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Heart, Lung and Circulation

Cardiovascular Disease in Women: From Pathophysiology to Novel and Emerging Risk Factors

      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.

      Keywords

      Introduction

      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 [
      Australian Institute of Health and Welfare
      Cardiovascular Disease in Australian Women - A Snapshot of National Statistics Report.
      ]. 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 [
      • Khan E.
      • Brieger D.
      • Amerena J.
      • Atherton J.J.
      • Chew D.P.
      • Farshid A.
      • et al.
      Differences in management and outcomes for men and women with ST-elevation myocardial infarction.
      ].
      It is becoming more evident that CVD in women differs from men with respect to disease pathophysiology, risk factors, and ultimately health outcomes [
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • Grines C.L.
      • Krumholz H.M.
      • Johnson M.N.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      ]. For example, there is evidence that women with atherosclerotic CVD are more likely to present with advanced disease, and experience worse outcomes, than men [
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • Grines C.L.
      • Krumholz H.M.
      • Johnson M.N.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      ,
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      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 [
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • Grines C.L.
      • Krumholz H.M.
      • Johnson M.N.
      • et al.
      Acute myocardial infarction in women: a scientific statement from the American Heart Association.
      ].
      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 [
      • Kenkre T.S.
      • Malhotra P.
      • Johnson B.D.
      • Handberg E.M.
      • Thompson D.V.
      • Marroquin O.C.
      • et al.
      Ten-year mortality in the WISE study (Women's Ischemia Syndrome Evaluation).
      ,
      • Pepine C.J.
      • Kerensky R.A.
      • Lambert C.R.
      • Smith K.M.
      • von Mering G.O.
      • Sopko G.
      • et al.
      Some thoughts on the vasculopathy of women with ischemic heart disease.
      ,
      • Garcia M.
      • Mulvagh S.L.
      • Merz C.N.
      • Buring J.E.
      • Manson J.E.
      Cardiovascular disease in women: clinical perspectives.
      ]. Additionally, as demonstrated in Figure 1, women tend to have smaller epicardial coronary vessels with more diffuse atherosclerotic disease [
      • Pepine C.J.
      • Kerensky R.A.
      • Lambert C.R.
      • Smith K.M.
      • von Mering G.O.
      • Sopko G.
      • et al.
      Some thoughts on the vasculopathy of women with ischemic heart disease.
      ], 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 [
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • Roe M.
      • Granger C.B.
      • Armstrong P.W.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      ,
      • Lam C.S.P.
      • Arnott C.
      • Beale A.L.
      • Chandramouli C.
      • Hilfiker-Kleiner D.
      • Kaye D.M.
      • et al.
      Sex differences in heart failure.
      ].
      Figure thumbnail gr1
      Figure 1Patterns of Coronary Artery Disease in Women and Men [
      • Pepine C.J.
      • Kerensky R.A.
      • Lambert C.R.
      • Smith K.M.
      • von Mering G.O.
      • Sopko G.
      • et al.
      Some thoughts on the vasculopathy of women with ischemic heart disease.
      ].
      The Women's Ischaemia Syndrome Evaluation (WISE) Study [
      • Kenkre T.S.
      • Malhotra P.
      • Johnson B.D.
      • Handberg E.M.
      • Thompson D.V.
      • Marroquin O.C.
      • et al.
      Ten-year mortality in the WISE study (Women's Ischemia Syndrome Evaluation).
      ,
      • Merz C.N.
      • Kelsey S.F.
      • Pepine C.J.
      • Reichek N.
      • Reis S.E.
      • Rogers W.J.
      • et al.
      The Women's Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report.
      ] 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 [
      • Pepine C.J.
      • Kerensky R.A.
      • Lambert C.R.
      • Smith K.M.
      • von Mering G.O.
      • Sopko G.
      • et al.
      Some thoughts on the vasculopathy of women with ischemic heart disease.
      ,
      • Reis S.E.
      • Holubkov R.
      • Lee J.S.
      • Sharaf B.
      • Reichek N.
      • Rogers W.J.
      • et al.
      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 [
      • Sedlak T.L.
      • Guan M.
      • Lee M.
      • Humphries K.H.
      • Johnson B.D.
      • Pepine C.J.
      • et al.
      Ischemic predictors of outcomes in women with signs and symptoms of ischemia and nonobstructive coronary artery disease.
      ]. 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 [
      • Woodward M.
      Cardiovascular risk in women with nonspecific chest pain.
      ].
      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 [
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • Adlam D.
      • Arslanian-Engoren C.
      • Economy K.E.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      ,
      • Saw J.
      • Aymong E.
      • Sedlak T.
      • Buller C.E.
      • Starovoytov A.
      • Ricci D.
      • et al.
      Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes.
      ,
      • Nishiguchi T.
      • Tanaka A.
      • Ozaki Y.
      • Taruya A.
      • Fukuda S.
      • Taguchi H.
      • et al.
      Prevalence of spontaneous coronary artery dissection in patients with acute coronary syndrome.
      ]. 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 [
      • Hayes S.N.
      • Kim E.S.H.
      • Saw J.
      • Adlam D.
      • Arslanian-Engoren C.
      • Economy K.E.
      • et al.
      Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association.
      ]. 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 [
      • Lam C.S.P.
      • Arnott C.
      • Beale A.L.
      • Chandramouli C.
      • Hilfiker-Kleiner D.
      • Kaye D.M.
      • et al.
      Sex differences in heart failure.
      ]. 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 [
      • Tsao C.W.
      • Vasan R.S.
      Cohort profile: The Framingham Heart Study (FHS): overview of milestones in cardiovascular epidemiology.
      ]. Some of these risk factors, however, portend differing levels of excess risk for the development of CVD between the sexes [
      • Millett E.R.C.
      • Peters S.A.E.
      • Woodward M.
      Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants.
      ,
      • Woodward M.
      Cardiovascular disease and the female disadvantage.
      ,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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 Mellitus

