Cardiovascular Health in Women-Across the Lifespan.

While CVD mortality continues to decline across all age groups, the rate of decline in younger women has plateaued in recent years [ 53 ]. Table  2 highlights pertinent issues related to managing coronary syndromes in young women. Women with acute coronary syndrome (ACS) often have symptoms such as weakness, nausea, palpitations, or back pain, leading to delays in seeking medical care, often 2–5 h later than men [ 1 ]. These delays, compounded by underutilisation of guideline‐directed therapies and invasive interventions, contribute to poorer outcomes. Important issues in the management of coronary syndromes in young women. Less plaque rupture, More plaque erosion Less plaque rupture, More plaque erosion Need for intravascular imaging for improved understanding but low uptake due to cost/clinical workflow reasons and no routine Medicare rebate Need for intravascular imaging for improved understanding but low uptake due to cost/clinical workflow reasons and no routine Medicare rebate Inaccurate or incomplete diagnosis with lower uptake of guideline directed therapy in INOCA/ANOCA Inaccurate or incomplete diagnosis with lower uptake of guideline directed therapy in INOCA/ANOCA Need for interventional testing (CMD and vasospasm) and/or cardiac MRI for more complete diagnosis. Need for interventional testing (CMD and vasospasm) and/or cardiac MRI for more complete diagnosis. Coronary microvascular dysfunction (CMD) can be detected as reduced coronary flow reserve (CFR) on positron emission tomography or cardiac MRI or invasive techniques Coronary microvascular dysfunction (CMD) can be detected as reduced coronary flow reserve (CFR) on positron emission tomography or cardiac MRI or invasive techniques Reduced uptake due to costs, time required for testing and lack of Medicare rebate Reduced uptake due to costs, time required for testing and lack of Medicare rebate Coronary spasm is defined by reversible vascular smooth muscle hypercontractility resulting in > 90% narrowing of the coronary artery confirmed on coronary provocative testing with intracoronary acetylcholine Coronary spasm is defined by reversible vascular smooth muscle hypercontractility resulting in > 90% narrowing of the coronary artery confirmed on coronary provocative testing with intracoronary acetylcholine Need for randomised trials Need for randomised trials Myocarditis The cause is commonly viral in young patients but could be related to other infections, immune‐chemotherapy or recreational drug use Presentation may be with arrhythmias and shock Early echo will guide progress and need for pulsed steroids + transfer to a specialist transplant centre for cardiac MRI and biopsy Presentation may be with arrhythmias and shock Early echo will guide progress and need for pulsed steroids + transfer to a specialist transplant centre for cardiac MRI and biopsy Spontaneous coronary artery dissection (SCAD) Associated with physical, emotional stress or hormonal stressors (use of contraceptive pills or hormone replacement therapy). Other risk factors include fibromuscular dysplasia (FMD), extracoronary vascular arteriopathies and heritable connective tissue disorders such as Marfan, Ehlers‐Danlos and Loeys‐Dietz syndromes. SCAD is known to be familial in some cases and a common SCAD risk allele has been identified at the PHACTR1 (phosphatase and actin regulator 1) /EDN1 (endothelin 1) locus Gradually improving recognition Use of imaging is low for fear of extending dissection Prolonged observation required Conservative management is first‐line Gradually improving recognition Use of imaging is low for fear of extending dissection Prolonged observation required Conservative management is first‐line Registry inclusion FMD screening Need for dedicated rehab Advise re genetic testing and utility currently restricted to multivessel or recurrent SCAD (cost vs. benefit) Need for randomised trials Registry inclusion FMD screening Need for dedicated rehab Advise re genetic testing and utility currently restricted to multivessel or recurrent SCAD (cost vs. benefit) Need for randomised trials Young women with ACS have distinct comorbidity profiles compared to men. Conditions including diabetes and hypertension confer significantly higher risk of AMI in women than in men [ 54 ]. Autoimmune diseases, more common in women, further elevate CVD risk. Sex‐specific risk factors like PCOS, premature menopause, and pregnancy complications also accelerate atherosclerosis. Cancer treatments can contribute to CV risk [ 55 ]. Indigenous women in Australia are disproportionately affected, being up to twice as likely to experience CVD and to die from coronary heart disease or stroke [ 56 ]. Myocardial infarction with non‐obstructive coronary arteries (MINOCA) is increasingly recognised