A Review of Traditional and Non-Traditional Cardiovascular Risk Factors in Women.

Although multiple predictive models exist for cardiovascular risk assessment, their accuracy in women remains limited due to sex-specific variation in disease presentation and pathophysiology. A 2019 systematic review identified 160 risk models tailored for women, however, only two incorporated female-specific risk factors such as preeclampsia or gestational diabetes ( Table 2 ). 137 Research evaluating the utility of current, commonly used CVD risk models for women demonstrated limited applicability, particularly in younger women. 138 This is in part due to the lack of any women below the age of 40 included in cohorts from which scores such as SCORE2 and the Pooled Cohort Equation were derived. 139 , 140 Furthermore, CVD is often seen as a “male” disease and awareness is suboptimal in both patients and clinicians. 141 This may result in reduced CVD screening and undiagnosed CVD risk factors, which are the cornerstone of such risk models. Table 2 Studies Assessing Risk Prediction Models with Female Specific Risk Factors Study Risk factors assessed Results Parikh et al (2016) 142 Number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility, breastfeeding C statistics 0.726 increase to 0.730 with addition of non-traditional risk factors ( No significant improvement ) van der Meer et al (2016) 143 Age at menarche, menopausal age, HRT use, Number of live births, GHTN, GDM No change in C statistic with non-traditional risk factors ( No significant improvement) Stuart et al (2018) 144 Hypertensive disorders of pregnancy and parity C statistic change from 0.691 to 0.693 ( No significant improvement) Ukah et al (2020) 145 Hypertensive disorders of pregnancy, caesarean delivery, stillbirth, neonatal death, previous pregnancy complications, gestational age at delivery, GDM C statistic of 0.66 – no comparison ( N/A ) Doust et al (2024) 146 Early menarche (<11 years), endometriosis, excessive, frequent or irregular menstruation, miscarriage, number of miscarriages, number of stillbirths, infertility, preeclampsia or eclampsia, gestational diabetes (without subsequent type 2 diabetes), premature menopause (<40 years), early menopause (<45 years), and natural or surgical early menopause (menopause <45 years or timing of menopause reported as unknown and oophorectomy reported at age <45) C statistic with traditional RFs – (0.710, 0.713, 0.718) C statistic with non-traditional + traditional RFs – (0.712, 0.715, 0.720) (No significant improvement) Notes : List of studies assessing utility of female specific non-traditional cardiovascular risk factors in CVD risk prediction models. 142–145 Abbreviations : CVD, cardiovascular disease; HRT, hormone replacement therapy; GHTN, gestational hypertension; GDM, gestational diabetes mellitus; RF, risk factors. Studies Assessing Risk Prediction Models with Female Specific Risk Factors Notes : List of studies assessing utility of female specific non-traditional cardiovascular risk factors in CVD risk prediction models. 142–145 Abbreviations : CVD, cardiovascular disease; HRT, hormone replacement therapy; GHTN, gestational hypertension; GDM, gestational diabetes mellitus; RF, risk factors. The largest prospective study to date, including over 135,000 women, evaluated reproductive factors such as early menarche, infertility, miscarriage, preeclampsia, gestational diabetes and early menopause. When used individually or cumulatively, these factors only yielded marginal improvements in risk model prediction, increasing the C-statistic from 0.726 to 0.730. However, mean age in the study was reported as 57.5, limiting the applicability to younger women. 146 Similarly, a 2016 study incorporating menarche, breastfeeding and fertility indicators reported only minor improvement, mainly through improved reclassification in women without cardiovascular events ( Table 2 ). 142–145 Conversely, other studies have found some improvement with pregnancy-related condition, especially hypertensive disorders, when integrated into 10-year predictive models. 145 Evaluations of combined models, incorporating traditional and non-traditional risk factors, demonstrated no change in 10-year risk prediction, however, once again within predominant focus on middle age to elderly women. 143 The future utility of female-specific risk factors with risk prediction models may lie in early identification of women at risk of developing modifiable cardiometabolic conditions, especially given the suboptimal awareness. These exposures often occur in early life stages, well before the emergence of most traditional risk factors, offering a critical window for preventative intervention. Risk factors such as pregnancy-related complications and breast arterial calcification may act as a marker of predisposition to cardiometabolic disease and a sign to instigate earlier screening.

Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Despite advances in the identification and management of at-risk individuals, there is limited awareness, particularly among healthcare providers and young women, of sex-specific risk factors and atypical presentations in female patients. Women often exhibit distinct symptom profiles and pathophysiological patterns of CVD in comparison to men, yet these differences are not adequately captured by widely used risk prediction models. Typical risk models incorporate traditional risk factors such as diabetes, hypertension, hyperlipidemia, smoking status and age. However, these variables manifest and impact women differently across the lifespan. In addition, cardiovascular risk in women is influenced by factors that fall outside of conventional models that can be broadly categorized as non-traditional factors. Female-specific risk factors represent a subset of non-traditional risk factors that arise from sex-specific biology and include conditions such as pre-eclampsia, polycystic ovarian syndrome and breast arterial calcification ( Figure 1 ). The discrepancy between traditional and non-traditional risk factors is especially evident in younger women who may have elevated risk in the absence of conventional risk factors. Figure 1 Visualization of traditional and non-traditional risk factors across the lifespan for women. Non-traditional risk factors, on average, are evident at an earlier age and precede a change in cardiometabolic phenotype, making them ideal as a risk marker for early identification and intervention of cardiovascular risk. Visualization of traditional and non-traditional risk factors across the lifespan for women. Non-traditional risk factors, on average, are evident at an earlier age and precede a change in cardiometabolic phenotype, making them ideal as a risk marker for early identification and intervention of cardiovascular risk. Recent years have seen growing interest in refinement of cardiovascular risk assessment to better reflect the nuances of sex-specific risk in women. In this review, we examine the current evidence on both traditional and non-traditional risk factors as they relate to women and how this evolving area informs clinical risk prediction and prevention strategies.

