Sex Variations in Heart Failure: A Rapid Review Volume 60- Issue 4

Adwait Bendre¹, Karima A M Shebani², Muhammad Armaghan³, Amna Naveed Butt⁴, Saniyal Farheen Khan⁵, Aroob Fatima⁶, Mishal Mohammed Koyappathodi Machingal⁷, Deepa Malla Panta⁸ and Noor Ali⁹*

• ¹K.J. Somaiya Medical College, Mumbai, India
• ²Department of Medicine and Surgery, Al Zawiya University, Az Zawiya, Libya
• ³Department of Medicine and Surgery, CMH Lahore Medical College and Institute of Dentistry, Lahore, Pakistan
• ⁴Allama Iqbal Medical College, Lahore, Pakistan
• ⁵Department of Medicine and Surgery, Dr. NTR University of Health Sciences, Vijayawada, India
• ⁶Department of Medicine and Surgery, University of Health Sciences, Lahore, Pakistan;
• ⁷Government Medical College, Kozhikode, India
• ⁸Department of Medicine and Surgery, Sun Yat-sen University, Guangzhou, China
• ⁹Dubai Medical College, Dubai, United Arab Emirates

Received: February 17, 2025; Published: February 24, 2025

*Corresponding author: Noor Ali, Dubai Medical College, Dubai, United Arab Emirates, Email ID: noorali.obgyn@gmail.com

DOI: 10.26717/BJSTR.2025.60.009488

Abstract PDF

Background: Heart failure (HF) is a global pandemic that affects over 64 million individuals worldwide, with significant morbidity and mortality, as well as financial and economic burdens. Appreciable differences prevail between sexes regarding incidence, clinical presentation, and therapeutic response in HF. However, data on optimal sex-specific treatment modalities is insufficient, and mortality remains high.
Objective: To review the literature on sex-related differences in HF, including risk factors and clinical presentation, and explore the relationship of the limited depiction of females in clinical trials to current HF outcomes.
Summary: Females display a higher baseline left ventricle ejection fraction (LVEF) than males. Obesity, diabetes mellitus, microvascular dysfunction, and heart failure with preserved ejection fraction (HFpEF) are more common in females. In contrast, coronary artery disease, macrovascular dysfunction, and heart failure with reduced ejection fraction (HFrEF) are more common in males. The frequency of cardiovascular drug prescriptions and the outcomes of HF management vary between sexes and are attributable to differences in physiology, like higher fat distribution in females. As well as the challenges of recruiting and enrolling a heterogeneous study population. To tackle these challenges and improve outcomes of all HF patients, it is vital to develop comprehensive inclusion criteria, adapt better inclusivity, and consider sex-specific risk factors.

Keywords: Female Representation in Heart Failure Trials; Sex-Based Outcomes; Heart Failure in Females; Physiologic Sex Differences in Heart Failure; Heart Failure

Abbreviations: HF: Heart Failure; LVEF: Left Ventricle Ejection Fraction; HFrEF: Heart Failure With Reduced Ejection Fraction; HFpEF: Heart Failure With Preserved Ejection Fraction; ATP: Adenosine Triphosphate; HRQOL: Health-Related Quality of Life; RCTs: Randomized Controlled Trials; NYHA: New York Heart Association; ARNIs: Angiotensin Receptor-Neprilysin Inhibitor; SGLT2Is: Sodium-Glucose Cotransporter-2 Inhibitors; ACEIs: Angiotensin-Converting Enzyme Inhibitors; ARB: Angiotensin Ii Receptor Blockers; ETIFI: European Trial of International Flights in Combination; QOL: Quality of Life

