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Sex Differences in Cardiovascular Disease

More women than men die of cardiovascular disease (CVD) each year in every major developed country and most emerging economies. Nonetheless, CVD has often been considered as men’s disease due to the higher rates of coronary artery disease (CAD) of men at younger age. This has led to the underestimation of the impact of CVD morbidity and mortality in women. In addition, the underrepresentation of women in clinical diagnostic, prognostic, and therapeutic studies further established the image of CVD being a male’s disease. Consequently, diagnostic tests for CVD and its treatment are predominantly based on observations in men. This limits their diagnostic and treatment accuracy in women. Improved insight in sex-specific features in the pathogenesis of CVD is warranted, especially since the aging of the population will further increase CVD mortality and morbidity in women. There is accumulating demographic and scientific evidence that sex differences exist in pathology and incidence of CAD and heart failure (HF) that, for this reason, will be the focus of this chapter.

Awareness of Cardiovascular Disease

Ever since the early 1980s, most cardiovascular research has focused on men. This phenomenon has led to the underappreciation of sex differences in CVD from an etiological, prognostic, diagnostic, and therapeutic perspective. Several initiatives to promote women’s health have been initiated and have changed the practice of cardiovascular disease prevention in women over the past decade such as the Women’s Health Initiative. This ultimately led to the first guidelines for cardiovascular disease prevention in women by the American Heart Association in 1999. These initiatives have increased the awareness that medical practice in cardiovascular disease may differ for women, yet worrying issues remain.

One of the factors that may worsen outcome in women is the perception of cardiovascular risk and the decision to seek medical care when experiencing complaints. Research shows that more than half of the women would still be hesitant to call the emergency number when thinking they are experiencing a myocardial infarction. The shortest time to either pharmacological therapy or mechanical reperfusion therapy is the key for the best outcome in patients with myocardial infarction.

Several studies report that time from symptoms to first medical contact and time from hospital arrival to reperfusion therapy in women are significantly longer in women as compared to men, with median delays in women between 15 min to more than an hour. These facts underscore the need for campaigns educating women and the first line of medical treatment about the importance of recognizing aspecific symptoms in order to improve survival.

Indeed, intensive public efforts to educate women about their risk of heart disease in the last decade have been quite successful as a recent survey showed that awareness of heart disease among women nearly doubled in 10 years. Yet, given the positive correlation between awareness and cardiovascular disease risk reductions in women, it is important that the emphasis on these campaigns remains. Also, attention raised to the warning signs of cardiovascular disease in women may help to increase their awareness of being at risk.

Statistics of CVD and Sex Differences

Sex and Atherosclerotic Disease

CAD refers to a narrowing of the blood vessels that supply blood and oxygen to the heart due to the buildup of atherosclerotic plaques. At a global scale, CAD and stroke incidence has increased in the last decades: 12.9 million deaths in 2010, or one in four deaths, compared to one in five in 1990. In that same period, the rate of death attributable to CAD declined 30.6 %, but rates are increasing among women below the age of 55 in the United States. However, this trend was not seen over the past three decades in Europe.

Angina pectoris is the most common symptom of CAD. Angina pectoris is an early indicator for acute manifestations due to thrombotic coronary occlusion. Angina also appears to prevail in women. A meta-analysis including studies from 31 countries showed that the sex ratio for angina prevalence was 20 % higher in both pre- and postmenopausal women as compared to men.

Rates of life-threatening manifestations of CAD increase with age for both men and women but with marked differences between them. The sex-associated difference in age at which the incidence of CAD increases has been known since the early reports from the Framingham Heart Study. Myocardial infarction occurs approximately 20 years later in women as compared to men. Yet, the clinical outcome following myocardial infarction is worse in women. Among those patients who suffered from a myocardial infarction under the age 50, women have a consistently worse prognosis in the period after the myocardial infarction. This excess short-term mortality has been attributed, at least in part, to diabetes.

Also, women aged 45–64 suffer from a higher risk to develop HF in the 5 years following myocardial infarction. In those above the age of 65, women are more likely to die within the first year of a manifestation of CAD as compared to men. Higher health-care costs are incurred in women with CAD due to the aforementioned higher incidence of angina complaints and myocardial infarctions as well as long-term increase in hospitalizations for the treatment of HF as compared to men.