      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 [
      • Kannel W.B.
      • Hjortland M.
      • Castelli W.P.
      Role of diabetes in congestive heart failure: the Framingham study.
      ,
      • Maas A.H.E.M.
      • Appelman Y.E.A.
      Gender differences in coronary heart disease.
      ] and more recently in the UK Biobank study [
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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.
      ]. Meta-analyses have reported an increase in CVD relative risk of 44% for coronary heart disease and 27% for stroke in women, compared to men [
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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.
      ,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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.
      ]. The sex differential is greater for type 1 diabetes than for type 2 [
      • Huxley R.R.
      • Peters S.A.
      • Mishra G.D.
      • Woodward M.
      Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis.
      ]. The cause of this increased relative risk of cardiovascular morbidity and mortality in women with diabetes remains unclear [
      • Woodward M.
      • Peters S.A.
      • Huxley R.R.
      Diabetes and the female disadvantage.
      ]. However, emerging evidence suggests heightened impairment of endothelium-dependent vasodilation, hypercoagulability and dyslipidaemia in women with diabetes [
      • Mascarenhas-Melo F.
      • Marado D.
      • Palavra F.
      • Sereno J.
      • Coelho Á.
      • Pinto R.
      • et al.
      Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women.
      ,
      • Carr M.E.
      Diabetes mellitus: a hypercoagulable state.
      ,
      • Pradhan A.D.
      Sex differences in the metabolic syndrome: implications for cardiovascular health in women.
      ].

      Hypertension

      Women develop hypertension later than men, becoming more prevalent in older women than men [
      • Giralt D.
      • Domingues-Montanari S.
      • Mendioroz M.
      • Ortega L.
      • Maisterra O.
      • Perea-Gainza M.
      • et al.
      The gender gap in stroke: a meta-analysis.
      ]. 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 [
      Australian Institute of Health and Welfare
      Cardiovascular Disease in Australian Women - A Snapshot of National Statistics Report.
      ]. Although sex differences in the clinical incidence of hypertension (with the exception of hypertensive pregnancy disorders) have not been detected [
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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.
      ], hypertension is often undertreated in women [
      • Lloyd-Jones D.M.
      • Evans J.C.
      • Levy D.
      Hypertension in adults across the age spectrum: current outcomes and control in the community.
      ,
      • Regitz-Zagrosek V.
      • Oertelt-Prigione S.
      • Prescott E.
      • Franconi F.
      • Gerdts E.
      • et al.
      EUGenMed Cardiovascular Clinical Study Group
      Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes.
      ]. 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 [
      • Benjamin Emelia J.
      • Virani Salim S.
      • Callaway Clifton W.
      • Chamberlain Alanna M.
      • Chang Alexander R.
      • Cheng S.
      • et al.
      Heart disease and stroke statistics—2018 update: a report from the American Heart Association.
      ]. 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) [
      • Levy D.
      • Larson M.G.
      • Vasan R.S.
      • Kannel W.B.
      • Ho K.K.
      The progression from hypertension to congestive heart failure.
      ]. The impact of hypertension on the risk of developing ischaemic heart disease seems to be broadly consistent across the sexes [
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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.
      ].

