key: cord-0921033-bpy4m5ap
authors: Chrysohoou, Christina; Aggeli, Constantina; Avgeropoulou, Katerina; Aroni, Maria; Bonou, Maria; Boutsikou, Maria; Brili, Stella; Chamodraka, Eftyhia; Dagre, Anna; Flevari, Panagiota; Fountoulaki, Aikaterini; Frogoudaki, Alexandra; Gkouziouta, Aggeliki; Grapsa, Julia; Hatzinikolaou-Kotsakou, Eleni; Kalantzi, Kallirroi; Kitsiou, Anastasia; Kostakou, Panagiota; Kourea, Roy; Koutrolou-Sotiropoulou, Paraskevi; Marketou, Maria; Mavrogeni, Sophie; Naka, Katerina K.; Nikolaou, Maria; Papazachou, Ourania; Papavasileiou, Lida Pieretta; Simeonidou, Eftihia; Theopistou, Artemisia; Triantafyllidi, Helen; Trikka, Chrysanthi; Tsekoura, Dorothea; Tzifa, Aphrodite; Vaina, Sophia; Vrettou, Agathi Rosa; Zaglavara, Theodora; Kolovou., Genovefa; Aggelopoulou, Eleni; Antoniou, Anna; Bistola, Vasiliki; Bilianou, Eleni; Boufidou, Αmalia; Demerouti, Eftyhia; Giannakopoulou, Vasiliki; Karvouni, Evaggelia; Komnou, Areti; Kyriakou, Panagiota; Limperi, Sotiria; Mavrogianni, Aggeliki; Michalopoulou, Helena; Nakou, Eleni; Nyhtari, Eva; Papavasiliou, Maria; Pietri, Panagiota; Petropoulou, Evdokia; Prappa, Efstathia; Riga, Maria; Sbarouni, Eftihia; Stavrati, Alexia
title: Cardiovascular Disease in Women: Executive Summary of the Expert Panel Statement of Women in Cardiology of the Hellenic Cardiological Society
date: 2020-10-09
journal: Hellenic J Cardiol
DOI: 10.1016/j.hjc.2020.09.015
sha: 732f802c79f00a045be7b9ff785cfa0d54f0ccff
doc_id: 921033
cord_uid: bpy4m5ap

The perception that women represent a low risk population for cardiovascular (CV) disease (CVD) needs to be reconsidered. Starting from risk factors, women are more likely to be susceptible to unhealthy behaviors and risk factors that have different impact on CV morbidity and mortality compared to men. Despite the large body of evidence as regards the effect of lifestyle factors on the CVD onset, the gender-specific effect of traditional and non-traditional risk factors on the prognosis of patients with already established CVD has not been well investigated and understood. Furthermore, CVD in women is often misdiagnosed, underestimated and undertreated. Women also experience hormonal changes from adolescence till elder life that affect CV physiology. Unfortunately, in most of the clinical trials women are under-represented, leading to limited knowledge of CV and systemic impact effects of several treatment modalities on women’s health. Thus, in this consensus a group of female Cardiologists from the Hellenic Society of Cardiology present the special features of CVD in women: the different needs in primary and secondary prevention, as well as therapeutic strategies, that may be implemented in daily clinical practice in order to eliminate underestimation and undertreatment of CVD in female population.

Over the last decades, epidemiological data have demonstrated high incidence of cardiovascular (CV) disease (CVD) in women. It seems that the current theory that women represent a low risk population needs to be reconsidered. Women are more likely to be susceptible to unhealthy behaviors and risk factors have different impact on CV morbidity and mortality between genders [1] . Despite the large body of evidence as regards the effect of lifestyle factors on the CVD onset, the gender-specific effect of traditional and nontraditional risk factors on the prognosis of patients with already established CVD has not been well investigated and understood. Furthermore, CVD in women is often misdiagnosed and underestimated and subsequently undertreated; while women also experience hormonal changes from adolescence till elder life that affect CV physiology. Unfortunately, in most of the clinical trials women are under-represented, leading to limited knowledge of CVD and general effects of several treatment modalities on women's health. It is utmost important to gather more scientific data on women with the potential to depict the progressive change in the lifestyle impact on cardiac health, from first to recurrent CV events, guiding prevention, therapeutic and rehabilitation strategies, tailor-made for the specific needs of women population [2] [3] [4] [5] .

Thus, in this consensus a group of female Cardiologists present the special features of CVD in women; the different needs in primary and secondary prevention, in therapeutic strategies, that maybe helpful for colleagues in daily clinical practice, in order to eliminate underestimation of CVD diagnosis in female population. For the present Expert Statement > 500 PubMed articles from January 2011 to November 2019 were considered in the context of a main text [in press].

