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From the Divisions of Internal Medicine (Pilote, Dasgupta) and Clinical Epidemiology (Pilote, Dasgupta, Libersan), The McGill University Health Centre Research Institute, McGill University, Montréal, Que.; Division of Cardiovascular Surgery, Sunnybrook and Women's College Health Sciences Centre, Insititute for Clinical Evaluative Sciences (Guru), University of Toronto, Toronto, Ont.; Centre for Health Evaluation and Outcome Sciences, St. Paul's Hospital (Humphries), University of British Columbia, Vancouver, BC; Department of Psychology (McGrath), Concordia University, Montréal, Que.; University of Alberta (Norris), Edmonton, Alta.; Faculty of Medicine, Department of Community Health Sciences (Rabi), Calgary, Alta.; Centre hospitalier de l'Université de Montréal Research Centre, Hôtel-Dieu (Tremblay, Hamet, Petrovich) and Groupe de recherche interdisciplinaire en santé, Département de médecine sociale et préventive (Barnett, O'Loughlin), University of Montreal, Montréal, Que.; Institut national de santé publique du Québec (Alamian, Paradis), Québec, Que.; New Halifax Infirmary Site, QEII Health Sciences Center (Cox), Dalhousie University, Halifax, NS; Department of Medicine and Community Health Sciences (Ghali), University of Calgary, Calgary, Alta.; York University (Grace), University Health Network, Toronto, Ont.; Department of Epidemiology and Biostatistics (Ho), McGill University, Montréal, Que.; Department of Community Health and Epidemiology (Kirkland), Dalhousie University, Halifax, NS; Département de pédiatrie (Lambert), Hôpital Ste-Justine and University of Montreal, Montréal, Que.; Centre for Clinical Epidemiology & Community Studies (Tagalakis), Jewish General Hospital-Sir Mortimer B. Davis, McGill University, Montréal, Que.
Correspondence to: Dr. Louise Pilote, The McGill University Health Centre Research Institute, Divisions of Internal Medicine and Clinical Epidemiology, 687 av. Des Pins Ouest, A4.23, Montréal QC H3A 1A1; fax 514 934-8293; louise.pilote{at}mcgill.ca
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in women. In fact, CVD is responsible for a third of all deaths of women worldwide and half of all deaths of women over 50 years of age in developing countries. The prevalence of CVD risk factor precursors is increasing in children. Retrospective analyses suggest that there are some clinically relevant differences between women and men in terms of prevalence, presentation, management and outcomes of the disease, but little is known about why CVD affects women and men differently. For instance, women with diabetes have a significantly higher CVD mortality rate than men with diabetes. Similarly, women with atrial fibrillation are at greater risk of stroke than men with atrial fibrillation. Historically, women have been underrepresented in clinical trials. The lack of good trial evidence concerning sex-specific outcomes has led to assumptions about CVD treatment in women, which in turn may have resulted in inadequate diagnoses and suboptimal management, greatly affecting outcomes. This knowledge gap may also explain why cardiovascular health in women is not improving as fast as that of men. Over the last decades, mortality rates in men have steadily declined, while those in women remained stable. It is also becoming increasingly evident that gender differences in cultural, behavioural, psychosocial and socioeconomic status are responsible, to various degrees, for the observed differences between women and men. However, the interaction between sex-and gender-related factors and CVD outcomes in women remains largely unknown.
Doreen Rabi and Jafna Cox
Although cardiovascular disease (CVD) is common, significant sex-related differences in its epidemiology have only recently been appreciated. The objective of this section is to demonstrate that there are sex-specific differences in the prevalence, complications and burden of CVD in terms of mortality, hospital admissions and quality of life.
Search strategy
A MEDLINE search was conducted using the MeSH terms "cardiovascular disease" OR "atrial fibrillation" OR "congestive heart failure." A second search used the terms "prevalence" OR "incidence" OR "mortality" and the final search combined the results of the first 2 searches and added the terms "gender" OR "sex." Articles identified in this manner were retrieved and their reference lists searched for additional relevant articles. The search was limited to English-language publications, but no other restrictions were applied. Other data sources included Web sites of the World Health Organization, the Canadian Institute for Health Information and the National Centre for Health Statistics. Thirty-three original studies were reviewed. Studies were included if they were cohort studies, case–control studies or nested cohort studies that examined the incidence, prevalence or mortality of CVD, congestive heart failure or atrial fibrillation. The studies had to include data on both men and women.
Cardiovascular disease
Prevalence
CVD is ubiquitous. Determining the extent of the burden this disease places on society is difficult as most databases and studies base the presence of CVD on presentation with an acute event, making the prevalence of asymptomatic disease difficult to establish. Public health surveys have been used to determine the prevalence of CVD in the ambulatory population. North American surveys indicate that CVD is diagnosed more frequently in men, with 5.4% of Canadian men (compared with 4.6% of women)1 and 8.4% of US men (compared with 5.6% of women)2 reporting a prior diagnosis of CVD.
Trends in CVD vary considerably from region to region.3 In North America, Europe, Australasia and middle-income developing countries, men are reported to have a higher prevalence of CVD compared with women (Table 1).4 However, the proportion of women presenting with clinically and angiographically significant disease has increased over the last 20 years. Overall, the incidence of CVD, and of coronary artery disease (CAD) in particular, has been declining in men but has remained stable in women.5
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Mortality
CVD remains a leading cause of mortality throughout the world, affecting both women and men.6 Trends in CVD mortality, like trends in prevalence, display regional variations (Fig. 1).7 Although the age-standardized mortality rates have been declining over the past 3 decades in Western Europe and North America, they have risen markedly in middle-income developing countries (Eastern Europe and China). Levi and colleagues8 demonstrated that these trends are consistent for both men and women (Fig. 2).
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Historically, men have had higher cardiovascular-related mortality rates than women. This finding is consistent across several countries. According to Manuel and colleagues,9 in 1999, Canadian men had an age-standardized CVD mortality rate of 288 per 100 000, while the rate for women was 175 per 100 000. Sex-specific, age-standardized CVD mortality rates were very similar in the United States in 2003: 307 per 100 000 for men and 158 per 100 000 for women.2 At the international level, CVD mortality rates are consistently higher in men (Table 2).6
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Hospital admissions
CVD is the leading cause of admission to hospital in North America for both men and women. In 2000, CVD accounted for 18% of all hospital admissions in Canada. Women experience longer stays in hospital related to CVD and suffer greater disability. The National Population Health Survey1 revealed that among respondents reporting a diagnosis of heart disease, women consistently reported higher levels of pain, discomfort, activity restriction and disability secondary to their heart disease than men.