in women presenting with AMI [ 57 ] (15% women vs. 8% men) [ 58 ] and can have several causes. Intravascular imaging and cardiac MRI (CMR) can be used to establish underlying aetiology in majority of MINOCA cases [ 59 ]. SCAD is a leading cause of ACS and MINOCA [ 60 , 61 , 62 ] in young women [ 63 ] of mean age 42–53 years [ 64 ]. Strong female preponderance and increased prevalence of SCAD in pregnancy suggests hormonal links to pathophysiology [ 61 ]. Diagnosis is typically by coronary angiography and management with conservative therapy being the preferred option. In < 10% of patients, SCAD can progress within the first 3–6 days [ 64 ], thus in‐hospital observation is recommended. Coronary intervention is reserved for high‐risk cases. Patients are cautioned to avoid extreme or elite competitive sports, heavy lifting or activities that require straining [ 61 ]. In a recent Australia‐New Zealand registry, recurrence was noted in 3.6% over 18 months of follow‐up [ 65 ]. Coronary microvascular dysfunction (CMD) is another key cause of MINOCA. CMD can affect epicardial and/or microvascular endothelial circulation, which reduces myocardial perfusion [ 66 ]. CMD can be detected as reduced coronary flow reserve (CFR) on positron emission tomography (PET) or CMR or using invasive techniques. Treatment based on interventional testing can improve quality of life [ 67 ]. Coronary spasm accounts for ~20% of MINOCA and is more common in men than women [ 68 ], characterised by reversible vascular smooth muscle hypercontractility [ 69 ]. Coronary spasm typically occurs at rest, but can be precipitated by stress, cold weather and hyperventilation. Diagnosis can be confirmed on invasive angiography and provocative testing with intracoronary acetylcholine [ 59 ]. Treatment includes calcium‐channel blockers nitrates and Nicorandil, and avoidance of triggers [ 59 ]. Nicorandil is not currently licensed in the US [ 70 ]. Atrioventricular (AV) node re‐entrant tachycardia is the most common cause for paroxysmal SVT and is twice more common in women than men [ 71 ]. Women have a greater tendency for atrial tachycardia. Automaticity is more common in premenopausal than postmenopausal women. Women are more likely to be diagnosed later, often being mislabelled with stress or anxiety and are more likely to choose medications over definitive therapy such as ablation [ 71 , 72 ]. Men have a higher prevalence of left ventricular outflow tract (LVOT), mitral, tricuspid, ventriculo‐septal and non‐outflow tract ventricular tachycardia (VT) than women. In terms of sex specific triggers, 59% of women in one survey reported right ventricular outflow tract (RVOT) VT initiation during periods of hormonal flux (premenstrual, gestational, perimenopausal or with administration of contraceptive pills) [ 71 ]. Medications including beta‐blockers or calcium‐channel blockers [ 73 ] and/or catheter ablation are recommended. After puberty, females with Long QT syndrome (LQT) 1 have a higher risk of ventricular arrhythmias [ 71 ]than men. Women with LQT2 have higher risk of arrhythmias pre and post puberty. This risk increases in the postpartum period. Implantable cardioverter‐defibrillator should be considered in women with LQT2 and a QTc> 500 ms. There is no clear sex difference in arrhythmia risk with LQT3. Although arrhythmogenic right ventricular cardiomyopathy (ARVC) affects an equal number of men and women genetically, more men than women manifest the phenotype and present with VT and sudden death [ 71 , 74 ]. POTS is one form of dysautonomia with orthostatic intolerance primarily affecting young women [ 75 ]. In a large observational data set of 8919 patients with POTS, ~94% were female [ 76 ]. Diagnostic delay was longer in women (1.5 y vs. 0.92 y in men, p  < 0.001) and both sexes saw a median number of 5 doctors before diagnosis. Symptoms include light‐headedness, palpitations and chest pain. More women experience gastrointestinal, allergic and neurological symptoms. More women report a preceding trigger such as a viral infection. More men report a family history of POTS. Diagnosis is clinical, although tilt‐table testing can be used as an adjunct to detect heart rate elevation of ≥ 30 bpm without fall in blood pressure on standing, with symptoms of orthostatic intolerance [ 77 ]. Treatment includes salt and electrolyte replacement, use of compressive wear, and medications such as beta blockers, ivabradine, selective‐serotonin‐reuptake inhibitors, fludrocortisone and midodrine. Rheumatic MS is the most common valvulopathy in young women [ 78 ]. AIHW data indicate that in 2019, 39% of RHD individuals were < 25 years of age and 66% were women [ 79 ]. Treatment of rheumatic MS includes diuretics, anticoagulation for atrial fibrillation and balloon valvulotomy or mitral valve replacement in severe cases.

