Hdl Levels And Oxidizability During Myocardial Infarction Are Associated With Reduced Endothelial-mediated Vasodilation And Nitric Oxide Bioavailability

Objective: Acute phase response modifies high-density lipoprotein (HDL) into a dysfunctional particle that may favor oxidative/inflammatory stress and eNOS dysfunction. The present study investigated the impact of this phenomenon on patients presenting ST-elevation myocardial infarction (STEMI). Methods: Plasma was obtained from 180 consecutive patients within the first 24-h of onset of STEMI symptoms (D1) and after 5 days (D5). Nitrate/nitrite (NOx) and lipoproteins were isolated by gradient ultracentrifugation. The oxidizability of low-density lipoprotein incubated with HDL (HDLaoxLDL) and the HDL self-oxidizability (HDLautox) were measured after CuSO4 co-incubation. Anti-inflammatory activity of HDL was estimated by VCAM-1 secretion by human umbilical vein endothelial cells after incubation with TNF-α. Flow-mediated dilation (FMD) was assessed at the 30th day (D30) after STEMI. Results: Among patients in the first tertile of admission HDL-Cholesterol (<33mg/dL), the increment of NOx from D1 to D5 [6.7(2; 13) vs. 3.2(-3; 10) vs. 3.5(-3; 12); p=0.001] and the FMD adjusted for multiple covariates [8.4(5; 11) vs 6.1(3; 10) vs. 5.2(3; 10); p=0.001] were higher than in those in the second (33-42mg/dL) or third (>42mg/dL) tertiles, respectively. From D1 to D5, there was a decrease in HDL size (-6.3±0.3%; p<0.001) and particle number (-22.0±0.6%; p<0.001) as well as an increase in both HDLaoxLDL (33%(23); p<0.001) and HDLautox (65%(25); p<0.001). VCAM-1 secretion after TNF-a stimulation was reduced after co-incubation with HDL from healthy volunteers (-24%(33); p=0.009), from MI patients at D1 (-23%(37); p=0.015) and at D30 (-22%(24); p=0.042) but not at D5 (p=0.28). Conclusion: During STEMI, high HDL-cholesterol is associated with a greater decline in endothelial function. In parallel, structural and functional changes in HDL occur reducing its anti-inflammatory and anti-oxidant properties.2372840846Rader, D.J., Molecular regulation of HDL metabolism and function: implications for novel therapies (2006) J.Clin. Invest, 116 (12), pp. 3090-3100Kontush, A., Chapman, M.J., Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities (2010) Curr. Opin. Lipidol., 21 (4), pp. 312-318Besler, C., Heinrich, K., Rohrer, L., Doerries, C., Riwanto, M., Shih, D.M., Chroni, A., Landmesser, U., Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease (2011) J.Clin. Invest, 121 (7), pp. 2693-2708Gomaraschi, M., Ossoli, A., Favari, E., Adorni, M.P., Sinagra, G., Cattin, L., Veglia, F., Calabresi, L., Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome (2013) Cardiovasc Res., 100 (1), pp. 36-43Zheng, L., Nukuna, B., Brennan, M.L., Sun, M., Goormastic, M., Settle, M., Schmitt, D., Hazen, S.L., Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease (2004) J.Clin. Invest, 114 (4), pp. 529-541Artl, A., Marsche, G., Lestavel, S., Sattler, W., Malle, E., Role of serum amyloid A during metabolism of acute-phase HDL by macrophages (2000) Arterioscler. Thromb. Vasc. Biol., 20 (3), pp. 763-772Kontush, A., Chapman, M.J., Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis (2006) Pharmacol. Rev., 58 (3), pp. 342-374Flammer, A.J., Anderson, T., Celermajer, D.S., Creager, M.A., Deanfield, J., Ganz, P., Hamburg, N.M., Lerman, A., The assessment of endothelial function: from research into clinical practice (2012) Circulation, 126 (6), pp. 753-767Quinaglia e Silva, J.C., Munhoz, D.B., Morato, T.N., Gurgel, A., Macedo, A.C., Sever, P., Sposito, A.C., Effect