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Background: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation., Methods: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO 2 ) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO 2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO 2 , and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity., Results: Peak VO 2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P =0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO 2 /dL blood; P <0.001). During single leg knee extension, there was no difference in peak leg VO 2 ( P =0.306), but the peripherally limited group had greater blood flow/VO 2 ratio ( P =0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO 2 /dL blood; P =0.013), and lower muscle oxygen diffusive conductance ( P =0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected ( P =0.199)., Conclusions: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O 2 ratio and poor muscle diffusive capacity., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844., Competing Interests: None.

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases nationwide and continues to rise in its prevalence. The complex, multi-organ involvement of the HFpEF clinical syndrome requires clinicians and investigators to adopt an integrative approach that considers the contribution of both cardiac and non-cardiac function to HFpEF pathophysiology. Thus, this symposium review outlines the key points from presentations covering the contributions of disease-related changes in cardiac function, arterial stiffness, peripheral vascular function, and oxygen delivery and utilization to exercise tolerance in patients with HFpEF. While many aspects of HFpEF pathophysiology remain poorly understood, there is accumulating evidence for a decline in vascular health in this patient group that may be remediable through pharmacological and lifestyle interventions and could improve outcomes and clinical status in this ever-growing patient population., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Interest in ketones as a cardiac "super fuel" has grown significantly following reports of a marked increase in cardiac output after exogenous ketone administration in heart failure. However, the extent to which this increase in cardiac output is related to changes in cardiac contractility, and dependent on the presence of heart failure, remains incompletely understood. Therefore, we performed a randomized, double-blind, placebo-controlled study of oral ketone ester in young healthy volunteers. Baseline cardiac magnetic resonance imaging was performed and repeated every 15 min for 60 min after ketone and placebo ingestion to assess changes in left ventricular function. As expected, circulating β-hydroxybutyrate increased rapidly after ketone ingestion, but did not change with placebo (interaction: P < 0.001). Consistent with prior investigations, ketone ingestion resulted in an average 1 L/min increase in cardiac output after 60 min that did not occur with placebo (interaction: P = 0.026). This increase in cardiac output was primarily driven by an increase in heart rate after ketone ingestion (interaction: P = 0.018), with only a modest increase in stroke volume (interaction: P = 0.037). Changes in left ventricular strain and twist mechanics were limited. Taken together, the increase in cardiac output following an acute elevation in circulating β-hydroxybutyrate is primarily driven by changes in cardiac chronotropy, with minimal inotropic contribution. NEW & NOTEWORTHY In this randomized, double-blind, placebo-controlled study of oral ketone ester in young healthy volunteers, we show a marked increase in cardiac output (∼1 L/min), driven primarily by changes in chronotropy. The cardiac magnetic resonance imaging data support the limited role for inotropy.

Competing Interests: Disclosures None.

Background: Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change., Methods: Cardiac magnetic resonance (CMR) imaging from 229 participants from the Alberta HEART Study (46 healthy controls, 77 individuals at risk for developing heart failure [HF], 70 patients with diagnosed HF with preserved ejection fraction [HFpEF], and 36 patients with diagnosed HF with reduced ejection fraction [HFrEF]) were evaluated. LV volume was assessed by the method of disks and strain/strain rate were assessed by CMR feature tracking., Results: Integrating endocardial circumferential and longitudinal strain provided a close approximation of LV ejection fraction (EF Strain ), when compared to gold-standard volumetric assessment (EF Volume : r = 0.94, P < 0.0001). Likewise, integrating circumferential and longitudinal strain rate provided a close approximation of peak ejection and peak filling rates (PER Strain and PFR Strain , respectively) compared to their gold-standard volume-time equivalents (PER Volume , r = 0.73, P < 0.0001 and PFR Volume , r = 0.78, P < 0.0001, respectively). Moreover, each integrated strain measure differentiated patients across the HF continuum (all P < 0.01), with the HFrEF group having worse EF Strain , PER Strain , and PFR Strain compared to all other groups, and HFpEF having less favorable EF Strain and PFR Strain compared to both at-risk and control groups., Conclusions: The data herein establish the theoretical framework for integrating discrete strain components into volumetric measurements across the cardiac cycle, and highlight the potential benefit of this approach for differentiating patients along the heart failure continuum., (© 2023. Society for Cardiovascular Magnetic Resonance.)