      Smoking

      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 [
      • Huxley R.R.
      • Woodward M.
      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.
      ]. This was later confirmed in the UK Biobank [
      • Millett E.R.C.
      • Peters S.A.E.
      • Woodward M.
      Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants.
      ], whilst a smaller (non-significant) excess relative risk in women was also found in a meta-analysis of stroke studies [
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      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 [
      • Kaminski P.
      • Szpotanska-Sikorska M.
      • Wielgos M.
      Cardiovascular risk and the use of oral contraceptives.
      ]. 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 [
      • Smith P.H.
      • Bessette A.J.
      • Weinberger A.H.
      • Sheffer C.E.
      • McKee S.A.
      Sex/gender differences in smoking cessation: a review.
      ].

      Inflammation

      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 [
      • Shanahan L.
      • Copeland W.E.
      • Worthman C.M.
      • Erkanli A.
      • Angold A.
      • Costello E.J.
      Sex-differentiated changes in C-reactive protein from ages 9 to 21: the contributions of BMI and physical/sexual maturation.
      ]. Moreover, measurement of pro-inflammatory markers can predict myocardial infarction, stroke and cardiovascular death in women [
      • Zhang S.
      • Wang L.
      • Leng J.
      • Liu H.
      • Li W.
      • Zhang T.
      • et al.
      Hypertensive disorders of pregnancy in women with gestational diabetes mellitus on overweight status of their children.
      ,
      • Ridker P.M.
      • Rifai N.
      • Rose L.
      • Buring J.E.
      • Cook N.R.
      Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.
      ,
      • Ridker P.M.
      • Hennekens C.H.
      • Buring J.E.
      • Rifai N.
      C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
      ,
      • Avan A.
      • Tavakoly Sany S.B.
      • Ghayour-Mobarhan M.
      • Rahimi H.R.
      • Tajfard M.
      • Ferns G.
      Serum C-reactive protein in the prediction of cardiovascular diseases: overview of the latest clinical studies and public health practice.
      ].
      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 [
      • Johnson B.D.
      • Kip K.E.
      • Marroquin O.C.
      • Ridker P.M.
      • Kelsey S.F.
      • Shaw L.J.
      • et al.
      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).
      ,
      • Kip K.E.
      • Marroquin O.C.
      • Shaw L.J.
      • Arant C.B.
      • Wessel T.R.
      • Olson M.B.
      • et al.
      Global inflammation predicts cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study.
      ,
      • Cosin-Sales J.
      • Pizzi C.
      • Brown S.
      • Kaski J.C.
      C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms.
      ].
      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 [
      • Tsao C.W.
      • Vasan R.S.
      Cohort profile: The Framingham Heart Study (FHS): overview of milestones in cardiovascular epidemiology.
      ,
      • Johnson B.D.
      • Kip K.E.
      • Marroquin O.C.
      • Ridker P.M.
      • Kelsey S.F.
      • Shaw L.J.
      • et al.
      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).
      ,
      • Kip K.E.
      • Marroquin O.C.
      • Shaw L.J.
      • Arant C.B.
      • Wessel T.R.
      • Olson M.B.
      • et al.
      Global inflammation predicts cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study.
      ,
      • AlBadri A.
      • Lai K.
      • Wei J.
      • Landes S.
      • Mehta P.K.
      • Li Q.
      • et al.
      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 [
      • Shah A.J.
      • Ghasemzadeh N.
      • Zaragoza-Macias E.
      • Patel R.
      • Eapen D.J.
      • Neeland I.J.
      • et al.
      Sex and age differences in the association of depression with obstructive coronary artery disease and adverse cardiovascular events.
      ]. 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 [
      • Shah A.J.
      • Ghasemzadeh N.
      • Zaragoza-Macias E.
      • Patel R.
      • Eapen D.J.
      • Neeland I.J.
      • et al.
      Sex and age differences in the association of depression with obstructive coronary artery disease and adverse cardiovascular events.
      ,
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • Dans T.
      • Avezum A.
      • Lanas F.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      ]. Furthermore, women are disproportionately affected by stress-induced (Takotsubo) cardiomyopathy, with a female-to-male ratio of 9:1 [
      • Templin C.
      • Ghadri J.-R.
      • Napp L.C.
      Takotsubo (stress) cardiomyopathy.
      ]. 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 [
      • Samad Z.
      • Boyle S.
      • Ersboll M.
      • Vora A.N.
      • Zhang Y.
      • Becker R.C.
      • et al.
      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.
      ].