of beta blockers (metoprolol or propranolol) on effect of simvastatin in lowering C-reactive protein in acute myocardial infarction (2009) Am. J. Cardiol., 103 (4), pp. 461-463. , Brasilia Heart Study GChapman, M.J., Goldstein, S., Lagrange, D., Laplaud, P.M., Adensity gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum (1981) J.Lipid Res., 22 (2), pp. 339-358Huang, J.M., Huang, Z.X., Zhu, W., Mechanism of high-density lipoprotein subfractions inhibiting copper-catalyzed oxidation of low-density lipoprotein (1998) Clin. Biochem., 31 (7), pp. 537-543Bendel, R.B., Afifi, A., Comparison of stopping rules in forward regression (1977) J.Am. Stat. Assoc., 72, pp. 46-53Mickey, J., Greenland, S., Astudy of the impact of confounder-selection criteria on effect estimation (1989) Am. J. Epidemiol., 129, pp. 125-137Jahangiri, A., de Beer, M.C., Noffsinger, V., Tannock, L.R., Ramaiah, C., Webb, N.R., van der Westhuyzen, D.R., de Beer, F.C., HDL remodeling during the acute phase response (2009) Arterioscler. Thromb. Vasc. Biol., 29 (2), pp. 261-267Khovidhunkit, W., Kim, M.S., Memon, R.A., Shigenaga, J.K., Moser, A.H., Feingold, K.R., Grunfeld, C., Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host (2004) J.Lipid Res., 45 (7), pp. 1169-1196Undurti, A., Huang, Y., Lupica, J.A., Smith, J.D., DiDonato, J.A., Hazen, S.L., Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle (2009) J.Biol. Chem., 284 (45), pp. 30825-30835Patel, P.J., Khera, A.V., Jafri, K., Wilensky, R.L., Rader, D.J., The anti-oxidative capacity of high-density lipoprotein is reduced in acute coronary syndrome but not in stable coronary artery disease (2011) J.Am. Coll. Cardiol., 58 (20), pp. 2068-2075Cho, K.H., Shin, D.G., Baek, S.H., Kim, J.R., Myocardial infarction patients show altered lipoprotein properties and functions when compared with stable angina pectoris patients (2009) Exp. Mol. Med., 41 (2), pp. 67-76Proudfoot, J.M., Barden, A.E., Loke, W.M., Croft, K.D., Puddey, I.B., Mori, T.A., HDL is the major lipoprotein carrier of plasma F2-isoprostanes (2009) J.Lipid Res., 50 (4), pp. 716-722Meagher, E.A., FitzGerald, G.A., Indices of lipid peroxidation invivo: strengths and limitations (2000) Free Radic. Biol. Med., 28 (12), pp. 1745-1750Bowry, V.W., Stanley, K.K., Stocker, R., High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors (1992) Proc. Natl. Acad. Sci. U S A, 89 (21), pp. 10316-10320Matsunaga, T., Hokari, S., Koyama, I., Harada, T., Komoda, T., NF-kappa B activation in endothelial cells treated with oxidized high-density lipoprotein (2003) Biochem. Biophys. Res. Commun., 303 (1), pp. 313-319Bhagat, K., Endothelial function and myocardial infarction (1998) Cardiovasc Res., 39 (2), pp. 312-317Mizuno, A., Baretti, R., Buckberg, G.D., Young, H.H., Vinten-Johansen, J., Ma, X.L., Ignarro, L.J., Endothelial stunning and myocyte recovery after reperfusion of jeopardized muscle: a role of L-arginine blood cardioplegia (1997) J.Thorac. Cardiovasc Surg., 113 (2), pp. 379-389Schmidt, A.M., Hori, O., Chen, J.X., Li, J.F., Crandall, J., Zhang, J., Cao, R., Stern, D., Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes (1995) J.Clin. Invest, 96 (3), pp. 1395-1403Otsuki, M., Hashimoto, K., Morimoto, Y., Kishimoto, T., Kasayama, S., Circulating vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic NIDDM patients (1997) Diabetes, 46 (12), pp. 2096-2101Silbernagel, G., Schottker, B., Appelbaum, S., Scharnagl, H., Kleber, M.E., Grammer, T.B., Ritsch, A., Marz, W., High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality (2013) Eur. Heart J.Corsetti, J.P., Ryan, D., Rainwater, D.L., Moss, A.J., Zareba, W., Sparks, C.E., Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels (2010) Arterioscler. Thromb. Vasc. Biol., 30 (8), pp. 1657-166

