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1.  Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials 
PLoS ONE  2014;9(1):e83094.
We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials.
Methods and Results
Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0–10 µg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9–27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination.
Lp-PLA2 inhibition does not enhance platelet aggregation.
Trial Registration
1) Study 1: NCT01745458 2) Study 2: NCT00387257
PMCID: PMC3903475  PMID: 24475026
2.  A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk 
PLoS ONE  2012;7(5):e36617.
Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk.
Trial Registration NCT00690417
Trial Registration NCT01049048
PMCID: PMC3346736  PMID: 22586483
3.  Growth in Height in Childhood and Risk of Coronary Heart Disease in Adult Men and Women 
PLoS ONE  2012;7(1):e30476.
Adult height is inversely associated with the risk of coronary heart disease (CHD), but it is still unknown which phase of the human growth period is critical for the formation of this association. We investigated the association between growth in height from 7 to 13 years of age and the risk of CHD in adulthood.
Methods and Findings
The heights of almost all children born 1930 through 1976 who attended school in the Copenhagen municipality (232,063 children) were measured annually from 7 to 13 years of age. Birth weight data were available since 1936. Fatal and non-fatal CHD events were ascertained by register linkage until 2008 (25,214 cases). Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression for height z-scores (standard deviation units) and change in height z-scores. Height z-scores were inversely related to the risk of CHD. The association was strongest at 7 years of age (HR = 0.91, CI 0.90–0.92 in boys and 0.88, CI 0.86–0.90 in girls) and steadily weakened thereafter, yet it still remained at 13 years of age (HR = 0.95, CI 0.94–0.97 and 0.91, CI 0.89–0.93, boys and girls respectively). The associations were not modified by birth weight. Independent of the age-specific risk, rapid growth was associated with an increased CHD risk, most pronounced between 9 and 11 years in girls (HR = 1.22, CI 1.14–1.31) and between 11 and 13 years in boys (HR = 1.28, CI 1.22–1.33) per unit increase in z-score. Adjustment for body mass index somewhat strengthened the associations of CHD risk with height and weakened the association with growth.
Risk of CHD in adulthood is inversely related to height at ages 7 through 13 years, but strongest in the youngest, and, independently hereof, the risk increased by growth velocity.
PMCID: PMC3265486  PMID: 22291964
4.  Oxidative Stress and Inflammation in Renal Patients and Healthy Subjects 
PLoS ONE  2011;6(7):e22360.
The first goal of this study was to measure the oxidative stress (OS) and relate it to lipoprotein variables in 35 renal patients before dialysis (CKD), 37 on hemodialysis (HD) and 63 healthy subjects. The method for OS was based on the ratio of cholesteryl esters (CE) containing C18/C16 fatty acids (R2) measured by gas chromatography (GC) which is a simple, direct, rapid and reliable procedure. The second goal was to investigate and identify a triacylglycerol peak on GC, referred to as TG48 (48 represents the sum of the three fatty acids carbon chain lengths) which was markedly increased in renal patients compared to healthy controls. We measured TG48 in patients and controls. Mass spectrometry (MS) and MS twice in tandem were used to analyze the fatty acid composition of TG48. MS showed that TG48 was abundant in saturated fatty acids (SFAs) that were known for their pro-inflammatory property. TG48 was significantly and inversely correlated with OS. Renal patients were characterized by higher OS and inflammation than healthy subjects. Inflammation correlated strongly with TG, VLDL-cholesterol, apolipoprotein (apo) C-III and apoC-III bound to apoB-containing lipoproteins, but not with either total cholesterol or LDL-cholesterol.
In conclusion, we have discovered a new inflammatory factor, TG48. It is characterized with TG rich in saturated fatty acids. Renal patients have increased TG48 than healthy controls.
PMCID: PMC3145638  PMID: 21829457
5.  Maternal Arterial Stiffness in Women Who Subsequently Develop Pre-Eclampsia 
PLoS ONE  2011;6(5):e18703.
Pre-eclampsia (PE) is associated with profound changes in the maternal cardiovascular system. The aim of the present study was to assess whether alterations in the maternal arterial stiffness precede the onset of PE in at risk women.