Cardiovascular disease is the most common cause of death in older women. Table  3 shows the issues related to coronary and VHD in older women. Important issues in management of coronary syndromes and valvular disease in older women. Symptoms considered atypical compared to men, including weakness, dyspnoea, malaise, nausea, palpitations or back pain are noted in women Symptoms considered atypical compared to men, including weakness, dyspnoea, malaise, nausea, palpitations or back pain are noted in women Risk of delays due to social dependence Social isolation and loneliness increase risk Risk of delays due to social dependence Social isolation and loneliness increase risk ACS Presentations: Acute myocardial infarction MINOCA (Myocardial infarction with no obstructive coronary disease) Takotsubo's cardiomyopathy Acute myocardial infarction MINOCA (Myocardial infarction with no obstructive coronary disease) Takotsubo's cardiomyopathy Transcatheter aortic valve implantation (TAVI) is a definitive alternative to surgical aortic valve replacement (SAVR) with reduced morbidity. Bleeding risk remains higher than men, although improved technologies have reduced vascular risks Transcatheter aortic valve implantation (TAVI) is a definitive alternative to surgical aortic valve replacement (SAVR) with reduced morbidity. Bleeding risk remains higher than men, although improved technologies have reduced vascular risks Septal bulge and left ventricular outflow tract gradient can preclude TAVI with need for alcohol septal ablation/surgical myectomy + SAVR. Bicuspid AS is discussed on a case‐by‐case basis for TAVI versus SAVR. Emphasis is on lifetime planning in patients that may require repeat aortic valve interventions subsequently Septal bulge and left ventricular outflow tract gradient can preclude TAVI with need for alcohol septal ablation/surgical myectomy + SAVR. Bicuspid AS is discussed on a case‐by‐case basis for TAVI versus SAVR. Emphasis is on lifetime planning in patients that may require repeat aortic valve interventions subsequently Mitral valve repair is the gold standard for primary MR. Mitraclip and transcatheter edge‐to‐edge repair (TEER) can be considered in high risk surgical cases, to improve MR intensity, heart failure and improve New York Heart Association dyspnoea class and quality of life. Requires referral to select specialist centres. Mitral valve repair is the gold standard for primary MR. Mitraclip and transcatheter edge‐to‐edge repair (TEER) can be considered in high risk surgical cases, to improve MR intensity, heart failure and improve New York Heart Association dyspnoea class and quality of life. Requires referral to select specialist centres. Surgery for isolated severe TR is uncommon due to morbidity related to recovery. TEER is a novel option in high surgical risk patients that may offer reduced frequency of right heart failure and improved quality of life. Requires referral to select specialist centres. Randomised data for mortality outcomes are lacking. Surgery for isolated severe TR is uncommon due to morbidity related to recovery. TEER is a novel option in high surgical risk patients that may offer reduced frequency of right heart failure and improved quality of life. Requires referral to select specialist centres. Randomised data for mortality outcomes are lacking. Atherosclerotic CVD rises in women with age, especially after 70 years [ 115 ]. Women present with ACS later than men, often with higher overall comorbidities [ 58 , 116 ] and more non‐obstructive CAD [ 58 , 117 , 118 ]. Management is challenging due to under‐recognition, underdiagnosis and under‐representation in clinical trials [ 117 , 119 ]. Elderly women are less likely to report typical chest pain/any chest pain with a longer symptom to balloon time than males [ 120 ]. Language barrier, frailty and cognitive decline [ 121 , 122 ] further complicate care. A US study of more than 57,000 older women, found that social isolation and loneliness increased CVD risk by 13% and 27% higher risk of incident CVD respectively compared to counterparts with less social isolation and loneliness. Aging women show faster increase in coronary calcification, calcified plaque progression and calcific nodules [ 118 , 123 ]. Women are more vulnerable to endothelial dysfunction and microvascular remodelling [ 118 ]. Following ACS, females across the lifespan receive fewer interventions including PCI and mechanical circulatory support. Females > 85 years are significantly less likely to undergo CABG [ 124 ]. They are also less likely to be prescribed guideline‐directed therapy for ACS including ACEi, beta blockers, aspirin and statins [ 124 , 125 ]. Women typically have higher risk of in‐hospital and short term mortality, and readmission at 30 days and 2 years post‐ACS, however, adverse events in older women are comparable to men [ 116 ]. A meta‐analysis looking at sex differences proposes that observed differences in mortality vary depending on clinical presentation and angiographic disease [ 58 ]. Ageing women have a greater increase in arterial stiffness compared to males, and more rapid blood pressure elevation [ 118 ], with hypertension being more prevalent among women than men after the age of 65 years [ 118 ]. The latest European Society of Cardiology guidelines for hypertension categorise recommendations for managing hypertension in older and frail patients [ 126 ]. HF phenotypes differ according to gender; women have a higher prevalence of heart failure with preserved ejection fraction (HFpEF) [ 117 , 127 , 128 ]. While ischaemia is a significant cause in males, hypertension and diabetes are key contributors in women [ 117 , 127 ]. Women with heart failure tend to be older [ 117 ], have greater comorbidities [ 128 ], and report worse symptoms and quality of life [ 127 , 128 ]. Despite this, women with heart failure have lower rate of cardiovascular death in women, likely due to significantly lower risk of sudden cardiac death and higher non‐cardiovascular mortality [ 127 ]. The TOPCAT trial (The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) [ 128 ], and I‐PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial [ 129 ] found women to have lower rates of cardiovascular mortality, HF hospitalisations and all‐cause mortality compared to men. Guidelines do not differentiate guideline‐directed medical therapy by gender [ 130 ] but optimal doses in older adults and whether doses should be adjusted by sex remain unclear. BIOSTAT‐CHF a prospective European study of patients with HFrEF showed that men achieved the lowest risk of adverse CV outcomes at 100% of guideline‐directed doses, whereas women reached 30% risk reduction at 50% of the guideline‐directed doses with no additional benefit at higher doses [ 131 ]. Current evidence does not support withholding medications or use of optimal doses in frailty. It remains important to tailor treatment to and be aware that optimal doses may be lower than those tolerated by younger populations studied in trials [ 130 ]. Pulmonary artery hypertension (PHT) is an under‐diagnosed cause for dyspnoea in women. Group 1 PHT is more prevalent in women [ 132 ]. While PHT can be related to left heart disease or lung disease, formal testing with right heart catheterisation and referral to specialist centres is required to identify suitability for vasodilator medications [ 133 ]. AF incidence increases with age in both sexes reaching 30.4 per 1000 patient years in women by 85–89 years of age [ 134 ]. Women have higher prevalence of hypertension and valvular disease, with higher left atrial dimensions. Female sex is an independent risk factor for stroke in AF [ 134 ] yet women are undertreated with anticoagulation for stroke prophylaxis. In a Canadian AF registry it was found that in patients > 75years of age, women with > 1 stroke risk factor were less likely to be on warfarin than males [ 135 ]. However women on warfarin were also three times more likely to experience a major bleed compared to males [ 135 ]. Similarly, women were less likely to receive a direct oral anticoagulant (DOAC) even when eligible with low bleeding risk (CHA 2 DS 2 VASc score of ≥ 2 and HAS‐BLED score of ≤ 3) [ 136 ]. Women also had a higher ischaemic stroke risk and lower intracranial haemorrhage compared to men, in this study which was partially due to anticoagulation disparities [ 136 ]. Mitral valve prolapse (MVP) is more common in women [ 78 ] and is more likely to be anterior or bileaflet prolapse [ 137 ]. Women with severe MR often do not reach echocardiographic parameters for surgical interventions as recommendations in guidelines are based on male populations and are not indexed for body surface area [ 137 ]. Consequently, women have later surgical referrals, undergo mitral valve surgery less frequently and have higher long‐term mortality [ 78 , 137 ]. While transcatheter edge‐to‐edge repair (TEER) improves clinical outcomes irrespective of sex compared to guideline‐directed medical therapy alone, the reduction of HF hospitalisations was lower in women beyond the first year after treatment [ 78 ]. Randomised trial data in severe symptomatic aortic stenosis have shown equal prevalence in high‐risk older women and men, with women demonstrating excellent outcomes with reduced morbidity after transcatheter aortic valve intervention compared to surgical aortic valve replacement [ 138 ].

There is growing recognition that CVD prevention, treatment, and management require a sex‐specific approach. Table  4 lists some future recommendations for the management of CVD in women. Figure  3 represents the central graphic for CV issues over the lifespan of a woman. Future recommendations for the management of cardiovascular disease in women. Design studies with adequate female representation and powered analyses. Explore under‐researched areas (e.g., non‐obstructive disease, SCAD, and device studies). Provide detailed informed consent processes and support, including interpreters and multilingual materials for culturally and linguistically diverse (CALD) patients. Aim for equal representation of women, including older women, and systematically screen to ensure inclusion. Offer alternatives to face‐to‐face follow‐up, such as electronic, text, or phone consultations. Ensure diversity among research staff, including more women. Design studies with adequate female representation and powered analyses. Explore under‐researched areas (e.g., non‐obstructive disease, SCAD, and device studies). Provide detailed informed consent processes and support, including interpreters and multilingual materials for culturally and linguistically diverse (CALD) patients. Aim for equal representation of women, including older women, and systematically screen to ensure inclusion. Offer alternatives to face‐to‐face follow‐up, such as electronic, text, or phone consultations. Ensure diversity among research staff, including more women. Involve specialists for non‐obstructive disease and SCAD. Refer for complete interventional diagnostic testing in in non‐obstructive disease patients with recurrent symptoms. Involve specialists for non‐obstructive disease and SCAD. Refer for complete interventional diagnostic testing in in non‐obstructive disease patients with recurrent symptoms. Reduce metabolic risks before pregnancy planning. Monitor CV risks during pregnancy (e.g., hypertension, diabetes, intrauterine growth restriction [IUGR], preterm labour). Provide longitudinal follow‐up postpartum to monitor for early CV disease development. Link postpartum women with metabolic complications of pregnancy to cardiology clinics for continued care. Reduce metabolic risks before pregnancy planning. Monitor CV risks during pregnancy (e.g., hypertension, diabetes, intrauterine growth restriction [IUGR], preterm labour). Provide longitudinal follow‐up postpartum to monitor for early CV disease development. Link postpartum women with metabolic complications of pregnancy to cardiology clinics for continued care. Perform careful risk assessment and aggressive primary prevention through risk factor modification. Consider hormone therapy for disabling vasomotor symptoms. Perform careful risk assessment and aggressive primary prevention through risk factor modification. Consider hormone therapy for disabling vasomotor symptoms. Central illustration—Cardiovascular issues over the lifespan of a woman. CVD risk factors often emerge in adolescence, underscoring the importance of early identification and prevention of atherosclerosis, by encouraging healthy lifestyles in teenagers, and their families [ 139 ]. Interventions should focus on the overall risk trajectory, with particular emphasis on vulnerable populations such as indigenous women. Women are less likely than men to discuss heart health with their general practitioner or undergo heart health checks, highlighting the need for targeted policy and education campaigns to raise awareness among both women and their clinicians. Female‐specific risk factors and impact on metabolism should be addressed before pregnancy planning [ 140 ]. Linking postpartum women with cardiology clinics for long‐term follow‐up is critical, as is ensuring that women with modifiable risk factors receive optimal care. Perimenopausal management with hormone replacement therapy (HRT), particularly for vasomotor symptoms, should not be discouraged. National health metrics should prioritise early presentation and reduced symptom‐to‐treatment times, with hospitals held accountable for these targets. The term atypical chest pain should be phased out and women should be considered for all presenting symptoms in the context of their risk factors [ 141 ]. Regular audits of guideline‐directed medical therapy uptake in women across all age groups are essential. Clinical research must increase the inclusion of women, accounting for caregiving roles and other barriers. Major funding bodies now mandate the inclusion of women and minorities in trials, with analyses of sex and racial differences. Journals should further support this policy by requiring authors to address sex and sex differences in their publications. The growing recognition of persistent sex‐based disparities in CVD is driving vital advancements in research, clinical practice, public awareness, and health policy.

