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Prognostic value of LDL to HDL cholesterol ratio in patients undergoing coronary stenting S. Novo, F. Macaione, E. Corrado, G. Novo, F. Bonura, S. Evola. Chair of Cardiovascular Disease, Center for the Early Diagnosis of Preclinical and Multifocal Atherosclerosis and for the Secondary PreventionUniversity Hospital “P. Giaccone” of the University of Palermo – Italy 100 There is overwhelming evidence that an elevated low-density lipoprotein cholesterol (LDL-C) concentration in plasma is atherogenic, whereas a higher high-density lipoprotein cholesterol (HDL-C) level is cardioprotective. A series of studies suggested that the use of the ratio of LDL-C to HDL-C, which can be obtained from a standard lipid profile, is superior to the use of HDL-C or LDL-C alone and that the ratio of LDL-C/HDLC may provide better risk assessment by concurrently accounting for both atherogenic and protective lipid fractions. In this work, we mainly clarified whether the LDL-C/HDL-C ratio would influence long-term clinical outcome in patients after PCI and evaluated the predictive usefulness of LDL-C/HDLC ratio after PCI. Methods We assessed a population composed of 1300 consecutive patients with acute coronary syndrome, undergoing percutaneous coronary intervention (PCI) with implantation of drug-eluting or bare metal stents from November 2006 and December 2008 in our Division of Cardiology. Exclusion criteria were, cardiogenic shock, previous stent in the target vessel area, coronary artery bypass graft (CABG) within 48 hours of coronary angioplasty, pregnancy, malignant tumor, life expectancy <1 years, implantation of two different kind of stent in the same patients, liver dysfunction; familiar hypercholesterolemia; serum triglycerides (TG) > 400 mg/dl, left ventricular ejection fraction < 30%. In this manner, a final sample size of 504 (48.76%) of 1300 patients were enrolled. Blood lipid profile data were evaluated on venous blood samples in the fasting state (12 hours) just before percutaneous coronary intervention (PCI). Total cholesterol (TC), triglycerides (TG), HDL-c were measured using conventional enzymatic methods. LDL-c levels were calculated using Freidewald’s method . After we calculated non-HDL-c, by difference between total cholesterol (TC) and HDL-c, and LDL-c/HDL-c, TG/HDL-c and non-HDL-c/HDL-c ratio. The endpoint was the rate of major adverse cardiac events (MACE) defined as occurrence of cardiac death, new hospitalization for ACS (Acute Coronary Syndrome), target vessel revascularization (TVR) and stroke. Follow up of clinical end points was conducted for up 3 years after PCI . Statistical analysis Spearman correlation analysis was performed between LDLc/HDL-c ratio and marker of inflammation. Multivariable logistic regression model with stepwise selection was used to identify independent factor associated with outcomes. The areas under the curve (AUC) of the receiver operating characteristic curves (ROC) were constructed to assess the degree of predictability of lipids and ratios of interest on cardiovascular risk. Table 1 Demographic, clinical, laboratory and angiographic characteristics of study patients Mean age (n/SD) Male n (%) Smokers n (%) Previous smokers n (%) Familiar history of CAD n (%) Hypertension n (%) Obesity ( BMI>30Kg/m2) Diabetes n (%) Previous CABG n (%) Previous IMA n (%) Previous PCI n (%) Previous HF n (%) Anemia n (%) Renal insufficiency n (%) ACE-Inhibitors n (%) ARBs n(%) β blockers n(%) Statins