Methodology/Principal Findings
This was a cross sectional study involving 70 pregnant women with normal and 70 women with abnormal uterine artery Doppler examination at 22–24 weeks of gestation. All women had their arterial stiffness (augmentation index and pulse wave velocity of the carotid-femoral and carotid-radial parts of the arterial tree) assessed by applanation tonometry in the second trimester of pregnancy, at the time of the uterine artery Doppler imaging. Among the 140 women participating in the study 29 developed PE (PE group) and 111 did not (non-PE group). Compared to the non-PE group, women that developed PE had higher central systolic (94.9±8.6 mmHg vs 104.3±11.1 mmHg; p = <0.01) and diastolic (64.0±6.0 vs 72.4±9.1; p<0.01) blood pressures. All the arterial stiffness indices were adjusted for possible confounders and expressed as multiples of the median (MoM) of the non-PE group. The adjusted median augmentation index was similar between the two groups (p = 0.84). The adjusted median pulse wave velocities were higher in the PE group compared to the non-PE group (carotid-femoral: 1.10±0.14 MoMs vs 0.99±0.11 MoMs; p<0.01 and carotid-radial: 1.08±0.12 MoMs vs 1.0±0.11 MoMs; p<0.01).
Increased maternal arterial stiffness, as assessed by pulse wave velocity, predates the development of PE in at risk women.
PMCID: PMC3086903  PMID: 21559278
6.  Anticoagulation after Anterior Myocardial Infarction and the Risk of Stroke 
PLoS ONE  2010;5(8):e12150.
Survivors of anterior MI are at increased risk for stroke with predilection to form ventricular thrombus. Commonly patients are discharged on dual antiplatelet therapy. Given the frequency of early coronary reperfusion and risk of bleeding, it remains uncertain whether anticoagulation offers additional utility. We examined the effectiveness of anticoagulation therapy for the prevention of stroke after anterior MI.
Methods and Findings
We performed a population-based cohort analysis of 10,383 patients who survived hospitalization for an acute MI in Ontario, Canada from April 1, 1999 to March 31, 2001. The primary outcome was four-year ischemic stroke rates compared between anterior and non-anterior MI patients. Risk factors for stroke were assessed by multivariate Cox proportional-hazards analysis. Warfarin use was determined at discharge and followed for 90 days among a subset of patients aged 66 and older (n = 1483). Among the 10,383 patients studied, 2,942 patients survived hospitalization for an anterior MI and 20% were discharged on anticoagulation therapy. Within 4 years, 169 patients (5.7%) were admitted with an ischemic stroke, half of which occurred within 1-year post-MI. There was no significant difference in stroke rate between anterior and non-anterior MI patients. The use of warfarin up to 90 days was not associated with stroke protection after anterior MI (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.37–1.26). The use of angiotensin-converting-enzyme inhibitors (HR, 0.65; 95% CI, 0.44–0.95) and beta-blockers (HR, 0.60; 95% CI, 0.41–0.87) were associated with a significant decrease in stroke risk. There was no significant difference in bleeding-related hospitalizations in patients who used warfarin for up to 90 days post-MI.
Many practitioners still consider a large anterior-wall MI as high risk for potential LV thrombus formation and stroke. Among a cohort of elderly patients who survived an anterior MI there was no benefit from the use of warfarin up to 90 days post-MI to prevent ischemic stroke. Our data suggests that routine anticoagulation of patients with anterior-wall MI may not be indicated. Prospective randomized trials are needed to determine the optimal antithrombin strategy for preventing this common and serious adverse outcome.
PMCID: PMC2921337  PMID: 20730096
7.  Socioeconomic Status and Subclinical Coronary Disease in the Whitehall II Epidemiological Study 
PLoS ONE  2010;5(1):e8874.
There are pronounced socioeconomic disparities in coronary heart disease, but the extent to which these primarily reflect gradients in underlying coronary artery disease severity or in the clinical manifestation of advanced disease is uncertain. We measured the relationship between socioeconomic status (SES) as indexed by grade of employment and coronary artery calcification (CAC) in the Whitehall II epidemiological cohort, and tested the contribution of lifestyle, biological and psychosocial factors in accounting for this association.
Methods and Findings
CAC was assessed in 528 asymptomatic men and women aged 53–76 years, stratified into higher, intermediate and lower by grade of employment groups. Lifestyle (smoking, body mass index, alcohol consumption, physical activity), biological (blood pressure, lipids, fasting glucose, inflammatory markers) and psychosocial factors (work stress, financial strain, social support, depression, hostility, optimism) were also measured. Detectable CAC was present in 293 participants (55.5%). The presence of calcification was related to lifestyle and biological risk factors, but not to grade of employment. But among individuals with detectable calcification, the severity of CAC was inversely associated with grade of employment (p = 0.010), and this relationship remained after controlling for demographic, lifestyle, biological and psychosocial factors. Compared with the higher grade group, there was a mean increase in log Agatston scores of 0.783 (95% C.I. 0.265–1.302, p = 0.003) in the intermediate and 0.941 (C.I. 0.226–1.657, p = 0.010) in the lower grade of employment groups, after adjustment for demographic, lifestyle, biological and psychosocial factors.