Coronary artery disease
Men continue to have higher rates of mortality related to acute myocardial infarction (AMI) and CAD than women. In Canada in 1999, the age-standardized CAD mortality rate for men was 188 per 100 000 compared with 97 per 100 000 for women.9 A similar sex difference was noted in the United States in 2003 when the CAD mortality rate per 100 000 was 187 for men and 77 for women.2 This difference appears to be consistent across international borders (Table 2).6 However, younger women with AMI have higher rates of mortality than men of the same age.10–12
Heart failure
Prevalence
Heart failure, a recognized complication of CAD and AMI, has become more prevalent over the past several years. Recent data from the Framingham study suggest that the lifetime risk of developing heart failure is about 20% for both men and women.13 Approximately 2% of people living in the Americas have a diagnosis of heart failure. The prevalence is similar in Europe, where it is estimated to be between 1.8% (95% confidence interval [CI] 1.4–2.3)14 and 3.9% (95% CI 3.0–4.7),15 and it is as high as 6.3% (95% CI 5.0–7.7) in Australia.16 The risk of left-ventricular systolic dysfunction increases steadily with age in both men and women. After the age of 75 years, the prevalence of heart failure secondary to systolic dysfunction is estimated to be 8.4%.17,18
In Canada, as elsewhere, most patients with heart failure are 65 years of age and older, with women comprising 51% of all new cases.19 As with ischemic heart disease, female patients with heart failure are older than males and more likely to be hypertensive and diabetic, but they tend to have better preserved systolic function, a lower prevalence of ischemic etiology and are less likely to have a history of prior AMI.20,21
Mortality
Once heart failure is present, the median survival time is 1.7 years for men and 3.2 years for women.13 Mortality following a diagnosis of heart failure remains significant. The 5-year mortality rate is approximately 50% for both women and men. Although mortality associated with heart failure has declined significantly over the past 20 years in men (28%–52%), the decrease has not been as significant in women (6%–33%).22
Hospital admissions
Heart failure is a leading cause of hospital admission throughout the world, and women account for about 50% of these admissions. In North America, admissions to hospital with a primary diagnosis of heart failure have increased by 34% since 1990, but this increase is more notable in women (39%) than men (29%). In fact, a review of the American National Hospital Discharge Survey23 noted that age-adjusted heart failure admission rates have been constant since 1991 for men, but have continued to increase for women (19%) (Fig. 3), suggesting that the increase in hospital admissions in recent years is largely the result of more women presenting with clinically significant disease. Once discharged from hospital, men and women appear to have similar rates of readmission (hazard ratio [HR] 0.89; 95% CI 0.71–1.11).21 Sex differences in length of hospital stays have also been noted, with women having significantly longer hospital stays than men.24
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Atrial fibrillation
Prevalence
Atrial fibrillation is the most common cardiac arrhythmia and is an established risk factor for stroke and premature death. North American and European studies indicate that about 0.95%–1.1% of the population experiences atrial fibrillation.25–27 The Framingham study demonstrated that men were 1.5 times more likely to develop atrial fibrillation than women,28 but because the number of women older than 75 years is almost twice that of men, the absolute numbers of those with atrial fibrillation are roughly equal.26 Incidence increases with age; the prevalence of atrial fibrillation at age 55 is 0.1% and increases to 9.0% in those over 80 years of age.26,29 This age-related increase in prevalence is most striking in men (Table 3).30
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Mortality
Mortality rates are significantly higher in both women and men with atrial fibrillation. In longitudinal studies, mortality rates were approximately 25% higher than age-and sex-matched controls.31,32 In the United States, in-hospital mortality rate following admission for atrial fibrillation is estimated at 0.8%. Men have a modestly higher (but statistically significant) risk of in-hospital mortality. Using administrative data (National Hospital Discharge Survey), Kairallah and colleagues33 demonstrated that male sex was an independent predictor of in-hospital mortality (odds ratio [OR] 1.10; 95% CI 1.06–1.14). However, analysis of administrative data from Scotland suggests that 1-year mortality may be higher in women; Stewart and colleagues34 found the 1-year case fatality rate in men to be 11.9% v. 16.2% in women. The distribution of ages in this cohort is not known; the higher mortality rate seen in women may reflect a greater number of very elderly women diagnosed with atrial fibrillation. Wattigney and colleagues35 have demonstrated in a US cohort that mortality remains higher among men after age standardization.
Hospital admission and stroke
Reflecting the sex differences in prevalence, admissions to hospital for atrial fibrillation are also more common in men at every age (Table 4).36 Among patients with atrial fibrillation, women seem to be at greater risk of stroke than men. In a cohort of US Medicaid patients, Wolf and colleagues31 found that, after controlling for other established risk factors, women with atrial fibrillation had a 22%–25% greater risk of stroke than women without atrial fibrillation (Table 5). In contrast, the increased risk of stroke in men with atrial fibrillation was completely attenuated by controlling for other stroke risk factors.31 Women have also been found to have higher readmission rates following stroke.36
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Health-related quality of life
Although men are more likely to die from CAD, women are more likely to live with CAD-related disability. In North American cohort studies, women with a history of CAD, heart failure or atrial fibrillation consistently report lower health-related quality of life and greater disability related to their heart disease than men. Women are also less likely to return to work following admission to hospital for complications related to CVD.37
Summary
• CVD is prevalent among both women and men.
• Women have a lower CVD mortality rate than men.
• CAD and atrial fibrillation are more prevalent among men than among women.
• Women appear to have a relatively higher risk of atrial fibrillation-related stroke than men.
• Clinically significant heart failure is on the rise in women.
• Women are more likely to live with more CVD-related disabilities and have a lower health-related quality of life.
Knowledge gap
• Why are CVD incidence and mortality rates decreasing among men but stable among women?
Cardiovascular risk factors in girls and boys
Jennifer McGrath, Tracie Barnett, MarieLambert, Jennifer O'Loughlin, GillesParadis, Arsham Alamian and Teresa Ho
Although most cardiovascular events occur in adulthood, the precursors of CVD manifest during childhood and adolescence.38,39 CVD is partly attributable to modifiable lifestyle behaviours, and childhood is a critical developmental period when these habits are established.40 Further, risk factors such as smoking, sedentary behaviour and poor diet in children and adolescents persist through young adulthood and are important predictors of subsequent risk of CVD.41–44 Consequently, it is essential to promote cardiovascular health and direct primary prevention efforts toward children and adolescents to disrupt the progression of CVD risk factors and thereby offset both the risk of CVD in adulthood and the unprecedented potential burden on health care systems.