J o u r n a l P r e -p r o o f

There are various conditions related to early atherosclerosis, even in young women with a normal endogenous estrogen concentration. Throughout their life women have gender specific diseases such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia and breast cancer; often use hormonal replacement therapy and experience pregnancy and menopause [5, 6] . Some of them will be briefly analyzed, for extensive analysis see main text [in press].

Arterial hypertension (AH) is a major risk factor for CV morbidity and mortality and is usually accompanied by other important risk factors (dyslipidemia, diabetes mellitus (DM)). Additionally, although AH prevalence increases over time, it often remains undiagnosed for a long time, especially in women. Moreover, it seems that there are multifactorial sexual differences in the pathophysiology of AH which include the role of sex hormones, sympathetic nervous system activation and variations in arterial stiffness. After menopause plasma renin increases, angiotensin I receptors are up-regulated while angiotensin II receptors are down-regulated and arterial stiffness increases. The rate of SBP increase tends to be accelerated in postmenopausal women (PMW) until the sixth decade of life and then it slows down. Regarding medical therapy, women are at a higher risk for thiazide-induced hyponatremia and hypokalemia and should be cautious when presenting lower filtration rate. Several beta blockers have sex specific pharmacokinetics (women experience greater exposure in propranolol and metoprolol but similar one compared with men for carvedilol, nebivolol and atenolol). Labetalol is generally considered well tolerated in pregnant women. Women may require larger dosages of angiotensin receptor blockers than men, while there are prone to develop angioedema and cough compared to men in J o u r n a l P r e -p r o o f response to treatment with ACE inhibitors. All RAAS inhibitors are contraindicated in women who intend to become pregnant due to their potential teratogenic effect. Blood pressure response to amlodipine as well as in the risk of peripheral edema is higher in women than men and particularly in elderly. [7] [8] [9] [10] [11] .

Women with AH should be treated according to guidelines. Table 1 2

Familial hypercholesterolemia (FH) is a common autosomal dominantly inherited disorder, characterized by cholesterol deposits in the corneas, eyelids and extensor tendons, elevated plasma low density lipoprotein (LDL) cholesterol concentration and rapidly progressing vascular disease, especially premature coronary artery disease (CAD). Also, the aortic valve may be affected. Heterozygous FH affects one per 200-500 births (according to the race and ethnic origin). The plasma total cholesterol concentration is usually more than 290 mg/dL. The triglycerides concentration is normal or moderately elevated.

In its heterozygous form, the clinical manifestation of CAD may become obvious after the second decade of life. In untreated patients, the disease will eventually lead to death the 50% of men and 15% of women until the age of sixty; it is noteworthy that the 85% of men will experience a myocardial infarction (MI) within the same period of time [12] .

The most prevalent underlying molecular defect of FH consists of one of several mutations in the gene coding for the LDL receptor protein. There are also other genes involved in LDL metabolism, which mutations may lead to the clinical manifestation of FH [13] [14] .

In rare cases (1:250,000-600,000 births) a child may inherit the abnormal gene from each parent (homozygous FH). In these patients, the plasma total cholesterol concentration may be >600 mg/dL and in some cases the concentrations more than 1000 mg/dL or even 1500 J o u r n a l P r e -p r o o f mg/dL were reported. Clinically evident atherosclerosis (i. e. MI, occlusion of carotid artery or aortic valve stenosis) is usually present at the age of 4-10 years.

Women with FH should be treated according to guidelines [12, 14] .

Metabolic syndrome (MetS) is defined as a constellation of 3 out of 5 CV risk factors which include: a). Increased waist circumference with specific cutoffs based on the population and sex, b). Elevated triglycerides (TG) >150 mg/dL (1.7 mmol/L), c). Reduced high density lipoprotein (HDL) cholesterol <40 mg/dL (1.0 mmol/L) in males and <50 mg/dL (1.3 mmol/L) in females, d). BP > 130/85 mm Hg and e). Elevated fasting glucose >100 mg/dL.

Other CV risk factors such as age, sex, family history, smoking and levels of LDL cholesterol are not included in the definition. MetS is associated with increased CV mortality and development of type 2 DM (T2DM) and some data suggest that is more common in women [15, 16] . Also, sparse data suggest that pre and post-menopausal women who are breast cancer survivors or women with polycystic ovary syndrome have a high risk of developing MetS [17, 18] .

Screening in order to identify and treat DM and MetS in women throughout the different phases in their life is mandatory since it can potentially decrease their long-term morbidity and mortality. 

Smoking is an important cardiac risk factor for development of CVD in both women and men [19] . Recent studies indicate that the proportion of young patients particularly women (<60 years), who present with smoking and/or obesity as their only risk factors at the time of their hospitalization for ST-segment elevation myocardial infarction (STEMI), has continuously increased between the years 1995 to 2010. The cardio protective effects of female hormones J o u r n a l P r e -p r o o f are well studied and recognized but it is important to emphasize that women smokers lose overtime their 'gender' protection against CVD [20, 21] .