Cardiovascular disease, particularly coronary heart disease, remains one of the major contributors to both mortality and morbidity in women. While men tend to experience CVD earlier in life, women often exhibit a delayed onset with incidence rates rising substantially in midlife and beyond. 1 A 2021 global commission reported a general decline in the prevalence of CVD since 1990, although the rate of decline has begun to slow in recent years. Notably, several regions – including parts of Asia, Africa and Oceania – have seen an increase in CVD prevalence during the same period. 2 In high-income countries, age-stratified data reveals a concerning trend among women. A Canadian cohort study found that while overall CVD rates have declined, reduction in young women, aged 20 to 49, has remained the slowest. 3 Furthermore, younger women with ST elevation myocardial infarction (STEMI) experience higher mortality rates than their male counterparts. 4 This paradox of lower prevalence of traditional risk factors in young women but poorer outcomes raises important questions about the adequacy of current risk prediction in this population. A key contributing factor may be limited awareness of sex-specific presentation and risk factors for CVD, both among the general public and healthcare professionals. Despite several public health campaigns focused on CVD in women, recent data shows that awareness of heart disease as the leading cause of death in women has declined over the past decade. Furthermore, one-third of post-graduate medical trainees report minimal or no training in sex-specific medicine and fewer than half of cardiologists feel adequately prepared to assess cardiovascular risk in women. 5 Bridging these gaps in awareness, education and clinical assessment is essential to improving cardiovascular outcomes and achieving equity in prevention and treatment strategies.

Over the past decade, there has been substantial growth in research examining cardiovascular disease in women; however, how best to translate sex-based differences in risk stratification and management strategies remains unclear. A central objective of ongoing research is to improve identification of women at increased CVD risk who are not adequately captured by current guideline-based risk models. While traditional risk factors remain fundamental to prevention strategies, increasing attention has been directed towards non-traditional and female-specific risk factors. At present, the evidence supporting many of these factors is largely observational, with limited interventional data. As such, their clinical utility lies not in defining treatment pathways alone, but in enhancing risk recognition and refining risk estimation, particularly in younger women and those classified low risk by conventional tools. Non-traditional risk factors such as breast arterial calcification, pregnancy-related complications and early menopause offer important insight into sex-specific pathways of cardiovascular pathology. Incorporating these variables into future risk prediction frameworks, alongside traditional risk factors, has the potential to enable earlier identification of at-risk women and support more individualized preventative strategies. For optimal cardiovascular risk assessment in women, clinicians should account for sex-specific differences in the impact of traditional risk factors and recognize non-traditional risk factors that may indicate elevated cardiovascular risk even in the absence of conventional high-risk features.

Preventing cardiovascular disease through risk-guided therapy remains a central objective in cardiovascular medicine and women’s health, yet challenges persist due to sex-specific variation in risk and historical underrepresentation of women in clinical research. Central to these efforts is accurate risk stratification and proactive management of cardiovascular risk factors. Statin therapy has long served as the cornerstone of primary prevention in individuals at elevated risk, supported by large-scale randomized controlled trials. 147 However, data on women are limited and in recent years, increased recognition of this evidence gap has led to evolving perspectives on non-traditional and sex-specific risk factors in CVD prevention. 148 Several pregnancy-related complications – including hypertensive disorders of pregnancy, gestational diabetes, intrauterine growth restriction, preterm birth and placental abruption – are linked to long-term cardiovascular risk and have gained traction as an actionable risk marker. 17 , 73 , 74 The 2020 ACC/AHA summary recommendations, in alignment with guidance from the American College of Obstetricians and Gynecologists, recommend that women with such complications undergo CVD risk assessment within three months post-partum. 149 A Postpartum cardiovascular intervention clinic has demonstrated feasibility with consumers and may be an option to integrate this recommendation at a population level. 150 The 2024 American Heart Association (AHA) statement on the postpartum cardiovascular care further expands upon these recommendations. Reflecting the elevated risk of diabetes and hypertension portended by gestational diabetes and hypertensive disorders of pregnancy respectively, the AHA advises intensified cardiometabolic screening in the first-year postpartum. In addition, they recommend routine cardiovascular risk factor screening for all women – regardless of pregnancy history – during the first 12 months after delivery. This approach seeks to address the current barrier of low attendance and participation in postpartum care, with only 18% to 25% of women with complications of pregnancy seeing their general practitioner within the first six months. The AHA also considers it reasonable to perform lipid screening during this period, given the historically low rates of lipid testing among young women. 