Search strategy
Studies included in this qualitative review of childhood cardiovascular risk factors were identified through the use of widely available computer databases (Ovid MEDLINE, Ovid EMBASE, PubMed, PsycInfo, the Cochrane Library). Boolean searches were carried out by combining the keyword ("boy" OR "girl" OR "child" OR "pediatric" OR "adolescent" OR "young adult") with each of the following keyword combinations using the AND operator: ("atherosclerosis" OR "cardiovascular" OR "coronary" OR "heart"), ("obesity" OR "overweight"), ("lipids" OR "lipoprotein"), ("hypertension" OR "blood pressure" OR "systolic" OR "diastolic"), ("cigarettes" OR "smoking" OR "tobacco"), ("diet" OR "nutrition"), ("exercise" OR "physical activity" OR "sedentary"), ("clustering" OR "behavior" OR "lifestyle"). Web sites of several well-known organizations, such as the World Health Organization, Centers for Disease Control and Prevention (CDC), Heart and Stroke Foundation of Canada and the American Heart Association, were reviewed for additional information and current recommendations. Finally, to obtain information from national and international statistical databases as well other "grey literature" and nonconventional documents, government Web sites (e.g., Statistics Canada, Health Canada, CDC) were examined. To reduce the copious amount of information this search strategy produced, the review emphasized children or adolescent populations; large studies with representative samples; longitudinal studies; and recent publications that reported sex-or gender-specific findings.
Overweight and obesity
Overweight and obesity are the most frequent nutritional disorders in industrialized countries in children as well as in adults; the prevalence of obesity has increased almost 3-fold over the past 2 decades.45,46 Although it is generally thought that girls are more likely to be overweight than boys, there are no differences in prevalence between girls and boys.
In a recent report based on heights and weights measured in the National Longitudinal Survey of Children and Youth47 and using Cole and colleagues'48 age-and sex-specific body mass index (BMI) threshold values for overweight and obesity, Shields46 estimated that the prevalence of overweight and obesity of Canadian boys and girls aged 2–17 years was 27% and 25%, respectively; the corresponding figures for obesity only were 9% and 7%, respectively. Although the overall prevalence of overweight and obesity was similar for boys and girls, trends varied for different age groups. The percentage of overweight and obese children 2–5 years old remained unchanged (21%) between 1978–1979 and 2004. However, the prevalence of overweight and obesity doubled among those 6–11 years (from 13% to 26%) and those 12–17 years (from 14% to 29%), and the prevalence of obesity tripled among those 12–17 years (from 3% to 9%). Secular trends in body mass of Canadian children are shown in Fig. 4.49 Part of these sex-based differences may be attenuated by the fact that age-and sex-specific thresholds are used to define overweight and obesity.
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In the United States, using height and weight measurements obtained in 1999–2000 as part of the National Health and Nutrition Examination Survey (NHANES) and the 2000 CDC growth chart reference values, Ogden and colleagues45 reported that the prevalence of overweight and obesity was 20.5%, 26.2% and 26.5% among non-Hispanic white youth aged 2–5, 6–11 and 12–19 years, respectively. The corresponding figures for obesity only were 10.1%, 11.8% and 12.7%. The prevalence of obesity was not significantly different for boys and girls.
Longitudinal studies have shown that measures of BMI taken during childhood and adolescence predict adult values. In the Bogalusa Heart Study,50 childhood and adult BMI were moderately correlated (Spearman's rank correlation coefficient 0.58), and this relation did not vary significantly with age, ethnic origin or sex. Similar results were observed in the Child and Adolescent Trial for Cardiovascular Health where the Kendall index of concordance for BMI was 0.86 over a follow-up period of 6 years and tracking was similar for both sexes.51
Summary
• The prevalence of obesity has increased almost 3-fold over the past 2 decades.
• There are no significant differences between girls and boys in the prevalence of overweight and obesity.
• A large proportion of obese adolescents will become obese adults.
Knowledge gap
• Additional research is needed on factors that contribute to the onset of overweight or obesity in childhood and adolescence and factors that contribute to its persistence into adulthood.
• The basic biologic characteristics of appetite, weight control, genetic susceptibility and environmental triggers remain elusive.
• We do not know specific prevention or treatment strategies that have sustained benefits in a broad spectrum of individuals.
Lipids and insulin resistance
Overweight and obesity are associated with significant health problems in the pediatric population and are important early risk factors for much of the adult morbidity and mortality associated with type 2 diabetes mellitus and CVD.
A large number of studies have consistently shown associations among childhood obesity, dyslipidemia, hyperinsulinemia and high blood pressure.52–54 The clustering of these CVD risk factors defines the metabolic syndrome called insulin resistance syndrome (IRS). The likelihood of IRS is the same for girls and boys. In the 1999 Quebec Child and Adolescent Health and Social Survey (QCAHS), a representative cross-sectional survey of Quebec youth, the overall prevalence of IRS was 11.5% in youth aged 9, 13 and 16 years.55 This is the only report on the prevalence of IRS in a provincially representative sample of youth in Canada. Findings from the third NHANES survey show a prevalence of IRS of 9.2% (95% CI 7.8–10.6) in US youth aged 12–19 years.56 Prevalence was comparable for girls (8.9%; 95% CI 7.1–10.7) and boys (9.5%; 95% CI 7.5–11.5) and for older (8.3%; 95% CI 6.5–10.1) and younger (10.3%; 95% CI 8.3–12.3) adolescents. The ethnic distribution was similar to that in adults: Mexican Americans (12.9%; 95% CI 10.4–15.4) and non-Hispanic white people (10.9%; 95% CI 8.4–13.4) had a greater prevalence of IRS compared with non-Hispanic black people (2.5%; 95% CI 1.3–3.7). Nearly a third (31.2%; 95% CI 28.3–34.1) of overweight or obese adolescents had IRS.
Given the link between excess weight and dyslipidemia, the increase in overweight and obesity among youth in North America is expected to affect trends in lipid and glucose levels adversely. However, comparing data from 2 NHANES surveys of US youth aged 4–17 years in 1988–1994 and 1999–2000, Ford and colleagues57 found that the mean concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were almost the same in the 2 groups. However, in 1999–2000, mean triglyceride concentration was almost 10% lower than in 1988–1994 and mean glucose concentration decreased by 3%. These inconsistent trends in CVD risk factors, especially in HDL cholesterol and triglyceride levels, are difficult to explain. Changes in mean levels may not be sensitive enough to detect variations occurring at the extremities of the distributions; it would have been interesting to compare selected percentiles in the 2 surveys.
Although longitudinal data for plasma lipid levels in Canadian youth are not available, mean concentrations of plasma lipids in the 1999 QCAHS and in the 1999–2000 NHANES were similar.55,57 Body composition and fat distribution are different between boys and girls and across ages, and these differences may influence the relation between fatness and lipids.