Heart failure (HF) is a major cause of morbidity and mortality worldwide, affecting 1-2% of the developed world’s population. In 2017 HF was labeled a global pandemic, affecting over 64 million people worldwide [1,2]. In the U.S. alone, HF affects around 6.7 million individuals. This number is predicted to increase steadily, reaching 11.4 million by 2050. The increased prevalence of HF is also associated with an increased lifetime risk, around 24%, that is 1 in 4 individuals will develop HF during their lifetime. Another concern is the rising portion of younger patients diagnosed with HF, and their associated annual mortality rates, which also appear greater compared to older adults (65-84 years old) [3]. In males, the incidence of HF increases 2-fold every 10 years between the ages of 65 and 85. Meanwhile, it increases 3-fold in females between the ages of 65 to 74 and 75 to 84 [4]. Apart from age, sex is another driving force in HF incidence. Recent studies support the presence of sex-specific variations in HF. These variations reflect the differences in biology and physiology of males and females driven by their unique genetic and hormonal dispositions [5]. This must be heavily integrated when conducting clinical trials as 50% of those affected by HF are females [1,6]. In 2023, marginally more new cases were observed in females than in males [7]. Further, compared to males with HF, females score poorer survival rates at 5, 10, and 15-year marks, with 44.0 versus 46.9%, 23.0% versus 25.8%, and 11.0% versus 14.1% respectively.

Females also have a 10% higher risk of dying from all causes relative to males [8]. One reason for these data trends is poor female representation in HF trials. Only 20-25% of HF clinical trial populations are female, making them highly underrepresented and underlies the current disparities in HF evidence between the sexes. Thus, male-predominant population data heavily govern current treatment guidelines, and substantial gaps in our understanding remain about sex-distinct HF mechanisms and prime drug dosages for females [9]. Other than the clinical ramifications, HF places a huge economic burden on patients and healthcare systems. In 2012, the cost of HF management was $20.9 billion. This cost is anticipated to rise to $53.1 billion by 2030 [10]. According to multiple sources, healthcare costs will rise by around 127-154% by 2030 [11]. This projection is detrimental to the welfare of many HF patients who require regular physician follow- up and frequent treatment alterations. Yet universally prescribed FDA-approved HF treatments yield varied responses between sexes and despite the advancements in HF therapy, mortality remains high, with the 5year mortality being 50-75% [12]. This paper discusses the current literature on sex differences in HF, particularly on the risk factors, clinical presentation, and management. It also highlights the uneven sex presentation in clinical trials and the challenges that hinder female participation, intending to encourage more inclusive studies resulting in increased management efficacy, lower adverse therapeutic reactions, and better outcomes.

Sex Differences in the Clinical Presentation of Heart Failure

Energy deficiency has been recently proposed as the root cause of the development and progression of HF [13]. To efficiently contract, the heart muscle relies on free fatty acids, glucose, and mitochondrial oxidative phosphorylation to produce high-energy phosphate adenosine triphosphate (ATP). This energy is then transferred to and used by the cardiac myofibers. Diverse HF etiologies lead to mitochondrial and endoplasmic reticulum stress that alters energy utilization and production, ultimately causing energy starvation. This results in a dysregulated microenvironment that prompts oxidative stress and inflammation and enforces adaptive changes in the cardiomyocytes, endothelial cells, fibroblasts, and the extracellular matrix. These adaptive changes manifest as hypertrophy, apoptosis, or necrosis [14-16]. Furthermore, systemic inflammation marked by proinflammatory mediators, namely interleukins and tumor necrosis factors, such as interleukin-1, interleukin-8, and tumor necrosis factor- alpha contributes to this intricate cardiac pathophysiological continuum, myocardial deformation, and cardiac remodeling [17]. Males and females respond differently to myocardial injury and stress. Cardiac response to hypertension is more commonly by eccentric remodeling in males and concentric remodeling in females. Moreover, males are more likely to suffer extensive damage from cardiac ischemia than females, with a cell death rate up to 10-fold higher than that observed in females [18].

