For many years the significance of heart disease in women was vastly underappreciated, and women were significantly underrepresented in cardiovascular clinical research. We now know that cardiovascular disease is the leading cause of death for women. Women and men share many similarities in the pathophysiology and manifestations of heart disease. However, as research advances with the continued inclusion of more women, knowledge about gender differences between the female and male heart, both on a physiological and pathophysiological basis, grows. These differences can be found in all domains of cardiovascular health and disease, including heart rhythm, heart failure, coronary disease and valvular disease. Further understanding of gender differences in the heart is crucial for advancing our ability to maintain a healthy population and identify and treat heart disease in both women and men. Specific examples within the spectrum of heart disease will be discussed in this review paper, and areas for further research will be proposed.

INTRODUCTION

Despite the fact that cardiovascular disease is the leading cause of death for women, they have been significantly underrepresented in cardiovascular research. The recognition that cardiovascular disease affects both women and men has been a major advance in cardiology. As research efforts have included more women, it has become apparent that there are significant differences between the female and male heart, both on a physiological and pathophysiological basis. These intrinsic distinctions, as well as the traditional underrepresentation of women in cardiovascular research, have led to both treatment and outcomes differences. Understanding the female heart, and acknowledging gaps in knowledge, is the first step toward improving the cardiovascular health of women. Specific examples within the spectrum of heart disease will be cited.

Substantial morbidity and mortality can be attributed to our lack of focus on the prevention and treatment of cardiovascular disease in women; although we are closing this gender gap, there is much work that needs to be done to rectify this significant disparity.

HEART RHYTHM

As the practice of clinical cardiac electrophysiology has matured, so has the understanding that sex differences are apparent even in the electrical system of the heart. The basic electrophysiology of the heart differs between women and men, as do the clinical manifestations of arrhythmias.

Basic electrophysiology

Women have a longer QT interval and a faster resting heart rate than men; these differences become most apparent after puberty and decrease after menopause, although they remain present. Women have shorter PR and QRS intervals [1]. Although some of these differences may be related to the smaller size of the female heart and differences in autonomic tone, hormonal differences play a large role, specifically via effects on the function and expression of ion channels. Both oestrogen and progesterone receptors are present in cardiac myocytes, in higher concentrations in the atria than in the ventricles and in endothelial cells. Oestrogen has negative inotropic and chronotropic effects via influence on calcium and potassium channels. The effects of progesterone are less well understood, but are thought to function in opposition to oestrogen.

Other gender differences in the electrocardiogram (ECG) exist. Men have higher QRS voltages than women, even after controlling for differences in body size and left ventricular mass. Multiple different methods of assessing for left ventricular hypertrophy (LVH) based on ECG perform better for men than women, suggesting a potential role for gender-specific ECG criteria for detecting LVH [2].

The flux of hormones during the menstrual cycle has direct electrophysiologic effects. There is some evidence that the QT interval shortens during the luteal phase, which occurs after ovulation when oestrogen levels are lowest and progesterone levels highest. These basic electrophysiological differences have direct clinical correlations [3]. For example, circulating androgens seem to shorten the QT interval and protect against torsades de pointes [4]. After puberty, women with both congenital and acquired long QT syndrome (LQTS) are at higher risk of cardiac events compared with men [3,5].

Supraventricular tachycardias

The incidence of atrioventricular nodal reentrant tachycardia (AVNRT) is higher in women, by a factor of 2, whereas atrioventricular reentrant tachycardia (AVRT) is more common in men. Inappropriate sinus tachycardia is also significantly more prevalent in women.