Elevated Cetp Activity During Acute Phase Of Myocardial Infarction Is Independently Associated With Endothelial Dysfunction And Adverse Clinical Outcome

Objective: Recent data suggests that cholesteryl ester transfer protein (CETP) activity may interact with acute stress conditions via inflammatory-oxidative response and thrombogenesis. We investigated this assumption in patients with ST-elevation myocardial infarction (STEMI). Methods: Consecutive patients with STEMI (n=116) were enrolled <24-hof symptoms onset and were followed for 180 days. Plasma levels of C-reactive protein (CRP), interleukin-2 (IL-2), tumor necrosis factor (TNFα), 8-isoprostane, nitric oxide (NOx) and CETP activity were measured at enrollment (D1) and at fifth day (D5). Flow-mediated dilation (FMD) was assessed by ultrasound and coronary thrombus burden (CTB) was evaluated by angiography. Results: Neither baseline nor the change of CETP activity from D1 to D5 was associated with CRP, IL-2, TNFα, 8-isoprostane levels or CTB. The rise in NOx from D1 to D5 was inferior [3.5(-1; 10) vs. 5.5(-1; 12); p<0.001] and FMD was lower [5.9(5.5) vs. 9.6(6.6); p=0.047] in patients with baseline CETP activity above the median value than in their counterparts. Oxidized HDL was measured by thiobarbituric acid reactive substances (TBARS) in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r=0.72; p=0.014) and FMD (r=-0.61; p=0.046). High CETP activity at admission was associated with the incidence of sudden death and recurrent MI at 30 days (OR 12.8; 95% CI 1.25-132; p=0.032) and 180 days (OR 3.3; 95% CI 1.03-10.7; p=0.044). Conclusions: An enhanced CETP activity during acute phase of STEMI is independently associated with endothelial dysfunction and adverse clinical outcome.2372777783Cazita, P.M., Barbeiro, D.F., Moretti, A.I., Quintao, E.C., Soriano, F.G., Human cholesteryl ester transfer protein expression enhances the mouse survival rate in an experimental systemic inflammation model: a novel role for CETP (2008) Shock, 30 (5), pp. 590-595Deguchi, H., Fernandez, J.A., Griffin, J.H., Plasma cholesteryl ester transfer protein and blood coagulability (2007) Thromb. Haemost., 98 (6), pp. 1160-1164Grion, C.M., Cardoso, L.T., Perazolo, T.F., Garcia, A.S., Barbosa, D.S., Morimoto, H.K., Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients (2010) Eur. J. Clin. Investig., 40 (4), pp. 330-338Frangogiannis, N.G., Smith, C.W., Entman, M.L., The inflammatory response in myocardial infarction (2002) Cardiovasc. Res., 53 (1), pp. 31-47Campo, G., Valgimigli, M., Ferraresi, P., Malagutti, P., Baroni, M., Arcozzi, C., Tissue factor and coagulation factor VII levels during acute myocardial infarction: association with genotype and adverse events (2006) Arterioscler. Thromb. Vasc. Biol., 26 (12), pp. 2800-2806Minnema, M.C., Peters, R.J., de Winter, R., Lubbers, Y.P., Barzegar, S., Bauer, K.A., Activation of clotting factors XI and IX in patients with acute myocardial infarction (2000) Arterioscler. Thromb. Vasc. Biol., 20 (11), pp. 2489-2493Sposito, A.C., Carvalho, L.S., Cintra, R.M., Araujo, A.L., Ono, A.H., Andrade, J.M., Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal (2009) Atherosclerosis, 207 (1), pp. 191-194Lagrost, L., Determination of the mass concentration and the activity of the plasma cholesteryl ester transfer protein (CETP) (1998) Methods