Heart failure with reduced ejection fraction (HFrEF) exhibits exaggerated sympathoexcitation and altered cardiac and vascular responses to muscle metaboreflex activation (MMA). However, left ventricular (LV) responses to MMA are not well studied in patients with HFrEF. The purpose of this study was to examine LV function during MMA using cardiac magnetic resonance imaging (MRI) in patients with HFrEF. Thirteen patients with HFrEF and 18 healthy age-matched controls underwent cardiac MRI during rest and MMA. MMA protocol included 6 min of isometric handgrip exercise followed by 6-min of brachial postexercise circulatory occlusion. LV stroke volume index (SVi), end-systolic volume index (ESVi), end-diastolic volume index (EDVi), and global longitudinal strain (GLS) were measured by two- and four-chamber cine images. Volumes were indexed to body surface area. Heart rate (via ECG) and brachial mean arterial pressure (MAP) were recorded. Cardiac output and total peripheral resistance (TPR) were calculated. SVi decreased during MMA in HFrEF ( P = 0.037) but not in controls ( P = 0.392). ESVi ( P = 0.007) and heart rate ( P < 0.001) increased during MMA in HFrEF but not controls ( P ≥ 0.170). TPR ( P = 0.021) and MAP ( P < 0.001) increased during MMA in both groups. Cardiac output ( P = 0.946), EDVi ( P = 0.177), and GLS ( P = 0.619) were maintained from rest to MMA in both groups. Despite similarly maintained cardiac output, LV strain, and increased TPR in HFrEF and control groups, SVi decreased, and heart rate increased during MMA in patients with HFrEF. These findings suggest an impaired contractility reserve in response to increased TPR during MMA in HFrEF. NEW & NOTEWORTHY Stroke volume decreases and end-systolic volume increases during muscle metaboreflex activation in patients with heart failure with reduced ejection fraction (HFrEF), suggesting impaired contractile reserve during muscle metaboreflex activation in patients with HFrEF. Total peripheral resistance increases similarly during muscle metaboreflex activation in patients with HFrEF compared to controls, indicating normal levels of peripheral vasoconstriction during muscle metaboreflex activation in patients with HFrEF.