Women should be advised to quit smoking and to avoid environmental tobacco smoke exposure. All cardiologists should provide counseling at each encounter and approved pharmacotherapy for smoking cessation should be discussed unless contraindicated.

Autoimmune rheumatic diseases (ARDs) affect 8% of the population and 78% of patients are women [22] . Gender differences are the result of various causes including sex hormones, microchimerism, genes on X or Y chromosomes, X chromosome inactivation and environmental factors [23] . Estrogens can increase directly the incidence of ARDs in women by elevating auto-antibodies and amplifying T-and B-cell responses [24] . Although ARDs affect several organs and tissues, their prognosis is mainly linked to CVD. However clinically overt heart involvement is not typical and can be misinterpreted as a demonstration of the underlying systemic disease [25] . Female predominance is observed in rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue diseases and dermatomyositis/polymyositis. In some types of systemic vasculitis there is a female preponderance as in Takayasu vasculitis, while in others, as in Kawasaki disease a male preponderance exists.

There is a female predominance in autoimmune rheumatic disease with CV implications.

Thus, patients with ARDs should be evaluated by cardiologist also. QRISK3 algorithm that has been developed by the UK National Health Service and includes non-traditional risk factors is useful in calculating 10years risk of heart attack and stroke [26] .

J o u r n a l P r e -p r o o f Atherosclerosis in women shows a delayed occurrence compared to men. There are anatomic differences between men and women that are related to pitfalls alterations in diagnostic performance of cardiac imaging modalities. Furthermore, clinical presentation of symptoms may differ between genders, making women more vulnerable for delayed diagnosis and therapeutic approach [27] . Women should undergo careful investigation, as clinical symptoms might be atypical. The diagnostic accuracy of the exercise ECG is even lower in women than in men, which is in part related to functional impairment, precluding some women from achieving an adequate workload. Stress echocardiography with exercise or dobutamine stress is an accurate, non-invasive technique for the detection of obstructive CAD and risk among women with suspected CAD [28] Tables 3 and 4

Myocardial bridging is a congenital benign abnormality in which a segment of an epicardial coronary artery runs deep and for varying lengths through the myocardial fibres. Myocardial bridging remains clinically silent, being an incidental finding on angiography or autopsy, in most cases. However, stable angina, acute coronary syndrome (ACS), ventricular rupture, life-threatening arrhythmia, hypertrophic cardiomyopathy (HCM), apical ballooning syndrome or sudden death have been described as rare clinical consequences of myocardial bridging without a clear pathophysiological explanation. [29] . There does not seem to be sex or age difference in prevalence of myocardial bridging.

In cases with clinical symptoms of CVD and no clear pathophysiological explanation the myocardial bridging should be excluded.

The true prevalence of anomalous aortic origin of a coronary artery (AAOCA) in both adults and children, although difficult to ascertain, is estimated between 0.1% and 1.0%. This rate ranges from 0.3%-5.6% in studies of patients undergoing coronary angiography, and in approximately 1% of routine autopsy [30] . The risk of sudden death amongst individuals with AAOCA is reported low throughout literature between 0.0001 -0.35%. There has been no documented difference between male and female sex. Interestingly, about 26% of AAOCA involve aortic root abnormality (such as bicuspid aortic valve), at least asymmetry of the aortic sinuses. Despite, the very low risk of sudden death, the consensus statement in the Guidelines for Management of Adults with Congenital Heart Disease supports that all cases of left coronary artery (AAOLCA) and the symptomatic patients with right coronary artery (AAORCA) should undergo surgical treatment [30] .

For symptomatic AAOCA, as well as for all cases of AAOLCA, surgical intervention is recommended. In asymptomatic AAORCA, therapy is tailored towards assumed risk profile.

Coronary artery embolism is a nonatherosclerotic cause of acute coronary syndromes (ACS) ranging from 3% to 13% according to angiographic or autopsy studies [31, 32] . Coronary artery embolism is classified into direct, paradoxical, iatrogenic and hypercoagulability related embolism. Embolic tissue may consist from platelets, fibrin, valvular material, 

Women have a high prevalence of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) which varies from 6% to 30% and tends to affect young women . Table 5 4

Spontaneous coronary artery dissection (SCAD) is a rare condition, accounting only the 1-4% of overall ACS cases [35] . SCAD healing is observed in the majority of the patients (70-97%) by one month. However, 5-10% of medically managed patients may develop recurrent MI related to extension of dissection during hospitalization; while there is a high risk of the extension of the dissection during percutaneous coronary intervention (PCI).