Table 1
Female-specific differences and disparities in cardiovascular disease (as described in comparison with male characteristics)
Heart rhythm 
Basic electrophysiology • Longer QT interval and shorter PR and QRS intervals 
 • Faster resting heart rates 
 • Oestrogen and progesterone receptors in cardiac myocytes with direct inotropic and chronotropic effects 
SVT • Higher incidence of AVNRT 
 • Treated more conservatively with less invasive procedures with regard to ablatable rhythms 
Atrial fibrillation • Higher relative risk of mortality 
 • Increased risk of stroke 
 • Tendency to be prescribed anticoagulation less frequently 
 • Worse quality of life with higher symptom burden 
 • Less commonly referred for catheter ablation 
SCD • Lower risk of SCD 
 • Lower risk of ventricular arrhythmias 
Use of ICDs • ICD use for primary and secondary prevention is two to three times lower in women 
Pregnancy and heart rhythm • Increased incidence of cardiac arrhythmias, specifically PACs, PVCs and paroxysmal SVTs 
Heart failure 
HFpEF • More prevalent in women, in some studies by a factor of 2 
 • Differences in the way the heart structurally remodels in response to chronic pressure overload 
HFrEF • Lower prevalence 
 • More likely to have non-ischaemic aetiology 
 • Survival benefit 
 • Greater benefit with CRT 
 • Less likely to receive ICD and CRT implantation 
 • Less likely to undergo advanced heart failure therapies including LVAD and heart transplant 
Female-specific causes of heart failure • PPCM is female specific 
 • >90% of cases of SCM occur in women 
Coronary heart disease 
Sex differences in risk factors • Higher rates of hypertension, physical inactivity 
 • Diabetes and smoking confer greater risk of CHD compared with men 
 • Female-specific risk factors of post-menopausal changes and pregnancy-related complications 
Sex differences in pathophysiology • Plaque erosion and SCAD more common 
 • Burden of non-obstructive disease confers worse prognosis 
 • Microvascular coronary dysfunction more common 
Sex differences in treatment and outcomes • Higher rates of mortality and recurrent MI following initial MI 
 • Less likely to receive evidence-based therapies for initial management and post-discharge care of AMI 
 • Less likely to receive PCI and CABG 
 • Less likely to be referred for cardiac rehabilitation 
Heart rhythm 
Basic electrophysiology • Longer QT interval and shorter PR and QRS intervals 
 • Faster resting heart rates 
 • Oestrogen and progesterone receptors in cardiac myocytes with direct inotropic and chronotropic effects 
SVT • Higher incidence of AVNRT 
 • Treated more conservatively with less invasive procedures with regard to ablatable rhythms 
Atrial fibrillation • Higher relative risk of mortality 
 • Increased risk of stroke 
 • Tendency to be prescribed anticoagulation less frequently 
 • Worse quality of life with higher symptom burden 
 • Less commonly referred for catheter ablation 
SCD • Lower risk of SCD 
 • Lower risk of ventricular arrhythmias 
Use of ICDs • ICD use for primary and secondary prevention is two to three times lower in women 
Pregnancy and heart rhythm • Increased incidence of cardiac arrhythmias, specifically PACs, PVCs and paroxysmal SVTs 
Heart failure 
HFpEF • More prevalent in women, in some studies by a factor of 2 
 • Differences in the way the heart structurally remodels in response to chronic pressure overload 
HFrEF • Lower prevalence 
 • More likely to have non-ischaemic aetiology 
 • Survival benefit 
 • Greater benefit with CRT 
 • Less likely to receive ICD and CRT implantation 
 • Less likely to undergo advanced heart failure therapies including LVAD and heart transplant 
Female-specific causes of heart failure • PPCM is female specific 
 • >90% of cases of SCM occur in women 
Coronary heart disease 
Sex differences in risk factors • Higher rates of hypertension, physical inactivity 
 • Diabetes and smoking confer greater risk of CHD compared with men 
 • Female-specific risk factors of post-menopausal changes and pregnancy-related complications 
Sex differences in pathophysiology • Plaque erosion and SCAD more common 
 • Burden of non-obstructive disease confers worse prognosis 
 • Microvascular coronary dysfunction more common 
Sex differences in treatment and outcomes • Higher rates of mortality and recurrent MI following initial MI 
 • Less likely to receive evidence-based therapies for initial management and post-discharge care of AMI 
 • Less likely to receive PCI and CABG 
 • Less likely to be referred for cardiac rehabilitation 

The occurrence of AVNRT is more likely during the luteal phase of the menstrual cycle, possibly related to higher levels of catecholamines or to the relative increase in progesterone levels. In studies of electrophysiology testing for supraventricular tachycardia (SVT), AVNRT is easier to induce in premenopausal women during the premenstrual phase or at the onset of menses [3].

Management trends appear to significantly differ between women and men with SVT. Women are managed more conservatively than men despite the positive success and safety profile of catheter ablation, regardless of sex. In one single centre study women had longer symptom duration, more frequent symptoms and more trials of antiarrhythmic drugs before referral for catheter ablation [6]. The reason for the difference in invasive management of SVTs is unclear; no gender differences have been identified in complication rates or short or long term success rates of ablation for SVTs [7,8].

Atrial fibrillation

Atrial fibrillation is the most common arrhythmia seen in clinical practice, both in the inpatient and outpatient settings. Globally, an estimated 33.5 million people are living with atrial fibrillation [9]. The estimated number of cases of atrial fibrillation in the US ranges from two to five million women and men, a number expected to more than double in the next few decades [10,11]. The prevalence rises with age, affecting over 9% of people over the age of 80 years. The rhythm has substantial associated morbidity and mortality. Atrial fibrillation is a major risk factor for stroke, increasing the risk 5-fold and increasing all-cause mortality by a factor of 2 [12].

Both incidence and prevalence of atrial fibrillation is higher in men than women; however, as women live longer than men, the absolute number of women and men living with atrial fibrillation is similar, if not slightly higher in women [13,14]. Despite the increased prevalence and incidence in men, women with atrial fibrillation have a higher relative risk of mortality, both globally and domestically [9,15,16].

The balance of evidence supports an increased risk of stroke in women compared with men, with a hazard ratio in the 1.5–2 range [1719]. This increased risk is highest at older ages, but persists across all CHADS2 and CHADS-VASC stratifications [17]. The cause of this increased risk is not apparent. A contributing factor is the difference in anticoagulation treatment between the sexes. Multiple observational studies show that women are prescribed anticoagulation less frequently than men, though this is not a consistent finding in all studies [17,20]. On a population basis, this disparity in anticoagulation explains some of the increased stroke risk in women with atrial fibrillation, but it does not account for the observed difference in stroke risk between women and men when studied off anticoagulation. Additional proposed mechanisms include a higher prevalence of hypertension in women with atrial fibrillation, structural differences in the left atrium between the sexes and a higher baseline propensity for endothelial dysfunction and thromboembolic risk in women [19,21].

