Heart Failure in Women

INTRODUCTION

The leading cause of death in women now is cardiovascular disease (CVD).^[1] Even though there was a reduction in mortality and morbidity of CVD in different populations, still remains high in young females. Multiple factors such as genetic, hormonal, and environmental factors singularly or in combination may explain this gender difference in CVD.^[2,3] In addition, females are underrepresented in clinical trials even though many associations’ recommendations say that at least 30% of the female population to be included in the trials. The guidelines drawn from these female less population will be advised for both sexes.^[4]

This disparity of gender is not only seen in a whole of CVD but also in all subgroups of CVD like heart failure (HF). As it is known from the previous studies, females present later, with more symptoms, in older age, with less ischemic cause, less aggressively treated, and higher mortality. In addition, the delay in diagnosis is compounded by the higher prevalence of HF with preserved ejection fraction (HFpEF) in females.^[5] This gender difference is present in genetic cardiomyopathies and in drug-induced cardiomyopathies for breast cancer. Furthermore, peripartum cardiomyopathy (PPCM) and pregnancy-associated complications such as preeclampsia are exclusive to women adding to long-term cardiovascular morbidity in females. Autoimmune diseases are also more frequent in females.^[6]

The possible reasons for this gender difference may be due to the:^[7]

1. Innate biological differences such as gender-related differences in the manifestation of the disease, treatment response, and the natural history of the disease

2. Unmeasured clinical variables such as confounding factors (e.g., disease severity or comorbidity) and differences in care as well as the difference in the application of clinical guidelines.

In this review, we want to highlight the gender differences in epidemiology, pathophysiology, response to therapies, and prognosis of HF. Along with the common risk factors for HF, special attention was given to specific risk factors in females, such as reproductive and hormonal challenges. At every step, the underrepresentation of females in the clinical and interventional trails and prominent research gaps was also discussed.

EPIDEMIOLOGY

HF is going to be the leading cause of death in both sexes.^[8,9] HF constitutes 1–2% of the general population in developed countries with an estimated 64.3 million people suffering now. By 2030, the expected increase in this HF incidence by 46%, out of the 50%, is going to be with HFpEF.

Even though there is a higher lifetime risk of developing coronary heart disease (CAD) in men before 40 years (one in two for men and one in three for women), by the age of 40, both sexes have equal lifetime risks of developing HF with the incidence of one in five. The incidence of new HF increases with age, the increment is faster in females than males (about double from 65 to 85 years in males whereas it is triple in females of the same age). Even though the overall incidence of HF in males is more than that of females in the younger age group, it equalizes by 80 years. Actually, after 80 years of age, the incidence of HF is almost 20% in males, more so in females.^[10,11]

According to the Swede-HF registry, HF in women is mostly due to HFpEF (in 55% HFpEF vs. 29% HF with reduced ejection fraction [HFrEF] patients). This higher percentage of women with HFpEF may be due to differences in the age distribution of the population at risk or higher life expectancy.^[12] The data from the Cardiovascular Health Study and the Multi-Ethnic Atherosclerosis Study also support that the lifetime risk for HFrEF was higher in men than women (10.6% vs. 5.8%), but the lifetime risk for HFpEF was similar for both sexes.^[13]

STAGES IN HF

HF could be acute or chronic, either left-sided or right-sided HF. There are four stages in HF (Stages A, B, C, and D). Stage A is the person who has a high risk of developing HF such as presence or hypertension (HT) or diabetes or CAD. In Stage B, the patient may have either left ventricular (LV) systolic or diastolic dysfunction but clinically does not have HF. Stage C – where the patient has clinical signs and symptoms of HF. In Stage D, the patient has advanced symptoms despite symptoms. Primary prevention can be implemented in Stages A and B to prevent HF development.

ETIOLOGY OF HF IN WOMEN

Common causes of HF are HT, valvular heart disease, diabetes, and coronary artery disease.^[14] These are the common causes of HF in women, especially in postmenopausal women. Less common causes include viral myocarditis and cardiomyopathies induced by alcohol/toxins, tachycardia, and stress. Other etiologies specific for women of HF are PPCM, autoimmune disorders, collagen vascular disorder, cardiotoxicity (such as chemotherapy with doxorubicin, trastuzumab, or other toxins), or genetic cardiomyopathies in select populations. HF due to stress-induced cardiomyopathy otherwise also known as takotsubo cardiomyopathy is one of the reversible causes of HF with a good long-term prognosis and is more frequent in postmenopausal women. In this type of cardiomyopathy, the major difference in gender is the type of stress. In females, emotional stress is the cause or precipitating event as physical stress in the case of males^[15,16] [Figures 1 and 2].