Female gender (> 90%, 10-35% of ACS in women <50 y), pregnancy (45% of ACS with 50% occurring in the post-partum period) and fibromuscular dysplasia are the most important risk factors for SCAD. There is 15-35% risk for recurrence for the next 3 years, Avoidance of further pregnancy is advised, if the patient elect to attempt subsequent pregnancy, close monitoring is recommended. Table 6 4.6 Takotsubo syndrome in women Takotsubo syndrome represents an acute myocardial disease mimicking an ACS with no identifiable culprit atherosclerotic coronary lesion. The syndrome is triggered by physical or emotional stress. Takotsubo syndrome mainly affects postmenopausal women, although 5-11% of cases have been reported in younger women <50y [36] . Mortality rates are higher for men than women (8.4% vs. 3.6%, p<0.0001) attributed to the increased incidence of a severe physical illness in men and to the increased rate of complications such as cardiogenic shock, respiratory failure and cardiac arrest. The InterTAK diagnostic score was developed to assess the likelihood of Takotsubo syndrome on presentation and to distinguish between Takotsubo J o u r n a l P r e -p r o o f syndrome and non-ST-segment elevation MI (NSTEMI). It includes 7 parameters. Those are female sex, physical trigger, emotional trigger, neurologic disorders, psychiatric disorders, non-ST elevation -except in lead avR and QT prolongation. An increased score of 70 points increases the probability of Takotsubo syndrome [36] .

Kounis syndrome is a result of coronary artery spasm with/or plaque rupture or erosion in the course of an allergic reaction. The prevalence of Kounis syndrome is a 3 times higher in men than women. A large number of etiologic factors have been described broadly categorized into drugs, environmental factors, food products and various conditions. The release of inflammatory mediators such as histamine, cathepsin-D, chymase, tryptase, heparin lead to vasoconstriction, platelet activation, plaque rupture, plaque erosion and thrombus destabilization and maturation respectively [38] .

About two thirds of women with ischemia symptoms do not present obstructive CAD in cardiac catheterization. Those women may have been presented with symptoms of effort angina or dyspnea, electrocardiographic alterations and segmental hypokinesis at rest or during exercise at cardiac imaging. Although any negative findings of coronary angiography provoke relief; one out of thirteen (1:13) of those women will express CV death and generally they experience high probability of hospitalization with symptoms of heart failure (HF) with preserved ejection fraction (HFpEF). This situation is due to coronary microvascular dysfunction which are the small blood vessels in the heart, called the coronary microvasculature, which carry most of the blood flow to the heart muscle, delivering oxygen [39] .

Idiopathic thrombocythemia J o u r n a l P r e -p r o o f Idiopathic thrombocythemia is a rare blood clotting disorder that produce too many platelets and mainly affects women [40] . Treatment should be adapted according to a classification into low risk or high risk based on the patients' age and history of thrombosis or hemorrhage (prescription of aspirin and cytoreductive drugs). Uncontrolled idiopathic thrombocythemia can cause pregnancy complications, including spontaneous abortion, fetal growth retardation, premature delivery, placental abruption. Pregnant patients may be treated with low-dose aspirin to reduce the risk complications.

Fibrinolysis disorders leading to the hyper-fibrinolytic bleeding can be caused by a deficiency of one of the inhibitors of fibrinolysis (plasminogen activator inhibitor type 1

[PAI-1] or α2-antiplasmin [α2-AP]), or an excess of one of the activators of fibrinolysis: tissue-type plasminogen activator or urokinase-type plasminogen activator. Recently, it was discovered that hyper-fibrinolytic disorders are associated with a high rate of obstetric complications such as miscarriage and preterm birth, especially in a PAI-1 deficient patient.

Contraceptives are one of the most frequently used drugs by women. They could lead to activated protein C resistance, increase prothrombin levels and decrease protein S levels producing a net prothrombotic effect. In women with inherited disorders of coagulation, the risk for vein thrombosis and pulmonary embolism due to contraceptive drugs increases 30-50-fold [41] .

Females demonstrate higher platelet reactivity on aspirin and clopidogrel therapy .

Aspirin for primary prevention is associated with a higher risk reduction for ischemic stroke in females and for MI in males [42] .

There is no interaction between gender and efficacy of aspirin for secondary CV prevention

There is lack of evidence that aspirin can modify risk in women both in primary and secondary CV prevention, as presented in Table 7 . Table 7 5

In women, HF with reduced ejection fraction (HFrEF) is a less common diagnosis compared to the more prevalent HFpEF. In-hospital mortality remains equal in both women and men as they share the same risk factors -namely age, blood pressure, heart rate and history of chronic renal disease [43] . However, women presenting with HFrEF are more symptomatic than men, with lesser ability in self-care and daily activities, more evidence of congestion, Therapy (MADIT-CRT) trial; perhaps due to an increased prevalence of left bundle branch block in female patients [44, 45] . HFpEF is more common in women than men. As such, this constantly increasing elderly population of female HFpEF patients associated with adverse J o u r n a l P r e -p r o o f clinical outcomes, in combination with a lack of effective treatment, render HFpEF an important clinical and social problem [46] . However, there have not been enough studies to establish extensive knowledge about how HF manifests in women, the effects of various medications, and the impact of external factors, such as social inequalities and limited access to healthcare system, on the actual figures for HF in women.