Summary
• There are no significant differences between girls and boys in prevalence of IRS.
• There are no significant differences in the trends in lipid and glucose profiles of girls and boys over the last decade.
Knowledge gap
• Little is known about the natural history of the metabolic consequences of excess adiposity in childhood and adolescence.
• Surveillance of trends in obesity and the potential effects on CVD risk factors is needed.
• Better understanding of the relative importance of genetic, biologic, environmental and psychosocial determinants of metabolic abnormalities associated with excess fat is required.
Blood pressure
Knowledge of blood pressure distributions in youth is important: both systolic and diastolic pressure persist from childhood to adulthood42,58,59 and the current youth obesity epidemic has important effects on blood pressure distribution in this segment of the population.60
There are few data on blood pressure distribution and the prevalence of elevated blood pressure in Canadian children. The 1999 QCAHS reported important increases in mean systolic blood pressure and in height-specific systolic blood pressure percentile values compared with reference values from the National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents61 for both boys and girls in all age groups.52 The proportion of children aged 9, 13, and 16 years with high-normal or elevated systolic pressure was 12%, 22% and 30%, respectively, for boys and 14%, 19% and 17% for girls. Elevated systolic pressure occurred in almost twice as many 16-year-old boys as girls. The mean systolic pressure of 13- and 16-year-old boys was 2 mm Hg (p = 0.004) and 10 mm Hg (p < 0.0001) higher, respectively, than that of girls. Less than 1% of youth had elevated or borderline diastolic blood pressure, and this did not differ between sexes. These findings were recently confirmed in a longitudinal study of Canadian adolescents. The likelihood of high systolic blood pressure values among boys compared with girls was 1.29 (95% CI 0.77–2.16) in grade 7, 1.98 (95% CI 1.35–2.93) in grade 9, and 2.74 (95% CI 1.52–4.94) in grade 11.62
A similar trend in high blood pressure has been observed in US children (Fig. 5).63 In age-matched boys and girls,64 cross-sectional analyses of the baseline data from the National Heart, Lung, and Blood Institute Growth and Health Study showed significantly higher systolic (105 v. 100 mm Hg) and diastolic (71 v. 65 mm Hg) blood pressure levels among overweight white girls aged 9 years than among those who were not overweight.65
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Limited data are available from representative samples of children from other parts of the world. Comparisons are further complicated by variations in sampling design and blood pressure measurement. For example, a recent survey of 809 boys and 842 girls aged 7–14 years from Belgrade, Serbia and Montenegro revealed average blood pressures of 113/70 mm Hg in boys and 115/71 mm Hg in girls. High systolic pressure was present in 5% of boys and girls, and high diastolic pressure was found in 6% of boys and 5% of girls.66 Conversely, a study of over 1200 children aged 6–11 years in Milan reported a significantly higher prevalence of elevated blood pressure in girls (5%) than in boys (3%).58 Sex differences in blood pressure may be due to differences in BMI between boys and girls at any given age, differences in activity levels and differences in pubertal stage at any given age.
Summary
• Elevated blood pressure persists from childhood to adulthood.
• Elevated blood pressure is prevalent in both girls and boys.
• Boys have higher systolic blood pressure than girls.
Knowledge gap
• Criterion-related reference values are necessary to clarify the significance of blood pressure levels in youth.
• More information is needed on blood pressure distribution and the prevalence of elevated blood pressure in groups of Canadian girls and boys.
• Sex differences in blood pressure require explanation at biologic, environmental and behavioural levels.
Smoking
Although data from the Global Youth Tobacco Survey67 and the National Tobacco Information Online System68 suggest that, in many developing countries, proportionately more boys than girls smoke, there have been few notable differences in the prevalence of smoking by boys and girls in developed countries over the last decade.69 Recent data for Canadian youth70,71 concur (Fig. 6).72 In Canada, 25% of girls 15–17 years old smoke compared with 19% of same-age boys, but by age 19 the prevalence is equal (31%).73 However, there appear to be sex differences in the number of cigarettes smoked per day, at least among young daily smokers. In 2002, Canadian boys in grades 5–9 smoked 8.8 cigarettes a day on average, compared with 7.3 cigarettes among girls.70 There are currently no nationally representative data comparing the incidence of smoking initiation by sex, although 1 prospective Canadian study suggests that boys are more likely than girls to escalate cigarette consumption rapidly after initiation.74 Although smoking cessation in youth is understudied, several surveys suggest that there are few differences in cessation attempts and successful cessation by sex.70
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Although prevalence does not differ markedly by sex, girls and boys may smoke for different reasons. Among adolescent girls, body image, eating disorders and targeted advertising by tobacco companies likely relate to initiation of and sustained smoking, whereas aggression and conduct disorders appear to be fairly consistent predictors of smoking among boys.75 However, the current literature on sex differences in the determinants of smoking is generally inconclusive because many studies are cross-sectional, the definitions of smoking and of the potential determinants of smoking are widely divergent across studies and most studies investigated only small subsets of potential determinants.
Summary
• The prevalence of smoking is similar in girls and boys.
• Boys who smoke daily smoke more cigarettes a day than girls who smoke daily.
• Determinants of smoking differ with sex.
Knowledge gap
• The sex-specific incidence and prevalence of smoking should be monitored throughout the life course.
• Longitudinal life-course studies based on socioecologic models of health behaviour are needed to determine whether girls smoke for different reasons than boys.
• Researchers should examine the relative importance of individual (genetic, sociodemographic, psychosocial, behavioural) and environmental (social influences, policy, advertising) factors that influence smoking.
Diet
Dietary habits are important lifestyle behaviours that develop in early childhood. Although food consumption patterns have changed over the last several decades, no differences in these patterns have been noted between US boys and girls (except for the expected sex differences in mean energy intake [Fig. 7]).76,77 Carbohydrate consumption by children and adolescents has increased by 150–200 kcal/day (1 kcal = 4.184 kJ), while fat intake has decreased by 100 kcal/day or less.78,79 Significant increases in consumption of carbohydrates such as pizza and salty snacks have also been reported. The percentage of foods eaten at home has decreased, as more food is eaten in restaurants and fast-food chains.80 The prevalence of snacking has increased among youth of all ages — both portion sizes and frequency — accounting for the increase in average daily intake attributable to snacks.81
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There are fewer data available for Canadian children and adolescents, but the results of the few studies that have been conducted largely parallel US findings. A survey of 5th-grade children in Nova Scotia found that almost half do not meet the recommendations for consumption of milk products (42.3%) or fruits and vegetables (49.9%).82 Carbohydrate intake contributed 56.7% of total energy intake, of which 11% (32 g/day) was sucrose. Of the children, 13.9% exceeded the recommended range for fat intake (25%–35% of total calories). In 1 study that examined "diet quality" as an index of dietary variety, adequacy, moderation and balance, boys were found to have poorer diet quality than girls.82 In the Canadian Community Health Survey,71 57.8% of boys aged 12–19 years and 54.5% of similarly aged girls consumed less than 5 servings of fruit and vegetables a day. Eating at a fast-food restaurant more than 3 times a week was associated with a 56% increase in risk of lower diet quality. The Food Habits of Canadians study also provided data on food consumption patterns of adolescents based on 24-h dietary recall.83 These Canadian teenagers frequently consumed cakes, cookies, sweetened beverages, salty snacks and other nutrient-poor foods.
