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1 Relation of Baseline Plasma Phospholipid Levels to Cardiovascular Outcomes at Two Years in Men With Acute Coronary Syndrome Referred for Coronary Angiography Erdal Cavusoglu, MD a,b, *, Sandeep Chhabra, MD b, Xian-Cheng Jiang, PhD c, Mohammad R. Hojjati, MD, PhD a, Vineet Chopra, MD b, Calvin Eng, MD b, Amit Gupta, MD a, Sunitha Yanamadala, PhD d, David J. Pinsky, MD d, and Jonathan D. Marmur, MD a In addition to cholesterol and triglycerides, plasma also contains phospholipids. The choline-containing phospholipids constitute >90% of total plasma phospholipids. To date, no studies have looked specifically at the prognostic significance of total phospholipids in patients with known or suspected coronary artery disease. The present study investigated the long-term prognostic significance of total choline-containing phospholipid levels in a well-characterized cohort of 193 men with acute coronary syndromes who were referred for coronary angiography at a Department of Veterans Affairs Medical Center. All patients were followed prospectively for the development of vascular outcomes. After controlling for a variety of baseline variables (including established biomarkers such high-sensitivity C-reactive protein and fibrinogen), plasma phospholipid values (analyzed as a continuous variable) were a strong and independent predictor of each of the individual end points of all-cause mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41 to 0.90, p ), cardiac mortality (HR 0.49, 95% CI 0.29 to 0.81, p ), and myocardial infarction (HR 0.71, 95% CI 0.52 to 0.98, p ) when using a Cox proportionalhazards model. In addition, baseline phospholipid values were also an independent predictor of the composite outcome of all-cause mortality, fatal or nonfatal myocardial infarction, or stroke (HR 0.66, 95% CI 0.49 to 0.90, p ). In conclusion, these data demonstrate that low baseline levels of total choline-containing phospholipid are a strong and independent predictor of cardiovascular outcomes (including mortality) in patients with acute coronary syndromes Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100: ) Phospholipids, cholesterol, and triglycerides are the major lipids in the circulation. The choline-containing phospholipids constitute 90% of total plasma phospholipids. 1 Along with free cholesterol and proteins, these phospholipids are located on the surface monolayer of human lipoprotein particles. 2 4 There is growing evidence to suggest that the blood levels of choline-containing phospholipids can affect the development of atherosclerosis. For example, the intravenous administration of dispersed phospholipid has been shown to produce rapid and substantial shrinkage of atherosclerotic lesions in experimental animals. 5 8 The antiatherogenic effects of phospholipids are believed to be caused by the mobilization of cholesterol from atherosclerotic plaques. 9,10 In addition, increases in plasma phosphatidylcholine (a major choline containing phospholipid) and a Division of Cardiology, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York; b Division of Cardiology, Department of Medicine, Bronx Veterans Affairs Medical Center, Bronx, New York; c Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York; and d Division of Cardiovascular Medicine, Department of Medicine, University of Michigan, Ann Arbor, Michigan. Manuscript received May 2, 2007; revised manuscript received and accepted July 1, 2007 *Corresponding author: Tel: ; fax: address: ecavusoglu@aol.com (E. Cavusoglu). decreases in plasma sphingomyelin (a minor choline containing phospholipid) have each been associated with a significant reduction of atherosclerosis in apolipoprotein E-null mice. 11,12 To date, however, there have been no studies specifically examining the prognostic significance of baseline plasma levels of total choline-containing phospholipids in patients with known or suspected coronary artery disease. Therefore, the goal of the present study was to investigate the utility of plasma levels of total phospholipids in predicting cardiovascular outcomes in a cohort of men with an established diagnosis of acute coronary syndrome (ACS) referred for coronary angiography. Methods This study was conducted at a United States Department of Veterans Affairs Medical Center and was approved by the local institutional review board. The study population and design have been previously described in detail elsewhere. 