Studies support a worse quality of life in women with atrial fibrillation. The RACE study showed increased cardiovascular morbidity and mortality in women for whom rhythm management with antiarrhythmic drugs was pursued. The largest absolute difference in outcomes was adverse events related to antiarrhythmic therapy [22]. Previous studies have shown that women are more sensitive to QT prolonging drugs with greater risk of developing torsades de pointes with medications that prolong repolarization [4]. In contrast with a rhythm control strategy with antiarrhythmic therapy, catheter ablation seems to have similar outcomes between women and men in success and complications rates. Despite this, women are less likely to be referred for catheter ablation, and have a higher symptom burden when referred [23].

Sudden cardiac death and implantable cardioverter defibrillators

The incidence of sudden cardiac death (SCD) in women is approximately half of that observed in men. With the exception of torsades de pointes in congenital and acquired LQTS, women are less prone to ventricular arrhythmias. Much of this lower incidence can be attributed to the lower rates of coronary heart disease (CHD) in women, but this does not fully explain the observed differences. It is proposed that hormonal differences may affect the heart's susceptibility to ventricular arrhythmias for as yet unidentified reasons [3].

Due to the lower risk of SCD in women, the question has arisen as to whether women benefit from implantable cardioverter defibrillators (ICDs). In the 1990s and 2000s most of the landmark studies investigating the efficacy of ICDs for primary prevention in patients with a reduced EF enrolled fewer than 30% women, often far less. The paucity of data on women affected the meta-analyses that suggested that women might not have mortality benefit from an ICD [24,25]. Women with ICDs seem to receive less appropriate therapies than men. It has been suggested that arrhythmogenic death is less likely in women than men, thus explaining the difference in survival benefit in women and men with ICDs [25].

However, a more recent study using registry data in women over the age of 65 who received ICDs compared with a matched cohort who did not receive ICDs found a significant reduction in mortality similar to that seen in men [26]. Indeed, the guidelines for ICD implantation for primary and secondary prevention make no distinction based on sex [27]. Perhaps related to the conflicting data on the benefit of ICDs in women, or due to reports of higher complication rates in women, ICD use for primary or secondary prevention of SCD remains substantially lower in women, by 2–3-fold [28,29].

Heart rhythm and pregnancy

Pregnancy affects the cardiovascular system in multiple ways. There is a 40% increase in blood volume, with a related increase in left ventricular end-diastolic and end-systolic volumes and dimensions, and an increase in left atrial area. Cardiac output increases by almost 50%, driven by an increase in both heart rate and stroke volume. Left ventricular myocardial wall thickness and myocardial contractility increase [30,31]. Although stroke work and global cardiac performance increase, left ventricular ejection fraction appears to remain unchanged. The vasculature is also affected; increased oestrogen causes hypertrophy of smooth muscle cells with loosening of the intercellular matrix, affecting the structure of arterial walls [32]. Systemic vascular resistance and pulmonary vascular resistance both fall. In the healthy heart these changes subside in the post-partum period, generally by 3–6 months, but some adaptations take up to a year to reverse [31].

There is a significantly increased incidence of cardiac arrhythmias in normal pregnancy. Most frequently this is observed as atrial and ventricular premature contractions, with a significant reduction in occurrence in the post-partum period [33]. However, more complex clinical arrhythmias have also been observed with a relative increased frequency during pregnancy, most commonly paroxysmal SVT. Pregnancy is associated with an increased risk of both onset and exacerbation of paroxysmal SVT, regardless of the mechanism of SVT [34]. Atrial fibrillation and atrial flutter are uncommon, and usually associated with structural heart disease [35]. Multiple proposed mechanisms for the increase in arrhythmias include haemodynamic, hormonal and autonomic changes. The increase in blood volume and cardiac chamber dimensions described above may lead to myocardial stretch-related arrhythmogenesis. Oestrogens may sensitize the myocardium to catecholamines, thereby increasing adrenergic responsiveness and myocardial excitability [36]. An elevation in resting heart rate, a normal physiological response in pregnancy, is thought to contribute to ventricular arrhythmogenesis [37]. Women with structural and congenital heart disease are particularly at risk of pregnancy-related arrhythmias. One multicentre study showed a 27% prevalence of arrhythmias in a cohort of pregnant women with repaired congenital heart disease, with an almost equivalent number of pre-existing and new-onset arrhythmias. These rhythm disturbances included SVTs, ventricular arrhythmias and conduction disease [38].

HEART FAILURE

Epidemiology

Heart failure is a clinical syndrome that affects over 5 million Americans and is the cause of over 20% of hospitalizations for patients older than 65 years of age. Incidence rises with age, and whereas the incidence and prevalence of heart failure is greater in men than in women, the absolute numbers are similar due to greater longevity in women. It is a highly morbid disease; treatment for heart failure during the past 60 years has significantly improved with associated improvement in outcomes, but the 5-year mortality remains poor at approximately 50% [39,40]. Heart failure can be broadly categorized as heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF); epidemiological data show about equal numbers of each subset for patients with heart failure, but sex differences are prominent [41]. For example, in both HFpEF and HFrEF, women have worse health-related quality of life measures compared with men [42].

Heart failure with preserved ejection fraction

Patients with HFpEF tend to be older, with more obesity and hypertension and less coronary artery disease than those with HFrEF. One of the most striking differences is that HFpEF is significantly more prevalent in women, in some studies by a factor of 2 [43]. A cross-sectional study of Medicare data found that for patients over age 65 hospitalized for heart failure, 66% had a reduced ejection fraction and 49% of those were women. In contrast, 71% of patients with preserved ejection fraction were women [44].