Objective: Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships between plasma OPN and surrogates of HIV-associated heart failure risk., Design: Prospective, cross-sectional., Methods: We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH)., Results: Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters., Conclusion: Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH., Clinicaltrialsgov Registration: NCT02874703., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Women with HIV (WWH) face heightened risks of heart failure; however, insights on immune/inflammatory pathways potentially contributing to left ventricular (LV) systolic dysfunction among WWH remain limited., Setting: Massachusetts General Hospital, Boston, Massachusetts., Methods: Global longitudinal strain (GLS) is a sensitive measure of LV systolic function, with lower cardiac strain predicting incident heart failure and adverse heart failure outcomes. We analyzed relationships between GLS (cardiovascular magnetic resonance imaging) and monocyte activation (flow cytometry) among 20 WWH and 14 women without HIV., Results: WWH had lower GLS compared to women without HIV (WWH vs. women without HIV: 19.4±3.0 vs. 23.1±1.9%, P<0.0001). Among the whole group, HIV status was an independent predictor of lower GLS. Among WWH (but not among women without HIV), lower GLS related to a higher density of expression of HLA-DR on the surface of CD14+CD16+ monocytes (ρ = -0.45, P = 0.0475). Further, among WWH, inflammatory monocyte activation predicted lower GLS, even after controlling for CD4+ T-cell count and HIV viral load., Conclusions: Additional studies among WWH are needed to examine the role of inflammatory monocyte activation in the pathogenesis of lower GLS and to determine whether targeting this immune pathway may mitigate risks of heart failure and/or adverse heart failure outcomes., Trial Registration: Clinical trials.gov registration: NCT02874703., Competing Interests: MT, MA, ZDD, TQ, MW, CGD, DAA, LTF, GASA, MDN, MJH, and CTL have no disclosures. TLS receives research funding to her institution from Pfizer, Inc., unrelated to the present project. THB has equity in Excision BioTherapeutics and is a member of their Scientific Advisory Board, unrelated to the present project. TGN has been a consultant to and received fees from Bristol Myers Squibb, AbbVie, Intrinsic Imaging, Roche, Genentech, Sanofi, CRO Oncology, C4 Therapeutic, and H3-Biomedicine, unrelated to the present project. TGN has received research funding from AstraZeneca and Bristol Myers Squibb, unrelated to the present project. MVZ is Principal Investigator of an Industry-Sponsored Research Grant from Gilead Sciences, Inc. to her institution, unrelated to the present project., (Copyright: © 2022 Toribio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Reduced exercise tolerance and fatigue are hallmark features in both breast cancer (BC) and heart failure with preserved ejection fraction (HFpEF) and are associated with decreased physical function and quality of life. This brief review focuses on the mechanisms of exercise intolerance in women with BC across the survivorship continuum and highlights how these disturbances within the oxygen transport cascade are similar to that of HFpEF patients. Specifically, the role that impaired cardiac, peripheral vascular and skeletal muscle function play in limiting peak oxygen uptake are discussed. We propose that women with BC are at increased risk of developing HFpEF potentially due to the adverse effects of chemotherapy and concurrent adverse lifestyle behaviors on cardiovascular and skeletal muscle function., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. The primary chronic symptom in HFpEF is exercise intolerance, associated with reduced quality of life. Emerging evidence implicates left atrial (LA) dysfunction as an important pathophysiologic mechanism. Here we extend prior observations by relating LA dysfunction to peak oxygen uptake (peak VO 2 ), physical function (distance walked in 6 minutes [6MWD]) and quality of life (Kansas City Cardiomyopathy Questionnaire)., Methods and Results: We compared 75 older, obese, patients with HFpEF with 53 healthy age-matched controls. LA strain was assessed by magnetic resonance cine imaging using feature tracking. LA function was defined according to its 3 distinct phases, with the LA serving as a reservoir during systole, as a conduit during early diastole, and as a booster pump at the end of diastole. The LA stiffness index was calculated as the ratio of early mitral inflow velocity-to-early annular tissue velocity (E/e', by Doppler ultrasound examination) and