151 As long-term breast cancer survival rates continue to improve, cardiovascular disease has emerged as a leading cause of morbidity and mortality in this population. 152 This concern is heightened by shared risk factors – such as obesity, age and smoking – as well as the cardiotoxic effect of many cancer therapies. 153 Cardioprotective agents such as beta blockers and angiotensin converting enzyme inhibitors have shown promise in small cohort studies for mitigating chemotherapy-induced cardiac dysfunction; however, results have been inconsistent and do not support routine use of these agents in breast cancer patients. 154 The use of aspirin and statins also remains investigational outside of established cardiovascular indications. A 2015 meta-analysis suggested that statin use may have some prognostic benefit for cancer survival, however there has been little assessing utility in CVD prevention. 155 Current clinical guidelines are limited on the use of breast arterial calcification detected on mammography for CVD risk assessment. The Canadian Society of Breast Imaging advise that BAC could be useful for CVD risk stratification and has proposed a 4-stage model for BAC grading. Reported awareness of BAC and CVD risk is 17% amongst Canadian physicians, however, over half agree that BAC grading/guidelines would be beneficial and that BAC reporting would prompt further investigation. 156 The role of BAC may be as an incidental finding during cancer screening that prompts CVD screening and is additive to CVD risk assessment. Despite the advances, standard CVD prevention strategies remain the cornerstone of management for women, including those with AIDs. 157 Hypertension, dyslipidemia and diabetes remain underrecognized and undertreated, highlighting the need for awareness of cardiovascular risk for women – in particular among young women and women from ethnically diverse backgrounds. 2 Moreover, few international studies have specifically evaluated lifestyle or pharmacologic strategies for CVD risk reduction in women with non-traditional risk factors, highlighting a gap and need for focus research in this area. 158 , 159

Despite decades of progress in cardiovascular medicine, our understanding of risk in women remains incomplete. While traditional risk factors are well established, their interpretation and clinical impact often differ in women, especially when considered alongside sex-specific non-traditional risk factors such as pregnancy complications, autoimmune diseases and early reproductive transitions. Many of these factors emerge early in life, long before routine cardiovascular screening begins. What emerges from this synthesis is not a lack of data but a lack of integration. Risk models remain narrowly focused and clinical guidelines seldom address the complexity of female cardiovascular risk across the lifespan. The opportunity now lies in reframing prevention – not simply through adapting existing tools but by redefining how we measure and intervene on risk in women. Doing so will require investment into longitudinal research, improved representation in clinical trials and a shift towards personalized, sex-specific care.

Diabetes is a well-established independent risk factor for both cardiovascular disease and cardiovascular related mortality. 6 Importantly, its impact appears to be disproportionately greater in women, associated with both an elevated mortality risk and an earlier onset of cardiovascular disease. 7–9 One of the largest pooled analyses to date by Wang et al, encompassing 49 studies and over five million patients found that compared to men, women with diabetes had a 58% increased risk of coronary heart disease mortality and a 13% increased risk of all-cause mortality ( Table 1 ). 10–24 They identified a pooled adjusted relative risk ratio for cardiovascular disease mortality in women as compared to men of 1.30 (95% CI 1.13–1.49, p < 0.001) ( Figure 2 ). 10 Table 1 Meta Analysis and Pooled Risk Ratios for Specific Cardiovascular Risk Factors and Cardiovascular Outcomes in Women Study N Risk Factor Risk ratio Adjustment *Wang et. al (2019) 12 1,148,188 Diabetes CHD – 2.79 (2.25–3.46) CVD mortality – 2.75 (1.88–4.01) Partial: CVD risk factors *Wang et al (2019) 10 5,162,654 Diabetes CHD mortality – 3.16 (2.61–3.82) CVD mortality – 2.42 (2.10–2.78) Full: Age Partial: smoking, HTN, BMI *Peters et al (2014) 20 858,507 Diabetes CHD – 2.63 (2.27–3.06) CHD mortality – 2.83 (2.25–3.54) Full: Age Partial: CVD risk factors **Lee et al (2000) 21 75,000 Diabetes CHD mortality – 2.58 (2.05–3.26) Full: Age Partial: CVD risk factors *Mongraw-Chaffin et al (2015) 25 1,219,187 Per 1 kg/m2 increase in body mass index CHD – 1.04 (1.05–1.05) *Peters et al (2016) 26 1,022,276  Per 1 mmol/L increase in cholesterol CHD – 1.20 (1.16–1.24) Partial: Maternal age, socioeconomic status, obstetric history and chronic diseases *Lin et al (2022) 27 535,263 Per 10mmHg increase in systolic blood pressure CVD – 1.19 (1.13–1.26) Partial: CVD risk factors *Huxley et al (2011) 11 3,912,809 Smoking CHD – 1.92 (1.66–2.23) Partial: CVD risk factors Kramer et al (2019) 18 5,390,591 GDM CVD – 1.98 (1.57–2.50) Partial: CVD risk factors ***Li et al (2018) 15 3,417,020 GDM CHD – 1.59 (1.30–2.08) CVD – 1.95 (1.83–2.08) Full: Mean age at pregnancy, data collection methods, sample size, GDM diagnostic criteria Wekker et al (2020) 22 286,754 PCOS Non-fatal CHD – 1.78 (0.99–3.23) CHD mortality – 14.48 (0.14–15,83) CVD mortality – 1.30 (0.62–2.74) Partial: CVD risk factors ***Tay et al (2023) 28 1,062,280 PCOS CVD – 1.68 (1.26–2.23) CHD composite – 1.48 (1.07–2.05) CVD mortality – 1.19 (0.53–2.69) Partial: CVD