Rates of hypertension and obesity, two of the primary risk factors for HFpEF, are both higher in women compared with men. Obesity rates are higher in women across all age groups, whereas hypertension rates are higher in women after the age of 65 [45,46]. However, this does not explain all the gender differences in HFpEF. Some of the difference in diastolic dysfunction may be related to gender differences in the way that female and male hearts structurally remodel. In response to chronic pressure overload, women are more likely than men to develop concentric hypertrophy and are less likely to dilate their left ventricular chamber size, leading to higher filling pressures. Arterial stiffness increases with age and is higher in women, which contributes to a net increase in ventricular afterload [47]. Obesity may contribute as well, as a trigger of inflammation leading to increased oxidative stress, which causes abnormalities in the coronary microvascular endothelium, and in turn, stiffer ventricles [48]. Obesity appears to have a more pronounced effect on ventricular remodelling in women than men. Lastly, there is evidence of hormonal modulation on calcium and nitric oxide handling in the cardiac myocytes, and on the renin–angiotensin–aldosterone system, with oestrogen serving a protective role; thus, women in the post-menopausal years are more vulnerable to negative ventricular remodelling [49,50].

Mainstays of treatment for HFrEF have failed to show benefit in HFpEF, including angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and β-blockers [51]. Data are conflicting on whether there is a mortality difference in these two broad categories of heart failure [52]. There is some evidence that outcomes in HFpEF differ for women and men; the I-PRESERVE trial, which looked specifically at HFpEF and had an unusually high enrolment of women at 60%, showed that women are ∼20% less likely to experience death or hospitalization compared with men, a finding similarly noted in other studies on HFpEF [53,54].

Heart failure with reduced ejection fraction

HFrEF of both ischaemic and non-ischaemic aetiologies is more common in men than in women, for incompletely understood reasons. Proposed mechanisms include gender differences in obstructive coronary disease, myocardial inflammation, cardiac remodelling and sex hormone effects on the heart [55]. Women with HFrEF are more likely to have a non-ischaemic aetiology, whereas men are more likely to have ischaemic cardiomyopathy [56]. Among the population with systolic heart failure, women survive longer than men, driven primarily by a significant difference in mortality between women and men with non-ischaemic cardiomyopathy. Women with ischaemic cardiomyopathy may have a slightly improved mortality compared with men, but this difference is not as pronounced as for non-ischaemic cardiomyopathy. It may be that the sex differences in ventricular remodelling that make women prone to develop HFpEF play a protective role in HFrEF, via higher relative left ventricular ejection fractions in women compared with men [57]. However, some studies have found that the survival benefit persists even in female and male populations with similar ejection fractions [56].

The foundation of treatment for improving morbidity and mortality in systolic heart failure is optimal medical therapy including β-blockers, ACE inhibitors or ARBs, aldosterone antagonists and hydralazine/nitrates. Women have been vastly underrepresented in all clinical trials that have proven the benefit of these medications. In the majority of trials women comprised <30% of study participants. A meta-analysis examining subgroups in the landmark clinical trials that proved the mortality benefit of β-blockers and ACE inhibitors showed that, in composite, women comprised only approximately 20% of study participants [58]. In fact, the V-HeFT I and II trials, which showed the benefit of hydralazine and isosorbide dinitrate in heart failure, included only men. The follow up study, A-HeFT, which focused on the benefit of these medications in black patients with heart failure, included a significant number of women, 40%, which is almost an outlier in cardiovascular clinical trials [59]. The aforementioned meta-analysis showed that β-blockers resulted in similar reduced mortality in women and men with HFrEF, whereas the data on ACE inhibitors shows some gender differences. Although men enjoyed a mortality benefit from ACE inhibitors whether they had symptomatic or asymptomatic LV systolic dysfunction, the meta-analysis data support that women may only derive a benefit with symptomatic LV dysfunction [58]. Digoxin, which can be used for patients with HFrEF who remain symptomatic despite optimal medical therapy, has been shown to improve symptoms and reduce hospitalizations; however, a post hoc subgroup analysis of the Digitalis Investigation Group study showed that women assigned to digoxin had a higher rate of death than women assigned to placebo, an association not found in the male subgroup [60]. The guidelines for management of heart failure acknowledge the underrepresentation of women in these clinical trials, but in the absence of further evidence make no distinction in recommendations for management of heart failure between the sexes [61].

One of the non-pharmacologic mainstays of HF therapy is ICD implantation to prevent SCD. The ACC/AHA guidelines recommend implantation of ICD for the primary prevention of SCD for patients with an LVEF ≤30% and New York Heart Association (NYHA) class I symptoms, or patients with LVEF ≤35% and NYHA class II–III symptoms on chronic guideline-directed medical therapy [61]. Despite this class I recommendation, many population-based studies have shown that a considerable number of qualifying people are not referred for ICD implantation, both women and men. Women, however, are significantly less likely to receive an ICD for primary or secondary prevention, by 2–3-fold [28,29].