n(%) TC (mg/dl) HDL-c(mg/dl) LDL-c(mg/dl) TG (mg/dL) non-HDL (mg/dL) L/H ratio non HDL-c/HDL-c TG/HDL-c CRP (mg/dL) ESR (mm/h) Fibrinogen (mg/dL) Emergency Procedure n (%) Multivessel disease n (%) Bare metal stent n (%) N° Stents Patients with adverse events n=179 63.99±11.45 139(77.65) 56(31.28) 52(29.05) 71(39.66) 116(64.80) 33(18.44) 73 (40.78) 15 (8.38) 49 (27.37) 40 (22.35) 11 (6.15) 51 (28.49) 21(11.73) 99 (55.31) 34 (18.99) 119 (66.48) 135 (75.42) 178.25±46.89 42.05±13.25 109.79±40.92 133.26±75.55 136.20±46.30 2.90±1.62 3.63±1.99 3.68±3 2.68±8.70 21.52±19.37 404.74±113.79 30 (16.76) 76 (42.46) 91 (50.84) 1.44±0.65 P 0.78 0.589 0.650 0.291 0.7026 0.104 0.560 0.448 0.542 0.904 0.986 0.958 0.0322 0.520 0.123 0.103 0.348 0.993 0.001 0.013 <0.001 0.919 <0.001 <0.001 <0.001 0.114 0.066 0.208 <0.001 0.991 0.978 0.307 0.848 Patients without adverse events n=325 64.27±10.82 244 (75.08) 94(28.92) 79(24.31) 136(41.85) 244(75.08) 52(16) 120 (36.92) 34 (10.46) 92 (28.31) 71 (21.85) 21(6.46) 64 (19.69) 31 (9.54) 156 (48) 84 (25.85) 201 (61.85) 248 (76.31) 165.08±42.37 45.02±12.46 93.55±35.43 132.55±74.30 120.06±39.63 2.19±0.955 2.84±1.184 3.30±2.31 1.56±2.72 18.22±17.13 360.61±98.62 56 (17.23) 139 (42.77) 182 (56) 1.45±0.51 Results However we searched for possible correlations between LDL-C/ HDL-C ratio and marker of inflammations (data not shown) and we found a significant correlation with fibrinogen (r = +0.094, p = 0.034) and CRP (r =+0.14, p = 0.004) concentrations. There were no significant differences for all other variable and all three groups did not differ with regard to medications use. At the end of three years follow up overall MACE were observed in 22 patients (20.95%) of the LDL-C/HDL-C ≤1.5 group, in 39 patients (27.85%) of the 1.5< LDL-C/HDL-C ≤2.0 group and in 118 patients (45.55%) of the LDL-C/HDL-C >2.0. (Table 2) We used logistic regression analysis in order to identify the independent predictor for occurrence of MACE during follow up. Multivariate logistic regression analysis was adjusted for all variables that at univariate analysis showed p value ≤0.10 and we found that LDL-C/HDL-C ratio (OR 1.593; 95%CI 1.3351.901; p <0.0001) and fibrinogen (OR 1.003; 95%CI 1.0011.005; p = 0.0004) were a significant predictors of MACE after PCI. (Table 3) Moreover, the specificity and sensitivity of the correlation between MACE and blood lipid profile was evaluated using ROC analysis to assess their predictive value. The ROC curve analyses showed that the best marker of MACE was LDL-C/HDL-C ratio, with an area under the ROC curve of 0.66 (95% CI 0,61- 0,69). (Table 4) The predictive sensitivity and specificity of the L/H ratio were 75.4% (95%CI 68.4 – 81.5) and 52% (95%CI 46.4 – 57.5), respectively, for predicting MACE, at the cut-off of 1.85. Table 2 Incidence of MACE MACE n (%) ACS n (%) Cardiac Death n (%) TVR n(%) Stroke n(%) LDL/HDL ratio < 1,5 (n= 105) LDL/HDl ratio 1,5-2 (n=140 ) LDL/HDL ratio>2 (n= 259) P value < 0,05 22 (20.95) 39 (27.85) 118 (45.55) < 0.001 15 (14.28) 1 (0.95) 22 (15.71) 3 (2.14) 69 (26.64) 10 (3.86) 0.006 0.269 5 (4.76) 1 (0.95) 14 (10) 0 36 (13.89) 3 (1.15) 0.032 0.45 Table 3 Logistic regression analysis The study population consisted of 504 patient with mean age of 65.01 ± 10.85 years, most of the patients were male (75.99%). The patient sample was divided up into 3 groups: LDL-C/ HDLC ≤1.5 group (Gp1 n= 105), 1.5< LDL-C/HDL-C ≤2.0 group (Gp2 n= 140), and LDL-C/HDL-C >2.0 groups (Gp3 n= 259). The groups were different regard to lipid