Low grade of employment did not predict the presence of calcification in this cohort, but was related to the severity of CAC. These findings suggest that lower SES may be particularly relevant at advanced stages of subclinical coronary artery disease, when calcification has developed.
PMCID: PMC2810334  PMID: 20111604
8.  Angiogenic and Inflammatory Markers of Cardiopulmonary Changes in Children and Adolescents with Sickle Cell Disease 
PLoS ONE  2009;4(11):e7956.
Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well.
Design and Methods
Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor–BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined.
Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P≤0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi.
Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated.
PMCID: PMC2776981  PMID: 19956689
9.  Common Polymorphisms Influencing Serum Uric Acid Levels Contribute to Susceptibility to Gout, but Not to Coronary Artery Disease 
PLoS ONE  2009;4(11):e7729.
Recently, a large meta-analysis including over 28,000 participants identified nine different loci with association to serum uric acid (UA) levels. Since elevated serum UA levels potentially cause gout and are a possible risk factor for coronary artery disease (CAD) and myocardial infarction (MI), we performed two large case-control association analyses with participants from the German MI Family Study. In the first study, we assessed the association of the qualitative trait gout and ten single nucleotide polymorphisms (SNP) markers that showed association to UA serum levels. In the second study, the same genetic polymorphisms were analyzed for association with CAD.
Methods and Findings
A total of 683 patients suffering from gout and 1,563 healthy controls from the German MI Family Study were genotyped. Nine SNPs were identified from a recently performed genome-wide meta-analysis on serum UA levels (rs12129861, rs780094, rs734553, rs2231142, rs742132, rs1183201, rs12356193, rs17300741 and rs505802). Additionally, the marker rs6855911 was included which has been associated with gout in our cohort in a previous study. SNPs rs734553 and rs6855911, located in SLC2A9, and SNP rs2231142, known to be a missense polymorphism in ABCG2, were associated with gout (p = 5.6*10−7, p = 1.1*10−7, and p = 1.3*10−3, respectively). Other SNPs in the genes PDZK1, GCKR, LRRC16A, SLC17A1-SLC17A3, SLC16A9, SLC22A11 and SLC22A12 failed the significance level. None of the ten markers were associated with risk to CAD in our study sample of 1,473 CAD cases and 1,241 CAD-free controls.
SNP markers in SLC2A9 and ABCG2 genes were found to be strongly associated with the phenotype gout. However, not all SNP markers influencing serum UA levels were also directly associated with the clinical manifestation of gout in our study sample. In addition, none of these SNPs showed association with the risk to CAD in the German MI Family Study.
PMCID: PMC2766838  PMID: 19890391
10.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
Methodology/Principal Findings
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
PMCID: PMC2649379  PMID: 19266101
11.  Carotid Artery Intima-Media Thickness, Carotid Plaque and Coronary Heart Disease and Stroke in Chinese 
PLoS ONE  2008;3(10):e3435.
Our aim was to prospectively investigate the association between carotid artery intima-media thickness (IMT) as well as carotid plaque and incidence of coronary heart disease (CHD) and stroke in Chinese, among whom data are limited.
Methods and Findings
We conducted a community-based cohort study composed of 2190 participants free of cardiovascular disease at baseline in one community. During a median 10.5-year follow up, we documented 68 new cases of coronary heart disease and 94 cases of stroke. The multivariate relative risks (RRs) associated with a change of 1 standard deviation of maximal common carotid IMT were 1.38 (95% confidence interval [CI], 1.12–1.70) for CHD and 1.47 (95% CI, 1.28–1.69) for stroke. The corresponding RRs with internal carotid IMT were 1.47 (95% CI, 1.21–1.79) for CHD and 1.52 (95% CI, 1.31–1.76) for stroke. Carotid plaque measured by the degree of diameter stenosis was also significantly associated with increased risk of CHD (p for trend<0.0001) and stroke (p for trend<0.0001). However, these associations were largely attenuated when adjusting for IMT measurements.
This prospective study indicates a significant association between carotid IMT and incidence of CHD and stroke in Chinese adults. These measurements may be useful for cardiovascular risk assessment and stratification in Chinese.
PMCID: PMC2562458  PMID: 18927612
12.  A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility 
PLoS ONE  2008;3(8):e2852.
Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke.
Methodology/Principal Findings
A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01).
Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy.
Trial Registration ISRCTN83673558
PMCID: PMC2481397  PMID: 18682741

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