Sex and Microvascular Disease

CAD Based on Microvascular Disease

As many as 50 % of women , presenting with symptoms of angina, have no or minor CAD on coronary angiography. Nonobstructive CAD is observed in 10–25 % of women compared with 6–10 % in men. However, this condition has always been thought to be associated with a better prognosis, yet the Women’s Ischemia Syndrome Evaluation study convincingly showed the opposite. Women without CAD but with persistent complaints had more than twice the rate of cardiovascular events, including myocardial infarctions, strokes, HF, and cardiovascular deaths, compared to women without complaints. These women are referred to as suffering from “cardiac syndrome X,” “coronary microvascular dysfunction,” or “microvascular angina.” Evidence points to a role of microvascular dysfunction as an underlying cause for complaints in women with absent lesions in larger epicardial arteries. In women with an acute coronary syndrome and normally appearing coronary arteries on angiography, subendocardial ischemia is a common finding. In early atherosclerosis, it was observed that men have more dysfunctional endothelium in epicardial coronary arteries, while women reveal impaired maximal coronary flow reserve potentially pointing to microvascular pathology. Microvascular damage in the coronary vascular bed is not easily diagnosed. The retinal vasculature is easily visualized, and it has been shown that narrowing of the retinal vasculature appears to be associated with cardiac remodeling independent of atherosclerosis. This supports the idea that this narrowing of the arteriolar caliber may be due to microvascular disease. In women with type 1 diabetes, this narrowing of the retinal vasculature is associated with CAD, while this phenomenon is not seen in men.

Microvascular damage is considered as a hallmark of HF with preserved ejection fraction, a disease that comes with serious morbidity and increased mortality and which is much more prevalent in women and often entitled as being a “female disease”.

Heart Failure with preserved Ejection Fraction (HFpEF) Based on Microvascular Disease

Among older patients, HF probably represents the greatest health burden in developed countries.

There are an estimated 23 million people with HF worldwide, and nearly 50 % of them are women.

Women with HF report a higher incidence of pain severity and sleep difficulties. Most studies agree that women have a worse quality of life after a diagnosis of HF. Yet, depression seems to affect both sexes equally. At least six methods to score HF have been developed to diagnose and score the severity. Clinical diagnostic criteria for HF have generally included history, physical examination, and chest radiographs. About 50 % of the HF patients suffer from the so-called HF with preserved ejection fraction (HFpEF), also referred to as diastolic HF. The etiology of systolic and diastolic HF and the subsequent treatment differ. The presence of diastolic left ventricular dysfunction evident from slow left ventricular relaxation and increased left ventricular stiffness is a clear sign of HFpEF. A consistent and unexplained finding among population-based studies is that women outnumber men with HFpEF with an impressive 2:1 ratio. The prevalence of HFpEF is around 4–6 % in men and 8–10 % in women for individuals 80 years and older. The prevalence in the community has been estimated to range from 1.1 % to 5.5 % of the general population. HFpEF is a growing epidemic with poor treatment options, and together with the longer life expectancy in women, there will be more elderly women living with disabling HFpEF.

The increasing group of diabetic patients has a significant risk to develop HFpEF. Percentages of prevalence of diastolic dysfunction between 27 % and 70 % have been reported in the growing asymptomatic diabetic population. Another female risk factor for development of HFpEF may be preeclampsia. Asymptomatic diastolic dysfunction diagnosed with echocardiography appears to arise within 3 years following pregnancy in 10 % of women with former preeclampsia (personal communication).

Sex and Non-Cardiac Vascular Disease

Peripheral Artery Disease (PAD)

Peripheral artery disease (PAD) is not only a major cause of disabling disease and limb loss, but patients suffering from claudication also suffer from an increased risk of myocardial infarction, stroke, and death. PAD is not a typical male disease. A recent study in low- and high-income countries including 34 studies that satisfied the inclusion criteria with a total of 112,027 participants showed broadly similar prevalence rates among sexes in the 9,347 patients who suffered from PAD.

Sex-specific prevalence rates increased with age and were broadly similar in high-income and low-income countries. Despite the fact that large population studies have demonstrated high rates of PAD in women, this demographic figure is underscored by the public and clinicians. Women with PAD are more likely to be asymptomatic as compared to men. In a Swedish population-based study of included participants aged 60–90 years, women were significantly more likely to have an abnormal ankle brachial index (<0.9) and be asymptomatic than men. Women with PAD experience higher rates of impairment of function and also report poorer outcomes after surgical treatment for PAD compared with men.

Abdominal Aortic Aneurysms (AAA)

The incidence of abdominal aortic aneurysms is approximately four to six times higher in men than in women. However, this is also partly explained by the later onset of the disease in females since the incidence in women also rises with older age. The treatment of abdominal aneurysms shows significant sex differences. The risk of rupture for small aneurysms is significantly greater in women compared with men, and women have a higher in-hospital mortality rates for all types of surgical interventions: open and endovascular repair.