13,14 Briefly, 193 men who underwent diagnostic coronary angiography for the evaluation of ACS (12% with ST-segment elevation myocardial infarction [MI], 43% with non ST-segment elevation MI, and 45% with unstable angina pectoris) were enrolled in the study. Fasting blood was obtained from all patients at the time of angiography for subsequent analysis. Total choline containing phospholipid /07/$ see front matter 2007 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 1740 The American Journal of Cardiology ( Table 1 Baseline characteristics of the acute coronary syndrome population stratified by the median value for phospholipid ( vs mg/dl) Characteristic Phospholipid mg/dl Phospholipid mg/dl p Value (n 87)* (n 87)* Age (yrs) (57.2,74.3) 66.2 (54.6,71.7) Race Black 33 (37.9%) 31 (35.6%) Hispanic 26 (29.9%) 25 (28.7%) White 28 (32.2%) 31 (35.6%) ST-segment elevation MI 10 (11.5%) 12 (13.8%) Non ST-segment-elevation MI 43 (49.4%) 32 (36.8%) Unstable angina pectoris 34 (39.1%) 43 (50.0%) Congestive heart failure on presentation 19 (21.8%) 20 (23.0%) Chronic renal insufficiency 9 (10.3%) 5 (5.8%) Family history of premature coronary artery disease 25 (28.7%) 24 (27.6%) Diabetes mellitus 39 (44.8%) 40 (46.0%) Hypertension 72 (82.8%) 73 (83.9%) History of tobacco use 72 (82.8%) 73 (83.9%) Active tobacco use 32 (36.8%) 33 (37.9%) Hyperlipidemia 46 (52.9%) 48 (55.2%) Obesity (body mass index 30 kg/m 2 ) 29 (33.3%) 37 (42.5%) Aspirin use 81 (93.1%) 77 (88.5%) blocker use 70 (80.5%) 63 (72.4%) Angiotensin-converting enzyme inhibitor use 52 (59.8%) 53 (60.9%) Statin use 45 (51.7%) 46 (52.9%) Fibrate use 6 (6.9%) 5 (5.8%) Previous coronary artery bypass graft surgery 6 (6.9%) 12 (13.8%) No. of diseased coronary arteries (11.5%) 11(12.6%) 1 19 (21.8%) 9 (10.3%) 2 16 (18.4%) 27 (31.0%) 3 35 (40.2%) 38 (43.7%) 4 7 (8.1%) 2 (2.3%) Left ventricular ejection fraction % 33 (41.3%) 24 (28.6%) 45% 54% 14 (17.5%) 26 (31.0%) 31% 44% 22 (27.5%) 20 (23.8%) 30% 11 (13.8%) 14 (16.7%) Troponin I (ng/ml) (0.3,10.0) 1.5 (0.2,14.8) Erythrocyte sedimentation rate (mm/h) (11,45) 20 (10,36) hs-crp (mg/l) (6.6,28.8) 14.1 (6.8,30.6) Fibrinogen (mg/dl) (313,479) 370 (312,445) WBC ( 10 9 /L) (5.6,9.0) 7.7 (6.1,8.8) Data are presented as frequency (percentage) for categorical variables and as mean SD and median (25th percentile, 75th percentile) for continuous variables. * The total number was 174 (not 193) because of missing phospholipid values in 19 patients. Hyperlipidemia was diagnosed in patients who had been given lipid-lowering medications or had histories of total cholesterol levels 240 mg/dl. 14 Takes into account the left main, left anterior descending, left circumflex, and right coronary arteries. WBC white blood count. levels were measured using a commercially available kit (Wako Diagnostics, Richmond, Virginia). Patients were followed for the occurrence of death (all-cause and cardiac), MI (fatal or nonfatal), and stroke. All strokes were confirmed with either magnetic resonance imaging or computed tomographic scan. Transient ischemic attacks were not classified as strokes. The study population was divided into 2 groups on the basis of the median plasma phospholipid value for the entire cohort of patients with ACS. Summary statistics for the continuous variables were presented as mean SD or medians with interquartile ranges, and comparisons between the 2 groups were performed with the nonparametric Wilcoxon rank-sum test. Data for the biomarkers (including

3 Coronary Artery Disease/Phospholipid and Cardiovascular Outcomes in ACS 1741 Table 2 Multivariate analysis for all-cause mortality at 24 months Baseline Variable p Value Hazard Ratio (95% CI) Phospholipid ( ) Age/10 yrs ( ) hs-crp ( ) Chronic renal insufficiency ( ) Twenty-five clinical, laboratory, and angiographic variables were initially studied (see Methods and Table 1) by univariate analysis. Only those predictors with p values 0.05 (age, chronic renal insufficiency, number of diseased coronary arteries, erythrocyte sedimentation rate, hs- CRP, phospholipid, and fibrinogen) were subsequently entered into a multivariate model, the results of which are listed in this table. Table 3 Multivariate analysis for cardiac mortality at 24 months Baseline Variable p Value Hazard Ratio (95% CI) Phospholipid ( ) hs-crp ( ) Chronic renal insufficiency ( ) Twenty-five clinical, laboratory, and angiographic variables were initially studied (see Methods and Table 1) by univariate analysis. Only those predictors with p values 0.05 (age, chronic renal insufficiency, hs-crp, phospholipid, and fibrinogen) were subsequently entered into a multivariate model, the results of which are listed in this table. phospholipid) were presented as medians with 25th and 75th percentiles. Log transformation was applied to all biomarkers (including phospholipid) to decrease the skewness and kurtosis of the