Close

Figure 1:

Traditional risk factors for heart failure development in females.

Export to PPT

Close

Figure 2:

Non-traditional for heart failure development in females.

Export to PPT

SEX DIFFERENCES IN HF

Gender differences are there in every component of HF such as in risk factors, pathophysiology, phenotypes, and outcomes including quality of life [Table 1]. Macrovascular obstruction leads to different varieties of coronary artery disease from myocardial infarction to chronic CAD, leading to decreased LV function causing HFrEF in men. Where in females, the predominant pathophysiology behind HF is the microvascular dysfunction, leading to HFpEF. The same mechanism was implicated even in takotsubo cardiomyopathy and PPCM.^[6]

GENDER-SPECIFIC RISK FACTORS FOR HF

Few risk factors are there which are specific only to women. These are reproductive factors, PPCM, and chemotherapy for breast cancer. Even though stress cardiomyopathy can occur in both sexes, it is discussed under this headline as it is more prevalent in postmenopausal women. So also, HF due to inflammatory cardiomyopathies and pulmonary artery hypertension-related right HF due to collagen vascular diseases are also more frequent in women.

REPRODUCTIVE FACTORS

The shorter reproductive period in postmenopausal women is a risk factor for HF. Nulliparous women are more likely to develop HFpEF.^[28] Pre-eclampsia, eclampsia, preterm delivery, abruption placenta, and gestational diabetes are known causes for future cardiovascular risk factors which subsequently may lead to HF.^[29] According to the Heart and Estrogen/Progestin Replacement Study trial, history of myocardial infarction, active smoking, diabetes, BMI >35 kg/m², atrial fibrillation, systolic blood pressure >120 mmHg, creatinine clearance <40 mL/min, left bundle branch block (LBBB), and LV hypertrophy were the strongest risk factor for the development of HF.^[30]

PPCM

A physiological stress test for women is a pregnancy that can mask the underlying cardiac diseases or predisposes them to new cardiac disease due to its innate effect on endothelial function and inflammatory profile, which, in turn, can lead to HF. PPCM is specific to the female sex and may occur during late pregnancy or in the early postpartum period. In addition to the particular period of pregnancy, the definition of PPCM by the European Society of Cardiology 2010 guidelines includes that there should not be any other known causes of HF with LV ejection fraction (LVEF) should <45% with or without LV dilatation. PPCM is diagnosed and offers many insights into the interplay between sex and HF.^[31]

PPCM is a global challenge. The incidence is about one in 3000 deliveries. Even though it is an unpredictable pregnancy-related disease, it occurs more frequently in women >30 years of age, those with a history of pregnancy-associated HT, and in those with multifetal gestations^[32] along with genetic predisposition and altered immune status (either the defective immune system or autoimmunity). Contributing factors may be a different type of stress during pregnancy like a hemorrhage of metabolic factors, which may alter the essential cardioprotective signaling pathway.^[33] It is better prognosis and it is detected early and treated promptly. About 50% of females recover completely, the rest of the PPCM patients may have partial recovery or downhill course, leading to chronic HF.

BREAST CANCER

It is surprising to know from the epidemiologic studies that therapy-related morbidity and mortality are more than disease-related mortality for CVD in long term in breast cancer surviving women.^[34] Anthracyclines and trastuzumab used in breast cancer chemotherapy are associated with a significant decline in LVEF adding to the burden of cardiovascular morbidity and mortality in these women. Because of the side effect of drugs, there is interruption of drug usage, leading to under-treatment of cancer as well as worsening of symptoms of HF due to already occurring side effects, ultimately leading to bad outcomes.^[35] Not only chemotherapy even radiotherapy and ovarian suppression therapy have long-term cardiovascular effects, especially HFpEF.^[36]

TAKOTSUBO CARDIOMYOPATHY

Takotsubo (stress) cardiomyopathy is an another important sex predilected HF defined as an acute and transient HF condition due to excess sympathetic activity, leading to a ballooning of LV (apical hypokinesia and basal hypercontractility). It is more frequent in females (F:M:9:1).^[37] Usually, the stress is the precipitating event that causes excess sympathetic surge and leads to myocardial stunning (adrenoceptor-mediated damage, direct catecholamine toxicity, increased cardiac workload, and epicardial and microvascular coronary vasoconstriction and/ or spasm). Even there is an evidence to say that myocardial stunning is the neurogenic origin as innervated coronary microcirculation, vasoconstrictive in this condition. There is a sex difference in the stress which precipitates this condition. In men usually, it is physical stress, whereas in women, it is mental stress. In fact, it was shown that mental stress-induced myocardial ischemia and a greater increase in platelet reactivity occur in women than in men.^[38] Not only that the previous studies proved that psychological distress was proved to associated with CVD events in females, but not in males.

