Person: Rifai, Nader
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Rifai
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Nader
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Rifai, Nader
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Publication Relationship of antihypertensive treatment to plasma markers of vascular inflammation and remodeling in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis study(Elsevier BV, 2012) Zamani, Payman; Ganz, Peter; Libby, Peter; Sutradhar, Santosh C.; Rifai, Nader; Nicholls, Stephen J.; Nissen, Steven E.; Kinlay, ScottBackground Antihypertensive agents lower the risk of cardiovascular events, but whether they affect pathways important in inflammation and plaque remodeling in atherosclerosis is uncertain. We assessed whether 2 commonly used antihypertensive agents affected plasma biomarkers reflecting specific inflammatory and remodeling processes over 2 years in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study. Methods The study was a randomized controlled trial of 2 antihypertensives (amlodipine and enalapril) compared with placebo in patients with coronary artery disease and diastolic blood pressure less than 100 mm Hg. In 196 subjects who had baseline and 2-year intravascular coronary ultrasound examinations, we measured plasma interleukin 18, interleukin 1 receptor antagonist, matrix metalloproteinase 9, neopterin, and C-reactive protein. Results for both treatment groups were pooled and compared with placebo. Results Antihypertensive treatment with either agent significantly lowered diastolic blood pressure (−4.7 vs placebo 1.3 mm Hg, P = .002) and progression of coronary atheroma (Δ percent atheroma volume 0.6 vs placebo 2.1, P = .031). Antihypertensive therapy did not affect plasma biomarkers of inflammation or plaque remodeling in the 135 subjects with baseline and 2-year biomarker samples. Progression in percent atheroma volume was significantly less in subjects taking statins at baseline (−2.5%, P = .0008). Conclusions In patients with coronary artery disease and well-controlled risk factors, antihypertensive therapy lowered blood pressure and progression of coronary atherosclerosis but did not affect plasma biomarkers of inflammation and remodeling. Antihypertensives may decrease atheroma progression by mechanisms other than those reflected by these plasma biomarkers.Publication Endogenous tissue plasminogen activator and risk of recurrent cardiac events after an acute coronary syndrome in the MIRACL study(Elsevier BV, 2009) Kinlay, Scott; Schwartz, Gregory; Olsson, Anders G.; Rifai, Nader; Bao, Weihang; Libby, Peter; Ganz, PeterObjective To examine the relationship of baseline tissue plasminogen activator (t-PA) to early cardiovascular risk after an acute coronary syndrome, and the effect of intensive statin therapy. Methods We measured plasma t-PA in 2860 of the 3086 (93%) subjects in the MIRACL study, an international randomized trial of atorvastatin 80 mg daily versus placebo in patients with acute coronary syndromes. The relationship of t-PA to death, non-fatal acute myocardial infarction, cardiac arrest, or worsening angina over 16 weeks was assessed by Cox Proportional Hazards. D-dimer was measured in a random sample of 395 subjects. Results Higher baseline t-PA was significantly related to the risk of recurrent events (HR = 1.25, p = 0.0014). This relationship was unaffected by adjustment for age, sex, troponin, hsCRP, and lipids (HR = 1.17, p = 0.029), but was attenuated by adjustment including body mass index and smoking (HR = 1.14, p=0.08). D-dimer and t-PA concentrations were not related. Atorvastatin reduced the risk of recurrent events, but did not affect t-PA or D-dimer concentrations or the relationship of t-PA to outcomes. Conclusion In patients with acute coronary syndromes, increasing t-PA concentration was related to a higher early risk of recurrent events, paradoxically reflecting impaired endogenous fibrinolysis. This relationship is due in part to the association of t-PA with age, body mass index and smoking. Although statins lower the risk of recurrent events after acute coronary syndromes, it is unlikely that