Carotid Artery Stenosis (CAS)

Men suffering from carotid artery stenosis are at higher risk of stroke than women. This increased risk is observed for any degree of carotid artery stenosis. The overall prevalence of stroke does not differ between men and women which may be explained by the varying incidence of stroke with age. A preferred treatment of carotid artery disease is carotid endarterectomy. Follow-up studies suggested that men benefit more from carotid endarterectomy compared with women. The Asymptomatic Carotid Atherosclerosis Study (ACAS) showed that after a median follow-up of 2.7 years, the surgery caused a relative risk reduction in ipsilateral stroke of 17 % in asymptomatic women compared with a risk reduction of 66 % in asymptomatic men. This difference was explained in part by an increased postoperative complication rate in women. A study in patients with asymptomatic carotid artery disease showed that women randomized to carotid endarterectomy had a 44 % higher relative risk of intraoperative stroke or death than men and also revealed a 50 % smaller long-term benefit. The effects of estrogen has been proposed an explanation for these unexplained sex-related differences in stroke. A protective effect of estrogen may have a stronger effect on the development of atherosclerosis in the carotid artery as compared to other vascular territories. Indeed postmenopausal women status has accelerated thickening of the carotid intima–media complex. On the other hand, the Women’s Health Initiative, a large randomized study analyzing the effects of hormone replacement therapy on the primary prevention of stroke, was ended early because of a probable increased vascular risk in women in the treatment arm.

Sex and the Diagnosis of CVD

CAD

Both patients and physicians often evaluate CAD to be a male’s disease. Women who were classified as being at intermediate risk to develop CVD the coming 10 years with the use of Framingham risk score are more likely to be assigned to a lower risk category by primary care physicians as compared to men. This trend was similar for cardiologists and other medical specialists. As assignment to risk categories determines treatment and lifestyle advice, these women at intermediate risk for CAD did not receive optimal preventive advice and treatment. These inventory studies also revealed the fact that less than one in five physicians were aware that more women than men die of CVD every year. There is conflicting evidence regarding the complaints of women when experiencing CAD and whether these complaints are different from men.

The 2003 National Institutes of Health (NIH) study, titled “Women’s Early Warning Symptoms of AMI,” was one of the first to investigate women’s symptoms when experiencing heart attacks and how this differs from men’s. Of the 515 women studied, 95 % said that a month or more prior to experiencing their heart attack they knew their symptoms were different. The symptoms most commonly reported were unusual fatigue (70.6 %), sleep disturbance (47.8 %), and shortness of breath (42.1 %). Many women never had chest pains, less than 30 % reported having chest pain or discomfort before their myocardial infarction, and 43 % reported having no chest pain during any phase of the attack. Another study reported that women with acute coronary syndrome reported spreading chest pain more often than men. Other studies in the emergency department report that women with ACS have more nausea, burning pain, and shortness of breath as compared to men.

In primary care, the reported differences between men and women related to pain episode. Women report pain episodes of hours (between 1 and 12), whereas men reported a shorter pain episode (30–60 min). Recent evidence points to racial differences in prodromal and acute symptoms of myocardial infarction in women (Fig. 1).

Fig. 1
figure 1

Summary of the frequency of the most pronounced symptoms for ACS in women

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Women are more likely than men to experience delays in emergency care for cardiac symptoms. Researchers examined time to treatment for 5,887 individuals with suspected cardiac symptoms who made a 911 call in 2004. They found that, on average, women arrived at the hospital 2.3 min later than men. Factors increasing the likelihood of delay included evening rush hour travel, bypassing a local hospital, and living in a densely populated neighborhood. Even after adjustments were made for these factors, women were significantly more likely than men to be delayed.