Cardiac remodeling eventually affects the left ventricle ejection fraction (LVEF), which is an important parameter when classifying HF patients and assessing their morbidity, mortality, and prognosis [19,20]. The current HF classification adheres to uniform LVEF thresholds for both sexes with LVEF ≤40% constituting HF with reduced ejection fraction (HFrEF), and LVEF >40% constituting HF with preserved ejection fraction (HFpEF). Meanwhile, an LVEF of 41% - 49% constitutes HF with mildly reduced ejection fraction (HFmrEF) [21]. However, studies reveal a consistent pattern of females manifesting higher LVEF values than males, even after adjusting for potential confounding variables [22-24]. Multiple reports note that the female gender is independently associated with HFpEF. Males on the other hand are more likely to experience HFrEF [25-29]. An observational study spanning 12 years monitored 30,000 participants for the occurrence of HF. It concluded that males exhibited a 2-fold increased risk of developing HFrEF compared to females. Supporting this is data from the Swedish Registry referred to as ‘SwedenHF’, wherein females constituted 55% of the patients diagnosed with HFpEF and only 29% of those diagnosed with HFrEF [30]. In another study, a secondary analysis of the European heart failure survey, 55% of females developed HFpEF versus only 29% of males [31]. These observations highlight the presence of sex-specific variations in LVEF, which point to differences in cardiac physiology and disease development.

They also potentially explain the sex-geared propensity for developing one type of HF over another. It has been proposed that males are more susceptible to macrovascular disease, whereas females are more prone to microvascular dysfunction and endothelial inflammation. Thus, their propensities to develop mostly either HFrEF or HFpEF [25]. Accordingly, males are more likely to present with HFrEF from alcohol-related cardiomyopathy or atrial fibrillation [32]. Females present with HFpEF from stress cardiomyopathy also known as Takotsubo cardiomyopathy, breast cancer radiotherapy-induced cardiomyopathy, and pregnancy. Pregnancy exposes females to HF due to a range of cardiac diseases, from peripartum cardiomyopathy to hypertensive diseases of pregnancy, namely preeclampsia and eclampsia. Peripartum cardiomyopathy has an incidence ranging from 1 in 1000 to 4 in 1000 deliveries. Approximately 13% of women who develop HFrEF during pregnancy fail to recover within the subsequent 6 months. Apart from pregnancy, anthracycline as well has been deemed a female-explicit risk factor for HF. Anthracycline cardiotoxicity leads to dilated cardiomyopathy. Standard anthracycline doses have been shown to decrease the LVEF by 10-15% in females [25,33]. Of note, around 30-50% of coronary angiographies performed on females presenting with chest pain turn out negative for obstructive coronary artery disease, a fact that supports the predominance of microvascular dysfunction in females [5]. Sex differences in the symptomatology of HF are evident as well.

Females tend to present with symptomatic HF more often than males and experience more pronounced symptoms which is mirrored in their physical exam, with more frequent edema, murmurs, rales, jugular venous distension, and gallop [1]. Furthermore, when compared to males, females experience more exertional dyspnea, edema, and limited exercise capacity, as well as report lower quality of life. They also exhibit a comparably unfavorable prognosis, partly due to coexisting comorbidities, such as iron deficiency anemia, iron, renal insufficiency, and thyroid dysfunction [34-36]. In a multicenter observational study that included 528 hospitalized HF patients, secondary analysis of self-reported symptoms revealed drastic sex-based and HF subtype variations. Fatigue, shortness of breath, and ankle edema were universal among both sexes. Reports of walking problems were more by females, whereas depressive symptoms were more by males. Compared to females with HFmrEF or HFrEF, those with HFpEF suffered poorer symptoms (P = 0.025). Females also had an increased chance of more adverse symptoms compared to males (OR: 1.78, 95% CI: 1.00-3.16) [37]. Another example of sex-based discrepancies in HF symptomatology is a narrative review study that comprehensively evaluated the health-related quality of life (HRQOL) of HF patients. Data from various studies including cross-sectional analyses, randomized controlled trials (RCTs), observational cohort studies, meta- analyses, and systematic reviews were analyzed.

