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Sydney Medical School, Sydney, NSW, AustraliaThe Kolling Institute, Royal North Shore Hospital, Sydney, NSW, AustraliaThe George Institute for Global Health, Sydney, NSW, Australia
The George Institute for Global Health, Sydney, NSW, AustraliaThe University of New South Wales, Sydney, NSW, AustraliaThe George Institute for Global Health, University of Oxford, Oxford, UKDepartment of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaSydney Medical School, Sydney, NSW, AustraliaThe George Institute for Global Health, Sydney, NSW, AustraliaThe University of New South Wales, Sydney, NSW, Australia
Cardiovascular disease is the leading cause of death in Australian women, as well as men, with clear disparities in treatment and outcomes between the sexes. Moreover, disease pathophysiology differs between the sexes, with women more likely to suffer from microvascular coronary disease, endothelial dysfunction and heart failure with preserved ejection fraction, as compared to men, who are more likely to experience macrovascular disease or heart failure with reduced ejection fraction. Evidence suggests that both traditional and novel cardiovascular risk factors are often under-recognised and under-treated in women. Certain ‘traditional’ risk factors, including diabetes mellitus and smoking, may also portend a greater risk of cardiovascular disease in women than men. Furthermore, a number of female-specific risk factors have been identified as increasing the risk of cardiovascular disease in women, including pre-term delivery, pre-eclampsia, gestational diabetes, and polycystic ovary syndrome. Currently, these factors are not included in primary prevention risk stratification tools, nor are they routinely considered in a cardiovascular assessment at a clinical level. This represents a missed opportunity, as early identification may allow for risk factor modification and possible amelioration of the disease burden. This review explores the role of traditional, sex-specific and novel risk factors for cardiovascular disease in women, in addition to pathophysiological differences between the sexes, and contributing societal and behavioural factors. These differences argue strongly for a ‘precision medicine’ approach to cardiovascular disease that includes sex as a key component.
Cardiovascular disease (CVD) has historically been considered a disease of men, which has translated into a lack of awareness and prioritisation of CVD risk in women at a research, health policy and clinical level. Indeed, CVD is the leading cause of death in both women and men, globally. In 2017–18, the Australian Institute for Health and Wellbeing estimated that 510,000 Australian women were living with CVD, with CVD accounting for around 30% of female deaths [
]. Moreover, evidence suggests that women with CVD have poorer outcomes than their male counterparts, including recent evidence from the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) registry that women presenting with an ST elevation infarction have twice the 6-month mortality of men, even after adjustment for age and comorbidity [
]. For example, there is evidence that women with atherosclerotic CVD are more likely to present with advanced disease, and experience worse outcomes, than men [
Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
]. Additionally, women are less likely to present with angiographically obstructive macrovascular coronary disease than men, but are more likely to possess microvascular/small vessel coronary disease, a condition poorly recognised and managed using traditional chest pain pathways [
Over the last 2 decades, sex-specific cardiovascular research has expanded exponentially, though translation into clinical care and improved outcomes has lagged behind. Accordingly, this review explores important sex differences in CVD risk factors (traditional and novel), disease process and pathophysiology and societal factors, all of which are likely to contribute to the morbidity and mortality attributed to CVD in women.
Pathophysiology
Clear, but under-appreciated sex differences exist with respect to the pathophysiology of CVD in women and men. With respect to acute coronary syndromes secondary to macrovascular coronary disease, women have a higher frequency of plaque erosion and distal embolisation, as compared to men who are more likely to experience plaque rupture [
], which can pose a challenge to invasive management (percutaneous or surgical). Conversely, men are more likely than women to have obstructive macrovascular disease and heart failure with reduced ejection fraction [
] is a prospective US national study of 936 clinically stable women with ischaemic symptoms who underwent diagnostic angiography. This study was fundamental in the understanding of the complexities of coronary disease in women. It identified that women were more likely than men to suffer from microvascular coronary disease and endothelial dysfunction [
Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study.