Although some older data seemed to support that women may not receive the same benefit of ICD implantation as men, cardiac resynchronization therapy (CRT) has been a different story. The early trials on CRT similarly enrolled lower rates of women, only 25% in the MADIT–CRT trial and 17% in the RAFT trial, but in pre-specified subgroup analyses both trials showed a definite trend to greater benefit in women in the primary outcome of death or heart failure event or hospitalization [62,63]. A large meta-analysis of CRT showed that women had better outcomes in all-cause mortality, cardiac death and heart failure events and a significantly greater improvement in echocardiographic evidence of reverse cardiac remodelling [64]. Despite these data, women are far less likely than men to receive CRT. A multinational European survey showed that only 23% of patients who underwent CRT implantation between 2008 and 2009 were women [65], and US data show similar trends [66].

Left ventricular assist devices (LVADs) provide mechanical support for end stage heart failure and have changed the face of this terminal illness. They are currently used as therapy for bridge to transplant (or to transplant candidacy) or as destination therapy. Similar to other cardiovascular advances, women have been significantly underrepresented in clinical trial data regarding LVADs, with an enrolment rate of less than 25%. In the older LVAD technology, female size was an issue, as lower body surface area prohibited implantation. With newer technology and smaller pumps, body size is no longer prohibitive, yet women remain underenrolled in LVAD studies. Across multiple trials the survival and complication rates are similar in women and men, with the exception of neurological events, which appear to be greater in women [67]. Nevertheless, women appear to be referred for LVAD later in their clinical course with more severe heart failure [68,69]. The rates of implant in women are significantly lower than in men; one study of Medicare beneficiaries who underwent LVAD implant between 2004 and 2011 showed only 17% of those receiving LVADs were women [70].

Heart transplantation is also heavily weighted toward male recipients. According to data from the Organ Procurement and Transplantation Network (US DHHS), between 2010 and 2015 only 29% of people who received heart transplants were women. Data on outcomes in women and men who receive heart transplants show similar long-term survival, although there seems to be an early mortality trend for men who receive hearts from female donors [71,72]. Multiple reasons for the large differential in heart transplant recipients have been proposed. At one transplant centre, women with heart failure were more likely to refuse transplantation, and no other evidence of sex bias was found [73]. Other factors include the older average age of women with advanced heart failure, the fact that women with heart failure are more likely to have HFpEF and prior pregnancy with its associated higher levels of immunological sensitization would prohibit finding a suitable donor. Some have proposed that body size is a factor, with a higher proportion of male donors that are better suited to match male recipients. However, there seems to be some sex bias in referral patterns for heart transplantation. Even in the aforementioned study of higher rates of self-refusal for transplantation in women, only 23% of those referred for cardiac transplantation were women. Women are less likely to be referred to a cardiologist for management of heart failure, and women seem to be referred for transplant with more severe heart failure and later in their clinical course [74,75], which may affect the consideration for transplant.

Female-specific aetiologies for heart failure

Women have unique causes of cardiomyopathy and heart failure. Although overall men are more likely than women to develop HFrEF, peripartum cardiomyopathy (PPCM) and stress cardiomyopathy (SCM) are two entities seen entirely or predominantly in women.

PPCM is an infrequent cause of cardiac dysfunction, phenotypically resembling a dilated cardiomyopathy. By definition, it is new onset systolic heart failure that presents between 1 month prior to delivery and 5 months after delivery. The estimated case rate in North America is 1 per 2500–4000 live births. The cause of PPCM is unknown. Proposed mechanisms include autoimmune dysregulation, stress activated cytokines, environmental factors, small-vessel disease, nutritional deficiencies and coronary artery spasm. Established risk factors include multiparity, older maternal age, hypertension, African descent and multifetal pregnancy. Studies on prognosis show that up to 50% of women fully recover heart function. For those who do not, their prognosis is similar to other cases of dilated cardiomyopathy [61]. Mortality has been as high as 7% over an 8 year follow up period [7678]. Treatment includes standard therapies for systolic heart failure. Use of mechanical support and even transplant has been necessary in cases of severe cardiogenic shock. Mouse models have shown that a prolactin fragment may play a role in the pathogenesis of PPCM, and for this reason some guidelines advise against breastfeeding, although this is not an evidence-based recommendation. Future pregnancies may be affected, and there is consensus that women with persistently reduced ejection fraction be strongly advised against future pregnancies. It is not clear as to the best recommendation for future pregnancies for women who fully recover their left ventricular function; although they are at risk for recurrent heart failure, some retrospective studies show healthy pregnancies in this cohort [78,79].

SCM, also known as Tako-tsubo cardiomyopathy, broken heart syndrome or transient apical ballooning, is a clinical syndrome that while not exclusive to women, is hugely predominant in post-menopausal women. Up to 90–96% of those with SCM are women, with a mean age of 68 years. The presentation mimics that of acute myocardial infarction (AMI), and it is a diagnosis of exclusion. The most frequently observed contraction abnormality is mid- and distal left ventricular dysfunction with preserved basilar function, although many other wall motion abnormalities have been described. A hallmark of SCM is wall motion abnormalities that extend beyond a single coronary artery territory. Although there is usually a preceding emotional or physical stressor that acts as trigger, infrequently no trigger is identified. The causative mechanism of SCM is unknown, although the most commonly accepted hypothesis is cardiac dysfunction due to catecholamine toxicity and excessive sympathetic stimulation, for reasons that have not been elucidated. Other proposed mechanisms include multivessel epicardial spasm or microvascular dysfunction. Sex-specific causes have been investigated due to the female predominance of the syndrome; one theory is that oestrogen is protective for coronary vasoreactivity, and a relative decline of oestrogen in menopause leaves the myocardium more susceptible to endothelial dysfunction. The prognosis in SCM is excellent. Serious complications of heart failure are rare, though cardiogenic shock, malignant arrhythmias, free wall rupture and thromboembolic events have been described. Virtually all patients fully recover ventricular function within weeks, although prolonged recovery time up to 12 months has been reported. If full recovery is not observed, alternate diagnoses should be entertained. Recurrence can occur, although it is uncommon, seen in <10% of cases. Management includes usual therapies for systolic dysfunction, monitoring for arrhythmias, mechanical support as needed for cardiogenic shock and anticoagulation for proven apical thrombus or perhaps empirically for those with severe apical dyskinesis or akinesis [8082].