data. Categorical data were summarized as frequencies and percentages, and comparisons between groups were performed with Pearson s chi-square test or Fisher s exact test if the number of observations per cell was 5. The predictors of all-cause mortality, cardiac mortality, MI, and the composite outcome of death (any), MI (fatal or nonfatal), or stroke (all at 24 months) were identified by univariate Cox regression. For each of the 4 end points, the following same baseline variables were studied by univariate analyses: age, family history of premature coronary artery disease, diabetes mellitus, hypertension, active tobacco use, history of tobacco use, hyperlipidemia, chronic renal insufficiency, obesity, congestive heart failure on presentation, MI on presentation, aspirin use, -blocker use, angiotensin-converting enzyme inhibitor use, statin use, angiotensin receptor blocker use, previous coronary artery bypass graft surgery, number of diseased coronary arteries, left ventricular function, troponin I, high-sensitivity C-reactive protein (hs-crp), fibrinogen, erythrocyte sedimentation rate, white blood cell count, and phospholipid. Phospholipid was analyzed as a continuous variable. For the biomarkers (hs-crp, fibrinogen, phospholipid, and white blood cell count), the hazard ratios represented an increase of 1 SD in the respective log-transformed biomarker. Only those univariate predictors with p values 0.05 were subsequently entered into multivariate models. Multivariate Cox proportional-hazard analyses were then performed as stepwise regressions with backward elimination to identify the independent predictors. Time to event at 24 months is presented with Kaplan- Meier curves for the composite outcome described previously. Comparison between the 2 groups identified by the median phospholipid value was performed with the log-rank test. All analyses used 2-sided tests, with an overall significance level of All statistical analyses were performed using SAS version 8 (SAS Institute Inc., Cary, North Carolina). Results In total, 193 men were enrolled in the study. Phospholipid values were available for 174 of these patients. Baseline characteristics of the study population stratified by the median phospholipid value ( vs mg/dl) are listed in Table 1. Lower phospholipid levels were seen only in association with older age. Two-year follow-up data were available for all patients. In the entire population, there were a total of 26 deaths (13.5%), of which 15 were classified as cardiac in origin (7.8%). Similarly, there were 37 MIs (19.2%) and 12 strokes (6.2%). The total number of events for the composite outcome of death (all cause), MI (fatal or nonfatal), or stroke was 52 (26.9%). Together with phospholipid, all baseline clinical, laboratory, and angiographic variables listed in Table 1 that were significant for their associations with clinical outcomes with p values 0.05 were entered into multivariate models to identify the independent predictors of outcomes (4 separate models for each of the 4 end points studied). After adjustment for these factors, decreasing phospholipid, analyzed as a continuous variable, was found to be a strong and independent predictor of all-cause mortality at 24 months (Table 2), with a hazard ratio of 0.61 (95% confidence interval [CI] 0.41 to 0.90, p ). Other independent predictors of all-cause mortality were increasing age, hs-crp, and chronic renal insufficiency. With respect to cardiac mortality (Table 3), phospholipid was again an independent predictor of this outcome, with a hazard ratio of 0.49 (95% CI 0.29 to 0.81, p ). hs-crp and chronic renal insufficiency were the other independent predictors of cardiac mortality. For the end point of MI, phospholipid was the only independent variable predictive of this outcome, with a hazard ratio of 0.71 (95% CI 0.52 to 0.98, p ). Finally, with respect to the composite end point of death, MI, or stroke, phospholipid was once again a strong and independent predictor of this outcome, with a hazard ratio of 0.66 (95% CI 0.49 to 0.90, p ). The other independent predictors of this composite outcome were hs-crp and older age. Using the median value of phospholipid values as a prespecified cut-off point ( vs mg/dl), Kaplan-Meier curves were derived for the composite outcome of death, MI, or stroke (Figure 1). Kaplan-Meier plots demonstrated a decrease in cardiovascular events for patients whose plasma phospholipid levels were at or less than the median value, compared with those whose baseline values were greater than the median. Specifically, at 24 months, the event-free survival rates for the 2 groups were 67.8% and 80%, respectively (p by log-rank test).