]. This poses diagnostic challenges, as the above conditions are not readily diagnosed on functional assessment or standard coronary angiography and thus can be missed or erroneously attributed to ‘non-cardiac’ causes. Further, traditionally, the importance of chest pain presentations/acute coronary syndrome presentations in women with non-obstructive macrovascular coronary disease has been under-appreciated. Evidence suggests, however, that ischaemia in women, secondary to non-obstructive coronary disease, is not a benign process, with an almost three-fold increase in death rates at 8.5 years as compared to those without evidence of an infarct [
]. Supporting this, women who present with ‘non-specific chest pain’ are at a higher relative risk of future hospitalised angina, myocardial infarction, stroke and coronary death [
Spontaneous coronary artery dissection (SCAD) represents another distinct coronary syndrome with a gender preponderance (90% female) that is under appreciated and poorly understood. SCAD is a spontaneous, non-atherosclerotic, tear in the wall of the coronary artery, either arising from an intimal tear or an intramural haemorrhage [
]. Acute and chronic management of SCAD is challenging, both due to technical difficulties during acute invasive treatment, and a lack of evidence-based treatment algorithms. Given that the underlying pathological process is fundamentally different to atherosclerotic disease, a tailored and disease-specific approach to acute and chronic management is required. Current treatment, unfortunately, is based on expert consensus rather than robust randomised clinical trial data [
]. Moreover, many SCAD patients continue to be managed as if they had ‘traditional’ atherosclerotic coronary disease and treated with interventions, or agents, that are not indicated and potentially harmful.
Heart failure with preserved ejection fraction (HFpEF) accounts for greater than half of all heart failure presentations and disproportionately affects women [
]. Whilst a thorough discussion of this condition is beyond the scope of this review, it is of great clinical relevance to female patients. This is yet another condition without any proven, evidence-based management that results in improved morbidity and mortality. Ongoing large, event-driven trials, such as Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER; NCT03619213), and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved; NCT03057951), will hopefully provide novel effective therapies for HFpEF patients, of both sexes.
Traditional Risk Factors
Sex-specific sub-group analysis of influential epidemiological studies, such as the Framingham Heart Study and The UK Biobank, have demonstrated that ‘traditional’ risk factors for CVD, including cigarette smoking, raised blood pressure, dyslipidaemia and diabetes mellitus are relevant to both women and men [
Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
There is significant evidence to suggest that being female confers a disadvantage in terms of cardiovascular morbidity and mortality in diabetes. Evidence to support this was noted many years ago in the Framingham Heart Study [
Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
]. However, emerging evidence suggests heightened impairment of endothelium-dependent vasodilation, hypercoagulability and dyslipidaemia in women with diabetes [
]. This delay is likely secondary to the vasodilatory effects of endogenous oestrogens in pre-menopausal women. In 2017–18, 20% of Australian women had uncontrolled hypertension [
]. Although sex differences in the clinical incidence of hypertension (with the exception of hypertensive pregnancy disorders) have not been detected [
Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: a systematic review and meta-analysis of 124 cohort studies, including 1.2 million individuals.
]. This is important, given that those with uncontrolled hypertension, defined as blood pressure >160/90 mmHg, have a 1.6 greater likelihood of developing heart failure relative to those with blood pressure <120/90 mmHg [
]. In the Framingham Heart Study, hypertension in women was associated with a greater risk of heart failure than in men (three-fold in women and two-fold in men) [
Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: a systematic review and meta-analysis of 124 cohort studies, including 1.2 million individuals.
Although the prevalence of cigarette smoking is higher in men, smoking is a more potent risk factor for CVD in women. In a meta-analysis of 2.4 million participants, Huxley and Woodward demonstrated that cigarette smoking conferred a 25% increase in the risk for coronary artery disease compared with men [
Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies.
Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes.
]. This risk is potentiated by concomitant use of the oral contraceptive pill. Combined oral contraceptive users who are current smokers have a 10-fold increased risk of myocardial infarction and a three-fold increased risk of stroke [
]. Accordingly, smoking cessation should be a key target area for primary prevention of CVD in women, particularly given evidence to suggest that women may be less likely to successfully abstain from smoking than men [
Inflammation is a key driver of both macro- and microvascular disease in women and men, and contributes to the pathophysiology of atherosclerosis, the development of acute cardiovascular syndromes, and heart failure. Importantly, women have higher C-reactive protein (CRP) levels than men as a result of accelerated increases in CRP levels during late adolescence [
Also, inflammatory cytokines predict major adverse cardiac events (MACE) but do not relate to angiographic coronary artery disease severity in women with preserved ejection fraction, suggesting that in these patients, inflammation plays a specific role in influencing pathologic changes in the microvasculature [
Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).
In women, inflammation also specifically contributes to the development of heart failure. For example, in an analysis from Framingham Heart Study, increased IL-6 was associated with an increased long-term risk of HF development in previously asymptomatic patients. Further, in a post-hoc analysis of the WISE study, in women with signs and symptoms of ischaemia, non-obstructive coronary artery disease and preserved ejection fraction at enrolment, IL-6 strongly predicted HF hospitalisations and all-cause mortality [
Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).
Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: a report from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).
These studies therefore show the importance of evaluating inflammatory biomarkers in women, as they appear to contribute and correlate with a range of cardiovascular disorders, potentially to a greater extent than in men, though this requires further evaluation.
Depression and Psychological Stress
Depression is a recognised risk factor for the development of coronary artery disease and portends a worse outcome following a cardiac event [
]. Whilst depression is prevalent amongst both women and men, this risk factor has been shown to have a greater contribution to the development of CVD in women [
]. Although the pathophysiology of this condition is not well characterised, there is a link between emotional and psychological distress and its development. This is perhaps related to increased psychological stress-induced platelet reactivity and myocardial ischaemia in women [
Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study.
In additional to ‘traditional’ CVD risk factors, it is clear that sex-specific risk factors exist, for both women and men. These risk factors are often under-appreciated in both research and clinical care but represent an important opportunity to identify women at risk and potentially attenuate their risk.
Hormonal Factors
The observation that pre-menopausal women have lower absolute rates of coronary disease than post-menopausal women has led to the assumption/belief that oestrogens are cardio-protective. In a pre-clinical context, oestrogen has been shown to be vasodilatory, exhibit antioxidant and anti-apoptotic properties, inhibit fibroblast proliferation and increase angiogenesis [
]. However, the idea that exogenous replacement of oestrogen was beneficial to reducing cardiovascular risk was subsequently refuted by randomised controlled trials for primary and secondary prevention of cardiovascular disease [
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
]. Current consensus is that low-dose hormone replacement therapy is an appropriate treatment for menopausal symptoms in early menopause in the absence of contraindications, but is not indicated for reduction of cardiovascular risk alone [
Other hormonal factors throughout the life-course of a woman also need to be considered. Data from the UK Biobank suggests that several hormonal factors: early menarche, early menopause, earlier age at first birth, history of miscarriage, stillbirth or hysterectomy, were each independently associated with a higher risk of CVD in later life [
]. In a large prospective Danish cohort study, Ranthe et al. demonstrated that women with still births had 2.69 times the relative risk of myocardial infarction (95% CI 2.06–3.50) and women with miscarriages had a 1.13 increased risk of the same [
]. The pathophysiology of spontaneous pregnancy loss and atherosclerotic disease may have shared features in terms of systemic inflammation and endothelial dysfunction [
Preterm birth (<37 weeks' gestation) is also associated with an increased risk of maternal CVD. A meta-analysis of 21 studies, comprising more than 5.8 million women, demonstrated that pre-term delivery was associated with an increased risk of CVD (RR 1.43, 95% CI 1.18–1.72) and CVD death (RR 1.78, 95% CI 1.42–2.21) [
]. Risk was shown to be greatest when delivery occurred prior to 32 weeks gestation.
The role of polycystic ovarian syndrome (PCOS) as an independent risk factor for the development of CVD has historically been contentious. However, a meta-analysis involving more than 10,000 women by Chao et al. demonstrated that PCOS was associated with a heightened risk of CVD (Odds ratio=1.30, 95% CI 1.09–1.56) and, in a stratified analysis, specifically associated with coronary artery disease (Odds ratio=1.44, 95% CI 1.13–1.84) [
]. Whilst it is well documented that these conditions share a number of common risk factors with CVD, it is not widely recognised that hypertensive and metabolic disorders of pregnancy are also independently associated with an increased maternal cardiovascular risk [
]. These conditions include gestational hypertension, pre-eclampsia, eclampsia and gestational diabetes.