Pregnancy triggers physiological adaptations to ensure adequate uteroplacental blood flow [ 23 ], including increase in cardiac output and systemic vasodilation, most marked in the first trimester [ 23 , 24 ]. Hormonal, metabolic and immunological changes also occur [ 25 ]. Pregnancy complications including gestational diabetes (GDM), pre‐eclampsia (PE), preterm birth, intrauterine growth restriction, stillbirth and placental abruption increase future CVD risk [ 26 ]. PE increases heart failure (HF) risk fourfold and coronary artery disease (CAD) twofold [ 27 ]. GDM raises type 2 diabetes (T2DM) and CVD [ 28 ] risk. Assisted reproductive therapies may also increase CVD risk [ 29 , 30 , 31 ], due to physiological changes causing a prothrombotic state and endothelial dysfunction. Around 4% of pregnancies worldwide are complicated by cardiac disease. CVD is the leading cause of pregnancy‐related deaths [ 32 ]. Figure  1 lists current guideline recommendations for management of CAD, arrhythmias, heart failure and adult congenital heart disease (ACHD) during pregnancy. Table  1 shows the risk‐stratified management of ACHD, and valvular presentations in pregnancy. Current guideline recommendations for management of cardiovascular disease during pregnancy. Cardiovascular disease in pregnancy. Pulmonary stenosis (small/mild) Patent ductus arteriosus (small/mild) Mitral valve prolapse (small/mild) Successfully repaired simple shunt defects (ASD, VSD, PDA, APVR) Unrepaired ASD or VSD Repaired tetralogy of fallot Turner syndrome without aortic dilatation Pulmonary stenosis (small/mild) Patent ductus arteriosus (small/mild) Mitral valve prolapse (small/mild) Successfully repaired simple shunt defects (ASD, VSD, PDA, APVR) Unrepaired ASD or VSD Repaired tetralogy of fallot Turner syndrome without aortic dilatation Systemic right ventricle (transposition of the great arteries) Cyanotic lesions without pulmonary hypertension Fontan‐type circulation. Marfan syndrome without aortic dilation Aortic dilation < 45 mm in bicuspid aortic valve aortopathy Repaired coarctation Systemic right ventricle (transposition of the great arteries) Cyanotic lesions without pulmonary hypertension Fontan‐type circulation. Marfan syndrome without aortic dilation Aortic dilation < 45 mm in bicuspid aortic valve aortopathy Repaired coarctation Pulmonary arterial hypertension (of any cause) Eisenmenger syndrome. Pulmonary arterial hypertension (of any cause) Eisenmenger syndrome. As well as increasing heart rate and cardiac output, pregnancy is associated with increased plasma catecholamines, adrenergic receptor sensitivity, atrial stretch and end‐diastolic volumes due to increased stroke volume [ 33 ]. This increases awareness of benign palpitations and increases arrhythmia risk in the setting of pre‐existing substrate. Arrhythmia risk is highest in the 3rd trimester [ 34 ] and is increased in those with prior history of arrhythmias and ACHD [ 35 ]. Premature atrial and ventricular complexes and non‐sustained arrhythmias occur in ~50% of pregnant women with palpitations [ 33 , 36 ]. AF is more common in those with underlying heart disease [ 37 ]. Current guidelines suggest routine anticoagulation with low weight molecular heparin [ 38 ]. AMI in pregnancy is rare, occurring in 1 per 16,000 deliveries [ 39 ]. with STEMI in 75% of cases [ 40 ]. Spontaneous coronary artery dissection (SCAD) is most common in the third trimester and postpartum [ 39 ]. Coronary angiography is the gold standard diagnostic tool [ 41 ]. HF is the leading cause of maternal morbidity and mortality [ 42 ] with Peripartum cardiomyopathy (PPCM) being the most common cardiomyopathy (68%). PPCM presents with LV ejection fraction (LVEF) < 45% occurring near delivery or post‐partum, in the absence of other causes [ 43 ]. Risk factors include age, PE, multiparity, multifetal gestation, hypertension, diabetes and obesity [ 43 ]. Complications include cardiogenic shock, thromboembolism, arrhythmias and sudden cardiac death [ 43 ]. Management recommendations are generally extrapolated from other HF cohorts [ 38 ]. ACE‐inhibitors, angiotensin receptor blockers and aldosterone antagonists are contraindicated in pregnancy due to risk of foetal malformations [ 42 ]. Women should continue HF medications until LV recovery. Contraception counselling is essential due to relapse risk and increased mortality risk in those with persistent LV dysfunction with subsequent pregnancies [ 44 ]. Given increased risk of thromboembolism with LV dysfunction, oestrogen‐based contraceptives should be avoided [ 44 ]. Implanon and Mirena are preferred. In women with valvular heart disease (VHD) significant haemodynamic changes occur throughout pregnancy and serial monitoring is warranted. Mitral stenosis (MS) secondary to RHD is the most common valvulopathy [ 45 ]. Common complications include HF, arrhythmias and thromboembolism. Vaginal delivery is preferred given less blood loss, faster recovery and reduced thrombotic and infection risk. Epidural is preferred over spinal anaesthesia given lower risk of hypotension. Maternal effort can cause a Valsalva effect which transiently reduces cardiac output. Thus, assisted second stage of labour is preferred in those with moderate‐severe obstructive left‐sided valvular lesions. Prevalence of ACHD in women of child‐bearing age is rising [ 46 ]. Validated risk‐stratification scores aid