Of all patients entering the office of the general practitioner with chest pain, about 10 % will be diagnosed with an acute coronary syndrome or CAD. The other 90 % will be sent home with a differential diagnosis that explains the chest discomfort. However, a significant number of these patients will appear to have CAD based on macrovascular disease and have a higher risk for detrimental outcome. Women are more likely to be managed with observation following first-line evaluation (serial ECGs and serial troponins), while men more often are subjected to stress testing. The critical distinguishing symptom that normally stimulates the initiation of diagnostic testing is chest pain. However, up to 35 % of patients with an acute coronary syndrome do not report the classical symptoms of chest pain. These patients are more likely to be misdiagnosed in the emergency department and at higher risk for death compared to those with chest pain. The underdiagnosis of the acute coronary syndrome in the emergency department has been reported to occur in up to 11 % of patients. Women are more likely to present without chest pain than men or have less severe chest pain symptoms. This has been attributed, at least in part, to their higher prevalence of comorbidities and their older age at time of presentation. Yet, a recent study among patients hospitalized for myocardial infarction below the age of 55 indicated that absence for chest pain was present in both sexes, but prevailed among women. The missed diagnosis at the emergency department has profound impact on the prognosis of the patient who suffers from high rates of readmission to hospital and an increased risk of death. The estimated incidence of unrecognized myocardial infarction in the Rotterdam study was an astounding 3.8 per 1,000 patient-years, with a higher proportion of unrecognized acute coronary syndrome in women (54 % vs. 33 %) compared with men.

An acute coronary syndrome based on acute thrombotic occlusion is diagnosed on the basis of ST elevation and T wave changes in the electrocardiogram (ECG). Patients with an ECG-based ST-elevated myocardial infarction will go for emergency coronary catheterization and subsequent angioplasty. In the absence of these classical ECG changes, the decision to undergo catheterization is based on increased levels of markers that indicate myocardial damage. Troponins are generally used to diagnose myocardial infarction without the classical ECG changes and thereby guide optimal treatment. Cardiac troponin T (cTnT) and troponin I (cTnI) increase within 3–12 h after a myocardial ischemic event. The diagnosis based on troponin levels implies a delay in treatment if the threshold for diagnosis of myocardial infarction is met in a later phase. The TACTICS-TIMI study showed that biomarkers were different between sexes upon unstable angina or non ST segment elevation myocardial infarction. Men were more likely to have elevated creatine kinases and troponins, and women were more likely to have elevated C-reactive protein and brain natriuretic peptide.

Yet, absence of ECG changes and/or increasing enzyme levels does not exclude the presence of an acute coronary syndrome due to CAD. Therefore, current guidelines for handling chest pain are focused on identifying those patients with an acute onset of symptoms at highest risk for myocardial infarction. The risk for an acute coronary syndrome at presentation can be calculated using one of three risk tools, the Global Registry in Acute Coronary Events (GRACE), the Thrombolysis in Myocardial Infarction (TIMI), and the PURSUIT trial. Little is known on how well these risk scores perform in women, especially because women with high score (TIMI) are less likely to undergo coronary angiography, possibly underestimating CAD in this high-risk group. The women with high TIMI who underwent coronary angiography had a similar degree of CAD as compared to men. Yet, these women were found to be at increased risk for recurrence and hospitalization for angina as compared to men.

Surprisingly, even in the hospital setting when the diagnosis of CAD is suspected, women are less likely to undergo catheterization or other diagnostic tests compared to men. Thus, the medical specialist is more likely to withhold optimal diagnostic testing and treatment in women, an observation that is difficult to explain to patient and society. This feature is also evident for non-cardiac manifestations of cardiovascular disease. For example, an Australian report shows that in elderly patients of 80 years and older, more women suffer from stroke but undergo 50 % less surgical endarterectomy procedures compared with men. Recent evidence from the BARI 2D trial shows that upon randomization to aggressive medical therapy alone or aggressive medical therapy with revascularization, no differences exist in outcome between men and women with diabetes and documented CAD.

Microvascular Disease

The diagnosis of microvascular coronary dysfunction (MCD) is challenging. Normal coronary angiography does not show vessels that are smaller than 0.5 mm in diameter and therefore have limited value in diagnosing microvascular disease. Endomyocardial biopsy in patients suspected of MCD reveals pathologic small coronary arteries with fibromuscular hyperplasia, hypertrophy of the media, swollen endothelial encroaching on the lumen, and myointimal proliferation. This invasive test cannot display vessels in between 200 and 500 μm and may underrepresent MCD that may be patchy. In vivo evaluation of the human coronary microcirculation relies on function and not on morphohistology. Currently, the gold standard for the diagnosis of MCD requires the exclusion of obstructive CAD by coronary angiography, followed by evaluation of microvascular coronary function. Currently, this is assessed by Doppler guidewire in the cardiac catheterization laboratory for endothelial function testing in response to intracoronary acetylcholine and measurement of coronary flow reserve in response to adenosine by coronary reactivity testing. Noninvasive imaging methods such as PET imaging and CMR hold promise for detection of MCD. MCD is associated with an increased risk of cardiovascular events; therefore, accurate diagnosis of this condition may lead to therapeutic interventions, reducing CVD in the future.