      Female-Specific Risk Factors

      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 [
      • Iorga A.
      • Cunningham C.M.
      • Moazeni S.
      • Ruffenach G.
      • Umar S.
      • Eghbali M.
      The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy.
      ]. This concept was supported clinically by a number of large, retrospective observational studies [
      • Stampfer M.J.
      • Colditz G.A.
      • Willett W.C.
      • Manson J.E.
      • Rosner B.
      • Speizer F.E.
      • et al.
      Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study.
      ,
      • Grodstein F.
      • Stampfer M.
      The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women.
      ,
      • Grodstein F.
      • Manson J.E.
      • Colditz G.A.
      • Willett W.C.
      • Speizer F.E.
      • Stampfer M.J.
      A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.
      ,
      • Wolf P.H.
      • Madans J.H.
      • Finucane F.F.
      • Higgins M.
      • Kleinman J.C.
      Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort.
      ,
      • Henderson B.E.
      • Paganini-Hill A.
      • Ross R.K.
      Decreased mortality in users of estrogen replacement therapy.
      ]. 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 [
      • Boardman H.M.
      • Hartley L.
      • Eisinga A.
      • Main C.
      • Roque i Figuls M.
      • Bonfill Cosp X.
      • et al.
      Hormone therapy for preventing cardiovascular disease in post-menopausal women.
      ,
      • Hulley S.
      • Grady D.
      • Bush T.
      • Furberg C.
      • Herrington D.
      • Riggs B.
      • et al.
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
      ,
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • LaCroix A.Z.
      • Kooperberg C.
      • Stefanick M.L.
      • et al.
      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 [
      RANZCOG
      Menopausal Hormone Therapy Advice.
      ].
      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 [
      • Peters S.A.
      • Woodward M.
      Women's reproductive factors and incident cardiovascular disease in the UK Biobank.
      ]. 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 [
      • Ranthe Mattis F.
      • Andersen Elisabeth A.W.
      • Wohlfahrt J.
      • Bundgaard H.
      • Melbye M.
      • Boyd Heather A.
      Pregnancy loss and later risk of atherosclerotic disease.
      ]. The pathophysiology of spontaneous pregnancy loss and atherosclerotic disease may have shared features in terms of systemic inflammation and endothelial dysfunction [
      • Germain Alfredo M.
      • Romanik Mary C.
      • Guerra I.
      • Solari S.
      • Reyes María S.
      • Johnson Richard J.
      • et al.
      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) [
      • Wu P.G.M.
      • Kwok C.S.
      • Wong C.W.
      • Narain A.
      • O'Brien S.
      • Chew-Graham C.A.
      • et al.
      Preterm delivery and future risk of maternal cardiovascular disease: a systematic review and meta-analysis.
      ]. 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) [
      • Zhao L.
      • Zhu Z.
      • Lou H.
      • Zhu G.
      • Huang W.
      • Zhang S.
      • et al.
      Polycystic ovary syndrome (PCOS) and the risk of coronary heart disease (CHD): a meta-analysis.
      ].