Cardiomyopathies (CMs) are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes [47] . They are classified into HCM, DCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), and unclassified CMs, for more details see main text [in press]. Table 10 6. Cardio-oncology CVD and cancer are the two main causes of death in both sexes. In women, the most common cancer diagnosis is invasive breast cancer with one out of 8 carrying an increased lifelong risk to develop, while the 5-year survival rate of the disease exceeds 90% [48] . The risk of a CVD event (hospitalization or death) among women with a low Framingham risk (<10%) is 44% higher in women with breast cancer compared with women without breast cancer. Furthermore, women with breast cancer have an adjusted 77% higher risk of death from CVD than women without breast cancer [49, 50] . Strategies for screening and detection Table 11   Table 12 7. Arrhythmia in women Τhe incidence of certain clinical arrhythmias undoubtably varies between men and women.

Clinical and experimental observations suggest that true differences in electrophysiologic variables exist between them and this is a sex hormones' effect through differences in expression of ion channel subunits and channel function modulation. Women with atrial fibrillation (AF) show a higher risk for AF-related morbidity due to stroke, a poorer tolerance to antiarrhythmic pharmacological therapy and a weaker quality of life; for this reason, a J o u r n a l P r e -p r o o f curative, catheter-based approach for AF appears very attractive in women. AF incidence and prevalence increase with aging, and it's known to be higher in men than in women; however, because there are almost twice as many women as men aged >75 years, the absolute expected number of men and women affected by AF is equal.

Symptoms of supraventricular arrhythmias in women are more likely to be attributed to panic, anxiety, or stress disorders than in men. Women are referred 3-times less frequently for catheter ablation. At the time of referral, they are significantly older, have more comorbidities, and are more sensitive to amiodarone side effects than men. Gender-related anatomical differences could theoretically affect procedure outcomes [50, 51] . Oral anticoagulant (OAC) use is similar in AF patients, but women were less often prescribed OAC and were given aspirin more often than male counterparts. Anticoagulation with warfarin may be less controlled in female AF patients (lower TTRs) [52] .

• Right ventricular outflow tract (RVOT)-Ventricular tachycardia is twice more common in females.

• Female patients are under-represented in randomized controlled clinical trials and registries of patients undergoing catheter ablation for ventricular tachycardia with structural heart disease, especially with CAD.

• Women with LQTS have an increased risk during the 9month post-partum period, particularly women with the LQT2 genotype. There is conflicting evidence on sex differences in ventricular arrhythmias in LQT3, both indicating higher risk in LQT3 men or indicating no additional risk in LQT3 according to sex. Beta-blocker efficacy may be greater in women with LQT3 compared with men.

• Clinical manifestations of Brugada syndrome are eight-fold more frequent in adult men than in adult women. It has been suggested that androgens may affect the Ito channel and aggravate ion channel dysfunction J o u r n a l P r e -p r o o f • In retrospective and prospective analyses, women have a higher incidence of sinus node dysfunction and men a higher incidence of atrioventricular node dysfunction Sex differences are presented in Table 13 Further studies are needed to better define the mechanisms underlying these sex-related differences: physical, autonomic and hormonal effects are certainly involved, but their role still needs to be fully characterized. More importantly, females are seldom represented in clinical research (i.e. one-fifth to one-fourth of the enrolled patients) and are infrequently referred for electrical treatments for arrhythmias and HF in clinical practice.

Pregnancy is a stress test for the CV system, while it can be complicated by maternal disease in 1-4% of cases. New data about the prevalence and incidence of pregnancy-related heart disease are limited from most parts of the world. Sudden adult death syndrome, peripartum cardiomyopathy (PPCM), aortic dissection, and myocardial infarction (MI) were the most common causes of maternal death in the UK over the period 2006-08. Knowledge of the risks associated with CVDs during pregnancy and their management in pregnant women who suffer from serious pre-existing conditions is of pivotal importance for advising patients before pregnancy. Pregnancy is associated with a three-to four-fold increase in acute myocardial infarction (AMI) risk compared with age-matched non-pregnant women. Risk factors include smoking, maternal age, hypertension, diabetes, obesity, and dyslipidaemia.

Additional risk factors include (pre-)eclampsia, thrombophilia, transfusion, post-partum infection, cocaine use, multiparity, and post-partum haemorrhage. The majority of CAD has non-atherosclerotic mechanisms, including pregnancy-related spontaneous coronary artery dissection (43%), angiographically normal coronary arteries (18%), and coronary thrombosis (17%) [53].