assessment [ 46 ] and preconception evaluation is crucial [ 47 ]. Cardiopulmonary exercise testing can determine cardiopulmonary reserve and functional status. Generally, risk factors include poor functional status, cyanosis, LVEF < 40%, left heart obstruction and prior history of complications [ 48 ]. ACHD risk in the foetus is also increased (3%–12% vs. 0.8% in mothers without ACHD) and a foetal echocardiogram at 18–22 weeks gestation is warranted [ 46 ]. ACHD also increases risk of postpartum haemorrhage, pre‐term delivery and small‐for‐gestational age babies [ 46 ]. Delivery plan should be outlined by 28 weeks [ 46 ] preferring vaginal delivery with an assisted second stage and epidural over a spinal anaesthetic [ 46 ]. Caesarean section is considered in high‐risk patients only. Table  1 shows low, moderate and high‐risk lesions and management options [ 46 , 47 , 48 , 49 ]. Implanon and Mirena are also first‐line contraception in this group [ 50 ]. Multidisciplinary collaboration across cardiology, obstetrics, maternal‐foetal medicine, anaesthetics and primary care is crucial. Preconception counselling should include risk assessment and optimisation. Pregnancy requires regular monitoring and tailored delivery planning. Medications must be reviewed for maternal and foetal safety throughout [ 51 ]. Post‐partum, management should emphasise contraception and CVD risk factor optimisation [ 52 ].

Manifestations of CVD In childhood, occur largely from congenital heart defects, inherited cardiomyopathies, rheumatic heart disease (RHD), and infective endocarditis [ 6 ]. The incidence of polycystic ovarian syndrome (PCOS) and postural orthostatic tachycardia syndrome (POTS) also peaks in the years following menarche, with the former being an important risk factor for CVD, and the latter causing substantial disability in young women. In addition, poor cardiovascular risk factor control in childhood is associated with cardiovascular events in adulthood. PCOS is defined by hyperandrogenism and ovarian dysfunction. These hormonal aberrancies have a detrimental effect on cardiometabolic health, as androgen excess causes central and visceral adiposity, thus facilitating atherogenic lipid profiles and insulin resistance. Compensatory hyperinsulinism further stimulates androgen secretion and subsequent adipose tissue dysfunction [ 7 , 8 ]. Women with PCOS are threefold more likely to develop diabetes, and 50% more likely to develop CVD [ 9 ]. Risk reduction involves lifestyle modifications with a focus on maintaining a healthy BMI, anti‐androgenic pharmacotherapy, blood glucose management and ongoing surveillance for insulin resistance and traditional risk factors of CVD. In addition to diet and exercise, studies have also found that GLP‐1 agonists and bariatric surgery are effective weight loss options, and result in significant decreases in serum levels of testosterone, as well as improvement in PCOS symptoms such as hirsutism and menstrual dysfunction [ 10 , 11 ]. First‐line medication for women with PCOS are combined oral contraceptives (COC). COCs containing a progestin that has either low androgen receptor affinity (third generation) or anti‐androgen action (fourth generation such drospirenone) are preferred in women with PCOS [ 12 , 13 ]. Similarly, anti‐androgenic medications such as spironolactone, flutamide, and 5α‐reductase inhibitors which are prescribed for symptoms of androgen excess in PCOS such as hirsutism and acne also ameliorate systemic hyperandrogenism, thus having a beneficial effect on body fat distribution and cardiometabolic health [ 8 , 14 ]. Oral hypoglycaemics, particularly metformin, are considered for insulin resistance. Endometriosis affects 10% of women worldwide, appearing following menarche, with peak incidence between 25 and 45 years of age [ 15 ]. Women with endometriosis are approximately 20% more likely to develop CVD, including acute myocardial infarction (AMI), heart failure and arrhythmias, and this risk further increases in those who undergo hysterectomy and bilateral salphingo‐oophorectomy likely due to lack of oestrogen and inflammation caused by endometriosis [ 16 ]. Higher oxidative stress and elevated pro‐inflammatory cytokines may contribute to higher prevalence of CVD [ 17 ]. Increased psychological distress in women with endometriosis may also increase risks of a poor cardiometabolic profile. Studies regarding the association between COC and arterial thromboembolism, particularly myocardial infarction (AMI), have yielded inconsistent results, with older studies indicating a positive association, whereas some newer studies have found that COC may even reduce CVD risk, especially with longer durations of use [ 18 , 19 ]. All women, before COC commencement, should however be screened for traditional risk factors such as high blood pressure, as COC choice should be individualised and tailored accordingly. First‐generation contraceptives containing higher doses of oestrogen have been found to confer a nearly threefold risk for CVD [ 19 ]. Hence, women with higher risk cardiometabolic profiles should receive third or fourth generation COCs with 20 μg of ethinyl estradiol or less. Women with PCOS would also benefit from the androgen‐suppressing effects of newer COCs. In women with a very high risk of thromboembolic events, progestin‐only pills (POPs) may be considered. However, POPs provide less anti‐androgenic