      Hypertensive and Metabolic Disorders of Pregnancy

      Women who experience hypertensive and metabolic complications of pregnancy are at increased risk of cardiovascular disease [
      • Ahmed R.
      • Dunford J.
      • Mehran R.
      • Robson S.
      • Kunadian V.
      Pre-eclampsia and future cardiovascular risk among women: a review.
      ,
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      ]. 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 [
      • Ahmed R.
      • Dunford J.
      • Mehran R.
      • Robson S.
      • Kunadian V.
      Pre-eclampsia and future cardiovascular risk among women: a review.
      ]. 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 [
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      ]. 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) [
      • Wu P.
      • Haththotuwa R.
      • Kwok C.S.
      • Babu A.
      • Kotronias R.A.
      • Rushton C.
      • et al.
      Preeclampsia and future cardiovascular health: a systematic review and meta-analysis.
      ]. Furthermore, it has been shown that the time of onset and severity of pre-eclampsia correlated with the magnitude of the CVD risk in later life [
      • Bellamy L.
      • Casas J.-P.
      • Hingorani A.D.
      • Williams D.J.
      Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
      ]. 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 [
      • Leon L.J.
      • McCarthy F.P.
      • Direk K.
      • Gonzalez-Izquierdo A.
      • Prieto-Merino D.
      • Casas J.P.
      • et al.
      Preeclampsia and cardiovascular disease in a large UK pregnancy cohort of linked electronic health records: A CALIBER study.
      ].
      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 [
      • Schoenaker D.A.J.M.
      • Mishra G.D.
      Association between age at menarche and gestational diabetes mellitus: the Australian longitudinal study on women's health.
      ,
      • Bellamy L.
      • Casas J.-P.
      • Hingorani A.D.
      • Williams D.
      Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis.
      ]. Multiple studies have shown, however, that GDM is also an independent risk factor for cardiovascular disease [
      • McKenzie-Sampson S.
      • Paradis G.
      • Healy-Profitós J.
      • St-Pierre F.
      • Auger N.
      Gestational diabetes and risk of cardiovascular disease up to 25 years after pregnancy: a retrospective cohort study.
      ,
      • Kramer C.K.
      • Campbell S.
      • Retnakaran R.
      Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis.
      ].

      Breast Feeding

      Recent evidence has suggested that breast feeding is protective against future hypertension [
      • Qu G.
      • Wang L.
      • Tang X.
      • Wu W.
      • Sun Y.
      Association between duration of breastfeeding and maternal hypertension: a systematic review and meta-analysis.
      ] and cardiovascular disease [
      • Peters S.A.E.
      • Yang L.
      • Guo Y.
      • Chen Y.
      • Bian Z.
      • Du J.
      • et al.
      Breastfeeding and the risk of maternal cardiovascular disease: a prospective study of 300 000 chinese women.
      ,
      • Peters S.A.
      • van der Schouw Y.T.
      • Wood A.M.
      • Sweeting M.J.
      • Moons K.G.
      • Weiderpass E.
      • et al.
      Parity, breastfeeding and risk of coronary heart disease: a pan-European case-cohort study.
      ] 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 [
      • Mehta L.S.
      • Watson K.E.
      • Barac A.
      • Beckie T.M.
      • Bittner V.
      • Cruz-Flores S.
      • et al.
      Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association.
      ]. 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 [
      • Abdel-Qadir H.
      • Austin P.C.
      • Lee D.S.
      • Amir E.
      • Tu J.V.
      • Thavendiranathan P.
      • et al.
      A population-based study of cardiovascular mortality following early-stage breast cancer.
      ]. 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 [
      • Drafts B.C.
      • Twomley K.M.
      • D'Agostino Jr., R.
      • Lawrence J.
      • Avis N.
      • Ellis L.R.
      • et al.
      Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease.
      ]. 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 [
      • Chen J.
      • Long J.B.
      • Hurria A.
      • Owusu C.
      • Steingart R.M.
      • Gross C.P.
      Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer.
      ,
      • Bowles E.J.A.
      • Wellman R.
      • Feigelson H.S.
      • Onitilo A.A.
      • Freedman A.N.
      • Delate T.
      • et al.
      Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study.
      ]. Interestingly, emerging pre-clinical research suggests that female sex may protect against the development of anthracycline-induced cardiotoxicity [
      • Meiners B.
      • Shenoy C.
      • Zordoky B.N.
      Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity.
      ,
      • Moulin M.
      • Piquereau J.
      • Mateo P.
      • Fortin D.
      • Rucker-Martin C.
      • Gressette M.
      • et al.
      Sexual dimorphism of doxorubicin-mediated 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 [
      • Clarke M.
      • Collins R.
      • Darby S.
      • Davies C.
      • Elphinstone P.
      • Evans V.
      • et al.
      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.
      ,
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • Bennet A.M.
      • Blom-Goldman U.
      • Brønnum D.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      ]. Radiotherapy has also been implicated in the development of heart failure with preserved ejection fraction, cardiomyopathic processes, valvular and coronary heart disease [
      • Garcia M.
      • Mulvagh S.L.
      • Merz C.N.
      • Buring J.E.
      • Manson J.E.
      Cardiovascular disease in women: clinical perspectives.
      ,
      • Saiki H.
      • Petersen I.A.
      • Scott C.G.
      • Bailey K.R.
      • Dunlay S.M.
      • Finley R.R.
      • et al.
      Risk of heart failure with preserved ejection fraction in older women after contemporary radiotherapy for breast cancer.
      ].