LA reservoir strain. HFpEF had a decreased reservoir strain (16.4 ± 4.4% vs 18.2 ± 3.5%, P = .018), lower conduit strain (7.7 ± 3.3% vs 9.1 ± 3.4%, P = .028), and increased stiffness index (0.86 ± 0.39 vs 0.53 ± 0.18, P < .001), as well as decreased peak VO 2 , 6MWD, and lower quality of life. Increased LA stiffness was independently associated with impaired peak VO 2 (β = 9.0 ± 1.6, P < .001), 6MWD (β = 117 ± 22, P = .003), and Kansas City Cardiomyopathy Questionnaire score (β = -23 ± 5, P = .001), even after adjusting for clinical covariates., Conclusions: LA stiffness is independently associated with impaired exercise tolerance and quality of life and may be an important therapeutic target in obese HFpEF., Registration: NCT00959660., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF); however, the mechanism(s) contributing to this progression remains unclear. Given that diastolic dysfunction is common in women with INOCA, defining mechanisms related to diastolic dysfunction in INOCA could identify therapeutic targets to prevent HFpEF., Methods: Cardiac MRI was performed in 65 women with INOCA and 12 reference controls. Diastolic function was defined by left ventricular early diastolic circumferential strain rate (eCSRd). Contributors to diastolic dysfunction were chosen a priori as coronary vascular dysfunction (myocardial perfusion reserve index [MPRI]), diffuse myocardial fibrosis (extracellular volume [ECV]), and aortic stiffness (aortic pulse wave velocity [aPWV])., Results: Compared to controls, eCSRd was lower in INOCA (1.61 ± 0.33/s vs. 1.36 ± 0.31/s, P = 0.016); however, this difference was not exaggerated when the INOCA group was sub-divided by low and high MPRI (P > 0.05) nor was ECV elevated in INOCA (29.0 ± 1.9% vs. 28.0 ± 3.2%, control vs. INOCA; P = 0.38). However, aPWV was higher in INOCA vs. controls (8.1 ± 3.2 m/s vs. 6.1 ± 1.5 m/s; P = 0.045), and was associated with eCSRd (r = -0.50, P < 0.001). By multivariable linear regression analysis, aPWV was an independent predictor of decreased eCSRd (standardized β = -0.39, P = 0.003), as was having an elevated left ventricular mass index (standardized β = -0.25, P = 0.024) and lower ECV (standardized β = 0.30, P = 0.003)., Conclusions: These data provide mechanistic insight into diastolic dysfunction in women with INOCA, identifying aortic stiffness and ventricular remodeling as putative therapeutic targets., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study tested the hypothesis that early left ventricular (LV) relaxation is impaired in older obese patients with heart failure with preserved ejection fraction (HFpEF), and related to decreased peak exercise oxygen uptake (peak V̇o 2 ). LV strain and strain rate were measured by feature tracking of magnetic resonance cine images in 79 older obese patients with HFpEF (mean age: 66 yr; mean body mass index: 38 kg/m 2 ) and 54 healthy control participants. LV diastolic strain rates were indexed to cardiac preload as estimated by echocardiography derived diastolic filling pressures ( E/e' ), and correlated to peak V̇o 2 . LV circumferential early diastolic strain rate was impaired in HFpEF compared with controls (0.93 ± 0.05/s vs. 1.20 ± 0.07/s, P = 0.014); however, we observed no group differences in early LV radial or longitudinal diastolic strain rates. Isolating myocardial relaxation by indexing all three early LV diastolic strain rates (i.e. circumferential, radial, and longitudinal) to E/e' amplified the group difference in early LV diastolic circumferential strain rate (0.08 ± 0.03 vs. 0.13 ± 0.05, P < 0.0001), and unmasked differences in early radial and longitudinal diastolic strain rate. Moreover, when indexing to E/e' , early LV diastolic strain rates from all three principal strains, were modestly related with peak V̇o 2 ( R  = 0.36, -0.27, and 0.35, respectively, all P < 0.01); this response, however, was almost entirely driven by E/e' itself, ( R = -0.52, P < 0.001). Taken together, we found that although LV relaxation is impaired in older obese patients with HFpEF, and modestly correlates with their severely reduced peak exercise V̇o 2 , LV filling pressures appear to play a much more important role in determining exercise intolerance. NEW & NOTEWORTHY Using a multimodal imaging approach to uncouple tissue deformation from atrial pressure, we found that left ventricular (LV) relaxation is impaired in older obese patients with HFpEF, but only modestly correlates with their severely reduced peak V̇o 2 . In contrast, the data show a much stronger relationship between elevated LV filling pressures and exercise intolerance, refocusing future therapeutic priorities.