Several researchers have consistently found an increase in the consumption of sweetened beverages84 that is similar for boys and girls. Health Canada data from 1990 to 1998 indicate similar rates of consumption of soft drinks, colas and other drinks containing sugar for children aged 11, 13 and 15 years. Adolescents aged 11–16 years participated in the 2001–2002 Canadian component of the World Health Organization Health Behaviour in School-Aged Children Survey, which associated increased soft drink consumption with greater odds of overweight and obesity.85 Sweetened beverages contribute 20%–24% of energy to the diet of children and adolescents,77 and the percentage of total energy intake from soft drinks is greater among boys than girls.86 Milk consumption has decreased, although the decrease has been greater among boys.
Summary
• Total energy intake has remained largely constant over the past 4 decades with boys having an expected higher daily caloric intake than girls.
• Dietary patterns, including consumption of sweetened beverages and percentage of foods eaten outside the home, are similar for boys and girls.
• Boys and girls are eating more energy-dense, nutrient-poor foods in larger portions, a pattern that is consistent with the obesity epidemic.
Knowledge gap
• Researchers should evaluate socioecologic influences (e.g., parental dietary habits, psychosocial and behavioural factors, social influences, media and advertising) on dietary behaviour.
• Researchers should improve assessment procedures to determine more accurately children's dietary intake (advancing 24-h dietary recall, food frequency questionnaires and prospective food records or diaries).
• The sex-specific prevalence and trends in dietary and total energy intake should be monitored throughout the life course.
Physical activity and sedentary behaviour
Data from recent national surveys suggest a favourable trend in physical activity among Canadian adolescents.87 Between 1994 and 2003, the proportion of 12–19-year-olds classified as active (i.e., average energy expenditure 
3.0 kcal/kg body weight a day) increased from 44.6% to 54.6% for boys and from 27.3% to 39.5% for girls. Despite this encouraging trend, the physical activity gap between boys and girls remains wide (Fig. 8).87 Girls report less physical activity than boys, both before and during adolescence.88–92 Sex differences are particularly apparent for vigorous physical activity, with girls less likely than boys to engage in such activity during their free time or in the context of organized physical activity, during school and outside school.93–95
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Although girls and boys are equally likely to be enrolled in organized physical activity and lessons outside school, girls are less likely to belong to sports clubs or participate in unorganized physical activity or in school sports outside physical education classes.96 Not surprisingly, boys and girls differ substantially in their physical activity preferences97,98 and in their patterns of involvement in physical activity.99,100 Boys and girls also differ in their attitudes and beliefs regarding physical activity,101,102 as well as their motivation for97,103 and barriers to104,105 engaging in physical activity.
Individual and environmental factors do not influence boys and girls equally.106,107 There is evidence that genetic effects are associated with sports participation and with leisure time physical activity to a greater extent in boys than in girls.108 Boys' and girls' physical activity levels are similarly affected by peer and family social support,109,110 but appear to be influenced by different neighbourhood factors. For example, perceived neighbourhood opportunities for physical activity are associated with girls' but not boys' activity levels,111 and physical features of the school environment appear to influence physical activity to a greater extent in boys.112,113 Finally, significant effects by sex are frequently observed in interventions promoting physically active lifestyles among youth.104,114
Data on sedentary pursuits are limited. A recent review concluded that total media use among youth in industrialized countries has remained stable in the past decades at approximately 5 h/day.104,115 The most recent data show that the proportion of adolescents aged 12–17 years who spend 30 h or more a week in sedentary activities (i.e., watching television, playing video games, spending time on the computer) is 30.0% in boys and 18.2% in girls.116 Most of the discrepancy between older boys and girls concerning time spent in sedentary pursuits relates to greater computer use and video game play in boys, not to television viewing.115,116
Sex and gender differences in physical activity and sedentary behaviour may be largely due to interactions between individual characteristics (e.g., physical maturation, personal motivation) and responses to environmental cues that enhance or inhibit involvement in these pursuits.
Summary
• Despite recent increases in physical activity in all youth, sex-related disparities in involvement in physical activity have not diminished.
• Boys are consistently more active than girls at all ages, and age-related decreases in physical activity occur earlier in girls than in boys.
• Most girls are not active enough to meet guidelines for optimal growth and development.
Knowledge gap
• Refine methods of physical activity assessment to capture the different dimensions and contexts of both sexes, including low-and moderate-intensity activities of daily living and active transportation, as well as the more traditional structured, free play and vigorous physical activities.
• Investigate the possible role of genetic inheritance in adaptation to sedentary or active lifestyles.
• Investigate how individual, familial, school and neighbourhood characteristics interact with sex and gender to determine involvement in physical activity.
• An increased understanding of the clustering of active and sedentary behaviours over the life course is required to help devise more effective sex-specific prevention and promotion programs.
Clustering of behavioural risk factors
According to the Canadian Cardiovascular Society's 1998 consensus on the prevention of CVD, the major CVD behavioural risk factors in youth include smoking, physical inactivity and obesity.117 These modifiable risk factors persist from childhood into adulthood41–44 and tend to cluster among youth.118–121 In the longitudinal Cardiovascular Risk in Young Finns Study, Raitakari and colleagues118 found that 15- and 18-year-old boys and girls who smoked were more likely to be regular users of alcohol and physically inactive compared with non-smokers. Obesity was more prevalent among physically inactive compared with active males (14% v. 8%, p < 0.05), female drinkers compared with non-drinkers (20% v. 9%, p < 0.001) and smokers compared with non-smokers (males 15% v. 9%, p < 0.05; females 16% v. 9%, p < 0.01). In males, those with 4 selected CVD behavioural risk factors, including smoking, physical inactivity, obesity and intake of dietary fat, had a 5.5 times greater risk of having an atherogenic lipid profile and high diastolic blood pressure compared with those with 0 or 1 behavioural risk factor.118 In another prospective study investigating the association between family socioeconomic status and an adverse cardiovascular risk profile among 14- and 17-year-old boys and girls in Sweden, Bergstrom and colleagues119 reported clustering of high BMI, low physical fitness and daily smoking among girls living in families of low socioeconomic status compared with girls of the same age in families of medium or high socioeconomic status.
