Eva Lonn

Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence

Cardiovascular disease remains the major cause of morbidity and death in developed countries and accounts for approximately 40% of all deaths in Canada (1). Smoking cessation and reductions in cholesterol levels and blood pressure have been shown to be effective strategies in the prevention of cardiovascular disease (2). However, these major, classic cardiovascular risk factors and such nonmodifiable risk factors as age, sex, and family history cannot fully explain why some persons develop myocardial infarction, stroke, and other cardiovascular disease but other persons do not (3-5). Other factors may also increase the likelihood of developing cardiovascular disease and contribute to atherogenesis. Pathologic and epidemiologic studies suggest that only about one half to two thirds of the variation in anatomic extent of atherosclerosis and risk for atherosclerotic vascular disease can be explained by classic risk factors (6-9). Therefore, many emerging risk factors have been investigated. Among these, elevated plasma or serum levels of homocyst(e)ine (hyperhomocyst[e]inemia) are of particular interest. Recent epidemiologic studies have shown that moderately elevated plasma homocysteine levels are highly prevalent in the general population and are associated with an increased risk for fatal and nonfatal cardiovascular disease, independent of classic cardiovascular risk factors. This association is usually consistent, strong, dose-related, and biologically plausible. Although simple, inexpensive, nontoxic therapy with folate and vitamins B6 and B12 is highly effective at reducing plasma homocyst(e)ine levels, it remains to be demonstrated that decreasing homocyst(e)ine levels reduces cardiovascular morbidity and mortality. Methods Data Sources We searched the scientific literature for all epidemiologic studies (prospective, casecontrol, cross-sectional, or geographic correlation) on cardiovascular disease (using the terms coronary heart disease, cerebrovascular disease, peripheral vascular disease, and atherosclerosis) and homocysteine or vitamins (using the terms homocysteine, B 12, B 6, and folic acid). We searched the MEDLINE database for articles published from January 1965 to January 1999 and identified additional studies by examining bibliographies of original articles, review articles, and textbooks. Study Selection We used standard definitions to define epidemiologic studies (10) and did not consider case series. The epidemiologic prospective cohort studies varied greatly in terms of patient selection, number of patients and controls, circumstances and techniques of measuring plasma homocyst(e)ine levels, definitions of elevated plasma homocyst(e)ine level, types and definitions of vascular outcome events and surrogate outcome measures, and statistical analyses. A formal meta-analysis of these studies was not performed because the results could have been misleading. We included all prospective epidemiologic studies (up to January 1999) but included only the largest retrospective studies (those that involved at least 150 cases) because prospective studies generally provide a robust estimate of association, whereas small retrospective studies are often subject to various biases. We further restricted the retrospective studies to those published after the meta-analysis by Boushey and colleagues (11) because that article provides a good critical review of the studies done up until 1995. Homocysteine Metabolism Homocysteine is a sulfur-containing amino acid produced during catabolism of the essential amino acid methionine. Homocysteine can be metabolized by two major pathways. When methionine is in excess, homocysteine is directed to the transsulphuration pathway, where it is irreversibly sulfoconjugated to serine by cystathionine -synthase in a process requiring vitamin B6 as a cofactor. However, under conditions of negative methionine balance, homocysteine is primarily metabolized through a methionine-conserving remethylation pathway. In most tissues, homocysteine is remethylated in a process that requires methionine synthase, vitamin B12 as a cofactor, and methyltetrahydrofolate as a cosubstrate. This pathway requires an adequate supply of folic acid and the enzyme methylene tetrahydrofolate reductase (MTHFR) (12). Genetic and acquired abnormalities in the function of these enzymes or deficiencies in folic acid, vitamin B6, or vitamin B12 cofactors can lead to elevated homocysteine levels. In the plasma, approximately 70% of homocysteine circulates in a protein-bound form; approximately 25% combines with itself to form the dimer homocystine; and the remainder (<5%) combines with other thiols, including cysteine, to form disulphide (a homocysteine-cysteine mix) or circulates as the free thiol compound (13). In North America, the term homocyst(e)ine is often used to refer to the total pool of circulating plasma homocysteine, whereas the term tHcy is more common in Europe. Homocyst(e)ine Theory of Atherosclerosis Severe hyperhomocyst(e)inemia associated with homocystinuria can be caused by several rare inherited disorders, including homozygous deficiency of cystathionine -synthase, MTHFR, or methionine synthase or defects in vitamin B12 metabolism (12, 14). These distinct genetic conditions share the following features: extreme elevations of plasma homocyst(e)ine levels and premature atherothrombotic disease with typical histopathologic features of endothelial injury, proliferation of vascular smooth-muscle cells, progressive arterial stenosis, and hemostatic changes suggestive of a prothrombotic state (15). The characteristic clinical and pathologic features of these genetically diverse conditions support the hypothesis that elevated plasma homocyst(e)ine levels are responsible for the vascular damage and led McCully and Wilson (16) to propose the homocyst(e)ine theory of atherosclerosis. Although these genetic errors of metabolism are extremely rare (homozygous cystathionine -synthase deficiency occurs in approximately 1 in 150 000 live births and is associated with plasma homocyst[e]ine levels as high as 400 mol/L), they provide a useful in vivo human model for vascular injury associated with high homocyst(e)ine levels . Laboratory Measurement of Homocyst(e)ine Levels Most assays for measuring homocysteine concentrations are based on chromatographic techniques; high-performance liquid chromatography is still the most widely used (13). However, a simple and relatively inexpensive immunoassay has become commercially available and may soon enable widespread measurement of plasma homocyst(e)ine levels in the clinical laboratory (17). Plasma homocyst(e)ine levels are usually measured in the fasting state and can be measured before or after methionine loading. Methionine loading, a method of stressing the homocyst(e)ine metabolic pathways, may be more sensitive than measurement of fasting homocyst(e)ine levels for detecting mild disturbances in the transsulfuration pathway that may be caused by vitamin B6 deficiency or partial cystathionine -synthase deficiency (18, 19). The procedure involves measuring the baseline fasting plasma homocyst(e)ine level, administering a standard oral dose of methionine, and measuring the plasma homocyst(e)ine level again 4 to 6 hours later. Methionine loading may help to discriminate between defects involving the transsulfuration and remethylation pathways (20); it may also help to identify patients who have impaired homocysteine metabolism despite a normal fasting total plasma homocysteine level and who may, therefore, be at increased risk for vascular disease (19). Reliable measurements of plasma homocyst(e)ine levels require the use of accurate assays as well as optimal procedures for collection and handling of blood samples (13). Patient characteristics (such as fasting state and posture) and recent vascular events may also affect measured total homocysteine levels (20-22). Definition and Prevalence of Hyperhomocyst(e)inemia Hyperhomocyst(e)inemia is usually defined by using arbitrary cut-off pointsfor example, above the 95th percentile or more than two SDs above the mean of values obtained from fasting, healthy controls. This is similar to the way in which high plasma cholesterol levels were originally defined. Normal plasma homocyst(e)ine levels usually range from 5 to 15 mol/L (17). However, the definition of elevated homocyst(e)ine levels is not standardized, and substantial differences exist in the normal reference levels used in the literature. Higher fasting values are arbitrarily classified as mild and moderate hyperhomocyst(e)inemia (16 to 100 mol/L) and severe hyperhomocyst(e)inemia (>100 mol/L). The prevalence of hyperhomocyst(e)inemia depends on the way in which the condition is defined and measured. When the common definition of hyperhomocysteinemialevels of total homocysteine exceeding the 95th percentile of the distribution in a healthy sample of controlsis used, 5% of the normal population will necessarily be defined as having an elevated homocyst(e)ine level (23). Between 13% and 47% of patients with symptomatic atherosclerotic vascular disease have been reported to have hyperhomocystein(e)mia (24). However, little evidence suggests a sudden increase in risk for vascular disease above a certain threshold level of plasma homocyst(e)ine; the relation between plasma homocyst(e)ine levels and risk for cardiovascular disease seems to be graded and linear (25). Causes of Mild and Moderate Hyperhomocyst(e)inemia One or a combination of genetic, physiologic, pathologic, and nutritional factors (Table 1) causes modest elevations in homocyst(e)ine levels without associated homocystinuria. Therefore, MTHFR mutations (for example, thermolabile MTHFR); older age; male sex; postmenopausal status; smoking; sedentary lifestyle; dietary factors, including increased intake of animal proteins (which have a higher methionine content); low intake of folic acid, vitamin B6, and vit

Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE)

BACKGROUND Cardiovascular disease rates vary greatly between ethnic groups in Canada. To establish whether this variation can be explained by differences in disease risk factors and subclinical atherosclerosis, we undertook a population-based study of three ethnic groups in Canada: South Asians, Chinese, and Europeans. METHODS 985 participants were recruited from three cities (Hamilton, Toronto, and Edmonton) by stratified random sampling. Clinical cardiovascular disease was defined by history or electrocardiographic findings. Carotid atherosclerosis was measured with B-mode ultrasonography. Conventional (smoking, hypertension, diabetes, raised cholesterol) and novel risk factors (markers of a prothrombotic state) were measured. FINDINGS Within each ethnic group and overall, the degree of carotid atherosclerosis was associated with a higher prevalence of cardiovascular disease. South Asians had the highest prevalence of this condition compared with Europeans and Chinese (11%, 5%, and 2%, respectively, p=0.0004). Despite this finding, Europeans had more atherosclerosis (mean of the maximum intimal medial thickness 0.75 [0.16] mm) than South Asians (0.72 [0.15] mm), and Chinese (0.69 [0.16] mm). South Asians had an increased prevalence of glucose intolerance, higher total and LDL cholesterol, higher triglycerides, and lower HDL cholesterol, and much greater abnormalities in novel risk factors including higher concentrations of fibrinogen, homocysteine, lipoprotein (a), and plasminogen activator inhibitor-1. INTERPRETATION Although there are differences in conventional and novel risk factors between ethnic groups, this variation and the degree of atherosclerosis only partly explains the higher rates of cardiovascular disease among South Asians compared with Europeans and Chinese. The increased risk of cardiovascular events could be due to factors affecting plaque rupture, the interaction between prothrombotic factors and atherosclerosis, or as yet undiscovered risk factors.

