Heart Failure Subtypes and Cardiomyopathies in Women.

Heart failure affects over 2.6 million women and 3.4 million men in the United States with known sex differences in epidemiology, management, response to treatment, and outcomes across a wide spectrum of cardiomyopathies that include peripartum cardiomyopathy, hypertrophic cardiomyopathy, stress cardiomyopathy, cardiac amyloidosis, and sarcoidosis. Some of these sex-specific considerations are driven by the cellular effects of sex hormones on the renin-angiotensin-aldosterone system, endothelial response to injury, vascular aging, and left ventricular remodeling. Other sex differences are perpetuated by implicit bias leading to undertreatment and underrepresentation in clinical trials. The goal of this narrative review is to comprehensively examine the existing literature over the last decade regarding sex differences in various heart failure syndromes from pathophysiological insights to clinical practice.

Gender Differences in Medical Student Perceptions of a Career in Cardiology.

BACKGROUND: Worldwide, the cardiology profession has an under-representation of women. We assessed medical students' perceptions of cardiology as a career choice with the aim of identifying barriers to gender diversity. METHOD: An anonymous survey was distributed to medical students studying at three Australian medical universities. Questions pertained to demographics, year and stage of medical training, desire to pursue cardiology, and perceived barriers to a cardiology career. Results were analysed according to identified gender and desire to pursue or not pursue a cardiology career. Multivariable logistic regression evaluated for independent associations. The primary outcome were barriers identified to pursuing a career in cardiology. RESULTS: From 127 medical student respondents (86.6% female, mean age 25.9±4.8 years), 37.0% stated they wanted to pursue a career in cardiology (39.1% of women versus 23.5% of men, p=0.54). The top four perceived barriers to a cardiology career included: poor work-life balance (92/127, 72.4%), physician training process (63/127, 49.6%), on-call requirements (50/127, 39.4%) and lack of flexibility (49/127, 38.6%), with no gender differences. Women were more likely to report gender-related barriers (37.3% versus 5.9%, p=0.01) and less likely to identify procedural aspects as a barrier (5.5% women versus 29.4% men, p=0.001). Students in their pre-clinical years were more likely to want a career in cardiology (odds ratio 3.0, 95% confidence interval 1.2-7.7, p=0.02). CONCLUSIONS: A high proportion of female and male medical students want to pursue a career in cardiology with both genders identifying major barriers of poor work-life balance, lack of flexibility, on-call requirements and the training process.

Diagnosis and management of arrhythmias in pregnancy.

Arrhythmias are the most common cardiac complications occurring in pregnancy. Although the majority of palpitations in pregnancy may be explained by atrial or ventricular premature complexes, the full spectrum of arrhythmias can occur. In this article, we establish a systematic approach to the evaluation and management of arrhythmias in pregnancy. Haemodynamically unstable arrhythmias warrant urgent cardioversion. For mild cases of benign arrhythmia, treatment is usually not needed. Symptomatic but haemodynamically stable arrhythmic patients should first undergo a thorough evaluation to establish the type of arrhythmia and the presence or absence of structural heart disease. This will ultimately determine the necessity for treatment given the potential risks of anti-arrhythmic pharmacotherapy in pregnancy. We will discuss the main catalogue of anti-arrhythmic medications, which have some established evidence of safety in pregnancy. Based on our appraisal, we provide a treatment algorithm for the tachyarrhythmic pregnant patient.

Sex differences in heart failure.

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Sex Differences in Cardiovascular Pathophysiology: Why Women Are Overrepresented in Heart Failure With Preserved Ejection Fraction.

Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preeclampsia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex-specific diagnostic criteria, improved risk stratification models, and targeted therapies.

Prevention of Cardiovascular Disease in Women With Pregnancy-Related Risk Factors: A Prospective Women's Heart Clinic Study.