Mol. Biol., 110, pp. 231-241Chapman, M.J., Goldstein, S., Lagrange, D., Laplaud, P.M., Adensity gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum (1981) J.Lipid Res., 22 (2), pp. 339-358Ye, D., Kraaijeveld, A.O., Grauss, R.W., Willems, S.M., van Vark-van der Zee, L.C., de Jager, S.C., Reduced leucocyte cholesteryl ester transfer protein expression in acute coronary syndromes (2008) J.Intern. Med., 264 (6), pp. 571-585Jahangiri, A., de Beer, M.C., Noffsinger, V., Tannock, L.R., Ramaiah, C., Webb, N.R., HDL remodeling during the acute phase response (2009) Arterioscler. Thromb. Vasc. Biol., 29 (2), pp. 261-267Blaschke, F., Takata, Y., Caglayan, E., Collins, A., Tontonoz, P., Hsueh, W.A., Anuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor (2006) Circ. Res., 99 (12), pp. e88-99Fang, C., Yoon, S., Tindberg, N., Jarvelainen, H.A., Lindros, K.O., Ingelman-Sundberg, M., Hepatic expression of multiple acute phase proteins and down-regulation of nuclear receptors after acute endotoxin exposure (2004) Biochem. Pharmacol., 67 (7), pp. 1389-1397Luo, Y., Tall, A.R., Sterol upregulation of human CETP expression invitro and in transgenic mice by an LXR element (2000) J.Clin. Investig., 105 (4), pp. 513-520Christison, J.K., Rye, K.A., Stocker, R., Exchange of oxidized cholesteryl linoleate between LDL and HDL mediated by cholesteryl ester transfer protein (1995) J.Lipid Res., 36 (9), pp. 2017-2026Matsunaga, T., Hokari, S., Koyama, I., Harada, T., Komoda, T., NF-kappa B activation in endothelial cells treated with oxidized high-density lipoprotein (2003) Biochem. Biophys. Res. Commun., 303 (1), pp. 313-319Ohmura, H., Watanabe, Y., Hatsumi, C., Sato, H., Daida, H., Mokuno, H., Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm (1999) Atherosclerosis, 142 (1), pp. 179-184Besler, C., Heinrich, K., Rohrer, L., Doerries, C., Riwanto, M., Shih, D.M., Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease (2011) J.Clin. Investig., 121 (7), pp. 2693-2708Luscher, T.F., Taddei, S., Kaski, J.C., Jukema, J.W., Kallend, D., Munzel, T., Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial (2012) Eur. Heart J., 33 (7), pp. 857-865Ehara, S., Ueda, M., Naruko, T., Haze, K., Itoh, A., Otsuka, M., Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes (2001) Circulation, 103 (15), pp. 1955-1960Norata, G.D., Ongari, M., Uboldi, P., Pellegatta, F., Catapano, A.L., Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells (2005) Int. J. Mol. Med., 16 (4), pp. 717-722Ray, K.K., Ditmarsch, M., Kallend, D., Niesor, E.J., Suchankova, G., Upmanyu, R., The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial (2014) Eur. Heart J., 35 (27), pp. 1792-1800Gomaraschi, M., Ossoli, A., Favari, E., Adorni, M.P., Sinagra, G., Cattin, L., Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome (2013) Cardiovasc. Res., 100 (1), pp. 36-43Sposito, A.C., Santos, S.N., de Faria, E.C., Abdalla, D.S., da Silva, L.P., Soares, A.A., Timing and dose of statin therapy define its impact on inflammatory and endothelial responses during myocardial infarction (2011) Arterioscler. Thromb. Vasc. Biol., 31 (5), pp. 1240-1246Guazzi, M., Reina, G., Gripari, P., Tumminello, G., Vicenzi, M., Arena, R., Prognostic value of flow-mediated dilatation following myocardial infarction (2009) Int. J. Cardiol., 132 (1), pp. 45-50Karatzis, E.N., Ikonomidis, I., Vamvakou, G.D., Papaioannou, T.G., Protogerou, A.D., Andreadou, I., Long-term prognostic role of flow-mediated dilatation of the brachial artery after acute coronary syndromes without ST elevation (2006) Am. J. Cardiol., 98 (11), pp. 1424-142