic role. However, some evidence indicates exacerbated CETP activity (CETPa) may also favor arterial thrombogenicity and impair endothelial function. In this context, we investigated the relation between CETPa and: 1) endothelial dysfunction; 2) coronary blood flow/myocardial perfusion after reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI). Methods: Consecutive thrombolytic-treated STEMI patients (n=116) were followed prospectively. Plasma C-reactive protein (CRP), IL-2, TNFα, 8-isoprostane, nitric oxide (NOx) levels and CETPa (%) were measured in the first 24 hours (D1) and at 5th day (D5) after MI onset. Culprit artery percutaneous coronary angioplasty (PCA) was performed at a mean 6 days after MI, when pre- and post-procedure myocardial blush grade (MBG) and TIMI flow were measured. At D30 we measured brachial artery flow-mediated dilation (FMD) by ultrasonography. In addition, all patients were genotyped for eNOS polymorphism rs1799983 (G/T). Results: Although admission CETPa had no relation with the change between D1 and D5 in CRP, IL-2, TNFα or 8-isoprostane plasma levels, patients with higher CETPa presented both poor coronary flow (TIMI flow<3, adjusted OR of 22.1 95% CI 2.7–180; p=0.004) and myocardial perfusion (MBG<3, OR 20.4 CI 1.8–101; p=0.001), compared to those with lower CETP activity. Logistic regressions showed admission plasma CETPa higher than median as an independent predictor of cardiac death and new MI in 30 days (OR=12.8, CI 1.25–132, p=0.032), as well as endothelial dysfunction (OR=3.08, CI 1.01–9.37,p=0.048). Consistently, the rise in NOx levels between D1 and D5 was less intense in patients with exacerbated CETPa (5.5 (-1; 12) vs 3.5 (-1; 10); p<0.001). In addition, in order to evaluate if eNOS activity would be critical for the association between CETP and endothelial dysfunction, we observed that only in the presence of the functional eNOS T allele polymorphism the correlation between CETP and FMD was maintained (R2=-0.4, p=0.002). T allele patients with admission CETPa lower than median also presented FMD of 12.2±4 vs 6.0±3mm in those with high CETPa (p=0.040). Conclusions: This is the first study to suggest a relation between high plasma CETP activity in acute STEMI and increased clinical outcomes at 30 days. Our study also indicates a positive association between exacerbated CETP activity in MI and both endothelial dysfunction and poor reperfusion quality post-angioplasty.