benefits, and there is limited evidence on how they affect cardiometabolic health in women with PCOS [ 12 ]. In addition to PCOS and endometriosis being sex‐specific risk factors, traditional CV risk factors in adolescents should also be assessed and managed. Recent WHO data highlights that 30% of children are overweight or obese, and up to 80% fail to meet daily physical activity guidelines [ 20 ]. Over 10% of teenagers report smoking, while a third report using e‐cigarettes, a habit with yet unclear cardiovascular implications [ 21 ]. In a prospective cohort study with a mean follow‐up of 35 years, it was found that adults who had poor cardiovascular risk profiles as children carried this risk into adulthood [ 22 ]. Promoting healthy lifestyle in children and adolescents is vital. In young, additional risk factors such as PCOS and endometriosis should be recognised.

Cardiovascular disease (CVD) remains the leading cause of mortality and morbidity among women worldwide [ 1 ]. Overall mortality and rehospitalization rates due to CVD are higher in women than men, especially among younger women [ 2 ]. CVD includes vascular dementia which accounts for 15%–20% of dementia cases, a leading cause of illness and morbidity in Australian women. However, CVD continues to be perceived as a predominantly male issue and therefore remains understudied, underrecognized and undertreated in women [ 3 , 4 ] Women have poorer clinical outcomes and reported patient experience than men [ 5 ]. A better understanding of the unique risk factors, manifestations, underlying biological mechanisms that contribute to sex‐specific differences in outcomes will have a positive impact not just on clinical outcomes in women but also reduce the economic burden due to repeat hospitalisations and missed workdays. Starting in adolescence and extending into older age, lifestyle factors, psychosocial stressors, hormonal changes and pregnancy, significantly influence the cardiovascular health of women. This review provides a comprehensive overview of CVD in women, focusing on sex‐specific risk factors, presentation, diagnosis, and treatment across the lifespan. The article seeks to raise awareness and provide insights into sex‐specific prevention, diagnosis and management strategies. We also highlight gaps in knowledge to underscore the importance of sex‐based research that is crucial to improving outcomes for women with CVD. The review includes sections addressing adolescence, pregnancy, young women, perimenopause and older women.

Menopause marks a period of steeply increasing cardiovascular risk. Women tend to develop CVD 7–10 years later than men, but women have a similar lifetime prevalence and mortality burden from heart disease to men [ 80 , 81 , 82 , 83 ]. Early‐onset menopause (< 45 years), particularly from a surgical cause at a young age, confers greater risk of CVD, including both coronary and heart failure [ 84 ]. As such menopause is an opportune time to evaluate and manage cardiovascular risk, to improve long‐term prognosis [ 85 , 86 ]. The exact pathophysiological links between reproductive hormone levels and CVD are still not fully understood, however, it can be clearly seen from longitudinal studies that post‐menopausal women have a vastly different cardiometabolic profile to premenopausal women [ 86 , 87 ]. Figure  2 highlights the pathophysiology contributing to CVD in peri‐menopause. Reduced oestradiol (E2) and increased follicle stimulating hormone (FSH in the perimenopausal period, are associated with a number of adverse cardiometabolic processes that are linked to atherosclerosis, including dyslipidaemia, inflammation, increased visceral adiposity, insulin resistance, vascular reactivity and endothelial dysfunction [ 86 , 88 , 89 ]. Pathophysiology contributing to cardiovascular disease in peri‐menopause. During the peri‐menopausal period, many women experience weight gain secondary to a slowing basal metabolic rate (BMR), physical inactivity, sarcopenia, sleep disturbance and depression. Studies have found a disproportionate increase in central adiposity and visceral fat deposition during the peri‐menopausal period [ 90 ]. This increased paracentral adiposity subsequently contributes to the development of diabetes mellitus (T2DM) through insulin resistance creating a systemic pro‐inflammatory state and adverse vascular remodelling [ 88 , 91 ]. Oestrogen is a potent vasodilator and modulates vascular reactivity. The low oestrogen state following menopause leads to decreased nitric oxide (NO) synthase, increased endothelin‐1, increased sympathetic activity and increased renin‐angiotensin‐aldosterone system (RAAS) activity [ 88 , 89 ]. As a result, oxidative stress, detrimental vascular wall remodelling, endothelial dysfunction, and hypertension occur [ 92 , 93 ]., The SWAN (Study of Women's Health Across the Nation) heart study found that women had increased arterial stiffness within 1 year of their final menstrual period [ 94 ]. Like hypertension, the rates of dyslipidaemia increase sharply in post‐menopausal women. Adult premenopausal women have lower total cholesterol (TC) and LDL‐C levels, and higher HDL‐C levels, than matched men [ 95 , 96 ] however post‐menopausal women see a reversal in their lipid profiles, having on average higher levels of LDL‐C, TC and apolipoprotein B, as well as lower HDL‐C than matched men [ 96 ]. Investigators