      Autoimmune 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 [
      • Garcia M.
      • Mulvagh S.L.
      • Merz C.N.
      • Buring J.E.
      • Manson J.E.
      Cardiovascular disease in women: clinical perspectives.
      ,
      • Manzi S.
      • Meilahn E.N.
      • Rairie J.E.
      • Conte C.G.
      • Medsger Jr., T.A.
      • Jansen-McWilliams L.
      • et al.
      Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.
      ]. 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 [
      • Durante A.
      • Bronzato S.
      The increased cardiovascular risk in patients affected by autoimmune diseases: review of the various manifestations.
      ]. Chronic glucocorticoid therapy in the treatment of these conditions, further potentiates cardiovascular risk by way of exacerbating traditional risk factors including hypercholesterolaemia and hyperglycaemia [
      • Svenungsson E.
      • Jensen-Urstad K.
      • Heimbürger M.
      • Silveira A.
      • Hamsten A.
      • de Faire U.
      • et al.
      Risk factors for cardiovascular disease in systemic lupus erythematosus.
      ].
      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) [
      • Avina-Zubieta J.A.
      • Thomas J.
      • Sadatsafavi M.
      • Lehman A.J.
      • Lacaille D.
      Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies.
      ,
      • Aviña-Zubieta J.A.
      • Choi H.K.
      • Sadatsafavi M.
      • Etminan M.
      • Esdaile J.M.
      • Lacaille D.
      Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies.
      ]. 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 [
      • van den Hoek J.
      • Boshuizen H.C.
      • Roorda L.D.
      • Tijhuis G.J.
      • Nurmohamed M.T.
      • van den Bos G.A.M.
      • et al.
      Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study.
      ]. 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 [
      • Roubille C.
      • Richer V.
      • Starnino T.
      • McCourt C.
      • McFarlane A.
      • Fleming P.
      • et al.
      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 Societal Factors