Purpose of the Review: This review summarizes sex-related changes in the heart and vasculature that occur with aging, both in the presence and absence of cardiovascular disease (CVD)., Recent Findings: In the presence of CVD risk factors and/or overt CVD, sex-specific changes in the number of cardiomyocytes, extent of the myocardial extracellular matrix, and myocellular hypertrophy promote unique patterns of LV remodeling in men and women. In addition, age- and sex-specific vascular stiffening is also well established, driven by changes in endothelial dysfunction, elastin-collagen content, microvascular dysfunction, and neurohormonal signaling. Together, these changes in LV chamber geometry and morphology, coupled with heightened vascular stiffness, appear to drive both age-related increases in systolic function and declines in diastolic function, particularly in postmenopausal women. Accordingly, estrogen has been implicated as a key mediator, given its direct vasodilating properties, association with nitric oxide excretion, and involvement in myocellular Ca 2+ handling, mitochondrial energy production, and oxidative stress. The culmination of the abovementioned sex-specific cardiac and vascular changes across the lifespan provides important insight into heart failure development, particularly of the preserved ejection fraction variety, while offering promise for future preventive strategies and therapeutic approaches.

Background: Women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) are at risk of heart failure with preserved ejection fraction (HFpEF); however, the mechanism for HFpEF progression remains unclear. Studies in INOCA have largely focused on left ventricular function. The left atrium serves an important role in maintaining transmitral flow, and is impaired in HFpEF; however, it remains unclear if left atrial function is impaired in INOCA., Hypothesis: Left atrial function is progressively worse in INOCA and HFpEF compared to controls., Methods: We compared 39 reference control subjects to 64 women with INOCA and 22 subjects with HFpEF. Left atrial strain was assessed by feature tracking using magnetic resonance cine images., Results: Peak left atrial strain was reduced in HFpEF compared to controls (22.9 ± 4.8% vs 25.9 ± 3.2%, P < .01), but similar in INOCA (24.8 ± 4.5%) compared to HFpEF and controls (P = .18). However, left ventricular end-diastolic pressure (LVEDP) was elevated in 33% of INOCA participants, suggesting that left atrial stiffness (LVEDP/LA strain) is elevated in a large portion of women with INOCA., Conclusions: Taken together, we interpret these data to support our working hypothesis that INOCA is a pre-HFpEF state, with left atrial stiffness preceding overt left atrial dysfunction; representing a putative therapeutic target to prevent HFpEF progression in this at-risk population., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: Women with evidence of ischemia and no obstructive coronary arteries (INOCA) often have coronary microvascular dysfunction (CMD) indicated by impaired coronary flow reserve (CFR) to adenosine. Low CFR is associated with an adverse prognosis, including incident heart failure. Because the CFR calculation relies on the baseline intrinsic coronary vasomotor flow velocity, a major determinate of CFR and the degree of variation in baseline flow alone may be an important contributor to risk of adverse outcomes in women with CMD. A better understanding of baseline blood flow in the setting of low CFR and its association with myocardial performance would be helpful., Methods: We evaluated 74 women who underwent invasive coronary reactivity testing in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study and had impaired CFR (<2.32). We assessed the relationship between coronary artery baseline average peak velocity (bAPV) at rest and cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function., Results: When stratified as low (<22 cm/s) versus high (≥22 cm/s) bAPV, there were no differences in cardiovascular risk factors, coronary plaque burden, or LV structure. However, low bAPV was associated with higher LV end-diastolic filling pressure (P = 0.04), lower LV ejection fraction (P = 0.001), and differences in late systolic and diastolic strain rates (P = 0.01 to 0.05)., Conclusions: In women with impaired CFR, low resting coronary flow velocity is associated with more adverse myocardial performance, which may contribute to risk for adverse outcomes and particularly heart failure in women with CMD., Competing Interests: Declaration of competing interest Dr. Bairey Merz has received personal fees paid through CSMC from Abbott Diagnostics, Sanofi and serves as Board of Director at iRhythm. Dr. Pepine has received research grants from GE Healthcare, Merck, Sanofi, CLS Behring, Biocardia, McJunkin Family Foundation, Brigham & Women's Hospital, Gatorade Trust through the University of Florida Department of Medicine, Athersys Inc., AMI MultiStem, and Mesoblast, Inc.; has received consultant fees/honoraria from Verily Life Sciences LLC Project Baseline OSMB (Google), Ironwood, XyloCor, Slack Inc., Imbria Pharmaceuticals, Milestone Pharmaceuticals Inc., Ventrix, Inc., AstraZeneca Pharmaceuticals, and Sanofi-Aventis. Dr. Handberg receives research grants from Aastrom Biosciences, Amorcyte, Biocardia, Brigham and Women's Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Everyfit Inc., Medtronic, Merck & Co., Mesoblast, National Institutes of Health (NIH), NIH through University of Rochester, NIH through Brigham and Women's Health, NIH through University of Texas, PCORI, and Sanofi Aventis; Research grant and educational grant from Gilead Sciences; Unrestricted educational grants for the Vascular Biology Working Group from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Ionis, and Relypsa; and Consultant fees from Bristol-Myers Squibb Company., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The syndrome of heart failure (HF) with preserved ejection fraction (HFpEF) is now recognized to account for up to half of HF cases and is the dominant form of HF in older adults, especially women. Multiple factors conspire in this predilection of HFpEF for older women. This review will discuss the epidemiology, pathophysiology, prognosis, and treatment of HFpEF with emphasis on the similarities and differences in cardiovascular aging changes, and the differential impact of comorbidities in women versus men. Responses to pharmacologic and lifestyle interventions are also reviewed. We conclude by suggesting future directions for both prevention and treatment of this common and highly morbid cardiovascular disorder., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure in the United States. The cardinal feature of HFpEF is reduced exercise tolerance (peak oxygen uptake, (Equation is included in full-text article.)O2peak) secondary to impaired cardiac, vascular, and skeletal muscle function. There are currently no evidence-based drug therapies to improve clinical outcomes in patients with HFpEF. In contrast, exercise training is a proven effective intervention for improving (Equation is included in full-text article.)O2peak, aerobic endurance, and quality of life in HFpEF patients. This brief review discusses the pathophysiology of exercise intolerance and the role of exercise training to improve (Equation is included in full-text article.)O2peak in clinically stable HFpEF patients. It also discusses the mechanisms responsible for the exercise training-mediated improvements in (Equation is included in full-text article.)O2peak in HFpEF. Finally, it provides evidence-based exercise prescription guidelines for cardiac rehabilitation specialists to assist them with safely implementing exercise-based cardiac rehabilitation programs for HFpEF patients.