Aortic dissection is a rare but catastrophic event, being the third cause of CV death, during pregnancy. Its prevalence is 4 in a million pregnancies [53] . Risk factors include known aortopathies, namely Marfan, vascular Ehlers-Danlos and Turner syndromes (risk of rupture 1-10%), bicuspid aortic valve (risk of rupture 1%), AH and advanced age. Risk of dissection relates to aortic diameter.

Arterial Hypertension (AH) can complicate up to 10% of pregnancies and is responsible for 

The aetiology of pregnancy-associated cardiomyopathy includes acquired and inherited diseases, such PPCM, toxic cardiomyopathies, HCM, DCM, Takotsubo cardiomyopathy, and storage diseases. Although rare, they may cause severe complications as HF and arrhythmias in pregnancy. Pregnancy is poorly tolerated in some women with pre-existing dilated cardiomyopathy DCM, with the potential for significant deterioration in LV function. PPCM is an idiopathic disorder defined as HF occurring in women during the last month of pregnancy and up to 5 months postpartum. Novel data strengthen the implication of J o u r n a l P r e -p r o o f endothelial function in PPCM pathogenesis. Bromocriptine may have a role in the treatment of PPCM, although it may confer to increased thrombotic risk.

Valvular heart disease is often due to rheumatic heart disease. Usually asymptomatic patients with severe aortic stenosis tolerate pregnancy without major adverse events, while even asymptomatic patients with severe mitral stenosis should be counselled against pregnancy.

Mechanical valves offer excellent hemodynamic performance and long-term durability, but the need for anticoagulation increases maternal and fetal mortality and morbidity, and the risk of major cardiac events during pregnancy is much higher than with bioprosthetic valves.

However, bioprosthetic valves in young women are associated with a high-risk of structural valve deterioration resulting in the risk of going through pregnancy with a dysfunctional valve, and eventually in the inevitable need for re-operation [52] .

In most women with congenital heart disease, pregnancy is well tolerated. Maternal cardiac complications are present in about 10% of completed pregnancies and are more frequent in mothers with complex disease . Pregnancy should be discouraged in patients with advanced heart disease [52] . 

CAD is the leading cause of morbidity and mortality in postmenopausal women. In general, CV mortality accounts for 40% of total women mortality, while breast cancer accounts for only 5%. Diagnosis of CAD in women can be challenging due to a higher rate of functional disorders and lower prevalence of obstructive CAD than in men. In asymptomatic women, the use of risk-estimation systems such as SCORE is recommended. 

Mitral valve prolapse is more common in women, but they present with lesser degrees of mitral regurgitation. Higher incidence of increased leaflet thickness and anterior and bileaflet mitral valve prolapse is more predominant in women, whereas posterior leaflet prolapse which is technically easier to repair is more common in men.

Women have higher prevalence of mitral valve calcification, rheumatic mitral valve disease and mixed regurgitation/stenosis. Degenerative aortic stenosis is the most common cause of aortic stenosis secondary to progressive sclerosis and calcification. Women have demonstrated a higher prevalence of paradoxical low flow-low gradient aortic stenosis, which has been related to worse outcome compared to high-gradient aortic stenosis. Surgical aortic valve replacement (SAVR) is less frequently chosen in women with severe symptomatic aortic stenosis than in men, reflecting the gender bias that results from the higher in-hospital mortality and complications among J o u r n a l P r e -p r o o f women. Contrary to SAVR, improved survival after transcatheter aortic valve replacement (TAVR) has been reported in women, particularly with transfemoral approach [61] .

The most common etiology of degenerative mitral regurgitation is mitral valve prolapse. Sex differences in mitral valve pathology have been described, which challenge women's candidacy for mitral valve repair. With regards to the percutaneous treatment of mitral regurgitation, MitralClip implantation has been demonstrated to be equally effective in both sexes.

Women who present for cardiac surgery are older, frailer, have a smaller body surface area, are more likely to require an urgent/emergent operation, and have a greater burden of comorbid conditions, such as DM, hypertension, dyslipidemia, HF, cerebrovascular disease and anemia. The diagnosis of CAD may be delayed in women compared to men; while women exhibit worse operative mortality and long-term survival in many cardiosurgical procedures. In addition, women with CVD often experience a delay in diagnosis and treatment when compared to men, which may in part, explain the more advanced coronary and/or valvular pathological conditions observed in women at the time of surgery [61] .

Women are mostly asymptomatic, without an obvious reason, that often leads to delayed diagnosis. Sex specific risk factors include use of oral contraceptives, history of complications during pregnancy such as intrauterine growth restriction, preeclampsia, and pregnancy-induced hypertension. In lower extremities revascularization women may be more prone to complications because of either open or endovascular revascularization; although Endovascular intervention generally in females appears to be associated with better patency rates [62] .