PATHOPHYSIOLOGY OF HF IN WOMEN

Innately, there are significant pathophysiologic differences in the cardiovascular systems of women and men, which can lead to the different manifestations when HF occurs in both sexes.^[39]

Compared to men, women have a faster resting heart rate, lower blood pressure, lower LV mass, preserved LV mass with aging, greater LV contractility, less catecholamine-mediated vasoconstriction, small coronary vessels, and a lower rate of apoptosis.

In normal women, LV mass and size are smaller. With aging normally, the LV mass increases in women whereas in men, it decreases. In addition, whenever this is injury or increased workload then disproportionate increase in LV mass occurs in women when compared to men [Figure 3]. With similar degrees of clinical impairment, women have better systolic cardiac performance than men. Hence, women more frequently have HFpEF. This disproportionate increase in LV mass is true for women with aortic stenosis (AS). These women tend to have smaller and thicker LV when compared to men.^[39,40]

Close

Figure 3:

The difference in the left ventricular hypertrophy as a response to myocardial injury in both sexes.

Export to PPT

Some other authors felt that the gender differences in HF may be explained by the sex hormones differences in both genders [Table 2]. Estrogen decreases the renin activity, so vasodilatation with decreased tissue fibrosis, producing the protective effect for HT development, whereas testosterone has the opposite effect.^[23] Because of these sex hormone changes men are more prone to macrovascular dysfunction, leading to MI and HF due to LV systolic dysfunction, whereas women are more prone to microvascular dysfunction, leading to HFpEF.^[41]

Table 2: Effect of sex hormones on cardiovascular system.

Site	Androgens	Estrogens
Heart
Contractility
Left ventricular mass
Fibrosis
Vessels	Vasoconstriction	Vasodilation
Musculoskeletal
Kidneys
Glomerulosclerosis
Renin

Supportive evidences for the endothelial inflammation-coronary microvascular dysfunction in women are

1. Takotsubo cardiomyopathy – neurogenically triggered coronary microvascular dysfunction

2. PPCM – oxidative stress-mediated cleavage of prolactin may inducing endothelial damage

3. Radiotherapy-induced cardiomyopathy – in breast cancer, microvascular endothelial damage occurs after radiotherapy, leading to microvascular rarefaction and myocardial inflammation, which, in turn, leads to more oxidative stress and fibrosis, manifesting as cardiomyopathy^[27,37]

4. Angina with normal coronaries – again microvascular dysfunction was implemented as the cause of angina.

All the above-mentioned diseases are common in women, which give clue for the “common soil hypothesis” to explain when women have HFpEF more frequently.^[42]

Even immune response in women high when compared to men may be partially due to the difference in endothelial damage. Women have heightened immune response, leading to greater pro-inflammatory cytokines, more activation of T lymphocytes, and high C-reactive protein levels.^[43] This effect is partial because of pro-inflammatory gene expression upregulation in the female myocardium, along with peripheral inflammatory activation. This hypothesis is further substantiated by the fact that autoimmune diseases are also common in women [Figure 4]. In fact, the autoimmune diseases themselves are associated with the development of diastolic dysfunction.^[44]

Close

Figure 4:

Factors contributing for gender differences in HF – epidemiological factors, phenotypic implications, and intrinsic sex difference.

Export to PPT

Another important cause leading to the HF is, abnormal pregnancies leading to HF on long term follow up. In women, special emphasis should be given to the pregnancy-associated complications such as pre-eclampsia, gestational diabetes mellitus, and placental syndromes. These complications lead to endothelial dysfunction and inflammation which persist in a number of females predisposing these females to increased risk of CVD decades later [Figure 5].

Close

Figure 5:

Pathophysiology of complicated pregnancy, leading to long-term maternal effects.

Export to PPT

PRESENTATION OF HF IN WOMEN

HF occurs more in old-age women than men. For similar low LVEF with HF, women are more symptomatic than men.^[45] Even after adjusting for age, EF and NYHA class females with HF have the worse quality of life.^[46] Women with HF have more frequent pedal edema, exertional dyspnea, and less exercise capacity than men. Depression is more frequent in females.^[47] There is no difference in signs of HF in males and females. Gender bias is existing in the present era also for referrals, revascularization, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), or mechanical circulatory support.