Background: Heart failure (HF) management requires the participation of patients, their significant others, and clinical providers. Each group may face barriers to HF management that may be unique or may overlap., Objective: The aim of this study was to compare the barriers and facilitators of HF management as perceived by patients, significant others, and clinical providers., Methods: Participants were recruited from a Veterans Health Administration facility. Eligible patients had a diagnosis of HF (ICD9 code 428.XX), 1 or more HF-related visit in the previous year, and a significant other who was their primary caregiver. Significant others were adults with no history of cognitive impairments caring for patients with HF. Providers were eligible if they cared for patients with HF. All participants completed semistructured interviews designed to elicit barriers to managing HF and strategies that they used to overcome these barriers. Interviews were transcribed and analyzed using latent thematic analysis, and recruitment continued until thematic saturation was attained., Results: A total of 17 couples and 12 providers were recruited. All 3 groups identified poor communication as a key barrier to HF management, including communication between patients and their significant other, between couples and providers, and providers with each other. Significant others noted that the lack of direct communication with clinical providers hindered their efforts to care for the patient. All 3 groups emphasized the importance of family members in optimizing adherence to HF self-management recommendations., Conclusions: Providers, patients, and significant others all play important and distinct roles in the management of HF. Tools to enhance communication and collaboration for all 3 and supporting the needs of significant others are missing components of current HF care.

Background: In women with evidence of ischemia and no obstructive coronary artery disease the underlying mechanism is most often attributed to coronary microvascular dysfunction. Higher rates of adverse cardiovascular events, specifically heart failure with preserved ejection fraction, are present in women with coronary microvascular dysfunction, leading to the hypothesis that coronary microvascular dysfunction may contribute to the progression of heart failure with preserved ejection fraction. A 55-year-old, Caucasian woman with a past medical history of chest pain and shortness of breath was referred to our tertiary care center and diagnosed as having coronary microvascular dysfunction by invasive coronary reactivity testing. After 10 years of follow-up care for coronary microvascular dysfunction, she presented to an emergency room in acute heart failure and was diagnosed as having heart failure with preserved ejection fraction., Discussion: The current case report provides a specific example in support of existing studies that demonstrate that coronary microvascular dysfunction may be a precursor of heart failure with preserved ejection fraction. Further research is needed to establish causality and management., Trial Registration: Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02582021 .

Background: The role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients., Methods: We searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients., Results: 18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI -0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF., Conclusions: In clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose of Review: This review summarizes recent developments highlighting the clinical utility of diastolic stress testing along the heart failure continuum., Recent Findings: Invasive hemodynamic assessment of cardiac filling pressures during physiological stress is the gold-standard technique for unmasking diastolic dysfunction. Non-invasive surrogate techniques, such as Doppler ultrasound, have shown excellent agreement with invasive approaches and are now recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. While cycle exercise is often advocated, recent evidence supports the use of isometric handgrip as a viable alternative stressor. Diastolic stress testing is a powerful tool to enhance detection of diastolic dysfunction, is able to differentiate between cardiac and non-cardiac pathology, and should be incorporated into routine clinical assessment.