In the United States, Pate and colleagues120 investigated the association between physical activity and other health-related behaviours, including smoking and dietary habits, in a representative sample of adolescents aged 12–18 years. Boys and girls who smoked 1 or more cigarettes over the past 30 days and who did not eat fruits or vegetables on the previous day were 1.5 and 2 times more likely to be less active than those who did not report these behaviours, respectively. In a more recent study, Pronk and colleagues121 reported that only 31% of US adolescents aged 13–17 years met recommended guidelines for multiple healthy lifestyle factors including physical activity, non-smoking, high-quality diet and healthy weight. This implies that more than two-thirds of US adolescents have 1 or more CVD behavioural risk factors, an estimate that is quite alarming given the potential synergistic effects associated with the presence of multiple behavioural risk factors on the risk of chronic diseases in adult life.122 Pronk and colleagues121 also found that depression is associated with clustering of health-related behaviours in adolescents. Specifically, non-depressed adolescents were 2.15 times more likely to engage in 4 healthy lifestyle factors. The clustering of health-related behaviours in US adolescents was similar for boys and girls.
Data on the prevalence and potential determinants of multiple CVD behavioural risk factors in Canada are scarce. The studies reviewed in this section suggest that CVD behavioural risk factors cluster in children and adolescents. Certain sociodemographic characteristics, including age and sex,109,110 and psychosocial variables, such as depression and family socioeconomic status,112 seem to be associated with the clustering of CVD behavioural risk factors in youth, but evidence in this area remains limited and inconsistent.
Critical analysis of studies
All the studies reviewed were observational, cross-sectional cohort or longitudinal studies. Wherever possible, results of studies specifically focusing on girls or on boys or providing sex comparisons have been included. The areas not sufficiently addressed by existing studies have been highlighted as knowledge gaps.
Why are there sex differences?
When sex differences in risk factors are apparent, they appear to be attributable to a combination of biologic (sex) and behavioural (gender) factors. Compared with age-matched boys, girls have lower systolic blood pressure. However, this sex difference is attenuated with age and may be partly attributable to sex hormones or their receptors. In terms of health behaviours, the prevalence of smoking does not differ markedly by sex, although boys smoke more cigarettes a day than girls, and they are more likely than girls to escalate cigarette consumption rapidly after initiation. Boys and girls appear to smoke for different reasons. Body image, eating disorders and targeted advertising by tobacco companies likely relate to initiation and sustained smoking among adolescent girls, while aggression and conduct disorders are predictors of smoking among boys. Sex differences in physical activity are also apparent; girls are less likely to engage in physical activity than boys, both before and during adolescence. This may be partly due to sex and gender factors.
Summary
• The major CVD behavioural risk factors, including smoking, physical inactivity and obesity, cluster among young boys and girls.
• Having multiple CVD behavioural risk factors increases the risk of atherogenic profile and high blood pressure among boys.
• Age, gender, depression and family socioeconomic status are associated with clustering of CVD behavioural risk factors in youth.
Knowledge gap
• Studies identifying the prevalence and determinants of multiple CVD behavioural risk factors in youth are warranted.
• A better understanding of the frequency and clustering patterns of CVD behavioural risk factors in young girls and boys is needed to facilitate health professionals' efforts to reduce the incidence of CVD.
Cardiovascular risk factors in women and men
Kaberi Dasgupta, Susan Kirkland, Doreen Rabi and Vicky Tagalakis
The Framingham Heart Study established the independent impact of cigarette smoking, elevated blood pressure, elevated total cholesterol and LDL cholesterol, low HDL cholesterol, diabetes, male sex and advancing age on the development of CVD.123 Based on Framingham cohort data, equations for the calculation of risk of CVD have been developed and treatment targets for blood pressure and lipid levels are now dictated by global recommendations.124,125
Excess weight and physical inactivity have an adverse impact on blood glucose levels, blood pressure and lipid profiles.126 Individuals in the Framingham cohort who lost at least 2.25 kg over 16 years had a 40%–50% reduction in their total cardiovascular risk factor score.127 Independent of its impact on weight, regular exercise has favourable effects on glucose control, blood pressure, serum lipids and fitness levels.126,128–133 Higher fitness levels have been demonstrated to be independently associated with a reduction in CVD events and mortality.134,135
A number of additional markers of risk for CVD have been identified, including biomarkers, such as C-reactive protein and plasminogen activator inhibitor type-1, and demographic factors, such as low socioeconomic status. It remains to be determined whether such markers are independent risk factors, predisposing or intermediary factors associated with established risk factors, or noncausally associated with CVD.
Although Framingham data indicate that men are generally at increased risk for CVD than women, the distribution and impact of other CVD risk factors and markers may also differ between men and women, with implications for prevention, detection and management of CVD in both sexes. In this section, we review the existing literature regarding sex differences in the prevalence and impact of overweight and obesity, physical activity, hypertension, diabetes, smoking, dyslipidemia, selected cardiovascular risk markers and socioeconomic factors.
Search strategy
Boolean searches of MEDLINE from 1966 to August 2005 were performed by combining the MeSH term "cardiovascular disease" with each of the following MeSH terms: "obesity," "physical activity," "hypertension," "diabetes," "socioeconomic status," "smoking," "C-reactive protein," "homocysteine," "apolipoprotein E," "dyslipidemia," "fibrinogen," "plasminogen activator inhibitor type-1" and "lipoprotein (a)." Each of these searches was combined using the term "AND" with a search that used the terms "gender" and "sex" and the term "OR." Searches were restricted to English-language publications, but no other restrictions applied. In addition, the references of the resulting publications were hand searched for further articles.