In the Cardiovascular Health After Maternal Placental Syndromes study (>1 million women in South Asia and Sub Saharan Africa) women with pre-eclampsia had twice the risk of CVD relative to women without [
]. This was compounded by the concomitant presence of metabolic syndrome, which conferred a 12-fold increase in the risk of developing CVD (hazard ratio [HR] 11.7, 95% CI 4.9–28.3). In a meta-analysis of 6.4 million women, it was demonstrated that women with pre-eclampsia have an increased risk of heart failure (relative risk [RR] 4.19; 95% CI 2.09–8.38), coronary artery disease (RR, 2.50; 95% CI, 1.43–4.37), cardiovascular mortality (RR, 2.21; 95% CI, 1.83–2.66), and stroke (RR, 1.81; 95% CI, 1.29–2.55) [
]. For example, those with early onset pre-eclampsia (<34 weeks onset) are at a significantly higher relative risk of a CVD event than those with late onset disease [
As discussed, diabetes mellitus is a particularly potent traditional risk factor for the development of CVD in women. Unsurprisingly, women with gestational diabetes (GDM) are at increased risk of CVD. A significant proportion of this increased risk may be attributed to the fact that more than 50% of those who develop GDM will go on to be diagnosed with chronic type 2 diabetes mellitus [
] in mothers and, by implication, women who are unable to breast-feed will not derive this benefit. Specifically, breast feeding for at least 6 months is recommended (World Health Organization). In addition to other adverse effects, this is an important issue in women's cardiovascular health, given the promotion of substitute products by the food industry, particularly in populations with low levels of education.
Breast Cancer Therapy-Related Factors
Breast cancer is the most common cancer in Australian women (after non-melanoma skin cancer) and shares a number of risk factors with CVD, including age, obesity and cigarette smoking [
]. In the context of improved oncologic survival, breast cancer survivorship is an area of significant research interest. In this group, late cardiotoxicity accounts for more mortality than oncologic progression or complication [
]. Accordingly, this particular population requires surveillance for cardiotoxicity secondary to cancer therapy including radiation, anthracycline, trastuzumab and hormonal treatment.
Anthracyclines are integral to the treatment of high-risk and triple-negative breast cancer. Anthracycline-induced cardiomyopathy is well-documented, with doxorubicin-induced reductions in left ventricular ejection fraction (LVEF) occurring in 10–15% of patients at standard dosages [
]. Treatment with the anti-HER2/neu monoclonal antibody, trastuzumab, also has documented cardiotoxic effects. A reduction in LVEF is noted in approximately 13% of patients who receive trastuzumab and 33% of those who receive sequential therapy with an anthracycline [
]. Interestingly, emerging pre-clinical research suggests that female sex may protect against the development of anthracycline-induced cardiotoxicity [
Radiation therapy is widely employed in the treatment of breast cancer and is also associated with an increased risk of cardiovascular morbidity and mortality by way of incidental cardiac exposure to ionising radiation [
Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
]. Radiotherapy has also been implicated in the development of heart failure with preserved ejection fraction, cardiomyopathic processes, valvular and coronary heart disease [
Whilst autoimmune connective tissue diseases are not specific to a particular sex, they disproportionately affect women with the female to male ratio 2.5:1 for rheumatoid arthritis and 9:1 for systemic lupus erythematosus. These diseases are associated with increased cardiovascular morbidity and mortality [
]. This is thought to be mediated by way of inflammation, increased oxidative stress, endothelial dysfunction, microvascular disease, peptide modification resulting in immune responses and alterations to lipoproteins [
]. Chronic glucocorticoid therapy in the treatment of these conditions, further potentiates cardiovascular risk by way of exacerbating traditional risk factors including hypercholesterolaemia and hyperglycaemia [
Cardiovascular disease is the leading cause of death in rheumatoid arthritis. Two (2) meta-analyses, which included more than 150,000 patients, demonstrated that rheumatoid arthritis was associated with a 48% risk of a cardiovascular event (RR: 1.38, 95% CI 1.36–1.62) and a 50% increased risk of cardiovascular death (age standardised mortality ratio 1.5, 95% CI 1.39–1.61) [
]. In a more recent prospective Dutch cohort study of 1,222 patients over 15 years, van den Hoek et al. showed that CVD accounted for the majority of deaths (32%) in patients with rheumatoid arthritis [
]. This figure is lower than that reported in earlier studies, perhaps reflecting the effect of widespread institution of disease-modifying anti-rheumatic therapy. Methotrexate, the cornerstone of rheumatoid arthritis therapy, has been associated with a 28% reduction in cardiovascular events (RR 0.72, 95% CI 0.57–0.91). Given the fact that these conditions disproportionately affect females, they must be specifically considered in a sex-specific approach to CVD prevention [
The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.