risk factors, ethnicity Wan et al (2024) 29 74,824,979 PCOS CVD – 1.51 (1.36–1.91) Partial: CVD risk factors Wu et al (2017) 17 6,456,379 Preeclampsia CHD – 2.50 (1.43–4.37) CHD mortality – 2.10 (1.25–3.51) CVD mortality – 2.21 (1.83–2.66) Partial: CVD risk factors and obstetric history Mcdonald et al (2008) 23 2,375,751 Preeclampsia CVD mortality – 2.29 (1.73 −3.04) Full: Age Partial: CVD risk factors Brown et al (2013) 24 2,010,656 Preeclampsia CVD – 2.28 (1.87–2.77) Not mentioned Bellamy et al (2007) 16 3,488,160  Preeclampsia CHD – 2.16 (1.86–2.52) Partial: Socioeconomic status, CVD risk factors Inversetti et al (2024) 30 13,162,030 Preeclampsia CVD mortality – 2.08 (1.70–2.54) CHD – 2.04 (1.76–2.38) Partial: Socioeconomic factors, CVD risk factors Galimzhanov et al (2023) 19 836,201 Breast cancer CVD mortality – 1.09 (1.07–1.11) CHD – 0.97 (0.90–1.02) Partial: Age, socio economic factors, CVD risk factors ***Osman et al (2022) 13 33,494 BAC CHD – 2.39 (1.68–3.41) Partial: Age, CVD risk factors Lo et al (2020) 14 3,601,192  GHTN CHD – 1.83 (1.33–2.51) CVD – 1.81 (1.41–2.32) Partial: CVD risk factors Notes : Compilation of meta-analyses of specific CVD risk factors in women and CVD/CHD event rate or mortality. Adjusted confounders for each study are given as full, where included in all studies or partial, where included in part. Adjustment for CVD risk factors refers to one or more traditional CVD risk factor. 10–24 * – Cohort included male and female participants (matched or unmatched), ** – Approximate cohort number (exact not available), *** – Odds ratio used as a surrogate for relative risk in setting of low event rate in population. Abbreviations : CHD, coronary heart disease; CVD, cardiovascular disease. Figure 2 Risk ratios for traditional and non-traditional risk factors, demonstrating low (green), moderate (yellow), high (Orange) and red (very high) increased risk of CHD events. All results are pooled risk ratios from large meta-analyses (see. Table 1 ). Note the end point for PCOS was a composite of CHD events that included elective admissions and may result in an elevated risk. 11–15 , 28 Abbreviations : CHD, coronary heart disease; CVD, cardiovascular disease; BAC, breast arterial calcification; GHTN, gestational hypertension; GDM, gestational diabetes mellitus; PCOS, polycystic ovarian syndrome. Meta Analysis and Pooled Risk Ratios for Specific Cardiovascular Risk Factors and Cardiovascular Outcomes in Women Notes : Compilation of meta-analyses of specific CVD risk factors in women and CVD/CHD event rate or mortality. Adjusted confounders for each study are given as full, where included in all studies or partial, where included in part. Adjustment for CVD risk factors refers to one or more traditional CVD risk factor. 10–24 * – Cohort included male and female participants (matched or unmatched), ** – Approximate cohort number (exact not available), *** – Odds ratio used as a surrogate for relative risk in setting of low event rate in population. Abbreviations : CHD, coronary heart disease; CVD, cardiovascular disease. Risk ratios for traditional and non-traditional risk factors, demonstrating low (green), moderate (yellow), high (Orange) and red (very high) increased risk of CHD events. All results are pooled risk ratios from large meta-analyses (see. Table 1 ). Note the end point for PCOS was a composite of CHD events that included elective admissions and may result in an elevated risk. 11–15 , 28 Several mechanisms have been proposed to explain this sex disparity. Earlier studies suggested that women develop diabetes at a more advanced stage of metabolic dysregulation, presenting with a higher burden of cardiometabolic risk factors than men. 6 Additionally, the relative cardio-protection observed in premenopausal women without diabetes appears to be lost upon diabetes onset. 8 Treatment disparities may also play a role; women with diabetes have been shown to receive less aggressive risk factor modification and achieve poorer glycemic, lipid and blood pressure control. 31–33 This raises a second possibility, that the difference is attributable to less aggressive treatment of diabetes and metabolic syndrome in women. These findings suggest that both biological differences and clinical inertia may contribute to the observed sex difference in risk. Given its major role in the pathogenesis of coronary artery disease, diabetes should be rigorously screened for and aggressively managed in all women. Body mass index (BMI) and body composition, while appearing simple on the surface, in reality has a complex relationship with cardiovascular disease. Elevated BMI has been linked to increased CVD outcomes. A meta-analysis of over 1 million participants demonstrated each increment of 1 kg/m 2 in BMI associated with a hazard ratio of 1.04 (1.03–1.05) of incident coronary heart disease in women. 25 This would advocate the hypothesis that increase weight and/or body fat is associated with CVD. However, body composition appears to have an interesting impact on CVD risk in women – high muscle and high fat mass is associated with a lower CVD mortality, while high muscle and low-fat mass is not. In comparison, men demonstrate a lower CVD mortality with high muscle mass irrespective of fat mass. 34 The distribution of body fat itself is also predictive, with higher truncal fat in women being associated with elevated CVD risk and higher leg fat associated with reduced CVD risk. 35 Cardiometabolic disease correlates with elevated visceral adipose tissue and the elevated risk from truncal adiposity may be a reflection of this. In premenopausal women, estrogen drives lower body rather than truncal and visceral fat deposition with a reversal in this pattern post menopause. 