4 1742 The American Journal of Cardiology ( Event-free survival rate Log rank test p-value = Phospholipid > Phospholipid Duration in months Figure 1. Kaplan-Meier curves for the composite outcome of death, MI, or stroke stratified by the median phospholipid value for the entire cohort ( vs mg/dl). By 24 months, the number of patients who had experienced events in the group whose phospholipid levels were at or less than the median value was 28 of 87 (32.2%), compared with 17 of 85 (20.0%) in the group whose phospholipid levels were greater than the median value (p by log-rank test). Discussion In the present study, we demonstrate for the first time that low plasma levels of choline containing phospholipids are powerful and independent predictors of cardiovascular outcomes in patients with ACS referred for coronary angiography. Specifically, we found that low plasma levels of phospholipid were associated with adverse outcomes. Despite a relatively small number of patients, low phospholipid levels were an independent predictor of not only the composite outcome of death, MI, or stroke but also of the individual hard end points of all-cause mortality, cardiac mortality, and MI. We believe that the consistency of the association with various different cardiovascular outcomes supports the validity of the findings. The mechanisms by which choline containing phospholipids exert a protective effect in humans remain unknown. Numerous experimental data support a preventive role for choline containing phospholipids in the development and progression of atherosclerosis. 8 12,15 The predominant mechanism of benefit probably relates to the effects of phosphatidylcholine (the major phospholipid in the circulation) on apolipoprotein A-I metabolism (causing an increase in both its synthesis and its secretion) and reverse cholesterol synthesis Such an effect may indeed be inflammation independent, as suggested by our data, which demonstrated that the prognostic power of phospholipid was independent of inflammatory markers such hs-crp and erythrocyte sedimentation rate. There are several limitations to the present study. First, it was conducted exclusively in men, and as such, the results cannot be extrapolated to women. Second, it is unknown whether the long-term storage of blood samples affects plasma phospholipid levels and whether multiple measurements of phospholipid, as opposed to a single assessment, would provide more reliable results. Third, in the present study, we measured the total choline containing phospholipids in plasma using a commercially available kit. As stated, because phosphatidylcholine constitutes most of the total phospholipids in the circulation, we assumed that the observed associations of plasma phospholipids with respect to outcomes were mostly reflective of phosphatidylcholine levels. With the recent development of a sensitive and high-throughput assay for the measurement of phosphatidylcholine, 22 confirmation of our data and assumptions using the direct measurement of phosphatidylcholine will be important and is under way. Finally, the size of our population was small, and the study was not designed with a priori calculations with respect to sample size or statistical power. As such, the findings need to be confirmed in larger and prospectively designed studies. In conclusion, we found that low baseline plasma levels of phospholipid are independently associated with an increased risk for both death and MI (as individual end points) at 2-year follow-up in a cohort of men with ACS. Furthermore, the prognostic ability of phospholipid in this regard is independent of inflammatory markers such as hs-crp. Importantly, this study is consistent with the recent experimental observations that phospholipids may have a preventive role in atherosclerosis that is most likely related to their favorable effects on apolipoprotein A-I metabolism and reverse cholesterol transport. 1. Phillips GB, Dodge JT. Composition of phospholipids and of phospholipid fatty acids of human plasma. J Lipid Res 1967;8: Sommer A, Prenner E, Gorges R, Stutz H, Grillhofer H, Kostner GM, Paltauf F, Hermetter A. Organization of phosphatidylcholine and sphingomyelin in the surface monolayer of low density lipoprotein and lipoprotein(a) as determined by time-resolved fluorometry. J Biol Chem 1992;267: Hevonoja T, Pentikainen MO, Hyvonen MT, Kovanen PT, Ala-Korpela M. Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. Biochim Biophys Acta 2000;1488: Eisenberg S. High density lipoprotein metabolism. J Lipid Res 1984; 25: Friedman M, Byers SO, Rosenman RH. Resolution of aortic atherosclerotic infiltration in the rabbit by phosphatide infusion. Proc Soc Exp Biol Med 1957;95: Adams CW, Abdulla YH, Bayliss OB, Morgan RS. Modification of aortic atheroma and fatty liver in cholesterol-fed rabbits by intravenous

5 Coronary Artery Disease/Phospholipid and Cardiovascular Outcomes in ACS 1743 injection of saturated and polyunsaturated lecithins. J Pathol Bacteriol 1967;94: Howard AN, Patelski J, Bowyer DE, Gresham GA. Atherosclerosis induced in hypercholesterolaemic baboons by immunological injury; and the effects of intravenous polyunsaturated phosphatidyl choline. Atherosclerosis 1971;14: Williams KJ, Vallabhajosula S, Rahman IU, Donnelly TM, Parker TS, Weinrauch M, Goldsmith SJ. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor deficient atherosclerosis. Proc Natl Acad Sci U S A 1988;85: Chung BH, Franklin F, Liang P, Doran S, Cho BH, Curcio CA. Phosphatidylcholine-rich acceptors, but not native HDL or its apolipoproteins, mobilize cholesterol from cholesterol-rich insoluble components of human atherosclerotic plaques. Biochim Biophys Acta 2005;1733: Williams KJ, Scalia R, Mazany KD, Rodrigueza WV, Lefer AM. Rapid restoration of normal endothelial functions in genetically hyperlipidemic mice by a synthetic mediator of reverse lipid transport. Arterioscler Thromb Vasc Biol 2000;20: Hojjati MR, Li Z, Zhou H, Tang S, Huan C, Ooi E, Lu S, Jiang XC. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoe-deficient mice. J Biol Chem 2005;280: Park TS, Panek RL, Mueller SB, Hanselman JC, Rosebury WS, Robertson AW, Kindt EK, Homan R, Karathanasis SK, Rekhter MD. Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 2004;110: Cavusoglu E, Chopra V, Gupta A, Clark LT, Eng C, Marmur JD. Usefulness of anemia in men as an independent predictor of two-year cardiovascular outcome in patients presenting with acute coronary syndrome. Am J Cardiol 2006;98: Cavusoglu E, Ruwende C, Eng C, Chopra V, Yanamadala S, Clark LT, Pinsky DJ, Marmur JD. Usefulness of baseline plasma myeloperoxidase levels as an independent predictor of myocardial infarction at two years in patients presenting with acute coronary syndrome. Am J Cardiol 2007;99: Navab M, Hama S, Hough G, Fogelman AM. Oral synthetic phospholipid (DMPC) raises high-density lipoprotein cholesterol levels, improves high-density lipoprotein function, and markedly reduces atherosclerosis in apolipoprotein E-null mice. Circulation 2003;108: Ohashi R, Mu H, Wang X, Yao Q, Chen C. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM 2005;98: Wang H, Roberson R, Du J, Eshun JK, Berschneider HM, Black DD. Regulation of apolipoprotein secretion by biliary lipids in newborn swine intestinal epithelial cells. Am J Physiol 1999;276:G353 G Wang H, Du J, Lu S, Yao Y, Hunter F, Black DD. Regulation of intestinal apolipoprotein A-I synthesis by dietary phosphatidylcholine in newborn swine. Lipids 2001;36: Nanjee MN, Doran JE, Lerch PG, Miller NE. Acute effects of intravenous infusion of ApoA1/phosphatidylcholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vasc Biol 1999;19: Chiesa G, Monteggia E, Marchesi M, Lorenzon P, Laucello M, Lorusso V, Di Mario C, Karvouni E, Newton RS, et al. Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res 2002;90: Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, et al. Effect of recombinant apoa-i Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290: Hojjati MR, Jiang XC. Rapid, specific, and sensitive measurements of plasma sphingomyelin and phosphatidylcholine. J Lipid Res 2006;47:

Plasma Interleukin-10 Levels and Adverse Outcomes in Acute Coronary Syndrome

CLINICAL RESEARCH STUDY Plasma Interleukin-10 Levels and Adverse Outcomes in Acute Coronary Syndrome Erdal Cavusoglu, MD, a,b Jonathan D. Marmur, MD, b Mohammad R. Hojjati, MD, PhD, b Vineet Chopra, MD,