Background Hypertensive disorders of pregnancy, gestational diabetes, and having a small-for-gestational-age baby are known to substantially increase a woman's risk of cardiovascular disease. Despite this, evidence for models of care that mitigate cardiovascular disease risk in women with these pregnancy-related conditions is lacking. Methods and Results A 6-month prospective cohort study assessed the effectiveness of a multidisciplinary Women's Heart Clinic on blood pressure and lipid control in women aged 30 to 55 years with a past pregnancy diagnosis of hypertensive disorders of pregnancy, gestational diabetes, or a small-for-gestational age baby in Melbourne, Australia. The co-primary end points were (1) blood pressure <140/90 mm Hg or <130/80 mm Hg if diabetes and (2) total cholesterol to high-density lipoprotein cholesterol ratio <4.5. The study recruited 156 women with a mean age of 41.0±4.2 years, 3.9±2.9 years from last delivery, 68.6% White, 20.5% South/East Asian, and 80.5% university-educated. The proportion meeting blood pressure target increased (69.2% to 80.5%, P=0.004), with no significant change in lipid targets (80.6% to 83.7%, P=0.182). Systolic blood pressure (-6.9 mm Hg [95% CI, -9.1 to -4.7], P<0.001), body mass index (-0.6 kg/m2 [95% CI, -0.8 to -0.3], P<0.001), low-density lipoprotein cholesterol (-4.2 mg/dL [95% CI, -8.2 to -0.2], P=0.042), and total cholesterol (-4.6 mg/dL [95% CI, -9.1 to -0.2] P=0.042) reduced. Heart-healthy lifestyle significantly improved with increased fish/olive oil (36.5% to 51.0%, P=0.012), decreased fast food consumption (33.8% to 11.0%, P<0.001), and increased physical activity (84.0% to 92.9%, P=0.025). Conclusions Women at high risk for cardiovascular disease due to past pregnancy-related conditions experienced significant improvements in multiple cardiovascular risk factors after attending a Women's Heart Clinic, potentially improving long-term cardiovascular disease outcomes. Registration URL: https://www.anzctr.org.au; Unique identifier: ACTRN12622000646741.

Left atrial enlargement is associated with pulmonary vascular disease in heart failure with preserved ejection fraction.

AIMS: Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF. METHODS AND RESULTS: Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m2 , >34 to ≤45 ml/m2 , >45 ml/m2 ). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (padjusted <0.001), higher resting mean pulmonary artery pressure (padjusted  = 0.003), with similar wedge pressure (padjusted  = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (padjusted <0.001). Larger LA volumes featured reduced LA strain (padjusted <0.001), with reduced strain associated with reduced PVR-compliance time (0.34 [0.28-0.40] vs. 0.38 [0.33-0.43], p = 0.03). CONCLUSION: Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR-compliance relationship, further augmenting impaired pulmonary haemodynamics.

Gender Disparities in Cardiogenic Shock Treatment and Outcomes.

Cardiogenic shock is associated with a high risk for morbidity and mortality. The impact of gender on treatment and outcomes is poorly defined. This study aimed to evaluate whether gender influences the clinical management and outcomes of patients with prehospital cardiogenic shock. Consecutive adult patients with cardiogenic shock who were transferred to hospital by emergency medical services (EMS) between January 1, 2015 and June 30, 2019 in Victoria, Australia were included. Data were obtained from individually linked ambulance, hospital, and state death index datasets. The primary outcome assessed was 30-day mortality, stratified by patient gender. Propensity score matching was performed for risk adjustment. Over the study period a total of 3,465 patients were identified and 1,389 patients (40.1%) were women. Propensity score matching yielded 1,330 matched pairs with no differences observed in baseline characteristics, including age, initial vital signs, pre-existing co-morbidities, etiology of shock, and prehospital interventions. In the matched cohort, women had higher rates of 30-day mortality (44.7% vs 39.2%, p = 0.009), underwent less coronary angiography (18.3% vs 27.2%, p <0.001), and revascularization with percutaneous coronary intervention (8.9% vs 14.2%, p <0.001), compared with men. In conclusion, in this large population-based study, women with cardiogenic shock who were transferred by EMS to hospital had significantly worse survival outcomes and reduced rates of invasive cardiac interventions compared to men. These data underscore the urgent need for targeted public health measures to redress gender differences in outcomes and variation with clinical care for patients with cardiogenic shock.

Work-life balance: a comparison of women in cardiology and other specialties.