36 While obesity is considered a marker of cardiovascular health, there are sex-based differences and perhaps a different optimal phenotype to aim for. Smoking represents one of the most significant and modifiable risk factors for cardiovascular disease. 37 While smoking prevalence among women has declined in many high-income countries, it continues to contribute substantially to preventable morbidity and morbidity worldwide, particularly in younger women and in low and middle income regions. 38 , 39 A meta-analysis involving over two million participants reported that women who smoke have a 25% greater relative risk of coronary heart disease events compared to their male counterparts. 11 Beyond cardiovascular disease, smoking increases the risk of several cancers and is associated with adverse pregnancy outcomes, including fetal growth restriction and preterm birth, enforcing the importance of encouraging smoking cessation. One proposed explanation for the heightened cardiovascular risk in women is the anti-estrogen effect of smoking. Estrogen is known to exert a protective effect on vascular endothelium and lipid metabolism. Smoking appears to disrupt estrogen bioactivity and elevate blood androgen levels, potentially accelerating vascular damage and attenuating the benefits of estrogen in premenopausal women. 40–42 Hypertension is a prevalent risk factor for cardiovascular disease (CVD) in both men and women, however, emerging evidence suggests that blood pressure impacts cardiovascular risk differently across sexes. 27 In a moderate-sized Iranian cohort of 7710 participants, predictors of hypertension at diagnosis differed by sex, with age common to both, while contraceptive use, pre-hypertension and kidney stones significant only in women. 43 The INTERHEART study showed that hypertension was amongst a group of risk factors that elevated the risk of myocardial infarction more significantly in younger women than in older women. 9 In one of the largest cohorts, with over 27,000 participants, examining sex differences in blood pressure, Ji et al observed that while hypertension increased CVD risk in both sexes, women exhibited elevated risk at a lower systolic blood pressure threshold. 44 Additionally, research indicates that while premenopausal women have a lower average blood pressure than men, this gap diminishes significantly post menopause. 45 Currently, hypertension guidelines are not sex-specific. However, given the observed differences in blood pressure patterns and associated cardiovascular risks between sexes, there is a compelling need for research to inform potential sex-specific recommendations and therapeutic targets. Kringeland et al found that in individuals in their early forties, stage 1 diastolic hypertension was more strongly linked to the development of acute coronary syndrome in women compared to men, suggesting that young women may benefit from more aggressive treatment of diastolic hypertension. 46 Amongst older women, perimenopausal women exhibit significant blood pressure variability and postmenopausal women are more prone to non-dipping nocturnal blood pressure patterns, both of which are associated with increased cardiovascular risk. 47 These observations underscore the necessity for sex-specific research to understand the underlying mechanisms of blood pressure regulation in women and to develop tailored management strategies. Dyslipidemia is a widely recognized risk factor for cardiovascular disease and a key therapeutic target. On average, a 1-mmol/L increase in total cholesterol corresponds to a similar risk in women (1.20 RR, 1.16–1.24 95% CI) as compared to men (1.24 RR, 1.20–1.28) of coronary heart disease. 26 However, in women, lipid profiles vary considerably across life stages, influenced by hormonal fluctuations and should be a consideration in interpreting and managing lipid disorders. In reproductive-age women, total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels tend to rise during the follicular phase and fall in the luteal phase, while high-density lipoprotein cholesterol (HDL-C) peaks during ovulation. The fall in LDL from follicular to luteal phase varies between 5% and 10%, while the fluctuation in HDL has been noted anywhere between 11% and 49%. 48 Early menarche has been associated with adverse lipid profiles, such as elevation of both triglycerides and LDL-C. 48 Oral contraceptives can further modify lipid metabolism, raising triglycerides and HDL-C while reducing LDL-C, depending on the estrogen potency of the pill. 49 Pregnancy also induces a physiologic rise in cholesterol and triglycerides, though its long term cardiovascular implications remain unclear. 49 Evidence suggests sex disparities in the management of dyslipidemia. Women with familial hypercholesterolemia are diagnosed later, receive less intensive lipid lowering therapy and were less likely to achieve guidelines recommended lipid targets. 50 Despite almost equal efficacy of lipid-lowering therapy in reducing cardiovascular events in both sexes, women are less likely to be offered therapy. 51 Statin discontinuation is also more common in women, which may be related to both clinician- or patient-related factors. 52 , 53 Potential reasons include a lack of awareness of CVD risk in women, both from the patient and practitioner, and an elevated rate of drug-related adverse events or intolerance. This is suggested by the literature which demonstrates a high rate of musculoskeletal side effects cited by women as a reason for cessation of lipid-lowering therapy. 54 In recent years, lipoprotein(a) has emerged as a novel biomarker of atherosclerotic risk, particularly for premature coronary artery disease. Elevated Lp(a) levels are independently associated with increased CVD risk across both general and high-risk populations. 