Compared to males, females exhibited more pronounced levels of edema, fatigue, and non-physical agony, such as anxiety and depression. Further, females across all HF subtypes reported inferior HRQOL than males [38]. Accordingly, females display increased vulnerability to symptomatic HF despite a preserved LVEF. This may be explained by their predisposition to cardiac dysfunction with an LVEF at lower limits of the normal range [39]. These distinctions advocate the formation of an updated HF classification that incorporates sexbased differences. The most important of which is an elevated LVEF threshold for females. Prior studies have proposed a 3-point percentage increase in LVEF for females [24]. The sex-based discrepancies presented in this paper are ultimately linked to the reported biological differences, specifically, cardiac anatomy and innervation, mainly sympathetic activation, and cardiac metabolism [21]. In addition to female-specific challenges including treatment gaps, limited healthcare access, and underrepresentation in HF clinical trials [38].

Sex Differences in the Risk Factors of Heart Failure

There are universally acknowledged traditional risk factors for HF development, namely, obesity, tobacco smoke, diabetes mellitus, hypertension, and coronary artery disease. Other less common risk factors include anemia, anorexia nervosa, iron and vitamin D deficiency, sleep apnea, and cardiotoxins. The frequency of these risk factors varies between sexes [40,41]. Addressing these differences presents an opportunity for better HF prevention and ultimately disease burden reduction.

Obesity: A clear connection exists between obesity and the risk of HF. Obesity affects about 50% of patients with HFpEF and it is a more predominant risk factor in females than males, especially post-menopausal females. Obesity is also more commonly associated with HFpEF than with HFrEF. These observations can be explained by reduced estrogen exposure during menopause. Estrogen carries protective properties against HF in pre-menopausal females. It is both an antioxidant and an anti-inflammatory hormone [24,40]. Reduced estrogen levels in post-menopausal females, coupled with an inactive lifestyle leads to obesity, specifically visceral obesity. Obesity is followed by insulin resistance which stimulates systemic inflammatory cascades. A prolonged systemic inflammatory state ultimately causes concentric cardiac remodeling and HFpEF [42]. In both males and post-menopausal females, visceral, central, or android-type fat distribution poses a high cardiometabolic risk for HF. However, overall, it appears more harmful in females than males. Thigh and gynoid fat distributions are considered protective in both sexes, although they are a more pertinent protective factor in males than in females [43].

Smoking: Being a current smoker is a risk factor for HF development. This correlation has been established time and time again [44,45]. Carbon monoxide from tobacco increases the levels of circulatory proteins such as calcineurin, vascular endothelial growth factor, and calmodulin. Resulting in increased left ventricle mass, impaired ventricular filling, and decreased stroke volume and ejection fraction [46,47]. There is no safe threshold; smoking as low as one cigarette a day raises the chances of both stroke and coronary artery disease, up to 40-50% in both sexes compared to those who smoke 20 cigarettes a day [48]. A higher risk for HF from smoking has been postulated in females than males, with 88% and 45% increased risk respectively [49,50]. The risks posed by newer smoking devices, both electronic and non-electronic are yet to be studied.

Diabetes Mellitus: Diabetes mellitus affects approximately 45% of patients with HFpEF and is a stronger risk for HF in females than in males [24]. In the Framingham study, females with diabetes were approximately 5 times more likely to develop HF, compared to males with diabetes who had a 2.4 increased risk [51]. In a more recent prospective study, a 22% higher risk of HF was noted in females with diabetes, especially type I diabetes, compared to males. Given that insulin deficiency or resistance is implicated in diabetes, systemic proinflammatory effects link diabetes to HFpEF [52].

Hypertension: Chronic hypertension is a leading cause of HF. The higher the blood pressure, the higher the risk of HF. A recent meta-analysis revealed that a blood pressure of 180/120 mmHg compared to a blood pressure of 100/60 mmHg causes a 3 to 5-fold increase in the relative risk of HF [53]. Females are more prone to developing HF from hypertension than males. Of all the HF risk factors, hypertension scored the highest in attributable risk for the population, 59% and 39%, for females and males respectively [32]. According to the Framingham heart study, the risk of HF was increased 3-fold in hypertensive females compared to only a 2fold increase in hypertensive males [54]. In another study, the arterial stiffness of females was more evident than that of males [40].