this benefit is achieved through thrombolytic and fibrinolytic pathways.Publication Interrelationship of Multiple Endothelial Dysfunction Biomarkers with Chronic Kidney Disease(Public Library of Science, 2015) Chen, Jing; Hamm, L. Lee; Mohler, Emile R.; Hudaihed, Alhakam; Arora, Robin; Chen, Chung-Shiuan; Liu, Yanxi; Browne, Grace; Mills, Katherine T.; Kleinpeter, Myra A.; Simon, Eric E.; Rifai, Nader; Klag, Michael J.; He, JiangThe interrelationship of multiple endothelial biomarkers and chronic kidney disease (CKD) has not been well studied. We measured asymmetric dimethylarginine (ADMA), L-arginine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), von Willebrand factor (vWF), flow-mediated dilation (FMD), and nitroglycerin-induced dilation (NID) in 201 patients with CKD and 201 community-based controls without CKD. Multivariable analyses were used to examine the interrelationship of endothelial biomarkers with CKD. The multivariable-adjusted medians (interquartile ranges) were 0.54 (0.40, 0.75) in patients with CKD vs. 0.25 (0.22, 0.27) μmol /L in controls without CKD (p<0.0001 for group difference) for ADMA; 67.0 (49.6, 86.7) vs. 31.0 (27.7, 34.2) μmol/L (p<0.0001) for L-arginine; 230.0 (171.6, 278.6) vs. 223.9 (178.0, 270.6) ng/mL (p=0.55) for sICAM-1; 981.7 (782.6, 1216.8) vs. 633.2 (507.8, 764.3) ng/mL (p<0.0001) for sVCAM-1; 47.9 (35.0, 62.5) vs. 37.0 (28.9, 48.0) ng/mL (p=0.01) for sE-selectin; 1320 (1044, 1664) vs. 1083 (756, 1359) mU/mL (p=0.008) for vWF; 5.74 (3.29, 8.72) vs. 8.80 (6.50, 11.39)% (p=0.01) for FMD; and 15.2 (13.5, 16.9) vs. 19.1 (17.2, 21.0)% (p=0.0002) for NID, respectively. In addition, the severity of CKD was positively associated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF and inversely associated with FMD and NID. Furthermore, FMD and NID were significantly and inversely correlated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF. In conclusion, these data indicate that multiple dysfunctions of the endothelium were present among patients with CKD. Interventional studies are warranted to test the effects of treatment of endothelial dysfunction on CKD.Publication Effects of Vitamin D Supplementation on C-peptide and 25-hydroxyvitamin D Concentrations at 3 and 6 Months(Nature Publishing Group, 2015) Chandler, Paulette; Giovannucci, Edward; Scott, Jamil B.; Bennett, Gary G.; Ng, Kimmie; Chan, Andrew; Hollis, Bruce W.; Rifai, Nader; Emmons, Karen M.; Fuchs, Charles; Drake, Bettina F.The link between African-Americans’ disproportionate rates of diabetes, obesity and vitamin D deficiency may be marked by C-peptide as an indicator of insulin secretion. We hypothesize that vitamin D supplementation will increase C-peptide, a marker of insulin secretion. During 3 winters from 2007-2010, 328 healthy African-Americans (median age, 51 years) living in Boston, MA were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 IU of vitamin D3. The differences in non-fasting C-peptide between baseline and 3 months were −0.44 ng/mL for those receiving placebo, −0.10 ng/mL for those receiving 1000 IU/d, 0 ng/mL for those receiving 2000 IU/d, 1.24 ng/mL for those receiving 4000 IU/d (C-peptide increased 0.42 ng/mL for each additional 1000 IU/d of vitamin D3, p < 0.001). Vitamin D supplementation increased C-peptide in overweight African-Americans and may be compatible with other recommendations for diabetes prevention and management including weight loss and increased physical activity.Publication Apolipoprotein(a) Size and Lipoprotein(a) Concentration and Future Risk of Angina Pectoris with Evidence of Severe Coronary Atherosclerosis in Men: The Physicians' Health Study(American Association for Clinical Chemistry (AACC), 2004) Rifai, Nader; Ma, Jing; Sacks, Frank; Ridker, Paul; Hernandez, W; Stampfer, Meir; Marcovina, SThe relationship of lipoprotein (a) [Lp(a)] concentrations with risk of coronary heart disease needs clarification, especially for threshold values for increased risk and for possible interactions with LDL-cholesterol concentrations and apolipoprotein (a) [apo(a)] size polymorphism. This study was designed to examine the ability of baseline Lp(a) concentration and apo(a) size