OBJECTIVE: Significant gender disparities exist in some medical specialties, particularly cardiology. We assessed work, personal life and work-life balance in women in cardiology in Australia and New Zealand (NZ), compared with other specialties, to determine factors that may contribute to the lack of women in the specialty. METHODS: This study is a prospective survey-based cohort study comparing cardiology and non-cardiology specialties. An online survey was completed by female doctors in Australia and NZ, recruited via email lists and relevant social media groups. The survey included demographics, specialty, stage of training, work hours/setting, children and relationships, career satisfaction, income and perceptions of specialty. RESULTS: 452 participants completed the survey (median age 36 years), of which 57 (13%) worked in cardiology. Of all respondents, 84% were partnered and 75% had children, with no difference between cardiology and non-cardiology specialties. Compared with non-cardiology specialties, women in cardiology worked more hours per week (median 50 hours vs 40 hours, p<0.001), were more likely to be on call more than once per week (33% vs 12%, p<0.001) and were more likely to earn an annual income >$3 00 000 (35% vs 10%, p<0.001). Women in cardiology were less likely to agree that they led a balanced life (33% vs 51%, p=0.03) or that their specialty was female friendly (19% vs 75%, p<0.001) or family friendly (20% vs 63%, p<0.001). CONCLUSIONS: Compared with other specialties, women in cardiology reported poorer work-life balance, greater hours worked and on-call commitments and were less likely to perceive their specialty as female friendly or family friendly. Addressing work-life balance may attract and retain more women in cardiology.

The Gut Microbiome of Heart Failure With Preserved Ejection Fraction.

Background Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial-derived metabolites such as short-chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors. Methods and Results We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α-diversity (eg, number of microbes) and ß-diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF (P=0.001). We did not find an association between ß-diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so (P=0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short-chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day; P=0.016). Conclusions We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.

The effect of parity on exercise physiology in women with heart failure with preserved ejection fraction.

AIMS: Women are overrepresented amongst patients with heart failure with preserved ejection fraction (HFpEF); however, the underpinning mechanism for this asymmetric distribution is unclear. Pregnancy represents a potential gender-specific risk factor for HFpEF. It leads to significant physiological adaption, and increasing parity has been associated with some cardiovascular risk. We sought to examine the relationship between prior parity with the rest and exercise haemodynamic and echocardiographic profile of women with HFpEF. METHODS AND RESULTS: Patients referred for assessment of exertional dyspnoea and confirmed to have a haemodynamic and clinical profile consistent with HFpEF were included. Detailed evaluation consisted of rest and exercise right heart catheterization and echocardiography. A socio-economic and obstetric history was also documented. Fifty-eight women were assessed and categorized as having either 0-2 births or ≥3 births, dividing the cohort equally. Women with ≥3 births achieved a lower symptom-limited workload than those with 0-2 births [38 (24-51) vs. 46 (31-68) W, P = 0.04]. Women with ≥3 births had a greater rise in pulmonary capillary wedge pressure indexed to workload with exercise [0.5 (0.3-0.8) vs. 0.3 (0.2-0.5) mmHg/W, P = 0.03], paralleled by a greater rise in right atrial pressure [10 (8-12) vs. 7 (3-11), P = 0.01]. Pulmonary vascular resistance was also higher in women with ≥3 births [1.9 (1.6-2.4) vs. 1.6 (1.4-1.9) mmHg/L/min rest, P = 0.046, and 1.9 (2.4-2.4) vs. 1.4 (1-1.8) mmHg/L/min exercise, P = 0.024]. Left ventricular ejection fraction was lower at rest [60 (57-61) vs. 63 (60-66), P = 0.008] and during exercise [65 (62-67) vs. 68 (66-70), P = 0.038] in women with higher parity. CONCLUSIONS: Higher parity is associated with greater impairments in multiple physiologic parameters of HFpEF severity in women, including diastolic reserve, pulmonary vascular resistance, and systolic dysfunction.

The role of the gut microbiome in sex differences in arterial pressure.

There has been intense interest in the role of the gut microbiome in human health and a broad range of diseases in recent years. In the context of cardiovascular disease, gut dysbiosis (defined as a change in the gut microbiome and the gut-epithelial barrier) has been linked to disturbances in blood pressure (BP) regulation. These findings build upon our understanding of the complex pathophysiology of essential hypertension. There are clear sex differences in the epidemiology of hypertension, with distinct trends in BP across the life-course in men and women. To date, a role for the gut microbiome in contributing to the sex differences in BP is yet to be clearly established. The purpose of this review is to summarise the current literature regarding how the gut microbiome differs between men and women and to investigate whether sex-determined differences in the gut microbiome influence the response to factors such as diet, obesity and inflammation. Finally, we will explore evidence for the possible interaction between sex-specific factors, including sex hormones and pregnancy, with the gut in the context of hypertension pathophysiology.

Impact of Sex on Ventricular-Vascular Stiffness and Long-Term Outcomes in Heart Failure With Preserved Ejection Fraction: TOPCAT Trial Substudy.