in the Framingham Study noted that the peri‐menopausal period marked a transition in LDL particles in women to smaller and more dense particles, conferring a higher atherosclerotic risk [ 97 ]. Finally, through the hypothalamic‐pituitary axis, reproductive hormones are also thought to be immunomodulatory [ 88 , 89 , 98 ]. Periods of hormonal flux, namely puberty, pregnancy and menopause, are associated with spikes and troughs in the incidence or exacerbations of various autoimmune diseases. On a cellular level, an increase in pro‐inflammatory serum markers (IL1, IL6, TNF‐alpha) is seen during menopause. Autoimmune conditions are independent risk factors for CVD, with patients who have one autoimmune disease 1.5 times more likely to develop CVD than the average population [ 85 , 99 ]. This ratio increases in those with multiple autoimmune disorders and is higher for specific disorders like SLE which has nearly 3 times more risk of CVD [ 99 ]. Clinical presentation and outcomes of CVD differ between men and women and across the lifespan [ 100 ], particularly in the early post‐menopausal group, women who have CAD are predisposed towards smaller overall plaque burden, fewer focal calcified lesions and less obstructive disease when compared to men [ 85 , 101 , 102 ]. When women do have calcified vessels however, these lesions tend to be longer segments and indicate higher CVD mortality than matched men [ 101 ]. A discussion of CVD prevention in middle‐aged women should begin with risk assessment, education and classical risk factor modification in peri and post‐menopause. The Australian guidelines recommend risk assessment begin at 45 years of age [ 103 ]. While recent movement towards developing sex‐specific risk calculators, such as with SCORE2 [ 104 ] is encouraging, this algorithm does not include female‐specific risk factors. Risk assessment for women should include nontraditional risk factors discussed in previous sections. There are currently no sex‐specific recommendations for CVD management. All women should receive nonpharmacological management addressing smoking, alcohol consumption, diet and exercise, and be placed on appropriate guideline‐directed medical treatment to reach lipid, blood pressure and glucose targets. Promoting regular physical exercise has the additional benefit of improving vasomotor symptoms during menopause [ 105 ]. MHT is well‐established as the most effective strategy for managing menopausal symptoms such as hot flushes, sleep disturbances, and general fatigue, providing a significant benefit to patient quality of life [ 106 ]. This improvement to quality of life enhances cardiac health by improving sleep, mental health, and physical activity rates. On a physiological level, oestradiol administration improves lipid and vascular markers. The 5‐year ELITE Trial showed reduced carotid intima‐media thickness progression when MHT was initiated in women < 6 years following menopause [ 107 ]. No benefits have been seen in women who begin MHT over 10 years following menopause, and in fact may cause higher risks of AMI, venous thromboembolism and stroke [ 108 ]. MHT is not currently indicated for primary or secondary CVD prevention, however both observational data and randomised trials suggest that when initiated in younger women, under 60 years of age or within 10 years of menopause, the risk of CAD and all cause mortality may be reduced [ 107 ]. Data from the Women's Health Initiative however shows harm from MHT in older women regarding CVD, stroke and venous thromboembolism [ 109 ], giving rise to the “timing hypothesis” whereby the timing of initiation of MHT determines the impact on cardiovascular health and specifically that MHT [ 107 ]. This may be especially important for women with severe vasomotor symptoms, who have been shown to have a particularly unfavourable cardiometabolic profile compared to their peers due to sympathetic overactivity and the effect of disabling vasomotor symptoms on lifestyle [ 110 , 111 ]. There is a lack of head‐to‐head trials comparing MHT regimens and routes of administration however transdermal preparations impact coagulation and inflammatory biomarkers to a lesser degree with data suggesting lower risk of stroke and venous thromboembolism with transdermal therapy [ 112 ]. Progestogens are necessary in women with intact uterus, who receive oestrogen, to mitigate risk of endometrial hyperplasia and carcinoma. Early trials suggested increased risk of CVD in women receiving combined oestrogen and progestogen, but not in those receiving oestrogen alone, driving a hypothesis that progestogen may impact CV risk. The 2010 E3N study showed that the use of micronized progesterone with oestrogen was not associated with increased venous thromboembolism risk, whereas use of norpregnane progestins was [ 113 ]. Similarly, the Oestrogen and Thromboembolism Risk study showed that the risk of developing idiopathic venous thromboembolism was not associated with micronised compared with norpregnane derived synthetic progestins [ 114 ]. In conclusion, increasing cardiovascular risk must be recognised alongside other physiological changes that occur during menopause. Management should always include careful risk assessment, aggressive primary prevention through risk factor modification, and consideration of hormone therapy for those with disabling symptoms, with attention to timing of initiation.