2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations

The present article represents the 2009 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult.

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.

2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult

Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population.

Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection

A ngiotensin-converting enzyme (ACE) inhibitors are commonly used drugs in the management of a variety of cardiovascular diseases. They are effective antihypertensive agents.1-3 Early studies have demonstrated reductions in mortality and symptoms of heart failure in patients with severe congestive heart failure.4 More recently, clinical trials have demonstrated reductions in mortality and in hospitalizations for heart failure when these agents were used in patients with moderate left ventricular dysfunction, with and without overt heart failure, further expanding the clinical value of these drugs in the management of patients with cardiac diseases. These benefits have been observed consistently in several trials,5-7 in patients with ischemic and nonischemic causes for the left ventricular dysfunction and with or without recent myocardial infarction. The reductions in progressive heart failure and mortality in these patients are at least partly related to a beneficial effect on left ventricular remodeling and reductions in left ventricular enlargement.8-10 Other potential beneficial effects of these agents, such as regression of left ventricular hypertrophy and retardation of the rate of loss of renal function in patients with diabetic nephropathy, have been brought into focus by recent trials and also by experimental studies that explore their mechanisms of action. A new and important potential role for ACE inhibitors is suggested by the recent trials in patients with low ejection fraction, which documented a significant reduction in major ischemic events such as myocardial infarction, unstable angina, and the need for coronary revascularization procedures. In addition, parallel epidemiological, genetic, and experimental studies suggest that the renin-angiotensin-aldosterone system may have a role in the development of coronary artery disease

Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction: A Meta-analysis

CONTEXT The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. OBJECTIVE To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. DATA SOURCES Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. STUDY SELECTION Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. DATA EXTRACTION Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. RESULTS We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. CONCLUSION The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Use of ramipril in preventing stroke: double blind randomised trial

Abstract Objective: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. Design: Randomised controlled trial with 2×2 factorial design. Setting: 267 hospitals in 19 countries. Participants: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. Outcome measures: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. Results: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. Conclusion: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure. What is already known on this topic Treatment with aspirin and lowering blood pressure reduce the incidence of stroke What this study adds Ramipril, an angiotensin converting enzyme inhibitor, reduces strokes in patients at high risk whose blood pressure is not elevated, despite only a modest lowering of blood pressure The benefits are observed even when patients receive aspirin and other blood pressure lowering treatments

Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease

BACKGROUND Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. METHODS In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). RESULTS During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). CONCLUSIONS In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

Comparative Impact of Multiple Biomarkers and N-Terminal Pro-Brain Natriuretic Peptide in the Context of Conventional Risk Factors for the Prediction of Recurrent Cardiovascular Events in the Heart Outcomes Prevention Evaluation (HOPE) Study

Background— Individual markers of inflammation may add incremental predictive value in the context of conventionally available risk factors. We evaluated the ability of 9 inflammatory biomarkers, microalbuminuria, and N-terminal pro-brain natriuretic peptide (Nt-proBNP) to improve cardiovascular risk prediction beyond that obtained from traditional risk factors in a secondary-prevention population. Methods and Results— We measured biomarkers representing the acute-phase reaction (C-reactive protein, fibrinogen, and interleukin-6), proinflammatory pathways (soluble tumor necrosis factor receptor-1 and -2, soluble interleukin-1 receptor antagonist, and interleukin-18), endothelial activation (soluble vascular adhesion molecule-1 and soluble intercellular adhesion molecule-1), Nt-proBNP, and microalbuminuria in 3199 study individuals of the Heart Outcomes Prevention Evaluation (HOPE) Study and assessed their association with risk of myocardial infarction, stroke, or cardiovascular death (primary outcome, n=501) over 4.5 years of follow-up. In a backward Cox regression procedure that included risk factors and biomarkers, Nt-proBNP (hazard ratio [HR] 1.72 per increment SD, 95% CI 1.39 to 2.12; P<0.0001), soluble intercellular adhesion molecule-1 (HR 1.46, 95% CI 1.19 to 1.80; P=0.0003), microalbuminuria (HR 1.55, 95% CI 1.22 to 1.98; P=0.0004), soluble interleukin-1 receptor antagonist (HR 1.30, 95% CI 1.05 to 1.61; P=0.02), and fibrinogen (HR 1.31, 95% CI 1.05 to 1.62; P=0.02) remained significantly related to the primary outcome. Only inclusion of Nt-proBNP provided incremental information above that obtained by models of traditional risk factors. Conclusions— Although levels of various inflammatory biomarkers are significantly related to future cardiovascular risk, their incremental predictive value is modest. A model consisting of simple traditional risk factors and Nt-proBNP provided the best clinical prediction in the secondary-prevention population.