Qilong Yi

Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events

Background—We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population. Methods and Results—Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7;P =0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4;P =0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4;P <0.001) than those in the lower quartile. Conclusions—In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.

Effects of Ramipril and Vitamin E on Atherosclerosis The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE)

Background —Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3×2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients. Methods and Results —A total of 732 patients ≥55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-&agr;-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (P =0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo. Conclusions —Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.

Risk factors, atherosclerosis, and cardiovascular disease among Aboriginal people in Canada: The study of health assessment and risk evaluation in Aboriginal peoples (SHARE-AP)

BACKGROUND Little is known about the rates of cardiovascular disease (CVD), atherosclerosis, and their risk factors among Canadas Aboriginal people. To establish the relative prevalence of risk factors, atherosclerosis, and CVD, we undertook a population-based study among people of Aboriginal and European ancestry in Canada. METHODS We randomly recruited 301 Aboriginal people from the Six Nations Reservation, and 326 people of European origin from Hamilton, Toronto, and Edmonton, Canada. Clinical CVD was defined by history or electrocardiographic findings, atherosclerosis was measured by B-mode carotid ultrasonography, and conventional and new CVD risk factors were measured using standardised methods. FINDINGS Aboriginal people had significantly more carotid atherosclerosis (mean of the maximum intimal-medial thickness 0.82 (SD 0.20) mm vs 0.78 (0.20) mm, p=0.027), and had a higher frequency of CVD (18.5% vs 7.6%, p=0.00002) compared with Europeans. Aboriginal people had significantly higher rates of smoking, glucose intolerance, obesity, abdominal obesity, and substantially higher concentrations of fibrinogen, and plasminogen activator inhibitor-1. Aboriginal people had significantly higher rates of unemployment and a lower annual household income. For any given income level, Aboriginal people had higher rates of risk factors and CVD compared with the Europeans. INTERPRETATION A significant proportion of Aboriginal people live in poverty which is associated with high rates of CVD and CVD risk factors. Improvement of the socioeconomic status of Aboriginal people might be a key to reduce CVD in this group.

Relationship of Metabolic Syndrome and Fibrinolytic Dysfunction to Cardiovascular Disease

Background—The clustering of impaired glucose metabolism, elevated triglycerides, low HDL cholesterol, and abdominal obesity is known as the metabolic syndrome. Individuals with this syndrome suffer an excess of cardiovascular disease (CVD) for reasons that are unclear. Methods and Results—We randomly sampled 1276 adults of South Asian, Chinese, European, and Native Indian ancestry from 4 communities in Canada. Participants provided fasting blood samples for glucose, lipids, and fibrinolytic measurements; had an oral glucose tolerance test; and underwent a B-mode carotid ultrasound examination. CVD was determined by history and ECG. The prevalence of the metabolic syndrome was 25.8% (95% CI, 23.5 to 28.2) and varied substantially by ethnic group: 41.6% among Native Indians, 25.9% among South Asians, and 22.0% among Europeans, compared with 11.0% among the Chinese (overall, P =0.0001). People with the metabolic syndrome had more atherosclerosis (maximum intimal medial thickness, 0.78±0.18 versus 0.74±0.18 mm; P =0.0005), CVD (17.2% versus 7.0%; P =0.0001), and elevated plasminogen activator inhibitor-1 (24.2 versus 14.6 U/mL; P =0.001) compared with levels among people without the metabolic syndrome. For the same amount of atherosclerosis, people with the metabolic syndrome had a greater prevalence of CVD, even among nondiabetic individuals. This difference in CVD prevalence among the groups was attenuated after adjustment for plasminogen activator inhibitor-1 levels, suggesting that fibrinolytic dysfunction mediates the increased risk of CVD in individuals with the metabolic syndrome. Conclusion—CVD among people with the metabolic syndrome is explained by their excess of atherosclerosis and impaired fibrinolysis. Interventions to prevent atherosclerosis progression and improve fibrinolytic function require evaluation in this high-risk group.

C-reactive protein as a screening test for cardiovascular risk in a multiethnic population.

Background—Small increases in the inflammatory marker C-reactive protein (CRP) are predictive of vascular events among asymptomatic individuals. There are few data supporting the use of CRP as a risk marker among nonwhite individuals. Methods and Results—1250 adults of South Asian, Chinese, European, and Aboriginal ancestry were randomly sampled from 4 communities in Canada. Participants provided fasting blood samples for CRP, glucose, lipids, and coagulation factors, and they had undergone a carotid B-mode ultrasound. Cardiovascular disease was determined by history and electrocardiogram. The age- and sex-adjusted mean CRP was 3.74 mg/L (standard error, 0.14) among Aboriginals, 2.59 mg/L (0.12) among South Asians, and 1.18 mg/L (0.13) among Chinese compared with 2.06 mg/L (0.12) among Europeans (overall P <0.0001). Differences in the CRP concentration between ethnic groups were substantially diminished, but not abolished, after adjustment for metabolic factors. CRP was independently associated with CVD after adjusting for the Framingham risk factors, atherosclerosis, anthropometric measurements, and ethnicity (OR=1.03 for a 0.1-increase in CRP; P =0.02). Conclusions—CRP varies substantially between people of different ethnic origin and is influenced by their differences in metabolic factors. Prospective validation of CRP as a risk predictor for cardiovascular disease among nonwhite ethnic groups is required.