Cardio-oncology is a growing field, fuelled by our successes in treating cancer over the past decades. As people are surviving their malignancies, they are confronted with long-term adverse treatment effects. The cardiotoxicity of many anti-cancer agents is well established, and expanding basic and clinical research efforts are being funnelled into understanding the mechanisms behind the cardiotoxicity, and ways to prevent and manage it. There is evidence that female sex is a risk factor for late cardiotoxic effects of some treatments for childhood cancers [83,84].

CORONARY HEART DISEASE

The cardiology community is increasingly aware that sex differences play a role in the pathophysiology and clinical manifestations of CHD. Heart disease, and coronary artery disease in particular, was once thought a man's disease. Although men have a significantly higher prevalence of CHD than women prior to age 50, the prevalence in women steadily rises in the post-menopausal years and reaches nearly equal numbers to men in the seventh decade of life [85]. Sex differences are apparent in the risk factors, clinical manifestations and outcomes of CHD.

Risk factors for coronary heart disease

Traditional risk factors for CHD are shared among women and men, although there are subtleties in the effects of these risk factors. Hypertension is present in 33% of US adults. Over the age of 65, women have higher rates of hypertension, and it seems to confer a greater risk for CHD in women [46,86]. Physical inactivity is more common in women starting in youth, even while the cardiovascular health benefits related to physical activity are more pronounced for women than men [87,88]. Women with diabetes have a higher associated risk of incident CHD and death from cardiovascular disease compared with men [89]. Although elevated LDL levels confer similar cardiovascular risk for women and men, non-fasting triacylglycerols affect women's risk of MI, CHD and death to a greater extent than in men. Furthermore, LDL levels show a dramatic rise in post-menopausal women, with a concurrent decline in HDL levels [90,91]. Rates of smoking have declined significantly from 1965 to 2009, but the rate of decline has been greater among men than women. Compared with men, women who smoke are more likely to develop CHD and to die from ischaemic heart disease [92,93]. Obesity is associated with CHD in women, independent of the risks associated with the components of the metabolic syndrome. Women with a BMI > 30 have a higher relative risk of CHD compared with men, and rates of obesity are higher in women across the age spectrum [45,94].

Beyond these traditional risk factors, women have both female-specific and female-predominant cardiovascular risk factors. During menopause endogenous oestrogen levels drop 90% from pre-menopausal levels. Although the mechanisms are not fully understood, oestrogen has protective properties for cardiovascular health. Proposed mechanisms include direct effects on the vascular wall with inhibition of smooth muscle cell proliferation and regulation of vasomotor tone, as well as indirect beneficial effects on lipids, hypertension, obesity and insulin sensitivity. Menopausal loss of these protective effects may in part explain the rise in cardiovascular events in post-menopausal women [9597]. Pregnancy-related complications including gestational diabetes, gestational hypertension and pre-eclampsia all increase the risk for future cardiovascular events [98,99]. Systemic autoimmune diseases, which are more frequently seen in women, are associated with accelerated atherosclerosis and increased risk of CHD [100].

Pathophysiology of coronary heart disease

The pathophysiology of CHD differs between women and men in significant ways. Although atherosclerotic disease is the predominant mechanism of CHD in both women and men, additional mechanisms of coronary pathophysiology occur more frequently in women. Plaque erosion, the cause of AMI in 25–30% of cases of acute coronary syndrome (ACS), is more common in women, and is the most common cause of acute coronary thrombosis in women under the age of 50 presenting with sudden coronary death [101,102]. SCM is the female-predominant phenomenon of a cardiac event that mimics AMI in the absence of obstructive coronary artery disease. It is estimated to be the underlying disease process in 1–2% of patients presenting with AMI [81,82]. Spontaneous coronary artery dissection (SCAD) is another cause of AMI that predominantly occurs in healthy, young women. Although there can be underlying atherosclerotic disease, SCAD often occurs in the absence of significant coronary plaque. Associated conditions include the peripartum state, connective tissue diseases, vasculidities and the Marfan syndrome. Up to 30% of cases of SCAD occur in the peripartum period. The mechanism appears related to the normal physiological state of pregnancy, in which increased cardiac output and blood volume place increased stress on the coronary arterial wall, already made more vulnerable due to hormonal effects on the intercellular matrix and the endothelium [32,103,104]. SCAD is not the only cause of AMI in pregnancy. Pregnancy increases the risk of AMI three to four times that of age-matched non-pregnant women. Other causes of AMI in pregnancy include atherosclerotic disease, thrombus without underlying atherosclerosis and vasospasm [105,106]. Other causes of non-atherosclerotic coronary disease that are more common in women include Takayasu's syndrome and coronary vasospasm [107].