      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 [
      • McDonnell L.A.
      • Pipe A.L.
      • Westcott C.
      • Perron S.
      • Younger-Lewis D.
      • Elias N.
      • et al.
      Perceived vs actual knowledge and risk of heart disease in women: findings from a Canadian survey on heart health awareness, attitudes, and lifestyle.
      ]. 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 [
      • Garcia M.
      • Mulvagh S.L.
      • Merz C.N.
      • Buring J.E.
      • Manson J.E.
      Cardiovascular disease in women: clinical perspectives.
      ,
      • Giardina E.G.
      • Sciacca R.R.
      • Flink L.E.
      • Bier M.L.
      • Paul T.K.
      • Moise N.
      Cardiovascular disease knowledge and weight perception among Hispanic and non-Hispanic white women.
      ,
      • Flink L.E.
      • Sciacca R.R.
      • Bier M.L.
      • Rodriguez J.
      • Giardina E.G.
      Women at risk for cardiovascular disease lack knowledge of heart attack symptoms.
      ,
      • Mosca L.
      • Hammond G.
      • Mochari-Greenberger H.
      • Towfighi A.
      • Albert M.A.
      • American Heart Association Cardiovascular Disease
      • et al.
      Fifteen-year trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey.
      ]. 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 [
      • Backholer K.
      • Peters S.A.E.
      • Bots S.H.
      • Peeters A.
      • Huxley R.R.
      • Woodward M.
      Sex differences in the relationship between socioeconomic status and cardiovascular disease: a systematic review and meta-analysis.
      ].
      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) [
      • Hyun K.K.
      • Redfern J.
      • Patel A.
      • Peiris D.
      • Brieger D.
      • Sullivan D.
      • et al.
      Gender inequalities in cardiovascular risk factor assessment and management in primary healthcare.
      ]. 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 [
      • Lee C.M.Y.
      • Mnatzaganian G.
      • Woodward M.
      • Chow C.K.
      • Sitas F.
      • Robinson S.
      • et al.
      Sex disparities in the management of coronary heart disease in general practices in Australia.
      ].
      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) [
      • Stehli J.
      • Martin C.
      • Brennan A.
      • Dinh D.T.
      • Lefkovits J.
      • Zaman S.
      Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
      ]. Women are also subsequently more likely to experience post-infarct complications than men [
      • Dreyer R.P.
      • Beltrame J.F.
      • Neil C.
      • Air T.
      • Tavella R.
      • Hoffmann B.
      • et al.
      Cardiac hemodynamics in men versus women during acute ST-segment elevation myocardial infarction.
      ,
      • Dreyer R.P.
      • Beltrame J.F.
      • Tavella R.
      • Air T.
      • Hoffmann B.
      • Pati P.K.
      • et al.
      Evaluation of gender differences in door-to-balloon time in ST-elevation myocardial infarction.
      ]. These data are reinforced by similar findings from the Australian CONCORDANCE registry [
      • Khan E.
      • Brieger D.
      • Amerena J.
      • Atherton J.J.
      • Chew D.P.
      • Farshid A.
      • et al.
      Differences in management and outcomes for men and women with ST-elevation myocardial infarction.
      ], 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 [
      • Khan E.
      • Brieger D.
      • Amerena J.
      • Atherton J.J.
      • Chew D.P.
      • Farshid A.
      • et al.
      Differences in management and outcomes for men and women with ST-elevation myocardial infarction.
      ,
      • Hay M.S.J.
      • Martin C.
      • Brennan A.
      • Dinh D.
      • Lefkovits J.
      • Zaman S.
      Sex differences in optimal medical therapy following myocardial infarction according to ventricular ejection fraction.
      ].
      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) [
      • Wu J.
      • Gale C.P.
      • Hall M.
      • Dondo T.B.
      • Metcalfe E.
      • Oliver G.
      • et al.
      Editor's choice - impact of initial hospital diagnosis on mortality for acute myocardial infarction: a national cohort study.
      ].
      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 [
      • Bagrov A.Y.
      • Dmitrieva R.I.
      • Fedorova O.V.
      • Kazakov G.P.
      • Roukoyatkina N.I.
      • Shpen V.M.
      Endogenous marinobufagenin-like immunoreactive substance. A possible endogenous Na, K-ATPase inhibitor with vasoconstrictor activity.
      ]. 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 [
      • Strauss M.
      • Smith W.
      • Wei W.
      • Bagrov A.Y.
      • Fedorova O.V.
      • Schutte A.E.
      Large artery stiffness is associated with marinobufagenin in young adults: the African-PREDICT study.
      ,
      • Strauss M.
      • Smith W.
      • Kruger R.
      • Wei W.
      • Fedorova O.V.
      • Schutte A.E.
      Marinobufagenin and left ventricular mass in young adults: the African-PREDICT study.
      ]. This supports previous observations that women are more salt-sensitive than men when consuming similar amounts of salt [
      • Strauss M.
      • Smith W.
      • Fedorova O.V.
      • Schutte A.E.
      The Na(+)K(+)-ATPase inhibitor marinobufagenin and early cardiovascular risk in humans: a review of recent evidence.
      ].
      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 [
      • Leopold J.A.
      • Loscalzo J.
      Emerging role of precision medicine in cardiovascular disease.
      ].

      Conclusion

      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 thumbnail gr2
      Figure 2The Current Landscape of Cardiovascular Disease in Women [
      Australian Institute of Health and Welfare
      Cardiovascular Disease in Australian Women - A Snapshot of National Statistics Report.
      ].
      Abbreviations: CVD, cardiovascular disease; HFpEF, heart failure with preserved ejection fraction; SCAD, spontaneous coronary artery dissection.

      Disclosures

      None.

      Funding Sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Acknowledgements

      None.

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