Autoimmune rheumatic diseases (ARDs) affect 8% of the population and 78% of patients are women. Although ARDs affect several organs and tissues, their prognosis is mainly linked to CVD. CVD in ARDs is the result of various pathophysiologic processes including myo-pericarditis, atherosclerotic or inflammatory coronary artery disease and/or spasm, microvascular disease, valvular heart disease and the effect of immunosuppressive medication. CVD in Systemic lupus erythematosus includes myo-pericarditis, DCM, macromicro-CAD, diastolic dysfunction, vasculitis or valvular disease and represents an important contributor to increased mortality. In systematic sclerosis cardiac inflammation presenting either as myocarditis or as acute, diffuse, subendocardial vasculopathy leading to diffuse subendocardial fibrosis may also contribute to increased CVD mortality [63] .

Pulmonary Hypertension is classified into five groups based on the WHO classification system. It is a proliferative vasculopathy of the pulmonary arterioles characterized by vascular remodelling (hyperplasia -hypertrophy of all three vascular wall layers) and neovascularization. Idiopathic, heritable and drugs/toxins related PAH (mainly appetitesuppressants medications) are the major subtypes in this group, accounting for more than 50% of the cases. All these three conditions affect women disproportionally to men, in a fashion more than 2:1. The median age of patients at presentation is 50 years. In early stage, most of the cases report exertional breathlessness Diagnosis is suspected based on Echocardiographic -Doppler findings after the exclusion of other cardiorespiratory conditions (chronic thromboembolic disease also included). Right heart catheterization is confirmatory (normal pulmonary capillary wedge pressure -PCWP, increased pulmonary vascular resistance) [64] .

Although published literature suggests that prevalence of congenital heart disease is higher in women compared with men in the adult population, aortic coarctation and bicuspid aortic valve are more prevalent in male patients Data from Mayo Clinic suggest that the ratio of isolated secundum atrial septal defect (ASD) with PH of women to men is 28/1.The underlying causes behind this might be due to sex differences in genetic polymorphisms or the effect of sex hormones, however further investigation is required to illuminate this [65] .

Early reports demonstrated that when compared to women, male COVID positive patients have more severe disease and a higher mortality. According to Global Health 5050, an organization that promotes gender equality in health care, the disproportionate death ratio in men may be explained by the higher contribution of comorbidities (i.e., CVD, hypertension, diabetes, and chronic lung disease), higher risk behaviours (i.e., smoking and alcohol use), and occupational exposure. Another biological difference may relate to sex differences in angiotensin-converting enzyme 2 (ACE2) receptors. Interestingly, there are marked differences in the density of ACE2 receptors in the reproductive organs: the testes have much higher levels of ACE2 than the ovaries [66] . Thus, may explain sex differences on heart injury among patients infected with SARS-CoV-2.

Diagnosis of CAD in women can be challenging due to a higher rate of functional limitations and lower prevalence of obstructive CAD than in men. Women have less epicardial disease than men suggesting other mechanisms of ischemic heart disease that include endothelial dysfunction, thrombophilia, and microvascular reactivity. Risk factors, reproductive status, clinical symptoms and functional status, help determine which diagnostic modality is best for identifying underlying CAD. In pharmaceutical therapy, available data J o u r n a l P r e -p r o o f shows different responses to antithrombotic therapy between males and females in both primary and secondary CV prevention. Additionally, women exhibit higher prevalence of non-atherogenic CAD than men; while pregnancy and menopause promote alterations in CV function and physiology. Postmenopausal status is identified as a risk factor for CVD. Sexspecific patterns of cardiac and vascular ageing play an important role; thus, differences between genders in patterns of age-related cardiac remodelling are associated with the relatively higher prevalence in women than in men of HFpEF. Similarly, gender variation in vascular structure and function changes with ageing contribute to differences in the manifestation of CAD. Both hormonal and non-hormonal factors underlie gender differences in CV ageing and the development of age-related diseases. Cancer therapy in women has shown positive results in reducing morbidity and mortality, although cardiotoxicity remains the most important side-effect. While primary prevention of cardiotoxicity is still in the research domain, secondary prevention has already entered clinical practice guidelines despite persistent unresolved questions. There is an ongoing need for greater emphasis on the sex-specific aspects of CV risk factors, manifestation of CVD states, and response to therapies; as well as it is crucial to promote diversity, health equity, and a broad range of perspectives in treating special needs for each gender, age category, demographic and social status [67] . 

In high-risk (or above) women with TG levels between 1.5- J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f It is often associated with fetal growth restriction due to placental insufficiency and is a common cause of prematurity. The only cure is delivery.

Severe pre-eclampsia Pre-eclampsia with severe hypertension and/or with symptoms, and/or biochemical and/or hematological impairment.

A convulsive (grand mal seizures) condition associated with preeclampsia.

HELLP syndrome Haemolysis, elevated liver enzymes and low platelet count.