Microvascular coronary dysfunction and non-obstructive coronary artery disease

Since the 1960s there has been awareness of the clinical syndrome of typical angina with positive ischaemic stress testing in the absence of significant epicardial coronary disease. Among people referred for coronary angiography to further evaluate chest pain, women are more likely than men to have angiographically normal epicardial coronary arteries. In the WISE study, up to 50% of women with chest pain and abnormal non-invasive test results but normal epicardial coronary arteries were found to have microvascular dysfunction [108,109]. This entity is not benign; it is associated a 2.5% annual adverse cardiac event rate [110].

In microvascular coronary dysfunction (MCD) there is dysfunction of the coronary microcirculation such that it does not appropriately or adequately respond to variations in myocardial oxygen requirements [111]. The cause of MCD is not fully understood. There is altered endothelial tone and adverse structural changes, possibly related to hormonal changes (specifically the decline of oestrogen in the post-menopausal years) or chronic inflammation [110,112,113]. There is no proven risk factor modification or treatment for MCD.

The burden of non-obstructive coronary disease also seems to hold more risk for women compared with men. One study of obstructive compared with non-obstructive coronary disease detected via coronary CT angiography found that non-obstructive disease was a significant predictor of mortality in women, with worse prognosis the higher the burden of non-obstructive disease, a relationship not observed in men [114,115].

The link between non-obstructive coronary disease, microvascular dysfunction and adverse cardiac outcomes is not yet understood. However, evidence is robust that women with chest pain and angiographically normal or non-obstructive coronary arteries do not represent a low risk group. Risk factor modification is key for this population. Future research is critical in managing this clinical syndrome and improving outcomes. As long as ischaemic heart disease is considered synonymous with obstructive coronary disease, we will miss the opportunity to prevent, diagnose and treat a substantial proportion of women with ischaemic heart disease.

Differences in treatment and outcomes in coronary heart disease

Women have higher rates of recurrent MI and mortality rates after their initial MI compared with men. Whereas CHD mortality in men has declined in recent years, it has risen in women. In particular, young women presenting with AMI have a higher risk of death [116]. Some of these differences can be attributed to delays in presentation and recognition of acute coronary events in women; multiple studies have shown that women present with atypical features more commonly than men [117]. Other potential causes include greater comorbidities in women who present with AMI. However, there is also evidence of treatment differences once the diagnosis of ischaemic heart disease or ACS has been made [112].

Registry data show significant gender disparities in the use of evidence-based therapies for both ST elevation and non-ST elevation myocardial infarctions. Data from the CRUSADE registry, which focuses on NSTEMIs, showed that women had a relative delay in obtaining an initial ECG, were less likely to be cared for by a cardiologist during the hospitalization, and were less likely to receive heparin therapy. They were more likely to undergo stress testing as opposed to diagnostic catheterization. Women were less likely to receive aspirin, ACE inhibitors and statins at discharge [118]. Similar results have been seen in STEMI registry data, with women less likely to receive aspirin, β-blockers, heparin and invasive procedures including revascularization [118]. The VIRGO study addressed younger women ages 18–55 with AMI, a subgroup with a relatively high mortality risk. Young women with AMI had longer lengths of stay, more comorbidity and higher in-hospital mortality compared with young men. They were less likely to receive reperfusion therapy, and they were more likely to have delays in reperfusion. In the year following AMI women had poorer scores than men on all health status measures [119121]. Overall women are less likely to receive coronary artery bypass grafting or percutaneous coronary intervention compared with men, despite the fact that newer data show little difference in morbidity or mortality between the sexes following revascularization. Women are also significantly less likely to be referred for cardiac rehabilitation programmes following revascularization [122,123].

VALVULAR HEART DISEASE

Mitral valve prolapse

Mitral valve prolapse has an estimated prevalence of 2.5% of the population. Women are more commonly affected, but compared with men they have a more benign course: less flail leaflets, lower regurgitation grades, higher ejection fractions, smaller chamber dimensions, and they are less likely to present with severe symptoms such as heart failure, atrial fibrillation and stroke. However, with severe mitral regurgitation, women are less likely to undergo valve surgery, and they have worse outcomes than men. This increased risk in women may be due to surgical trends, as women and men share similar positive post-surgical survival rates [124].

Aortic stenosis

Calcific aortic stenosis (AS) is a common disease in the elderly. AS of any degree has a prevalence of 12% in the elderly population, and severe AS has a prevalence of over 3% [125]. Once a uniformly fatal disease without surgical valve replacement, AS can now be treated with percutaneous intervention, known as TAVR, transcatheter aortic valve replacement. Among patients who are high risk for surgery and undergo TAVR, women have higher rates of post-procedural complications than men, including major vascular complications, bleeding events and stroke; however, there is no difference in procedural or 30 day mortality. Furthermore, women have less para-valvular aortic insufficiency following TAVR, and significantly better late survival rates than men [126,127]. As discussed previously, the female and male hearts respond differently to chronic pressure overload in the ways they structurally remodel; similarly, with the reduction in pressure overload after aortic valve replacement, women have a more frequent and more rapid left ventricular mass regression [128].