to predict future severe angina pectoris in apparently healthy men. METHODS: Baseline Lp(a) concentration and apo(a) size were determined in 195 men who subsequently developed angina and in 195 men who remained free of cardiovascular disease for 5 years. RESULTS: Cases had higher median Lp(a) concentrations than did controls (30.6 vs 22.5 nmol/L; P = 0.02). Lp(a) concentration was predictive of angina [relative risk (RR) from lowest to highest quintiles: 1.0, 1.5, 1.0, 1.8, and 2.6; P for trend = 0.015]. The increased risk was approximately 4-fold (95% confidence interval, 1.4- to 11-fold) among men who had Lp(a) above the 95th percentile (>158 nmol/L). Men with Lp(a) concentrations in the highest quintile and LDL-cholesterol concentrations >1600 mg/L had a 12-fold increased risk (95% confidence interval, 1.5- to 43-fold). Small apo(a) size isoforms also significantly predicted risk of angina (RR for lowest quintile = 4.1; P for trend = 0.004). When the independent effect of Lp(a) concentration and apo(a) size was assessed by including them in the same multivariate model, only the association between apo(a) size and risk remained significant. CONCLUSIONS: High Lp(a) predicts risk of angina, and the risk is substantially increased with high concomitant LDL-cholesterol. Small apo(a) size predicts angina with greater strength and independence than Lp(a) concentration.Publication STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies(BMJ Publishing Group Ltd., 2015) Bossuyt, Patrick M; Reitsma, Johannes B; Bruns, David E; Gatsonis, Constantine A; Glasziou, Paul P; Irwig, Les; Lijmer, Jeroen G; Moher, David; Rennie, Drummond; de Vet, Henrica C W; Kressel, Herbert; Rifai, Nader; Golub, Robert M; Altman, Douglas G; Hooft, Lotty; Korevaar, Daniël A; Cohen, Jérémie FIncomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting Diagnostic Accuracy (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies.Publication Inflammatory Biomarkers, Death, and Recurrent Nonfatal Coronary Events after an Acute Coronary Syndrome in the MIRACL Study(Blackwell Publishing, 2013) Zamani, Payman; Schwartz, Gregory G.; Olsson, Anders G.; Rifai, Nader; Bao, Weihang; Libby, Peter; Ganz, Peter; Kinlay, ScottBackground: In acute coronary syndromes, C‐reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome. Methods and results: We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin‐6 (IL‐6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E‐selectin, P‐selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.006), SAA (P=0.012), and IL‐6 (P<0.001) were related to death, but not to recurrent nonfatal acute coronary syndromes. VCAM and tPA related to the risk of death (P<0.001, P=0.021, respectively) and to nonfatal acute coronary syndromes (P=0.021, P=0.049, respectively). Adjusting for significant covariates reduced the strength of the associations; however, CRP and SAA continued to relate to death. Conclusions: In acute coronary syndromes, the CRP inflammatory axis relates to the risk of death and may reflect myocardial injury. VCAM and tPA may have greater specificity for processes reflecting inflammation and thrombosis in the epicardial arteries, which determine recurrent coronary events.Publication Interleukin-6 Receptor Gene, Plasma C-Reactive Protein, and Diabetes Risk in Women(American Diabetes Association, 2009) Qi, Lu; Rifai, Nader; Hu, FrankOBJECTIVE—Recent genome-wide association studies (GWASs) related common variants in the interleukin-6 (Il-6) receptor (IL6R) gene to plasma C-reactive protein (CRP) concentrations. Because IL6R variants were previously associated with IL-6 levels, we tested whether the associations with CRP were independent of IL-6 and the interactions between IL6R variants and CRP in relation to diabetes risk. RESEARCH DESIGN AND METHODS—Plasma CRP and IL-6 levels and 10 IL6R polymorphisms were determined in a nested case-control study of 633 diabetic and 692 healthy Caucasian women. RESULTS—In both nondiabetic and diabetic women, IL6R polymorphisms were associated with plasma CRP levels, independent of IL-6 concentration. After adjustment of IL-6 levels, CRP concentrations in the genotype AA, AC, and