Overweight and obesity
Obesity-related complications include
• Vascular risk factors — Hypertension, dyslipidemia and type 2 diabetes
• Vascular disease — Ischemic heart disease, hypertensive heart disease, stroke, renal failure, peripheral vascular disease and retinopathy
• Other conditions — Osteoarthritis, malignancy (breast cancer), depression and polycystic ovary syndrome
Sex differences in prevalence of overweight conditions
In the United States, data from NHANES indicate that the overall prevalence of overweight (BMI 25 kg/m2) was 55.9% in 1988,136 rising to 64.6% by 1999.137 Data from the Canadian Community Health Survey indicate that the prevalence of overweight remained stable at 48% between 1994/95 and 2000/01 in the population aged 20–64 years, although 2% of individuals shifted from the overweight (BMI 25–30 kg/m2) to the obese (BMI 30 kg/m2) category.138
Sex differences in overweight and obesity are influenced by geography and ethnic background (Table 6). For example, among white and Mexican Americans, the prevalence of overweight is higher among men than among women. However, among black Americans, the prevalence of overweight is higher among women than men. The prevalence of obesity is higher among US women than men, with the highest prevalence among black American women.139
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In Canada, for both men and women, the prevalence of overweight is lower among black Canadians (50%) than white Canadians (60%).140 Consistent with this, among men, the prevalence of obesity is lower among black Canadians (10%) than white Canadians (15%), although among Canadian women, the prevalence of obesity is higher among black people (20%) than white people (15%). The ethnic group with the highest rates of overweight and obesity is the Aboriginal population (60% overweight in women and 65% in men; 25%–30% obesity in men and women). Between 1994/95 and 2000/01, the prevalence of obesity increased in all age and sex groups in Canada, with the exception of women 20–34 years of age. These trends are consistent with those documented in other countries.141–144
Overweight and obesity are also prevalent in many developing countries. Nishida and Mucavele145 found that the prevalence of obesity was higher in women than in men in the following countries: Brazil, 11.7% v. 4.8%; Egypt, 33.0% v. 12.6%; South Africa, 30.1% v. 9.4%; Seychelles, 28.2% v. 8.5%. The prevalence of overweight was similar for the 2 sexes, but countries reporting higher levels of overweight among women were located in Africa, Latin America, Asia and Oceania, whereas male overweight was more prevalent than women's in countries of Europe and North America.
Recommendations for the prevention and treatment of obesity
• Reduced consumption of energy-dense foods
• Regular physical activity
• Weight loss for those with BMI 25 kg/m2 (diet and exercise counselling, behavioural counselling)
• Those with BMI 35 kg/m2 or with BMI 30 kg/m2 and obesity-related complications may consider bariatric surgery
Periods of risk
Women appear to be particularly susceptible to significant weight increase during adolescence,146 pregnancy136 and menopause.147 The weight increase that occurs during menopause has been shown to be associated with a significant increase in blood pressure.148 The period after marriage appears to be a period of risk for weight gain among men.149
Knowledge gap
• Does the utility of weight loss for the prevention of CVD differ between women and men?
• Why do obese people appear to have lower rates of fatal recurrent cardiovascular events?
• What weight-loss strategies are particularly effective among men?
• What weight-loss strategies are particularly effective among women?
• Why are black women in both the United States and Canada at high risk of obesity?
Physical activity
Sex differences in activity levels
Many studies suggest that women are more likely to be sedentary than men. A questionnaire administered by Pitsavos and colleagues150 in the Attica region of Greece revealed that, overall, 53% of men and 48% of women were physically active, and men tended to be more physically active than women across all age groups. In an interview-based survey conducted in Portugal, 79% (95% CI 75.7–81.6) of men and 86% (95% CI 84.0–88.0) of women were found to be sedentary.151 In Finland, the proportion of people classified as sedentary or only moderately active during their leisure time was 75% among males and 82% among females.152 Men in Japan have also been found to be more active than women.153
There is some evidence that, although both men and women are both less likely to be active when weather conditions are unfavourable, women are less likely to increase activity levels when weather conditions become more favourable. In community-dwelling adults in Massachusetts, mean physical activity during the summer increased by 51 minutes/day (95% CI 20–82) in men, but only by 16 minutes/day (95% CI -12–45) in women.154
Potential mechanisms
Low levels of physical activity render weight maintenance difficult, contribute to the development of insulin resistance, with associated increases in blood pressure, blood glucose level, dyslipidemia and thrombogenic factors. In addition, there is increasing evidence that low levels of activity and fitness are directly related to increased CVD risk. In a prospective cohort study that examined the impact of physical activity on mortality, Blair and colleagues155 found that women in the lowest tertile of physical activity had a greater than 5-fold increased risk of mortality compared with women in the highest physical activity tertile. Men in the lowest physical activity tertile were at a 3-fold higher increase in risk of mortality compared with men in the highest fitness tertile.
Barriers to physical activity in women
Findings from Canada's National Population Health Survey demonstrate that the presence of children in the household is a significant deterrent to becoming active for women, but not for men.156 The most commonly reported barrier to women's participation in physical activity is lack of time due to family responsibilities.157,158 Middle-aged and older women appear to have positive attitudes toward exercise, but are unable or unwilling to take action.159
Physical activity recommendations
• To remain healthy and maintain body weight — moderate exercise (e.g., walking) 30 minutes daily or vigorous exercise (e.g., jogging) 20 minutes daily.
• To lose weight — vigorous exercise 30 minutes daily.
Knowledge gap
• What are the barriers to physical activity in women?
• Are the barriers largely related to child care or competing work–home responsibilities or both?
• How can activity levels among women be increased?
Hypertension
Excess body weight and physical inactivity may promote the development of a number of CVD risk factors, including high blood pressure (see Table 7 for the general classification of blood pressure levels).
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Hypertension-related comorbidities
• ischemic heart disease
• hypertensive cardiomyopathy
• stroke
• renal failure
Sex differences in blood pressure
In the third NHANES (1988–1994) evaluation, among US adults under 45 years of age, men had higher systolic blood pressure levels than women.160 By 60–69 years of age, non-Hispanic white women had blood pressure levels similar to those of men and by 70–79 years of age, had higher levels than men.161 By 60–69 years of age, non-Hispanic black and Hispanic women had higher blood pressure levels than men of similar ethnic background.161 Overall, among those 45 years of age and older, systolic blood pressure levels were higher among women.160 In a cohort study conducted in Denmark, 24-h mean blood pressure levels were 6–10 mm Hg higher among men than women until 70–79 years of age, but similar thereafter.162 Women from developing countries have higher mean systolic blood pressure than their male counterparts.163 It is also noteworthy that women from these countries have higher blood pressure than women from developed countries. Women from the African region have the highest mean systolic blood pressure.
Among young and middle-aged adults, population surveys report hypertension to be more frequent among men compared with women, with sex differences of 4% in the United States, 8% in Canada and 11% in Western Europe.164 After 60 years of age, however, the prevalence of hypertension appears to be higher among women than among men.
Potential mechanisms
Androgen is thought to play a role in the sex differences in blood pressure. One possible mechanism may be the blunting of the pressure-natriuresis relation.165 Female sex hormones and their receptors may also be implicated in blood pressure differences between men and women. A genetic association study by the Victorian Family Heart Study investigators found that men inheriting the "a" allele on the estrogen receptor a gene had significantly higher systolic blood pressure levels (5 mm Hg) than men with other genotypes.166 No significant associations between estrogen receptor genes and blood pressure were detected among women.