Background Women have higher vascular stiffness with aging. The aim of this study was to characterize sex differences in vascular and ventricular structure and function, and to investigate the impact on the primary outcome in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). Methods and Results Data from the Americas cohort of the TOPCAT trial were analyzed. Patients with echocardiography (n=654) were compared according to sex, and achievement of the primary end point (a composite of death from cardiovascular causes and heart failure hospitalization) assessed. Echocardiography revealed higher arterial, systolic, and diastolic ventricular elastance and worse ventricular-vascular coupling in women. Women had better overall survival and heart failure hospitalization outcomes (hazard ratio 0.74, 95% CI 0.57-0.98, P=0.034), however, determinants of achievement of the primary outcome differed between the sexes. Pulse pressure was a key determinant of outcome in women (hazard ratio 1.04, 95% CI 1-1.09, P=0.034) whereas in men heart rate (hazard ratio 1.61, 95% CI 1.02-2.52 per 10 mm Hg increase, P=0.04) and B-type natriuretic peptide (hazard ratio 1.01, 95% CI 1-1.02 per 10 ng/mL increase P=0.02) were associated with poorer outcome. Conclusions Outcomes in patients with heart failure with preserved ejection fraction appear to be differentially influenced by key physiological factors that vary according to sex. In women, ventricular-vascular stiffening was the most significant determinant of outcome, whereas in men overall survival was influenced by heart rate and B-type natriuretic peptide; this highlights key sex differences in the pathophysiology and outcomes of heart failure with preserved ejection fraction and warrants further exploration. Clinical Trial Registration URL: https://clinicaltrials.gov . Unique identifier: NCT00094302.

The effect of diet on hypertensive pathology: is there a link via gut microbiota-driven immunometabolism?

Over the past decade, the immune system has emerged as an important component in the aetiology of hypertension. There has been a blooming interest in the contribution of the gut microbiota, the microbes that inhabit our small and large intestine, to blood pressure (BP) regulation. The gastrointestinal tract houses the largest number of immune cells in our body, thus, it is no surprise that its microbiota plays an important functional role in the appropriate development of the immune system through a co-ordinated sequence of events leading to immune tolerance of commensal bacteria. Importantly, recent evidence supports that the gut microbiota can protect or promote the development of experimental hypertension and is likely to have a role in human hypertension. One of the major modulators of the gut microbiota is diet: diets that emphasize high intake of fermentable fibre, such as the Mediterranean diet and the Dietary Approaches to Stop Hypertension, promote expansion of protective microbes that release gut metabolites such as short-chain fatty acids, which are immune-, BP-, and cardio-protective, likely acting through G-coupled protein receptors. In contrast, diets lacking fibre or high in salt and fat, such as the Western diet, reduce prevalence of commensal microbial species and support a pathogenic and pro-inflammatory environment, including the release of the pro-atherosclerotic trimethylamine N-oxide. Here, we review the current understanding of the gut microbiota-driven immune dysfunction in both experimental and clinical hypertension, and how these changes may be addressed through dietary interventions.

Iron Deficiency in Acute Decompensated Heart Failure.

The aim of this study was to characterize iron deficiency (ID) in acutely decompensated heart failure (ADHF) and identify whether ID is associated with dyspnea class, length of stay (LOS), biomarker levels, and echocardiographic indices of diastolic function in patients with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Consecutive patients admitted with ADHF at a single tertiary center were included. Demographic information, pathology investigations, and metrics regarding hospital stay and readmission were recorded. Patients were classified as having 'absolute' ID if they had a ferritin level <100 ng/mL; or 'functional' ID if they had a ferritin 100-200 ng/mL and a transferrin saturation <20%. Of 503 patients that were recruited, 270 (55%) had HFpEF, 160 (33%) had HFREF, and 57 (12%) had heart failure with mid-range ejection fraction. ID was present in 54% of patients with HFrEF and 56% of patients with HFpEF. In the HFpEF group, ID was associated with a LOS of 11 ± 7.7 vs. 9 ± 6 days in iron replete patients, p = 0.036, and remained an independent predictor of increased LOS in a multivariate linear regression incorporating comorbidities, age, and ID status. This study corroborates a high prevalence of ID in both HFrEF and HFpEF, and further shows that in patients with HFpEF there is a prolongation of LOS not seen in HFrEF which may indicate a more prominent role for ID in HFpEF.

Electrocardiographic findings in elite professional cyclists: The 2017 international recommendations in practice.