HFpEF

Also for HF, there are profound sex differences in clinical manifestations resulting in subsequent diagnostic challenges. HF is mainly associated with CAD and hypertension which immediately covers the two phenotypes: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). HFrEF is mostly caused by myocardial ischemia and mainly evident in men. HFpEF is associated with female sex, age, hypertension, and diabetes. Both phenotypes occur in 50:50 proportion. The problem of HFpEF will increase in the future as women tend to have longer life expectancies and common treatment strategies are ineffective. The common symptoms include dyspnea, chest pain, and palpitations. To stage HF, the New York Heart Association (NYHA) classification has been used based on clinical symptoms, especially breathlessness symptoms. Peripheral edema is commonly seen but aspecific in HFpEF. Symptoms of HF may be due to unrecognized ischemia and paroxysmal atrial fibrillation. The prevalence of atrial fibrillation has been estimated to be 30 % in patients with incident HFpEF. Hospital admission in patients with HFpEF is commonly due to unstable angina. Non-cardiac symptoms of HF may include anorexia, nausea, bloating, fatigue, weakness, oliguria, nocturia, and cerebral symptoms like anxiety, memory impairment, and confusion. In the older adult, HFpEF can present atypically with confusion, falls, anxiety, dizziness, or syncope. According to recent literature, the diagnosis of HFpEF requires the following conditions to be satisfied: signs or symptoms of HF, normal or mildly abnormal systolic left ventricular function, and evidence of diastolic left ventricular dysfunction. Normal or mildly abnormal systolic left ventricular function implies both a left ventricle ejection fraction of >50 % and a left ventricular end-diastolic volume index >97 mL/m2. If plasma levels of natriuretic peptides are elevated, diagnostic evidence of diastolic left ventricular dysfunction also requires additional noninvasive investigations such as tissue Doppler, blood flow Doppler of mitral valve or pulmonary veins, echo measures of left ventricular mass index or left atrial volume index, or electrocardiographic evidence of atrial fibrillation. A similar strategy is proposed for the exclusion of HFpEF in patients with breathlessness and no signs of congestion.

Sex-Specific Pathology of Heart Disease

When diagnosed with heart disease, men tend to have predominantly blockade of the blood supply of the main arteries, also referred to as macrovascular disease. Blockage of the smaller arteries, called microvascular disease or small vessel disease, is more prevalent in women. This paragraph will describe the pathogenesis of macro- and microvascular disease that may underlie differences in clinical presentation of CAD and explains pointing to heart disease and the response to treatment between sexes.

Macrovascular Disease

Atherosclerosis underlies the occurrence of cardiovascular disease and develops over decades with a prolonged asymptomatic phase during which it is possible to modify its course. Although there is very limited data available on sex differences, it is known that women have smaller and stiffer macro- and microvasculature, with more diffuse atherosclerosis. Also, their microvessels appear to be more frequently dysfunctional compared with men. The pathophysiology of CAD appears to be different in men and women. Women have smaller coronary artery diameters than men do, and upon complaints, women are less likely to suffer from obstructive CAD, as indicated from coronary angiography. Also in early stages of atherosclerosis, men have greater atheroma burden, more eccentric atheroma, and epicardial endothelial dysfunction, whereas women have more disease of the microvasculature, as will be reviewed in the next paragraph. In the presence of a thrombotic coronary occlusion, the underlying pathology differs between men and women. Autopsy data reveal that plaque rupture is a more common cause of coronary thrombosis in men (∼80 %) than in women (∼60 %) and that plaque rupture is especially rare in premenopausal women. In a small autopsy study in patients who died of acute myocardial infarction, a male–female ratio of 4.5:1 was observed in the presence of plaque rupture which was 1:1 when a plaque erosion was observed. In a larger autopsy study in almost 300 patients, the male–female ratio for plaque rupture was approximately 2.5:1 and for plaque erosion 1:1. Coronary death due to plaque erosion was relatively more frequently observed in younger females. Data on sex differences in atherosclerotic plaque characteristics are largely available for carotid arteries. Symptomatic and asymptomatic plaques obtained from the carotid artery region show more stable features in women compared to men: lower number of macrophages and higher collagen and smooth muscle cell content. In addition, the expression of matrix metalloproteases and interleukins 6 and 8 is significantly lower in plaques obtained from women as compared to men. The stated differences between men and women may affect the predictive value of biomarkers that are being tested and used to identify high-risk individuals. Indeed, data from our group show that atherosclerotic plaque hemorrhage and measures of plaque hypoxia are less prevalent among women compared to men. Moreover, even when plaque hemorrhage is present, we found that this plaque hemorrhage relates to secondary events in the Athero-Express Study in men, but not in women. With similar numbers of plaque neovessels, this points to differences in endothelial integrity between men and women (Fig. 2).