Objectives: This study sought to test the hypothesis that older obese patients with heart failure with preserved ejection fraction (HFpEF) have significantly greater abdominal, cardiac, and intermuscular fat than healthy, age-matched controls, out of proportion to total body fat, and that these abnormalities are associated with objective measurements of physical function., Background: Recent studies indicate that excess total body adipose tissue contributes to exercise intolerance in patients with HFpEF. However, the impact of the pattern of regional (abdominal, cardiac, intermuscular) adipose deposition on exercise intolerance in patients with HFpEF is unknown., Methods: We measured total body adiposity (using dual-energy x-ray absorptiometry) and regional adiposity (using cardiac magnetic resonance), peak oxygen uptake (Vo 2 ), 6-min walk distance (6MWD), short physical performance battery (SPPB), and leg press power in 100 older obese patients with HFpEF and 61 healthy controls (HCs) and adjusted for age, sex, race, and body surface area., Results: Peak Vo 2 (15.7 ± 0.4 ml/kg/min vs. 23.0 ± 0.6 ml/kg/min, respectively; p < 0.001), 6MWD (427 ± 7 m vs. 538 ± 10 m, respectively; p < 0.001), SPPB (10.3 ± 0.2 vs. 10.9 ± 0.2, respectively; p < 0.05), and leg power (117 ± 5 W vs. 152 ± 9 W, respectively; p = 0.004) were significantly lower in patients with HFpEF than HCs. Total fat mass, total percent fat, abdominal subcutaneous fat, intra-abdominal fat, and thigh intermuscular fat were significantly higher, whereas epicardial fat was significantly lower in patients with HFpEF than in HC. After we adjusted for total body fat, intra-abdominal fat remained significantly higher, while epicardial fat remained significantly lower in patients with HFpEF. Abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intermuscular fat:skeletal muscle ratio were inversely associated, whereas epicardial fat was directly associated with peak Vo 2 , 6MWD, SPPB, and leg power. Using multiple stepwise regression, we found intra-abdominal fat was the strongest independent predictor of peak Vo 2 and 6MWD., Conclusions: In metabolic obese HFpEF, the pattern of regional adipose deposition may have important adverse consequences beyond total body adiposity. Interventions targeting intra-abdominal and intermuscular fat could potentially improve exercise intolerance. (Exercise Intolerance in Elderly Patients With Diastolic Heart Failure [SECRET]; NCT00959660)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is a major health care burden associated with high morbidity and mortality. Approximately 50% of HF patients have reduced ejection fraction (HFrEF) while the remainder of patients have preserved ejection fraction (HFpEF). A hallmark of both HF phenotypes is dyspnoea upon exertion and severe exercise intolerance secondary to impaired oxygen delivery and/or use by exercising skeletal muscle. Exercise training is a safe and effective intervention to improve peak oxygen uptake (VO 2peak ) and quality of life in clinically stable HF patients, however, evidence to date suggests that the mechanism of this improvement appears to be related to underlying HF phenotype. The purpose of this review is to discuss the role of exercise training to improve VO 2peak , and how the central and peripheral adaptations that mediate the improvements in exercise tolerance may be similar or differ by HF phenotype (HFrEF or HFpEF)., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Ischemic heart disease, in the absence of obstructive coronary artery disease, is prevalent in women and constitutes a major risk factor for developing major adverse cardiovascular events, including myocardial infarction, stroke, and heart failure. For decades, diagnosis was considered benign and often minimized; however, it is now known that this etiology carries much risk and is a significant burden to the health care system. This review summarizes the current state of knowledge on nonobstructive ischemic heart disease (NOIHD), the association between NOIHD and left ventricular diastolic dysfunction, potential links between NOIHD and the development of heart failure with preserved ejection fraction (HFpEF), and therapeutic options and knowledge gaps for patients living with NOIHD., (Copyright © 2017 the American Physiological Society.)

Background: Women with signs and symptoms of ischemia, no obstructive coronary artery disease, and preserved left ventricular ejection fraction enrolled in the National Heart Lung and Blood Institute (NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study have an unexpectedly high rate of subsequent heart failure (HF) hospitalization. We sought to verify and characterize the HF hospitalizations., Methods: A retrospective chart review was performed on 223 women with signs and symptoms of ischemia, undergoing coronary angiography for suspected coronary artery disease followed for 6±2.6years. Data were collected from a single site in the WISE study., Results: At the time of study enrollment, the women were 57±11years of age, all had preserved left ventricular ejection fraction, and 81 (36%) had obstructive CAD (defined as >50% stenosis in at least one epicardial artery). Among the 223 patients, 25 (11%) reported HF hospitalizations, of which 14/25 (56%) had recurrent HF hospitalizations (>2 hospitalizations). Medical records were available in 13/25 (52%) women. Left ventricular ejection fraction was measured in all verified cases and was found to be preserved in 12/13 (92%). HF hospitalization was not related to obstructive CAD., Conclusion: Among women with signs and symptoms of ischemia undergoing coronary angiography for suspected obstructive CAD, HF hospitalization at 6-year follow-up was predominantly characterized by a preserved ejection fraction and not associated with obstructive CAD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function., (Copyright © 2016 the American Physiological Society.)