J o u r n a l P r e -p r o o f 

One-vessel CAD without proximal LAD stenosis

One-vessel CAD with proximal LAD stenosis 

Sex-related differences 1. Women have larger LV wall thickness, more concentric LV geometry, with smaller annular sizes and LV outflow tract dimensions.

Women preserve better LV systolic function (measured as EF or GLS), independently of LV size.

Women present greater increase in LVMI and LVRI for smaller changes in hemodynamic loads.

Men have higher myocardial stiffness, more interstitial fibrosis and abnormal collagen architecture with increased cross-hatching. 

Effectiveness-based guidelines for the prevention of cardiovascular disease in women-2011 update: a guideline from the

Temporal Trends of Women Enrollment in Major Cardiovascular Randomized Clinical Trials

Participation of Women in Clinical Trials Supporting FDA Approval of cardiovascular Drugs

Cardiovascular Disease in Women: Clinical Perspectives

Summary of Updated Recommendations for Primary Prevention of Cardiovascular Disease in Women

Body mass index, lipid metabolism and estrogens: their impact on coronary heart disease

The Association of Elevated HDL Levels With Carotid Atherosclerosis in Middle-Aged Women With Untreated Essential Hypertension

Genes and genetic variations involved in the development of hypertension: focusing on a Greek patient cohort

Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European J o u r n a l P r e -p r o o f Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension

Gender-specific therapeutic approach in arterial hypertension -Challenges ahead

Sex differences in barriers to antihypertensive medication adherence: findings from the cohort study of medication adherence among older adults

LDL-cholesterol target attainment according to the 2011 and 2016 ESC/EAS dyslipidaemia guidelines in patients with a recent myocardial infarction -nationwide cohort study

MTP Gene Variants and Response to Lomitapide in Patients with Homozygous Familial Hypercholesterolemia

Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the ACC/AHA Task Force on Clinical Practice Guidelines

The effect of Mediterranean diet on metabolic syndrome and its components: a metaanalysis of 50 studies and 534,906 individuals

Metabolic Syndrome and Arteries Research (MARE) Consortium. Metabolic syndrome across Europe: different clusters of risk factors

Metabolic disturbances in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis

Effect of chemotherapy and aromatase inhibitors in the adjuvant treatment of breast cancer on glucose and insulin metabolism-A systematic review

Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies

Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use

Smoking and gender

Gender and autoimmunity

Atherosclerotic and Non-Atherosclerotic Coronary Heart Disease in Women

Cardiac and muscular involvement in idiopathic inflammatory myopathies: noninvasive diagnostic assessment and the role of cardiovascular and skeletal magnetic resonance imaging

The burden and measurement of cardiovascular disease in SSc

Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study

Imaging of Heart Disease in Women

ESC Guidelines for the diagnosis and management of chronic coronary syndromes

Unmasking Myocardial Bridge-Related Ischemia by Intracoronary Functional Evaluation

Expert consensus guidelines: Anomalous aortic origin of a coronary artery

Coronary Embolus. An Underappreciated Cause of Acute Coronary Syndromes

Prevalence, clinical features, and prognosis of acute myocardial infarction attributable to coronary artery embolism. Clinical perspective

Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease A Scientific Statement From the

Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the J o u r n a l P r e -p r o o f National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) angiographic core laboratory

Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes

International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management

Role of cardiovascular magnetic resonance in assessing patients with chest pain, increased troponin levels and normal coronary arteries

Kounis syndrome: A review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome

Coronary Microvascular Dysfunction Causing Cardiac Ischemia in Women

Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study

Effects of estrogens on atherogenesis

Female-friendly focus: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease

at a glance: ischaemic heart failure and sex-related differences

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF

Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial

Sex-Related Differences in Heart Failure With Preserved Ejection Fraction

Sex differences in cardiomyopathies

Management of Cardiovascular Disease in Women With Breast Cancer

Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab

Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (The Copenhagen City Heart Study)

Sex differences in cardiac electrophysiology and clinical arrhythmias: epidemiology, therapeutics, and mechanisms

Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association

Comparison by meta-analysis of mortality after isolated coronary artery bypass grafting in women versus men

ESC Guidelines for the diagnosis and management of chronic coronary syndromes

Sex Differences in the Progression of Aortic Stenosis and Prognostic Implication: The COFRASA-GENERAC Study

Gender Differences in Peripheral Vascular Disease

Pseudo-infarction pattern in diffuse systemic sclerosis. Evaluation using cardiovascular magnetic resonance

Epidemiology and treatment of pulmonary arterial hypertension

Adult congenital heart disease in Greece: Preliminary data from the CHALLENGE registry

Sex Differences in Mortality from COVID-19 Pandemic: Are Men Vulnerable and Women Protected? JACC Case Rep

Consideration of sex differences in medicine to improve health care and patient outcomes