Fig. 2
figure 2

Sex differences in composition of carotid plaques, harvested during carotid endarterectomy, from the Athero-Express biobank. Panel A shows a typical example of a stable carotid plaque – harvested during carotid endarterectomy – that mainly consists of collagen or connective tissue. Panel B shows a typical example of a carotid vulnerable plaque with a large lipid-rich necrotic core and a thin fibrous cap. Panel C shows the distribution of different carotid plaque phenotypes in men and women, stratified for inclusion diagnosis. Atheromatous or vulnerable plaques are more common in men, whereas women more often have fibrous or stable plaques. Panel D shows the semiquantitative measure of macrophages in carotid plaques for men and women, stratified for inclusion diagnosis. Staining for macrophages – the hallmark for the vulnerable plaque – is more heavy in men as compared to women for symptomatic and asymptomatic patients

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Microvascular Disease

Studies on CMD have revealed that patients suffer from a number of problems including endothelial dysfunction, reduced coronary flow reserve, and autonomic imbalance. Hypertension and diabetes are probable contributors to CMD, in particular by affecting the endothelium-dependent vasodilatation. Other factors such as insulin resistance, estrogen deficiency in women, and low-grade inflammation may cause CMD. Several pathophysiological mechanisms have been proposed for CMD such as abnormalities in the microcirculation. More specifically, hypertrophy of smooth muscle cells have been implicated in the pathophysiology of CMD. Also, swelling and degeneration of endothelial cells with narrowing of the lumen of capillaries was most consistently found in CMD, next to myofibers with degenerative foci and lipofuscin deposits. Also, autonomic imbalance has been proposed. Patients with CMD have increased adrenergic function, and the abnormal handling of norepinephrine in cardiac sympathetic nerve endings has been shown to be present in 75 % of patients. Similarly, parasympathetic tone was reduced in approximately two thirds of patients with CMD.

HFpEF

The major difference between HF with reduced and preserved left ventricular ejection fraction is the degree of left ventricular dilatation and shape change of left ventricular remodeling. The mechanisms that explain why women suffer more frequently from HFpEF are poorly understood. Interestingly, women have a different hemodynamic response of the left ventricle to rapid saline loading. Women display increased pulmonary capillary wedge pressure relative to the infused volume. Also their mean pulmonary arterial pressure relative to cardiac output is higher compared to men. Concomitant with the diagnosis of HFpEF, women tend to develop more concentric left ventricular remodeling instead of eccentric remodeling that is more frequently observed in men. Next to hemodynamic determinants, metabolic changes of the myocardium seem to be implicated in the cellular and molecular changes that precede HFpEF. This is underscored by the observed effect of obesity on left ventricular geometry which has a considerably larger impact in women compared to men, according to the Strong Heart Study. Also, diabetes mellitus has been recognized to be associated with diastolic dysfunction. Diabetes has been proposed to worsen HFpEF through a variety of mechanism including myocardial fibrosis, advance glycation end product deposition, and high cardiomyocyte stiffness. Therefore, the high diastolic left ventricular stiffness may not only result from fibrosis of the myocardium but also from cardiomyocyte stiffness. This stiffness is especially prominent in HFpEF patients with diabetes and was recently related to the giant elastic protein titin. This protein proved to be targeted by in vitro by administration of protein kinase A or G. Experimental studies reveal that increasing the myocardial PKG activity by administrating sildenafil improves HFpEF in a dog model and in patients with HFpEF and pulmonary hypertension. Metabolic derangements may therefore underlie diastolic left ventricular dysfunction in HFpEF and are a potential target in future HFpEF treatment strategies.

Cardiovascular Risk Prediction

The sex/differences in the natural history of CVD are explained by specific pathophysiological mechanisms and hormonal influences, especially during pregnancy and menopause. During these times, women are more vulnerable to cardio-metabolic dysregulation due to major hormonal fluctuations. In addition, women have unique risk factors for developing coronary heart disease such as complications during pregnancy. Indeed, women with a history of preeclampsia have double the risk of subsequent ischemic heart disease, stroke, and venous thromboembolic events over the 5–10 years following the pregnancy.