55 Some studies have shown a correlation between Lp(a) levels and coronary artery disease amongst women. 56–58 However, in a pooled analysis of the Women’s Health Study, Women’s Health Initiative and JUPITER trials, the incremental value of Lp(a) in risk prediction for women was limited. 59 Ongoing research is needed to clarify its role in sex-specific CVD risk assessment. Cardiovascular disease has traditionally been regarded as a condition of aging and remains an independent predictor of cardiovascular events. 60 The contribution of age may in part reflect the cumulative prolonged exposure to risk factors such as hypertension and dyslipidemia. 61 , 62 Notably, in women, the rise in cardiovascular risk with age appears steeper than in men. A Finnish cohort study of 14,000 men and women found that age-related increases in coronary heart disease incidence and mortality were more pronounced in women. The role of CVD risk factors in increasing CHD risk was similar in both sexes, and the overall risk factor level was lower in women. However, risk began to plateau at 45 to 50 in men, whereas in women risk continues to sharply increase until 60 to 65. 63 The disparity is particularly evident during menopause, when withdrawal of estrogen is associated with a sudden increase in cardiovascular risk. Estrogen has well-documented vasoprotective effects, including favorable modulation of lipids and vascular function. Although hormone replacement therapy (HRT) was initially hypothesized to mitigate CVD risk during the perimenopausal period, large randomized trials such as those in the Women’s Health Initiative (WHI) demonstrated contradictory results to previous observational studies by showing an increase in vascular events with HRT. 64 , 65 This discordance is still a matter for debate; however, it may be related to a higher proportion of younger women in early menopause who enrolled in observational studies. Recent evidence suggests that there is a potential benefit in a younger subgroup but without a large enough signal to advocate change in clinical practice. 66 , 67 The transition from low to elevated risk following menopause may contribute to lower awareness and under-recognition of cardiovascular disease and risk factors in women that are pre-menopausal. This underscores the importance of assessing cardiovascular risk throughout the lifespan in women.

While many non-traditional risk factors for cardiovascular disease in women are supported primarily by observational evidence, emerging data suggests their cardiovascular effects may converge on shared biological pathways. These include endothelial dysfunction, chronic low-grade inflammation, metabolic dysregulation, vascular remodeling and microvascular disease. These are all processes that may be differentially modulated by sex hormone exposure. 68 Importantly, for several female-specific risk factors, mechanistic evidence remains incomplete and association should be interpreted as markers of heightened susceptibility rather than direct causal pathways. Several complications during pregnancy are now recognized as sex-specific risk enhancers for long-term maternal cardiovascular disease. 69 Risk enhancers, as defined in the American College of Cardiology (ACC) blood cholesterol management guidelines, are clinical features that complement the established risk models to inform decisions regarding preventative strategies. 70 The most commonly described are preeclampsia, gestational hypertension (GHT) and gestational diabetes (GDM). 16 , 71 , 72 Preeclampsia is theorized to induce metabolic, endothelial and vascular dysfunction and has been associated with a higher frequency of spiral arterial lipid deposition. 73 , 74 Even after adjustment for traditional risk factors, it remains strongly associated with elevated long-term risk of cardiovascular death, coronary artery disease, heart failure and stroke. 17 , 30 Large population-based studies have also demonstrated a higher prevalence and earlier onset of subclinical atherosclerosis. Women with a history of preeclampsia exhibit premature and increased development of coronary artery calcification at ages 45 to 50 compared to women without. 75 In addition to this independent risk, affected women are also more likely to develop cardiometabolic risk factors – including hypertension, elevated body mass index and insulin resistance, suggesting a prolonged trajectory of metabolic dysfunction. 76 GDM and GHTN have both been implicated in the development of chronic diseases such as renal dysfunction, liver disease and cardiovascular diseases. 77–81 A 2019 meta-analysis demonstrated a two-fold increased CVD risk in women with prior GDM, even in those who do not progress to overt type 2 diabetes mellitus (T2DM). 18 In the absence of GDM, hyperglycemia also predicts future CVD and may be part of the spectrum of disease. 79 , 82 Hypertensive disorders during pregnancy other than preeclampsia are also a significant consideration for future CVD risk given an incidence of 10%. 83 Women with hypertension in a first pregnancy have an increased risk of future hypertension, stroke and ischemic heart disease. 17 , 84–88 However, the risk associated with GHTN appears to be less pronounced than that of preeclampsia. 14 This observation aligns with the concept that preeclampsia represents a more severe phenotype along the spectrum of hypertensive disorders of pregnancy, characterized by systemic vascular and end-organ involvement. Furthermore, while the elevated CVD risk in both conditions is partially mediated through co-existing cardiovascular risk factors, preeclampsia shows a greater relative risk and a higher proportion of that risk which is not attributable to this. 89 Other pregnancy outcomes, such as miscarriage, stillbirth and preterm birth, are increasingly recognized as potential predictors of future cardiovascular events. A recent meta-analysis demonstrates that stillbirth and recurrent miscarriage are significantly associated with increased risk of coronary artery disease. 