Behavioural and social factors likely also contribute to the gender disparities observed in CVD diagnosis, treatment, and outcomes. Data suggests that awareness of both CVD risk factors and the personal relevance of CVD is poor in women [
]. This is particularly relevant to young women (<34 years), culturally and linguistically diverse women and minority groups, in whom awareness of CVD risk is particularly low [
]. When awareness is low, women are less likely to seek out a CVD risk assessment or prioritise monitoring and improving modifiable risk factors. The contribution of competing priorities, such as family responsibilities and time constraints, has been suggested to the relevant to these observed sex differences, but requires further study. Compounding this, a study of data from over 22 cohort studies suggested that lower socioeconomic status is a more powerful risk factor for the development of CVD in women than men [
This unconscious bias also extends into primary health care. A study of 60 Australian primary health care services revealed that women are less likely than men to have cardiovascular risk factors measured (HR 0.88, 95% CI 0.81–0.96). There was interesting heterogeneity in the use of guideline indicated medications, with appropriate CVD preventative medications more often prescribed in older women (>65 years) than men, but less frequently prescribed in younger women (35–54 years) [
]. This has been re-enforced by a further study of >130,000 patients in general practice across Australia which demonstrated lower guideline directed medications in women and a lower proportion of women as compared to men had a cardiovascular risk assessment [
Compounding these issues, data suggest that women are more likely to have a delayed presentation to hospital with chest pain/ischaemic symptoms than men. For example, a large Victorian (Victoria, Australia) study of acute ST elevation myocardial infarction reported that women presented almost 30 minutes later than men to hospital (geometric mean symptom to door time 198 minutes in women versus 169.2 minutes in men, p<0.001). Thereafter, they experienced delayed management with respect to the time taken for them to receive a guideline-indicated coronary angiogram and opening of their coronary artery (door to balloon time 88.4 minutes in women versus 81.1 minutes in men, p=0.01) [
Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
], with women less likely to receive acute evidence-based invasive management. Moreover, women are less likely than men to be discharged on guideline-directed secondary prevention medications or to be referred for cardiac rehabilitation [
The importance of delayed diagnosis of acute coronary syndromes, and the subsequent effect this has on outcomes, should not be under-estimated. The long-held mantra, ‘time is myocardium’, is supported by evidence. For example, a UK study revealed that women with an ST elevation infarct were 37% more likely than men to receive an incorrect initial diagnosis, with the corresponding value in non-ST elevation infarction of 29%. Thereafter, those with an incorrect diagnosis were more likely to die at 12 months than those with a correct diagnosis (time to death was 10% shorter for misdiagnosed ST elevation cases and 14% shorter for misdiagnosed non- ST elevation cases, after adjustment) [
The above paints a picture of unconscious societal and behavioural bias at almost every health care delivery level. These factors almost definitely contribute to not only the high rates of death from CVD seen in women, one in three female deaths, but also to the disparate levels of CVD related complications seen in women.
Novel and Emerging Risk Factors
Whilst several traditional risk factors are used in clinical practice to detect and treat CVD in women, investigations are ongoing to better describe the phenotype of women with increased risk. For instance, a novel biomarker for salt-sensitivity— marinobufagenin— has been identified [
]. This cardiotonic steroid and Na+/K+-ATPase inhibitor was recently shown to be strongly and positively related to salt intake in humans. However, marinobufagenin was more prominently associated with large artery stiffness and left ventricular mass index in young healthy women than men— despite having lower salt intake and subsequent marinobufagenin levels than men [
In modern medicine, such single biomarkers and current behavioural and traditional risk factors only partly explain the clear sex-specific disparities in CVD development. Novel approaches are needed to better detect and manage CVD in women. One approach that holds promise is through precision medicine, which will not only take into account female sex, but also integrate numerous other genetics, lifestyle and health exposures as determinants of CVD phenotype. By using big data, standard health record data are incorporated with advanced polyomics (such as genomics, transcriptomics, proteomics and metabolomics), providing precision medicine the potential to uncover previously unrecognised sex-specific disease phenotypes [
Cardiovascular disease is a cause of significant morbidity and mortality in women, with clear differences from CVD in men (as summarised in Figure 2). In addition to pathophysiological differences, risk factor profile, potency and management also differ between the sexes, highlighting the need for a ‘precision medicine’ approach. Most notably, women are less likely to have guideline-directed CVD care and are more likely to suffer cardiac complications. Attention to the differing potency of certain risk factors, such as diabetes, and sex-specific risk factors such as hypertensive disorders of pregnancy is vital to improving outcomes for women. This cannot be achieved without considering the contributing societal and behavioural factors.
Figure 2The Current Landscape of Cardiovascular Disease in Women [
Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study.
Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: a systematic review and meta-analysis of 124 cohort studies, including 1.2 million individuals.
Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies.
Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes.
Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).
Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: a report from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).
Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study.
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.
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