Appreciating the fact that mortality from CAD has not declined in women, the recent years support the view that accurate sex stratified risk prediction is of great importance for the prevention of major cardiovascular events. Also, the age–cardiovascular risk relation depends on sex: in men aged 45–64 years, mortality rates are higher compared with women. However, this phenomenon is reversed after age 65 years, when cardiovascular death rates in women exceed those in men by more than 20 %. Especially because most women who die of CHD did not report earlier manifestations of cardiovascular disease, risk factor diagnosis and subsequent preventive treatment are essential.

Women have a high prevalence of cardiovascular risk factors and may have of these risk factors a great impact. Especially the metabolic syndrome which is a cluster of risk factors is common in women after menopause. Women with the metabolic syndrome are at highest risk for developing CVD compared to men with and without the metabolic syndrome. The Framingham risk score or Reynolds risk score can be used to estimate a women’s 10-year risk for CVD, yet Framingham risk score often underestimates this risk. The use of Reynolds risk score would require screening with high-sensitive CRP (hsCRP), and evidence that a reduction in hsCRP would improve outcome is currently lacking.

The current guidelines for women recommend use of a new cut point for defining high risk as ≥10 % 10-year risk for all CVD, not just CHD alone. This in contrast with the guidelines that recommended to classify individuals at high risk when absolute cardiovascular risk was >20 % in the next 10 years.

Additional risk markers that have been proposed to improve overall risk prediction include lipid measures, inflammatory biomarkers, markers of glycemic control, and imaging biomarkers such as coronary calcium scoring and intima–media thickness. Coronary artery calcium scoring has improved risk prediction in women. In the MESA (Multi-Ethnic Study of Atherosclerosis), over 3,500 women were scored for coronary calcium, and 90 % of these women were classified in the low-risk category. The presence of any sign of coronary artery calcium was associated with a sixfold increased risk for CAD in a multivariate model. Also, problems associated with hormonal status, ovaries, and pregnancy that arise may shed light on women at highest risk for CVD.

Sex Differences in Therapy for Heart Disease

Evidence-based medications are a cornerstone of cardiovascular risk reduction. Treatment for heart disease is similar for men and women, yet there may be differences in prescription of medication, efficacy, and adherence between men and women. Also, more adverse side effects in women are consistently reported for cardiovascular drugs such as thrombolytics. Differences between men and women in efficacy and side effects of cardiovascular drugs may be related to different pharmacokinetics, evidence base for men, and changes in hormone status (pre- vs. postmenopausal). Also, trial and registry data indicate that women with heart disease are treated less aggressively than men are. This paragraph deals with the outcomes of medical and invasive strategies that are currently present for men and women. In addition, we will touch upon differences in efficacy of available medical treatment between men and women.

Statin Therapy and Blood Pressure-Lowering Medication

For both primary and secondary prevention, the prescription of statins for reducing cardiovascular risk is common. Yet women have not participated in primary prevention trials as much as men, and this has led to debate about the evidence of benefits of statin therapy among women. Meta-analyses on pooled data have shown that the magnitude of benefit in terms of relative risk is equal in men and women in both primary and secondary prevention. Of note is that in primary prevention, the absolute risk for women to develop CVD is lower compared to that of men. This lower risk will then of course lead to an absolute lower benefit of statin therapy in women. Next to absolute benefit, women are less likely to adhere to statin therapy as compared to men; a 10 % higher odds of nonadherence was reported in women. Recently, a meta-analysis of 31 studies has shown that blood pressure lowering has similar benefit on cardiovascular disease in men as compared to women, while the difference in blood pressure reduction was greater in men as compared to women.

Hormone Replacement Strategy

The Women’s Health Initiative changed clinical practice for women in 2002 when the first data became available showing the hormone replacement therapy did not have a beneficial effect on incident CHD and increased the risk for stroke in asymptomatic women. A subgroup analysis in women with a previous hysterectomy did not show an increased risk for stroke in the 10-year follow-up study. Yet, in terms of proof, this study was of observational nature and may be therefore interpreted with caution. Also, selective estrogen receptor modulators showed to have detrimental side effects on stroke and venous thromboembolic events in both primary and secondary prevention of CHD. As a consequence, any modulation of hormones or its receptors is recommended against by the guidelines in women for cardiovascular disease prevention.