90 Less commonly studied factors, such as parity and fertility therapy, have shown heterogenous results related to CVD over the past two decades. 91–93 Recent data however, leans towards an absence of a relationship and safety of fertility therapy from a cardiovascular perspective. A cohort of 27,000 women demonstrated an adjusted relative risk of 0.93 (0.82 to 1.05 95% CI) of CVD hospitalization with a history of fertility treatment. 94 In regard to parity, recent long-term outcomes from the WHI did not demonstrate any excess risk at differing parity levels. These results appear to conflict with previous evidence demonstrating an increased risk; however, this may be explained by the age of the first pregnancy. Parity of three to five was associated increased CVD events, but this association was not significant when adjusted for age at first child birth. Furthermore, an age of less than 20 and 20 to 24 at first child birth was associated with a 32.3% and 11.4% elevated risk of CVD, respectively, compared to women who first gave birth at ages 25 to 29. 95 This data suggests that age during first pregnancy rather than parity may be a more relevant CVD risk factor. In a 2023 Swedish cohort study, of over 2 million women, participants were evaluated for pregnancy-related complications and CVD over a median follow-up period of 22.7 years. Adjusted hazard ratios for cardiovascular mortality were elevated for several pregnancy-related conditions: preeclampsia (HR 2.10; CI 1.47–2.99), gestational hypertension (HR 1.79; CI 1.20–2.66), gestational diabetes (HR 3.03; CI 1.49–6.16), preterm birth (HR 1.84; CI 1.38–2.44), small for gestational age (HR 1.77; CI 1.19–2.64) and stillbirth (HR 3.14; CI 1.81–5.44). Notably, while these results were adjusted for multiple confounders, they did not include dyslipidemia. Nevertheless, these findings underscore the importance of incorporating pregnancy history into cardiovascular risk assessment and better post-natal screening. 96 Menstrual cycle abnormalities have recently gained recognition as a sex-specific risk factor for CVD. Menopause has been the most studied area, with estrogen deficiency hypothesized to increase CVD risk. 97 , 98 However, as noted previously, randomized controlled trials – including the Women’s Health Initiative – found that hormone replacement therapy (HRT) does not reduce cardiovascular events. Consequently, current guidelines recommend HRT for symptomatic relief, not for CVD prevention. 99 , 100 Menstrual cycle irregularity is increasingly recognized for its links to metabolic dysfunction and is associated with insulin resistance, low-grade inflammation and cardiometabolic syndrome. 101–103 Although results from cohort studies are variable, overall evidence supports a relationship between menstrual irregularity and future cardiometabolic risk. 104 A recent large cohort study demonstrated that both short (35 days) cycle lengths were associated with increased risk of coronary heart disease and atrial fibrillation. 105 History of early or late menarche has also been shown to be associated with CVD risk albeit with a small strength of association. Estrogen exposure does not appear to account for this although there does appear to be a correlation with markers of inflammation. 106 Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women and is associated with cardiometabolic conditions including insulin resistance, dyslipidemia, obesity and type 2 diabetes. 107 The association between PCOS and CVD varies amongst studies often attributed to the confounding from traditional CVD risk factors. Given its increasing prevalence, PCOS is an important consideration in women’s long-term cardiovascular health. 108 , 109 Three separate meta-analyses have now confirmed an increased risk of both cardiovascular disease and cardiovascular events among women with PCOS, though no clear excess in cardiovascular mortality was observed. 28 , 29 , 110 Longitudinal studies have demonstrated that this risk emerges as early as young adulthood and may be independent of body mass index (BMI). 111 Whether PCOS independently contributes to CVD or does so primarily through metabolic dysfunction remains an area of active investigation. Management of PCOS includes a combination of pharmacological and lifestyle interventions often involving use of combined oral contraceptives (COC). 112 Early studies raised concern for an increased thrombotic risk with COC use and caused caution regarding usage. 113 Over the last decade, studies have had conflicting results regarding the magnitude of thrombotic and CVD risk associated with COC. 114 Recent large-scale cohort data from the United Kingdom found the use of COC was not associated with an increased risk of CVD and may potentially be protective in patients with PCOS. 115 These findings offer reassurance in the continued use of COC for symptom control when clinically appropriate. Metformin is also frequently used in PCOS, particularly in women with insulin resistance or metabolic syndrome. 112 Clinical trial evidence of metformin use in patients with PCOS suggests a significant reduction in diastolic blood pressure and total cholesterol. 116 Given the known association between metabolic diseases and PCOS highlights metformin as a therapy of interest outside of traditional indications. Although autoimmune diseases (AIDs) are not inherently sex-specific, they are significantly more prevalent in women, comprising up to 80% of diagnosed cases and they represent an important sex-specific cardiovascular risk modifier. 