Knowledge gap
• How can the postmenopausal increase in hypertension be prevented?
• Should the threshold for hypertension diagnosis in women be lower to prevent the postmenopausal increase in hypertension?
• Can earlier detection of hypertension in boys and young men reduce the sex–gender differential in incidence of CVD between men and premenopausal women?
Diabetes
Diabetes is highly prevalent; over 151 million people live with this condition worldwide (Table 8). Diabetes is an established risk factor for the development of CVD.167 People with diabetes have a 2- to 4-fold greater risk of developing CVD compared with those without diabetes.168 CVD is the leading cause of morbidity and mortality for those living with diabetes.
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Although the prevalence of diabetes is lower in developing countries, these countries have experienced the greatest increase in diabetes. The prevalence is highest in the Eastern Mediterranean and Middle East (7.0%), South and Central America (5.6%), Southeast Asia (5.6%), Western Pacific (3.1%) and Africa (2.4%). The prevalence of diabetes is higher among women than among men in Latin America (57.5% v. 42.5%) and in the Western Pacific (53.7% v. 46.3%).169
Diabetes-related vasculopathy
Microvasculature
• retinopathy
• nephropathy
Macrovasculature
• peripheral vascular disease
• cerebrovascular disease
• ischemic heart disease
Because CVD is more prevalent among men, it follows that most studies that have examined the significance of diabetes as a risk or prognostic factor have predominantly male participants. However, Hu and colleagues170 examined the prognostic significance of diabetes in their analysis of the Nurse's Health Study Cohort and found that women with diabetes had surprisingly high cardiovascular-related mortality. This study demonstrated that the adjusted relative risk (RR) for cardiovascular-related death among women who had established CVD, after controlling for other vascular risk factors, such as smoking status, family history of ischemic heart disease and BMI, was 13.6 (95% CI 8.45–21.8). However, it should be noted that there was no control for differences in hypertension, hypercholesterolemia or socioeconomic status, risk factors that are well known to be more prevalent among both women and men with diabetes.
Diabetes as a prognostic factor among patients with CAD
Although diabetes is an established risk factor for the development of CVD, the significance of diabetes as a prognostic factor following an ischemic event remains less clear. Numerous studies have demonstrated that patients with diabetes appear to have poorer clinical outcomes following myocardial infarction (MI), stroke and percutaneous and surgical revascularization compared with non-diabetic patients. However, in a prospective cohort study of 11 468 patients presenting for coronary catheterization (17% of whom had diabetes), Ghali and colleagues171 demonstrated that, after controlling for all clinically relevant variables, the survival of patients with diabetes was the same as for those without diabetes at 1 year (OR 1.1; 95% CI 0.8–1.3) and 3 years (HR 1.2; 95% CI 1.0–1.4).
Graham and colleagues172 completed a large prospective cohort study examining sex differences in the prognostic significance of diabetes following coronary catheterization. After adjusting for several clinical variables, they demonstrated a trend toward increased mortality in women with diabetes, although this was not statistically significant. Several systematic reviews and meta-analyses have been carried out to determine the association between sex and CVD mortality.173–175 Lee and colleagues173 found that women with diabetes had a relative risk of coronary death from diabetes of 2.58 (95% CI 2.05–3.26) compared with non-diabetic women, which was significantly higher than for men with diabetes (RR 1.85; 95% CI 1.47–2.33). This review was limited in that the included studies had variably controlled for other coronary risk factors. When Kanaya and colleagues174 reviewed studies that adjusted for age, hypertension, hyperlipidemia and smoking status, they found that there was no longer a significant difference in cardiovascular-related mortality between men and women with diabetes. Reviewing data from North America, Europe and the Asian Pacific Cohort Studies Collaboration, Huxley and colleagues 175 found, like Lee and colleagues, that women with diabetes had a 3.5-fold (95% CI 2.7–4.5) increase in CVD mortality compared with non-diabetic women and that this was significantly higher than for their male counterparts (RR 2.1; 95% CI 0.81–2.34). Sensitivity analyses that corrected for coronary risk factors revealed that this sex difference was attenuated, but remained statistically significant (Table 9).
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A recent cohort study demonstrated that a history of diabetes in women was associated with a 37% increase in CVD-related mortality compared with a history of AMI. However, the presence of a previous AMI in men increased the risk of CVD-related mortality by 43% compared with a history of diabetes.176
Potential mechanisms
Several mechanisms may explain the apparent sex difference in CVD mortality among patients with diabetes. There is evidence that different pathophysiologic processes — in terms of endothelial function, dyslipidemia and thrombosis — may result in different cardiovascular outcomes among men and women with diabetes.
Diabetes has been shown to abrogate the vascular protection afforded to premenopausal women. Steinberg and colleagues177 elegantly demonstrated that premenopausal women have an enhanced vasodilatory response to endogenously produced nitric oxide compared with men. This study also illustrated that the development of diabetes is associated with abnormal endothelial-dependent vasodilation in both sexes. This loss of vasodilation is most striking in women. Sowers178 has further demonstrated that hyperglycemia significantly decreases estrogen-mediated nitric oxide production. It seems that a unique interaction between diabetes and sex makes women more vulnerable to endothelial dysfunction.
The noted sex differences in CVD outcomes may be influenced by factors beyond biology. A study by Wexler and colleagues179 suggests that sex differences in CVD mortality may be due to disparities in medical management. This prospective cohort study demonstrated that women with diabetes were less likely to be treated until they reached established therapeutic targets than men with diabetes, even if the women had established CVD. Whether these disparities are related to physician factors (underappreciation of cardiovascular risk in women, hesitation to use vasoprotective medications in reproductive women) or patient factors (adherence to or tolerance of prescribed medications) remains unclear.
Dyslipidemia
Abnormal levels of lipoprotein cholesterols are significant predictors of atherosclerosis in all populations, with a fifth of global stroke events and about 56% of global heart disease attributable to high cholesterol levels. In particular, elevated levels of total cholesterol, LDL cholesterol and triglycerides and low levels of HDL cholesterol have been associated with CAD, stroke and peripheral vascular disease and are often associated with such significant comorbidities as diabetes, hypertension and obesity. In both US and Canadian populations, abnormal cholesterol levels are highly prevalent across different age and ethnic groups (Table 10 and Table 11),180 and there appear to be sex differences in the prevalence of elevated cholesterol181,182 (see Table 12 for classification of lipoprotein levels).
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