Coronary Heart Disease: Ischemic causes of HF are more robustly correlated with males. The lifespan risk of HF for males with a prior history of myocardial infarction is 1 in 5 versus 1 in 9 for the rest of the male population, signifying the impact of previous myocardial infarctions in HF development among males [32]. Early-onset menopause, onset < 40 years old, and hypertensive diseases of pregnancy are atherosclerosis risk-augmenting factors for females. In a study that examined the role of estrogen in 28,000 females, nulliparity and a shorter premenopause period were associated with increased HF risk. The correlation between premature menopause and HF still requires further research [9]. One hypothesis suggests estrogen upregulates and activates nitric oxide within the endothelium, thereby partially preventing ischemia. Other female predominant risk factors for the development of HF are psychological disorders like stress, anxiety, and depression [55].

Sex Differences in the Management of Heart Failure

A couple of significant limitations exist in the current guidelines for HF management, particularly those of HFrEF. Firstly, real-world use of the New York Heart Association (NYHA) classification is limited, given it is symptom-based i.e. a subjective measure. In addition, current HF guidelines mostly apply to NYHA classes II and III, since past clinical trials constituted fewer patients from classes I and IV [56]. Secondly, suboptimal therapy has been detected in evaluations of multidisciplinary teams treating HF patients and compliance with HFrEF guidelines was questioned. Although the prescription of endorsed therapies was high, many patients did not achieve target doses and 20% underwent up-titration. This failure to reach target optimum doses was equated to biological differences rather than drug resistance. Being female, of older age, or having a history of stroke or transient ischemic attack all led to suboptimal dosing [57]. Thirdly, the current standard of care is only marginally affordable, and its cost-effectiveness has been linked to the patient’s ability to negotiate discounts on routinely prescribed drugs like angiotensin receptor-neprilysin inhibitor (ARNIs) and sodium-glucose cotransporter- 2 inhibitors (SGLT2Is) [58]. Fourthly, females remain vastly underrepresented in major HF clinical trials. Most studies conducted on HF are done on predominantly male patients, yet results are applied universally to both sexes, a ‘one size fits all approach’ that best be questioned [9].

Commonly prescribed cardiovascular drugs include angiotensin- converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), aspirin, β-blockers, diuretics, and statins. Drug efficacy varies due to physiological and biological differences between males and females that affect drug pharmacokinetics and pharmacodynamics. When given the same dose, females exhibit higher plasma concentrations than males, which is explained mostly by the lower body weight and higher body fat in females [59]. Studies show that females are more susceptible to cough as an adverse reaction to ACEI than males [60]. They are also at higher risk of developing statin-induced myopathy with statins, and bradycardia and hypotension with β-blockers than males. Aspirin is shown to be more effective in stroke prevention in females and cardiac ischemia prevention in males. Apart from differences in drug efficacy. The effect of sex on the frequency at which cardiovascular drugs are prescribed is of interest [59]. Earlier studies did not observe a strong relationship between sex and the prescription of guideline-based medications. In a Europe-based observational, cross-sectional study, that looked at factors influencing cardiovascular medications’ prescription patterns, the overall prescription rates for both sexes were as follows: diuretics 75%, ACEIs or ARBs 69%, digitalis: 41%, βblockers 30%, and oral anticoagulants 18%. The only appreciable sex difference was that females had a lower chance of being prescribed oral anticoagulants (OR = 0.74; 95% CI: 0.65-0.84).