OBJECTIVES: To categorize ECG findings into normal, borderline or abnormal in a team of professional elite cyclists according to the 2017 international recommendations. DESIGN: A cross-sectional study was performed. METHODS: Twelve-lead ECGs collected between 2012 and 2015 as part of an annual routine examination for a team of professional elite cyclists were analysed, and findings classified as normal, borderline or abnormal according to the 2017 recommendations. Information on exercise capacity testing was also collected. RESULTS: A total of 43 professional cyclists, all Caucasian males ranging between 21 and 38years of age, were included. Given most were followed up for multiple years, a total of 103 ECGs were collected. Normal variations were found in 43 (100%) athletes; borderline findings in 4 (9.3%), and 2 (4.7%) athletes had abnormal findings. No pathology was identified on further investigation of the four cyclists with two concurrent borderline or any abnormal ECG findings, reflecting a false positive rate of 9.3%. CONCLUSIONS: In this team of professional cyclists, the prevalence of abnormal ECG findings requiring further investigation, and the false positive rate were low, despite a very high prevalence of normal variations expected in athletes. This may be as a result of heightened specificity of the new international recommendations for ECG interpretation in athletes.

Iron deficiency in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Objective: Iron deficiency (ID) has an established impact on outcomes in patients with heart failure with reduced ejection fraction; however, there is a lack of conclusive evidence in patients with heart failure with preserved ejection fraction (HFpEF). We sought to clarify the prevalence and impact of ID in patients with HFpEF. Methods: A systematic search of Cohcrane, MEDLINE, EMBASE, Web of Science and CINAHL electronic databases was performed to identify relevant studies. Included studies defined HFpEF as heart failure with an ejection fraction ≥50%. We used a random-effects meta-analysis to determine the composite prevalence of ID in patients with HFpEF across the included studies. Other outcomes were assessed with qualitative analysis due to a paucity of studies with comparable outcome measures. Results: The prevalence of ID in the included studies was 59% (95% CI 52% to 65%). ID was associated with lower VO2 max in three of four studies reporting VO2 max as an outcome measure, lower functional status as determined by dyspnoea class or 6 min walk test in two of three studies, and worse health-related quality of life in both studies reporting on this outcome. Conversely, ID had no impact on death or hospitalisation in three of the four studies investigating this. Conclusions: ID is highly prevalent in patients with HFpEF and is associated with worse exercise capacity and functional outcomes, but not hospitalisation or mortality. Our study establishes that ID may play an important a role in HFpEF.

Sex Differences in Heart Failure With Preserved Ejection Fraction Pathophysiology: A Detailed Invasive Hemodynamic and Echocardiographic Analysis.

OBJECTIVES: This study sought to identify sex differences in central and peripheral factors that contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) by using complementary invasive hemodynamic and echocardiographic approaches. BACKGROUND: Women are overrepresented among patients with HFpEF, and there are established sex differences in myocardial structure and function. Exercise intolerance is a fundamental feature of HFpEF; however, sex differences in the physiological determinants of exercise capacity in HFpEF are yet to be established. METHODS: Patients with exertional intolerance with confirmed HFpEF were included in this study. Evaluation of the subjects included resting and exercise hemodynamics, echocardiography, and mixed venous blood gas sampling. RESULTS: A total of 161 subjects included 114 females (71%). Compared to males, females had a higher pulmonary capillary wedge pressure (PCWP) indexed to peak exercise workload (0.8 [0.5 to 1.2] mm Hg/W vs. 0.6 [0.4 to 1] mm Hg/W, respectively; p = 0.001) and lower systemic (1.1 [0.9 to 1.5] ml/mm Hg vs. 1 [0.7 to 1.2] ml/mm Hg, respectively; p = 0.019) and pulmonary (2.9 [2.2 to 4.2] ml/mm Hg vs. 2.4 [1.9 to 3] ml/mm Hg, respectively; p = 0.032) arterial compliance at exercise. Mixed venous blood gas analysis demonstrated a greater rise in lactate indexed to peak workload (0.05 [0.04 to 0.09] mmol/l/W vs. 0.04 [0.03 to 0.06] mmol/l/W, respectively; p = 0.007) in women compared to men. Women had higher mitral inflow velocity to diastolic mitral annular velocity at early filling (E/e') ratios at rest and peak exercise, along with a higher ejection fraction and smaller ventricular dimensions. CONCLUSIONS: Women with HFpEF demonstrate poorer diastolic reserve with higher echocardiographic and invasive measurements of left ventricular filling pressures at exercise, accompanied by lower systemic and pulmonary arterial compliance and poorer peripheral oxygen kinetics.