AREAS FOR ADVANCEMENT

Every aspect of cardiovascular health and disease requires advancing our knowledge of sex-specific differences. Doing so can improve outcomes for both sexes and the health of our population. This is particularly relevant given the aging population and the many cardiac diseases that increase in prevalence with age. The 10Q Report, a consensus document written by leaders in cardiovascular diseases and published in 2011, outlined the significant evidence gaps in our knowledge of cardiac-specific gender differences, but almost 5 years later we have made few strides in narrowing these gaps [129]. The many differences in cardiovascular disease between women and men as highlighted in this review are certainly hypothesis generating, and offer a multitude of avenues for exciting and meaningful research.

  • Hormonal effects on cardiovascular health: Sex hormones, particularly oestrogens, have multiple effects on the cardiovascular system, from neurohormonal adaptations to basic cellular physiology. However, the details of these complex interactions, their true extent, and whether there is any way to modify their effects for the benefit of women's health are yet to be determined.

  • Female-specific risk calculators: Female-specific risk factors, such as pregnancy-related complications, are not included in traditional methods of assessing risk of future coronary events. Increasing practitioners' awareness of these links, studying whether female-specific risk calculators might have increased sensitivity for this population, and investigating the causes of the heightened risks and methods to modify those risks are critical to improving women's cardiovascular health

  • HFpEF: Although this clinical entity comprises almost half of cases of heart failure, our understanding of the pathophysiology of HFpEF and effective ways to treat it is incomplete. Clinical trials of medical therapy have been disappointingly negative. The differences in structural remodelling seen in female hearts are striking; further elucidation of this process could result in meaningful breakthroughs in preventive and therapeutic efforts.

  • Chest pain in the absence of obstructive coronary disease: Non-obstructive coronary artery disease in the setting of positive stress testing is now understood to not merely be a ‘false positive stress test’, but to portend a worse outcome in women. The cumulative burden of non-obstructive coronary lesions also has a higher associated risk of mortality in women compared with men. We are just beginning to understand the impact of MCD, its diagnosis and management. Further research into non-invasive testing is a promising area for advancing our ability to diagnose this syndrome. Interestingly, microvascular dysfunction is implicated in both pre-eclampsia and CHD, and may indicate a shared pathophysiology.

  • Awareness of gender differences: Awareness of gender differences in approaches to the treatment of cardiovascular disease, both invasive and non-invasive measures, and pharmacological and non-pharmacological therapies, is critical to ameliorating differences in outcomes that are a function of these treatment decisions. Although no physician would declare partiality in the management of female compared with male patients, subconscious biases may be present and affect the use of evidence-based therapies. Further study of the presence or absence of gender differences in treatment practices is critical to understanding our gaps in management. Without this awareness, we cannot work toward narrowing these gaps.

CONCLUSION

Although the cardiac clinical and research communities have advanced considerably in recognizing sex-specific issues in cardiovascular health and disease, we have much to learn before we can optimize the health of our population.

Those disease states that are shared among women and men must have equal representation of both sexes in future clinical trials. Female-specific questions require focused attention, and should not be considered deviations from the norm, but rather relevant variations in the manifestations of cardiovascular disease. We are at an exciting time in cardiology, when our scientific community abounds with seemingly infinite new technologies and innovations. This intersection, between our ever-expanding capability to study and treat disease, and our increased awareness of sex differences in cardiovascular disease, promises ongoing breakthroughs in our ability to prevent and treat cardiovascular disease for the entire population. However, we need targeted, large-scale initiatives focusing on women to achieve these breakthroughs, and the necessary funding to do so.

Substantial morbidity and mortality can be attributed to our lack of focus on the prevention and treatment of cardiovascular disease in women. We cannot afford to lose more ground for one-half of the world's population.

DECLARATIONS OF INTEREST AND FUNDING

The authors have no relevant funding to declare.

Abbreviations

     
  • ACE

    angiotensin converting enzyme

  •  
  • ACS

    acute coronary syndrome

  •  
  • AMI

    acute myocardial infarction

  •  
  • ARB

    angiotensin II receptor blocker

  •  
  • AS

    aortic stenosis

  •  
  • AVNRT

    atrioventricular nodal reentrant tachycardia

  •  
  • CABG

    coronary artery bypass grafting

  •  
  • CHD

    coronary heart disease

  •  
  • CRT

    cardiac resynchronization therapy

  •  
  • ECG

    electrocardiogram

  •  
  • HFpEF

    heart failure with preserved ejection fraction

  •  
  • HFrEF

    heart failure with reduced ejection fraction

  •  
  • ICD

    implantable cardioverter defibrillator

  •  
  • LQTS

    long QT syndrome

  •  
  • LVAD

    left ventricular assist device

  •  
  • LVH

    left ventricular hypertrophy

  •  
  • MCD

    microvascular coronary dysfunction

  •  
  • MI

    myocardial infarction

  •  
  • NYHA

    New York Heart Association

  •  
  • PAC

    premature atrial contraction

  •  
  • PCI

    percutaneous coronary intervention

  •  
  • PPCM

    peripartum cardiomyopathy

  •  
  • PVC

    premature ventricular contraction

  •  
  • SCAD

    spontaneous coronary artery dissection

  •  
  • SCD

    sudden cardiac death

  •  
  • SCM

    stress cardiomyopathy

  •  
  • SVT

    supraventricular tachycardia

  •  
  • TAVR

    transcatheter aortic valve replacement

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