Aside from that, the prescription of β-blockers for patients aged 75-85 was significantly decreased (OR = 0.49; 95% CI: 0.43-0.56) [61]. More recently, studies note sex as a prominent factor in the prescription of HF medications, where males are treated with ACEIs and digoxin less often than females. In comparison, females are prescribed aspirin, β-blockers, nitrates, and lipid-lowering therapies less frequently than males. Other HF treatment drugs are used without any notable gap between the sexes [62]. Reports of higher adverse drug reactions with ACEIs and higher mortality from digoxin in females partially explain this discrepancy in drug prescriptions [63]. Differences in HF drug dosing haven’t been heavily studied. The European Trial of International Flights in Combination (ETIFIC) trial, a multicenter randomized study investigated the differences in HF drug titration of β-blockers, mineralocorticoid receptor antagonists, ACEIs, and ARBs between sexes. No substantial differences were observed in drug dosage, hospitalizations, or deaths in 320 patients hospitalized with HF [64]. Factoring the physiological differences between males and females, as well as, incorporating more female representation in cardiovascular drug trials will allow the development of more targeted therapies that achieve optimum results in terms of drug efficacy and reduced adverse reactions. Clinician awareness of the variable sex-related drug responses is also important in enhancing patient medication compliance and overall satisfaction.

Sex Differences in Outcomes, Hospitalization, And Readmission of Heart Failure

Sex differences in the response to HF treatment have also been documented. In a secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, females with HFpEF using spironolactone, a mineralocorticoid antagonist, had lower all-cause mortality (HR 0.66; 95% CI: 0.48- 0.9; p = 0.01), while males did not. This could be due to spironolactone affecting cardiac remodeling differently in males and females [65]. Another drug that affects cardiac remodeling and has been shown to improve results preferentially in females is the ARNI, sacubitril-valsartan. It reduces oxidative stress, cardiac fibrosis, hypertrophy, and vascular stiffness. It also enhances endothelial function and left ventricle function [66,67]. In the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON HF) trial, females with HFpEF treated with sacubitril-valsartan instead of only valsartan were 26% less likely to be hospitalized. However, no effect was observed in males. This may be explained by multiple differences between males and females, including but not limited to, females demonstrating a higher normal LVEF, higher age-related arteriolosclerosis, and lower baseline natriuretic peptide levels than males, therefore displaying more obvious results from sacubitril-valsartan [68,69]. The rate of hospitalization and in-hospital mortality is also affected by sex. Females are less likely to be hospitalized [63]. Higher hospitalization incidences have been reported in males, along with a higher inhospital death rate compared to females [21].

Studies on HFpEF note a lower in-hospital mortality in females than males (4.2% versus 4.6%, p < 0.01), but worse female-reported outcomes, identified as quality of life (QOL) [26]. Other studies report the opposite. The Journey HF-TR study was a monumental cross-sectional, observational study conducted in Turkey regarding in-hospital patients with acute heart failure. It included a 42.8% female population, a percentage that well exceeded the usual female representation in HF clinical trials. Females had better LVEFs, while males had increased chances of reduced LVEF (72.4% versus 51.0%). Despite this finding, mortality was higher in females than in males (9.3% versus 6.4%). Higher mortality was associated with a lower estimated glomerular filtration rate (eGFR), an increased baseline N-terminal pro-B type natriuretic peptide (NT-proBNP) level, a higher NYHA class, and a requirement for assisted ventilation. Being female was not a factor for increased mortality. Of note, females in this study were more senior than males, had more co-morbidities, and underwent fewer in-hospital medical intrusions [6]. Another recent massive observational HF study with a female-majority population (60.5%) concluded that females had a 31% lesser risk of hospitalization than males, but higher mortality (24.2% versus 16.5%) [70]. Existing LVEF differences between sexes with females having higher baseline LVEFs than males might explain the variations in hospitalization [1,68].

A retrospective observational study investigated the effects of LVEF on patient outcomes. It concluded that adverse outcomes decreased as LVEF increased, up to a limit. LVEF of 35% reduced HF hospitalization, LVEF of 40% reduced progressive cardiac failure, and LVEF of 50% reduced all-cause and cardiovascular mortality. Relevant reductions in the chances of previously mentioned outcomes were not observed with LVEF thresholds beyond 50%. Notably, the critical LVEF point for HF differed between sexes, with females having a higher threshold than males (30% versus 40%) [21]. Regardless of LVEF, the probability of readmission is higher in females, as detected in a study involving 1,239 HF patients (OR = 1.37; 95% CI: 1.04-1.82, p = 0.02) [39].