Treatment for ACS

Data from four registries spanning a 10-year time frame revealed that women with ACS (~14,000 in this study) are more likely to be treated conservatively. Female sex was associated with a lower in-hospital use of coronary angiography, despite similar GRACE risk scores among men and women. In this registry study, the rationale for not performing coronary angiography in these women was that it is “not supported by evidence.” Indeed, clinical trials of NSTE-ACS have consistently demonstrated a benefit with an invasive strategy for men, but results in women have been conflicting. In randomized clinical trials, an invasive strategy as compared to a conservative approach was only evident among women with positive biomarker levels, whereas women without positive biomarker levels did not have any benefit or even potential harm from an invasive approach. Therefore, a conservative strategy is recommended for low-risk women.

Registry data reveal that pharmacological therapy for CAD also differed between the sexes in stable CAD patients from 45 countries. Women are more likely to receive calcium channel blockers, but fewer ACE inhibitors, more antidiabetic drugs, but fewer lipid-lowering drugs than men. There were no differences in the use of beta-blockers between men and women. A more detailed review on differences in cardiovascular drug benefit between sexes is displayed below.

Antiplatelet, Anticoagulation, and Fibrinolytic Therapy

In primary prevention men and women are opposite in their response to aspirin. The Physicians’ Health Study showed that aspirin significantly reduced the risk of myocardial infarction, by 44 % in men 50 years of age or older who did not have symptomatic CAD. This study showed that there was no significant effect on the risk of stroke and no effect on mortality from other cardiovascular causes. Contrastingly, in women 65 years of age or older, the Women’s Health Study reports no effect on the risk of myocardial infarction or risk of death from cardiovascular causes. Yet, they report that aspirin is associated with a 24 % reduction in the risk of ischemic stroke and a 17 % reduction in the risk of overall stroke. One may conclude that women derived most of their benefit from a reduction of stroke, whereas men had the most benefit in reducing the risk for myocardial infarction. Given the differences in the cardiovascular pathology between men and women, differences in response to medication may not be a surprise. Also, the response to another group of antiplatelet agents – glycoprotein IIb/IIIa receptor inhibitors – was also sex specific. Men with acute coronary syndromes had a reduced risk for death or myocardial infarction of death or myocardial infarction upon treatment, and not benefit for women. Clopidogrel is one of the most frequently prescribed drugs. A recent meta-analysis shows that clopidogrel reduced the risk for cardiovascular events, with no differences between men and women. For anticoagulation therapy such as heparin, thrombin inhibitors, and indirect factor Xa inhibitors, the scientific results show minor differences in benefit between men and women. Also for fibrinolytic therapy, similar benefits were reported in men and women suffering from ACS. The effectiveness of fibrinolytic therapy is dependent on the time of presentation since symptoms. Given that women overall have longer symptoms when presenting with ACS, this may explain that women are less often treated with fibrinolytic therapy. Also, a higher risk for bleeding has been reported in women. This higher risk of bleeding in women has been reported by major clinical trials with different anticoagulation therapies. Several factors may contribute to this risk such as older age, more prevalent comorbidities, and renal impairment.

Treatment for HF

Women remain underrepresented in clinical trials investigating therapies for HF. Of the nine multicenter HF trials in the last decade, only 28 % women were included on average.

Digoxin is approved for HF treatment based on the positive results of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials. A post hoc subgroup analysis showed that digoxin was associated with a significantly higher risk of death among women taking digoxin compared with those taking placebo, an effect that was not observed in men. These safety concerns in women may have led to the decrease in its use that was reported.

Sex differences are small for the benefit of beta-blockers, calcium channel blocker, and angiotensin receptor blockers. Yet, most evidence is derived from trials where women only contributed 20–30 % to the population. Adverse effects of ACE inhibitors are more frequent in women as compared to men. Cardiac resynchronization therapy is a well-established therapy in patients with moderate to severe HF on optimal medical therapy. Cardiac resynchronization therapy seems to improve survival more in women as compared to men. This is thought to be explained by clinical factors such as a lower prevalence of nonischemic cardiomyopathy.

Treatment of HFpEF remains uncertain as many large clinical trials yielded neutral results, possibly explained by testing treatment based on the pathophysiology of HFrEF. Statins may delay progression of HFpEF due to the antioxidative properties. In experimental hypertensive HF, statins were known to favorably affect concentric myocardial remodeling such as regression hypertrophy and prevention of myocardial fibrosis. Also, a preliminary study of statin therapy in HFpEF showed a relative risk reduction of 22 % for death.

Summary

There are profound differences in heart disease diagnosis, mechanisms, and therapy between men and women. Although this is increasingly being acknowledged, further research to personalize cardiovascular care for men and women is eagerly awaited.