DIAGNOSIS

Along with clinical signs and symptoms of HF, investigations are also important to diagnose and prognostic of HF such as are NT pro-BNP, and echocardiogram. In some cases, computed tomography scan or magnetic resonance imaging, and coronary angiogram are also important. Although the same tests are used to diagnose HF in women and men, the results may not be the same. The LV dimensions including volumes should be indexed to body surface area (BSA), as these normal values depend on age and sex.^[48] Even biomarkers for HF that is natriuretic peptide levels are usually higher in women than in men.^[49] Women have lower peak VO₂ than men, which may be due to a higher percentage of body fat than men. Hence, indexing to BSA is important.^[50]

The poor prognosis of HF in females in addition to natural differences between the genders is a delay in referral, diagnosis, and limited invasive management in females. They often do not receive guideline-directed care. Usage of sex-specific cutoffs for high-sensitivity troponin I may detect more females with MI and early treatment can be started. Compounding factors to angina or MI management are more frequent non-obstructive coronary artery disease (MINOCA). Even though females with MINOCA have fewer chances of having a recurrence of MI, the mortality rate is similar to men. However, this subset of patients does not receive important drugs such as statins and angiotensin-converting enzyme inhibitors (ACEIs), which are proven to have mortality benefits, as there are normal coronaries.

MANAGEMENT

Management of HF during pregnancy

Special mention is required about the management of HF during pregnancy. Table 3 shows the list of drugs which are contraindicated or to use cautiously were mentioned.^[64]

Table 3: Drugs used for heart failure in pregnancy.

Drug	Safety during pregnancy
ACEI/ARB	Contraindicated because of renal and other fetal toxicity
Hydralazine and long-acting nitrates	Safe to use
β-blocker	β1 selective drugs preferred, β2-receptor blockers have antitocolytic effect.
Diuretics	Should be used sparingly as can cause reduced placental flow
Frusemide and hydrochlorothiazide	Can be used
Aldosterone antagonists	Teratogenic, to be avoided
Amiloride	Can be used, not teratogenic
Digoxin	Can be used
Ivabradine	No known data, to be avoided
ARNI	Contraindicated
Amiodarone	Contraindicated, hypothyroidism in 9%, hyperthyroidism, growth retardation, and premature birth
UFH and LMWH	Can be used in the prevention and treatment of thromboembolism, mechanical valve, and atrial fibrillation
NOACs	Contraindicated
VKA	Teratogenic, to be avoided in first trimester, can be used in second trimester if dose of acenocoumarol<3 mg or phenocoumarol<5 mg
Nitroglycerine	Can be used in ADHF management secondary to hypertension, left ventricular dysfunction, or severe valve regurgitation

ACE: Angiotensin-converting enzyme, ARB: Angiotensin receptor blocker, ARNI: ARBs and neprilysin inhibitor, UFH: Unfractionated heparin, LMWH: low-molecular-weight heparin

Even though PPCM is known to occur in the peripartum period, there other conditions such as congenital heart disease or valvular heart disease or pulmonary embolism can produce HF at any stage of pregnancy. In Figure 6, the algorithm to follow in this type of complicated pregnancy is mentioned.^[64] In Figure 7, the overall management principals are mentioned for HF complicated pregnancy.

Close

Figure 6:

Steps to follow in women with heart failure during pregnancy.

Export to PPT

Close

Figure 7:

Algorithm for the management of acute heart failure during pregnancy.

Export to PPT

FEMALE REPRESENTATION IN CLINICAL TRIALS

Even though the clinical trial registry recommended a minimum of 33% of females or depending on the prevalence of the particular disease, to be included in clinical trials, to effectively conclude the solutions, in practice, it does not happen. About <25% of females with HF were included in all the studies^[39] except in A-HoFT and Companion trials [Table 4]. There is no decided study on HF in females. As already mentioned due to differences in pharmacokinetic and pharmacodynamic properties of drugs along with small stature, dedicated HF trials only in females are required.

PREVENTION OF HF IN WOMEN

As the prevention is better than after the manifestation of HF, different preventive strategies are required for HF with reduced and preserved EF.