Female Representation in Heart Failure Clinical Trials

Female participation in landmark HF clinical trials has remained stationary at roughly 20-30% over the last 40 years. From 2000-2017, the female-to-male participant ratio was at its lowest [71]. In 2018, females’ participation in trials involving novel FDA drug supplication was evaluated. 35 drugs, including 3 drugs for HFrEF were studied across 57 trials. In HF trials, the trial participation to disease prevalence ratio (PPR) was 0.5-0 [72]. Further, a study investigating female participation trends examined 118 HF trials published between 2001 and 2016. It concluded that 27% of enrolled participants were females. This percentage did not considerably improve over the 15- year follow-up period [73]. This is an insufficient representation and hinders the development of adequate treatment modalities to reduce the disease burden, as nearly 50 % of HF patients in the U.S. are female [11]. Numerous barriers exist that limit female participation in major HF trials. A survey analyzing 97 females who declined an invitation to participate in HF studies found that low appeal, limited time, deficient health, and travel burden were among the factors deterring females from participating [74]. Similarly, 75% of 317 HF RCTs under- enrolled females. Reasonings included sex-related trial criteria, out-patient setting recruitment, trial coordination in medical and surgical interventions, and males leading the trial [75]. A multifaceted approach is necessary to overcome these limitations and optimize HF management guidelines.

This includes extensively testing the current quadruple HF therapy on patients of all NYHA classes and making it cost-effective so that it is feasible for patients of all socioeconomic groups. Moreover, healthcare providers should avoid sub-optimal dosing by ensuring that each patient reaches their target dose per guidelines and being up to date with the latest sex-based pharmacology research. Since decision-making differs between sexes, trial methodologies should include an individualized and more detailed method of education and consent that considers psychological, socioeconomic, and cultural factors. Females will be more willing to participate if given access to diverse resources, like transportation and in-home helpers to care for their families while away. Supporting this are reports that associate recruiting older female patients with higher enrollment rates [76]. Researchers are becoming more aware of sex discrepancies in clinical trials and creative strategies for female enrolment in cardiovascular studies are starting to be employed. For example, sex and ethnically heterogeneous populations are recruited for studies evaluating HF care via culturally appropriate stepwise participation methods. Communication preferences, transit, and relevant pre-enlisting education are included [71].

Diligently monitoring sex distribution during trial recruitment, eliminating male-based eligibility criteria, incorporating female-specific risk factors, and stratifying standard eligibility standards that reflect inherent sex differences, such as age at the time of HF diagnosis, reproductive hormone status, and cardiac biomarkers are essential to formulate a study pool that most accurately reflects the composition of the female population with HF [77].

HF is a notable universal health threat, with a consistently increasing frequency rate, requiring ongoing research to advance patient treatment outcomes and well-being. Although HF management is evolving, sex related discrepancies in HF have not been heavily incorporated into clinical trials. Varying comorbidities, clinical presentations, and prescription patterns in male and female populations, as well as limited female participation in clinical trials, have created obstacles in governing effective treatment modalities for HF. Thus, the current diagnostic and therapeutic modalities require extensive evaluation in a sex-balanced patient population. Future HF clinical trials must aim for broader eligibility criteria to enhance and encourage female participation. In addition, cultural, domestic, and socio-economic barriers that prevent or hinder female enrollment must be addressed. This ensures -in part- that the trial populations reflect the general population. In addition, etiological-based studies should interpret their findings considering the established physiological sex variations. Moving forward with diversity, inclusion, and sex-neutral enrollment will lead to equitable results and a superior comprehension of HF and its management, thereby providing targeted interventions to reduce the morbidity and mortality of HF.

All authors declare that no conflicts of interest exist.

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