Development of renal disease in people at high cardiovascular risk: results of the HOPE randomized study.

In people with diabetes, renal disease tends to progress from microalbuminuria to clinical proteinuria to renal insufficiency. Little evidence has been published for the nondiabetic population. This study retrospectively analyzed changes of proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation) study, which compared ramiprils effects to placebo in 9297 participants, including 3577 with diabetes and 1956 with microalbuminuria. This report is restricted to 7674 participants with albuminuria data at baseline and at follow-up. Inclusion criteria were known vascular disease or diabetes plus one other cardiovascular risk factor, exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (>1+), and serum creatinine >2.3 mg/dl (200 microM). Baseline microalbuminuria predicted subsequent clinical proteinuria for the study participants overall (adjusted odds ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859 participants; 1542 developed new microalbuminuria, and 317 participants developed clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87; 95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at high risk for cardiovascular disease are also at risk for a progressive rise in albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic and in diabetic people. Ramipril prevents or delays the progression of albuminuria.

Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) study

Background—Limited prospective epidemiological data are available on the relation between exposure to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and hepatitis A virus (HAV), individually or as a total pathogen score, and human cardiovascular (CV) disease. Methods and Results—We analyzed enrollment sera from 3168 Canadian patients in the Heart Outcomes Prevention Evaluation (HOPE) study for antibodies to C pneumoniae, H pylori, CMV, and HAV and measured the relation between serostatus and 494 adjudicated trial outcomes of myocardial infarction, stroke, or CV death over 4.5 years of follow-up. CV events were associated with CMV serostatus (covariate-adjusted hazard ratio [HR], 1.24; 95% CI, 1.01, 1.53). Neither C pneumoniae IgG (adjusted HR, 0.87; 95% CI, 0.68, 1.10), C pneumonia IgA (adjusted HR, 1.10; 95% CI, 0.90, 1.34), H pylori IgG (HR, 0.99; 95% CI, 0.82, 1.19), nor HAV IgG (HR, 1.01; 95% CI, 0.83, 1.24) predicted CV events. Total pathogen score was associated with CV events (adjusted HR for 4 versus 1 or 0=1.41; 95% CI, 1.02, 1.96). Conclusions—Exposure to CMV but not to C pneumoniae, H pylori, or HAV was associated with a slight excess risk of subsequent myocardial infarction, stroke, or CV death in HOPE study patients, and total pathogen score based on these infections predicted a small increased hazard of CV events.

Endothelial and Platelet Activation in Acute Ischemic Stroke and Its Etiological Subtypes

BACKGROUND AND PURPOSE Activation of endothelial cells and platelets is an important mediator of atherothrombosis. Markers of endothelial cell and platelet activation such as soluble adhesion molecules can be measured in plasma. We hypothesized that patients with acute ischemic stroke would have increased blood concentrations of soluble E-selectin and von Willebrand factor (vWF), primarily reflecting activation of endothelial cells, and increased concentrations of soluble P-selectin and platelet-derived microvesicles (PDM), primarily reflecting activation of platelets, compared with healthy controls. We also hypothesized that these markers would be differentially elevated in ischemic stroke caused by large- and small-artery atherothrombosis compared with cardiogenic embolism. METHODS We conducted a case-control study of 200 hospital-referred cases of first-ever ischemic stroke and 205 randomly selected community controls stratified by age, sex, and postal code. Using established criteria, we classified cases of stroke by etiological subtype in a blinded fashion. The prevalence of vascular risk factors and blood concentrations of E-selectin, P-selectin, vWF antigen, and PDM were determined in stroke cases within 7 days and at 3 to 6 months after stroke and in controls. RESULTS Mean blood concentrations of soluble E-selectin, P-selectin, and PDM within 7 days of stroke onset were all significantly higher in cases compared with controls. At 3 to 6 months after stroke, the mean blood concentrations of E-selectin and P-selectin fell significantly below that of controls, and PDM concentrations remained elevated. There was a strong, graded, and independent (of age, sex, and vascular risk factors) association between increasing blood concentrations of E-selectin during the acute phase and all etiological subtypes of ischemic stroke, particularly ischemic stroke caused by large-artery atherothrombosis. There was also a significant, graded, and independent association between increasing blood concentrations of vWF during the acute phase and ischemic stroke caused by large-artery atherothrombosis. CONCLUSIONS We have demonstrated significant associations between acute elevation of blood markers of endothelial cell and platelet activation and ischemic stroke and between acute elevation of blood markers of endothelial cell activation and ischemic stroke caused by large-artery atherothrombosis. Persistent elevated blood concentrations of PDM may be a marker of increased risk of ischemic stroke.

Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism: A Randomized Trial

Context In observational studies, elevated plasma homocysteine levels were associated with venous thromboembolism. A multicenter trial of folic acid and B vitamins to reduce cardiovascular events investigated the effect of homocysteine lowering on venous thromboembolism. Contribution In this trial, 5522 adults were randomly assigned to receive placebo, or folic acid and vitamins B6 and B12 daily for 5 years. Vitamin therapy decreased homocysteine levels, but the incidence of venous thromboembolism was the same in both groups, even in participants with the highest levels of homocysteine. Caution Venous thromboembolism events were not centrally adjudicated. Implication Decreasing homocysteine levels with supplements containing folic acid and vitamins B6 and B12 does not reduce the incidence of venous thromboembolism. The Editors Observational studies have found an association between elevated total plasma homocysteine levels and venous thromboembolism (14). Homocysteine is thought to promote thrombosis through enhanced platelet activation, increased thrombin generation, and impaired fibrinolysis and by causing endothelial dysfunction (5). Although homocysteine levels can be decreased by 25% by using a supplement of folic acid and vitamins B6 and B12 (6), whether the risk for venous thromboembolism is reduced as a result is not known. The Heart Outcomes Prevention Evaluation 2 (HOPE-2) evaluated the effect of homocysteine-lowering therapy on the risk for major vascular arterial disease (7). In conjunction with the trial, we collected data prospectively to determine whether decreasing homocysteine levels would reduce the occurrence of symptomatic venous thromboembolism. Methods Design The design of HOPE-2, a large randomized, placebo-controlled clinical trial, is described elsewhere (7, 8). Soon after HOPE-2 began, a decision was made to include venous thromboembolism as a study outcome. A diagnosis of venous thromboembolism was based on prespecified, accepted criteria (7). An independent data and safety monitoring board evaluated the safety of the participants and the overall quality and scientific integrity of HOPE-2. The research ethics review board of each participating center approved the trial, and all participants provided written informed consent. Participants The HOPE-2 included 5522 participants 55 years of age or older who had a history of coronary, cerebrovascular, or peripheral vascular disease; diabetes mellitus; and at least 1 additional risk factor for cardiovascular disease, regardless of baseline homocysteine level (7, 8). Persons taking daily vitamin supplementation that contained more than 0.2 mg of folic acid were excluded. A history of venous thromboembolism or the presence or absence of risk factors for venous thromboembolism did not affect eligibility. A complete list of inclusion and exclusion criteria appears elsewhere (7, 8). Data on all persons who were enrolled in HOPE-2 are included in the current report. Centers Individuals were recruited from 145 centers in 13 countries, including Canada (n= 3568), the United States (n= 414), Brazil (n= 265), western European countries (n= 426), and Slovakia (n= 849). Intervention and Randomization Between January 2000 and December 2000, participants were randomly assigned to receive a once-daily supplement containing 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or matching placebo. Randomization was computer generated, with a block size of 4; was stratified by clinical center; and was performed by having clinical centers call an automated centralized system. Information about block size and whether it was random or fixed was kept confidential for all study investigators. The randomization sequence was concealed, and all study personnel and study participants were masked to treatment allocation. The vitamin and placebo pill formulations were indistinguishable by size, color, weight, taste, or dissolution in water. Changes in blood levels of folate, vitamins B6 and B12, and homocysteine, which are affected by the study intervention, are not commonly measured in clinical practice, and the results of any such measurements that were performed as part of the study were kept confidential. No request was made to unmask treatment allocation for a participant. Baseline Measurements and Follow-up Baseline demographic data; medical history; and medication use, including current anticoagulant therapy, were recorded for all participants at study entry. History of venous thromboembolism was not documented. Baseline homocysteine levels were obtained in 3306 randomly selected participants (60% of total) who had fasted overnight. Stratified random sampling was used to achieve proportional representation of a subset of participants in countries with folic acid food fortification (Canada and the United States) and countries without this standard (all other countries with participating centers). Homocysteine was measured by using a fluorescence polarization immunoassay (Abbott IMx, Abbott Laboratories, Abbott Park, Illinois). The distribution of homocysteine was statistically significantly skewed; thus, these measures were log-transformed and inverse transformations were used to generate geometric mean values. The first evaluation for venous thromboembolism occurred 18 months after randomization; at this visit, all participants were assessed for any venous thromboembolism event arising between trial entry and the 18-month visit. Thereafter, venous thromboembolism was assessed routinely every 6 months, to an average follow-up of 5 years. The trial used simple case report forms, which were faxed toll-free to the study coordinating office and were entered into a database by using optical character recognition (DataFax, Clinical DataFax Systems, Hamilton, Ontario, Canada). The database was fit for quality control assessments and statistical analyses. At each 6-month interval, participants were assessed in the study clinics. These assessments were directed primarily to ascertain study end points. Side effects were also evaluated, and adherence to treatment was assessed by interview and pill count. When in-person visits were not possible, participants were contacted by telephone. Outcomes The primary outcome in our study was symptomatic venous thromboembolism, which included deep venous thrombosis or pulmonary embolism (or both). In the original HOPE-2 report (8), venous thromboembolism was included under other outcomes. Diagnosis of deep venous thrombosis required confirmation with duplex leg ultrasonography or venography. Diagnosis of pulmonary embolism required confirmation with ventilationperfusion lung scanning, computed tomographic pulmonary angiography, or conventional pulmonary angiography. When diagnostic testing had indeterminate results or was not done, which rarely occurred, we required oral anticoagulant therapy to be initiated at the same time that new-onset venous thromboembolism was recorded on the case report form. A maximum of 1 episode of venous thromboembolism per participant was counted during follow-up. We subcategorized episodes as unprovoked venous thromboembolism if they occurred in participants who did not have cancer at baseline and occurred 90 days or more after a lower limb fracture or 30 days or more after a hospitalization. We ascertained all events with concealment to randomization for study participants and assessors. Statistical Analysis Our primary analysis was a comparison of the incidence of venous thromboembolism in the 2 study groups. We prespecified secondary analyses and included comparisons between the groups of rates of venous thromboembolism (including unprovoked events) according to subgroups and strata (Figure 1). Figure 1. Risk for venous thromboembolism ( VTE ) in prespecified subgroups. We used an intention-to-treat analysis to compare the effect of homocysteine-lowering therapy with that of placebo on the subsequent development of venous thromboembolism. We conducted the time-to-event analysis by using a Cox proportional hazards regression model and expressed unadjusted risk as hazard ratios and 95% CIs. We examined the proportional hazards assumption by fitting the models with the interaction terms between time and treatment. We estimated a survival curve according to the KaplanMeier procedure and compared treatment groups by using a log-rank test. At each interval clinic visit, follow-up was greater than 99%. In the rare circumstance that an individual could not be assessed at a clinic visit and could not be contacted by telephone, we considered the individual to be free of venous thromboembolism at that point. Individuals who were lost to follow-up were censored at the time of last contact. The original HOPE-2 was designed to recruit 5000 participants, with a mean of 5 years of follow-up, to detect a relative risk reduction of 17% to 20% and a statistical power of 80% and 90% in the primary composite outcome of cardiovascular death, myocardial infarction, and stroke, given an annual event rate of 4% in the placebo group and a 2-sided P value of 0.05. We did not estimate a formal sample size. A 2-sided P value less than 0.05 was considered significant for all analyses, which we performed by using SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The study was funded by the Canadian Institutes of Health Research and Jamieson Laboratories. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Study Participants and Homocysteine Levels Of the 5522 study participants, 2758 were randomly assigned to receive homocysteine-lowering therapy and 2764 were assigned to receive placebo (Table 1). A total of 3982 participants (72%) were from Canada and the United States, where universal food fortification with folic acid was in place before the start of the trial. Adherence to th