The targets and strategies to prevent HF with reduced EF with ischemia are blood pressure control, reaching target lipid levels, cessation of smoking, exercise, and preservation of the myocardium, whereas the targets are different in HFrEF without ischemia. The preventive measures of HF in this condition are paying attention to adjusting the appropriate dose of anticancer therapy, complicated pregnancies management to do in a tertiary care center with a multidisciplinary approach, reduction of both mental and physical stress to prevent stress-induced cardiomyopathy, and measures to prevent the microvascular disease and effective management of diabetes.

The targets and strategies to prevent HF with preserved EF are weight reduction, blood pressure control, preventive measures for atrial fibrillation, exercise, control of inflammation, preservation of endothelial function, prevention of myocardial fibrosis, insulin resistance, and microvascular diseases.

Depending on the stage of HF, either primary or secondary prevention strategies can be planned [Table 5].^[65]

Table 5: Preventive strategies in different stages of HF.

Primary		Secondary
Stage A	Stage B	Stage C	Stage D
HfrEF
CAD risk factor management Exercise/Physical activity	Treat HTN, HLD, DM2 Exercise/physical activity Smoking cessation ACE/ARB and BB	ACE/ARB and BB Sodium restriction Diuretics Mineralocorticoid-receptor antagonist Neprilysin inhibition Cardiac rehabilitation	Cardiac resynchronization therapy Inotropes Left ventricular assist device Heart transplant
HfpEF
Maintain a healthy weight Weight loss for overweight and obese women Statin Blood pressure control Exercise/Physical activity	Treat HTN Weight loss for overweight and obese women Glucose control in women with DM2, pre-diabetes or history of GDM Physical activity	Treat HTN Diuretics Sodium restriction Use of new antiglycemic agents Neprilysin inhibition	Treat HTN Diuretics Supportive care

HTN: Hypertension, GDM: Gestational diabetes mellitus, CAD: Coronary heart disease, HF: Heart failure, ACE: Angiotensin-converting enzyme, ARB: Angiotensin receptor blocker, HfpEF: HF with preserved ejection fraction, HFrEF: HF with reduced ejection fraction

PROGNOSIS

In the past five decades, the survival rates are improved in both sexes, even though there is increase of HF more in women than in men.^[66] There are larger survival gains in men and young HF patients than in women and the elderly. Women with HF, on the whole, have better survival than men, especially this difference is more prominent when HF is of non-ischemic origin. In ischemic cardiomyopathies, there are no sex differences in mortality, over that females twice likely to develop HF after MI than men (which may be partially due to under-treatment), even though females have better EF.^[67]

Similar sex difference exists in HFpEF also. Even females have more severe HF clinical symptoms, there is no increase in the rate of hospitalization due to recurrence of HF. In fact, females with HFpEF have better survival than men.^[68]

PROPOSED RECOMMENDATIONS FOR FEMALES WITH HF

• Even though the risk factors profiles and clinical symptomatic status are more in females, they are underdiagnosed, undertreated, and underrepresented in clinical trials.

• Important physiological stress in female is pregnancy, which is an important risk factor for HF development and management differs.

• Few of cancer therapies unique to females.

• Major pathophysiology is that the HF in females is nonischemic microvascular dysfunction with HFpEF.

• Individualize in each female depending on risk–benefit profile before ICD implantation.

• There is an urgent need to design smaller LV assist devices for females.

• Overall, all women irrespective of age cardiac rehabilitation programs showed benefit and this is indicated.

• Pregnant women with HF require multidisciplinary approach.

• Dedicated HF trails and guidelines only in females with HF are required.

CONCLUSIONS AND FUTURE DIRECTIONS

There is a gender difference at every component of HF, from epidemiology to pathophysiology to adoption of LV to the management. Diabetes and HT are stronger risk factors in females when compared to men. HFrEF is more frequent in males, whereas HFpEF in females. Mental stress is cause for takotsubo cardiomyopathy in females, whereas physical stress in the precipitating factors in males. There are some sex-specific risk features only to females such as pregnancy-related HF as well as breast cancer-related therapy side effects.

There are large gaps in the knowledge of HF in females, as there are underrepresented trails and guidelines are formed from the male predominant studies, for similar dose, the drug response is worse in females. The major knowledge gaps in females with HF are lack of understanding and appreciation of sex-specific risk factors, limited understanding of pathophysiology of HF especially in takotsubo cardiomyopathy, lower quality of life, higher rates of medication-related adverse events, greater adverse LV remodeling, no female specific criteria for device implantation and more importantly lack of data and guidelines on optimal management of medication, and dosage for females. Hence, there is an urgent need of separate clinical trails only in females and formulate the appropriate guidelines for HF management in females.