profile, moreover the patients of Group 3 had significantly higher proportion of diabetes compared with patients of group 1 and group 2 (p = 0.034). In contrast, in the Group 1 and 2 was a significantly higher proportion of previous IMA compared with group 3 (p = 0.003). In addition, among three groups, there was a clear trend for higher C-reactive protein (CRP) levels and fibrinogen associated with increasing of LDL-C/ HDL-C ratio, but the differences did not reach statistical significance. Variable Coefficient Std. Error Odds ratio 95% CI 0.09012 P value <0.05 <0.0001 LDLc/HDL-c Fibrinogen 0.4660 1.593 0.0009480 0.0004 1.003 1.335 1.901 1.001 1.005 0.003369 LDL-c LDL/HDL ratio TC HDL-c TG/HDL ratio TG non HDL non HDL/HDL ratio SE 95% CI p-value 0.62 0.0262 0.57-0.66 0.0001 0.66 0.58 0.56 0.53 0.508 0.602 0.630 0.0257 0.0266 0.0267 0.0270 0.0273 00265 0.0261 0.61-0.69 0.54-0.62 0.52-0.61 0.49-0.57 0.46-0.55 0.56-0.64 0.58-0.67 0.0001 0.0023 0.0102 0.2056 0.7574 0.0001 0.0001 60 40 LDL LDL-c/HDL-c non HDL-c/HDL-c 20 0 0 20 40 60 100-Specificity 100 Figure 1 Comparison receiver operating characteristic (ROC) curves with AUC > 0. 60. Conclusion This study showed that the three groups were significant different about lipid profile and ratios but that only LDL-C/HDLC ratio was significant predictor of occurrence of MACE in patient undergoing PCI, on long term outcome after PCI. From multivariate analysis came up from, too, that the fibrinogen was an important predictor for MACE. Another very interesting aspect was that, after comparison the area under the ROC curve, built only for lipid profile, the area under the ROC curve was largest for the LDL-c/HDL-c ratio, than that for another lipids and lipid ratios. Especially, after the receiver operating characteristic (ROC) curve analysis, the cut-off point of LDLC/HDL-C ratio to identifying of occurrence of MACE, was ≥1.85. In conclusion, pending further studies to confirm these results, in light of these data, it would be important to be able to better define the role of to assess if pre-procedural risk stratification with lipid ratio of LDL-c/HDL-c might be used as an integrated and simple lipid measure to the risk of adverse events after PCI, so as secondary prevention as an adjunct to established clinical risk factors may be useful as form of prevention for early identification of high risk patients for MACE, and a better understanding the relationship between the LDL-c/HDL-c ratio and fibrinogen is needed. Research now in progress will almost certainly help clarify the picture. - Rizzo M, Berneis K, Corrado E, Novo S The significance of low-density-lipoproteins size in vascular diseases. Int Angiol 2006; 25: 4-9 Matsumoto I, Miyake Y, Mizukawa M, Takagi Y Impact of lowdensity lipoprotein cholesterol/high-density lipoprotein cholesterol ratio on long-term outcome in patients undergoing percutaneous coronary intervention Circ J. 2011; 75:905-10 Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE(2005) Non-HDL cholesterol, apolipoproteinA-I and B100, Standard Lipid Measures, Lipid Ratios, and CRP as Risk Factors for Cardiovascular Disease in Women. JAMA 2005; 94:326-33 Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007; 357:1301-10 Declaration of interest: There is no conflict of interest with any financial organization regarding the material Printed by Insert Footer or Copyright Information Here 80 References Table 4 Comparison of areas under the ROC curves (95% CI) for blood lipid regard to MACE AUC 80 Sensitivity Purpose