Development and evaluation of cultural food frequency questionnaires for South Asians, Chinese, and Europeans in North America

We developed three ethnic food frequency questionnaires (FFQs) to characterize the diets of South Asian, Chinese, and European immigrants. FFQs were developed from foods reported in the diet records and recalls of 29 South Asians, 25 Chinese, and 20 Europeans participating in a pilot study from 1995-1996 in Hamilton, Ontario, Canada. The FFQ and a seven-day diet record were then administered to 342 South Asians, 317 Chinese, and 346 Europeans participating in the Study of Health Assessment and Risk in Ethnic groups (SHARE) in three Canadian centers from 1996-1998. For FFQ validation, a subset of these participants completed a second seven-day diet record and second FFQ 8 to 10 months later. The FFQ generally underestimated macronutrient and overestimated micronutrient intake compared with the records. Consumption of most macronutrients was lower among South Asians. Energy-adjusted deattenuated correlation coefficients between the records and second FFQ ranged from 0.32 to 0.73 (South Asians), 0.17 to 0.84 (Chinese), and 0.30 to 0.83 (Europeans). The FFQs generally performed well and will be used to investigate diet-disease relations in SHARE. Lower correlations for dietary fats among Chinese persons (0.17 to 0.31) may be improved with more direct questions on the FFQ regarding brand, type, and amount of oil consumed in stirfry servings.