117 These conditions are associated with accelerated atherosclerosis and microvascular dysfunction, likely mediated by chronic inflammation, immune cell activation and subsequent endothelial injury. 118 Cardiovascular events are a known phenomenon in autoimmune disease and often present at a younger age compared to the general population. In a recent cohort study, Restivo et al reported an increased relative risk of symptomatic cardiovascular events with lupus (1.98, 95% CI 1.18–3.31) and rheumatoid arthritis (1.55, 95% CI 1.18–2.02). 119 Systemic sclerosis has also been associated with a fourfold increased CVD risk, potentially driven by vascular fibrosis and a high incidence of arrhythmias. 120 Pooled odds ratios demonstrate an elevated risk in patients with autoimmune disease and hypertension (1.67, 95% CI 1.58–1.76) and ischemic heart disease (1.38, 1.21–1.57). 121 The burden of multiple autoimmune diseases compound this risk, with hazard ratios rising from 1.41 for a single condition to 2.73 for two or more. 122 Although autoimmune-related cardiovascular risk may be lower than that conferred by hypertension or diabetes, it is now recognized as a clinically relevant non-traditional risk enhancer, particularly in young women. AIDs are among few non-traditional female-specific risk factors currently integrated into cardiovascular risk prediction models. For instance, rheumatoid arthritis (RA) is incorporated in the QRISK-2 calculator, while high sensitivity C-reactive protein (hsCRP) is included in the Reynolds Risk Score. 123 , 124 The Expanded-Risk-Score in RA and the Trans-Atlantic Cardiovascular Consortium for RA Score are two smaller but RA specific risk models that account for more extensive disease features; however, they have not proven incremental benefit beyond traditional scores. 125 , 126 While not female specific, breast cancer is a condition that predominantly impacts women and therefore should be a sex-specific consideration. Long-term cardiovascular outcomes following breast cancer have become a growing concern, particularly due to the cardiotoxic effects of anthracycline-based chemotherapy, HER-2 targeted therapy and thoracic radiotherapy. Survivors of breast cancer are at an increased risk of CVD with HR of 1.32 in the first 10–15 years although they have no increased risk beyond 15 years. 127 A 2019 meta-analysis further identified a modest rise in cardiovascular mortality during the first year post-treatment (HR 1.09). 19 Furthermore, women with advanced breast cancer stage at diagnosis are more likely to have prevalent cardiovascular disease. 128 Interestingly, modification of cardiovascular health also improves cancer-related mortality outcomes, suggesting a dual benefit for CVD risk monitoring in these patients. 129 Although this excess risk is less pronounced than that associated with traditional risk factors, it is clinically relevant given the lifetime incidence of breast cancer in women, estimated at 12.4%. 130 Contemporary cardio-oncology guidelines now recommend early cardiovascular risk assessment and proactive monitoring of cardiac function in women undergoing breast cancer treatment, particularly in the early years following diagnosis. 131 Breast arterial calcification (BAC) identified on screening mammography, is a novel marker of vascular calcification that is increasingly recognized for its role in cardiovascular risk stratification in women. Unlike coronary artery disease, which involves intimal plaque deposition, BAC presents as linear or sheet-like calcification in the medial layer of arteries, similar to cerebrovascular and peripheral arterial disease. 132 , 133 Despite these histological differences, numerous studies have shown an association with cardiovascular disease and certain cardiometabolic risk factors. A 2015 meta-analysis reported an adjusted hazard ratio of 1.32 to 1.44 for the association between BAC and coronary heart disease, with BAC also associated with age, diabetes and chronic kidney disease. 134 While some smaller studies have found no association, the majority of studies in the past two decades have supported the relationship. 135 Mammography is slowly becoming a potential tool for cardiovascular screening with the combination of BAC and low breast density (BD), which correlates with cardiometabolic disease. Combination of BAC and BD has an independent association with coronary artery disease and has utility by improving standard coronary risk prediction models. 136 Artificial-intelligence-based quantification of BAC is also possible and research demonstrates an independent and incremental association between BAC scores with mortality and CVD. Importantly, BAC is detectable on routine screening mammograms, offering a non-invasive, low risk and cost-effective opportunity for cardiovascular assessment at a population level. 135 BAC holds promise as an imaging specific personalized risk marker and its additive value to traditional and non-traditional risk factors is a subject of ongoing exploration. These non-traditional risk factors are discussed as discrete entities for clarity; however, cardiovascular risk in women is a cumulative and dynamic process across the life span. Female-specific exposures frequently coexist with each other and traditional cardiometabolic risk factors. Pregnancy-related complications, for example, may unmask underlying metabolic or vascular vulnerability that subsequently predisposes to risk of obesity, hypertension or diabetes which accelerates cardiovascular disease later in life. Recognition of this interaction is important in understanding that both female-specific risk factors are not used in isolation but as an adjunct to traditional risk modelling.