CC of the GWAS polymorphism rs8192284 were 0.32, 0.26, and 0.24 pg/ml, respectively, among nondiabetic women (P for trend = 0.003; false discovery rate [FDR] = 0.01) and 0.63, 0.48, and 0.43 pg/ml among diabetic women (P for trend less than 0.0001; FDR = 0.0001). Haplotypes inferred from polymorphisms within a linkage disequilibrium block including rs8192284 were also significantly associated with CRP levels (P = 0.0002). In an exploratory analysis, rs8192284 showed significant interactions with CRP levels in relation to diabetes risk (P for interaction = 0.026). The odds ratios across increasing quartiles of CRP were 2.19 (95% CI 1.42–3.36), 2.03 (1.27–3.23), and 2.92 (1.77–4.82) in the carriers of allele-C and 2.21 (1.18–4.12), 3.77 (1.87–7.57), and 5.02 (2.4–10.5) in the noncarriers. CONCLUSIONS—IL6R variants were significantly associated with plasma CRP, independent of IL-6 levels. IL6R variants may interact with CRP in predicting diabetes risk.Publication Circulating Levels of Resistin and Risk of Type 2 Diabetes in Men and Women: Results from Two Prospective Cohorts(American Diabetes Association, 2009) Chen, Brian H.; Song, Yiqing; Ding, Eric L.; Roberts, Christian K.; Manson, JoAnn; Rifai, Nader; Buring, Julie; Gaziano, John; Liu, SiminOBJECTIVE—The purpose of this study was to investigate the role of circulating resistin levels in the development of type 2 diabetes using two prospective cohorts of well-characterized men and women. RESEARCH DESIGN AND METHODS—We conducted two prospective case-control studies nested in the Women's Health Study (WHS) and Physicians’ Health Study II (PHS II). In the WHS, during a median of 10-years of follow-up, 359 postmenopausal women, who were apparently healthy at baseline and later developed type 2 diabetes, were prospectively matched with 359 healthy control subjects. In the PHS II, with 8 years of total follow-up, 170 men, who were apparently healthy at baseline and later developed type 2 diabetes, were matched with 170 healthy control subjects. Control subjects were matched by age, race, and time of blood draw. RESULTS—Resistin levels at baseline were significantly higher in women than in men (P = 0.003) and in case patients than in control subjects for both women (P < 0.001) and men (P = 0.07). After adjustment for matching factors, physical activity, alcohol intake, smoking, and family history of diabetes, the relative risk of type 2 diabetes comparing the highest to the lowest quartile of resistin in women was 2.22 ([95% CI 1.32–3.73]; P\(_{trend}\) = 0.002). This association was attenuated after further adjustment for BMI (1.51 [0.86–2.65]; P\(_{trend}\) = 0.20) or C-reactive protein (1.18 [0.68–2.07]; P\(_{trend}\) = 0.60). A similar but weaker pattern was observed in men. CONCLUSIONS—Elevated levels of circulating resistin were significantly related to increased risk of type 2 diabetes, which appears to be partially accounted for by adiposity and the inflammatory process.Publication Novel Association of ABO Histo-blood Group Antigen with Soluble ICAM-1: Results of a Genome-wide Association Study of 6,578 Women(Public Library of Science, 2008) Paré, Guillaume; Kellogg, Mark; Badola, Sunita; Miletich, Joseph P.; Gibson, Greg; Chasman, Daniel; Zee, Robert Yuk Lung; Rifai, Nader; Ridker, PaulWhile circulating levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) have been associated with diverse conditions including myocardial infarction, stroke, malaria, and diabetes, comprehensive analysis of the common genetic determinants of sICAM-1 is not available. In a genome-wide association study conducted among 6,578 participants in the Women's Genome Health Study, we find that three SNPs at the ICAM1 (19p13.2) locus (rs1799969, rs5498 and rs281437) are non-redundantly associated with plasma sICAM-1 concentrations at a genome-wide significance level (P<5×10\(^{−8}\)), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1×10\(^{−29}\)) at the ABO (9q34.2) locus is highly correlated with sICAM-1 concentrations. The novel association at the ABO locus provides evidence for a previously unknown regulatory role of histo-blood group antigens in inflammatory adhesion processes.