Background: In nondiabetic patients hospitalized with multiorgan failure, neurohormonal activation can lead to stress-induced hyperglycemia (>140 mg/dL), as could Mg(2+) and Zn(2+) deficiencies. However, it is currently uncertain whether nondiabetic African Americans (AA) hospitalized with either chronic, decompensated biventricular failure (DecompHF) having hepatic and splanchnic congestion, ionized hypomagnesemia and hypozincemia, or acute left heart failure (LHF) would exhibit hyperglycemia at admission., Methods: We retrospectively examined admission serum glucose in 77 AA patients without a history of diabetes, who were hospitalized with heart failure. This examination included 41 patients admitted during a 4-month period with chronic DecompHF and whose clinical presentation included findings of expanded intra- and extravascular volumes, together with echocardiographic evidence of marked tricuspid regurgitation and distended inferior vena cava, without respiratory variation. These patients were compared with 14 nondiabetic patients hospitalized during the same time period with acute LHF. We also studied admission serum glucose in 22 patients who were admitted with DecompHF having documented hypomagnesemia and hypozincemia., Results: Admission serum glucose (mean +/- standard error of mean) in patients with chronic DecompHF was 105.41 +/- 4.08 mg/dL and was modestly elevated (140-160 mg/dL) in 3 patients. In those with acute LHF, glucose was 94.86 +/- 3.96 mg/dL and did not exceed 140 mg/dL in any patient. Glucose (103.2 +/- 4.3 mg/dL) was not elevated in patients having chronic DecompHF and reduced ionized Mg(2+) and serum Zn(2+) (0.44 +/- 0.01 mmol/L and 69.6 +/- 3.2 mug/dL, respectively)., Conclusions: Hyperglycemia at admission was infrequent in nondiabetic AA patients hospitalized with either acute LHF or chronic DecompHF, which may have also included hypomagnesemia and hypozincemia. This calls into question the need for intensive insulin therapy in these patients.

Background: A reduction in relative lymphocyte count (%L) has been reported in whites with heart failure that inversely correlated with jugular venous pressure thereby implicating systemic venous hypertension with splanchnic congestion., Objectives: : To study whether a reduced %L (<20%) occurs in African-Americans (AA) with heart failure and to address pathophysiologic mechanisms having the potential to influence lymphocyte biology and survival, we monitored patients with or without systemic venous hypertension, hypoalbuminemia, hypovitaminosis D, and secondary hyperparathyroidism., Methods: In 131 AA (90 men; 53 +/- 12 years): 113 were hospitalized, 50 with decompensated biventricular failure (DecompHF), 24 with acute left heart failure, and 39 with heart disease, but no heart failure (HDNHF); and 18 were outpatients with compensated heart failure. At the time of admission or outpatient visit, we monitored: white blood cell count and %L; and serum albumin, 25(OH)D, and parathyroid hormone (PTH)., Results: White blood cell count did not differ among the groups, whereas %L was reduced only in those with DecompHF (15 +/- 1%; P < 0.05) versus 25 +/- 2% with left heart failure, 29 +/- 1% in HDNHF, and 28 +/- 3% in compensated heart failure. Serum albumin was reduced in DecompHF (2.8 +/- 0.1; P < 0.05), but not in any of the other groups. Reduced 25(OH)D (<30 ng/mL), in keeping with hypovitaminosis D, was found in all AA, whereas elevated serum PTH (>65 pg/mL) was found only in those with DecompHF (123 +/- 22 pg/mL)., Conclusions: A relative lymphocytopenia, together with hypoalbuminemia and elevated PTH, were found only in hospitalized AA with DecompHF. These findings implicate splanchnic congestion and the enteric loss of lymphocytes and albumin with an associated secondary hyperparathyroidism.

Background: Factors contributing to heart failure (HF) in African Americans (AA) are under investigation. Reduced 25(OH)D confers increased cardiovascular risk, including HF., Methods: We monitored serum 25(OH)D, 1,25(OH)2D3, parathyroid hormone (PTH), and creatinine clearance in 102 AA residing in Memphis: 58 hospitalized with decompensated HF of >or=4 weeks in 34 (21 men; 53.3 +/- 1.8 years) or of 1 to 2 weeks in 24 (17 men; 49.6 +/- 2.4 years) and associated with a dilated cardiomyopathy and reduced ejection fraction (<35%); 19 outpatients with compensated HF (14 men; 52.6 +/- 2.7 years) with comparable ejection fraction; 16 outpatients (9 men; 55.4 +/- 2.9 years) with heart disease, but without HF; and 9 healthy volunteers (3 men; 35.8 +/- 3.5 years)., Results: Serum 25(OH)D 65 pg/mL was found in all AA with decompensated HF of >or=4 weeks (132.4 +/- 12.0 pg/mL) and 67% with 1 to 2 weeks duration (82.3 +/- 7.9 pg/mL), but only 11% with compensated HF (45.8 +/- 6.1 pg/mL), 12% without HF (29.6 +/- 5.4 pg/mL), and none of the volunteers (31.1 +/- 3.9 pg/mL). Creatinine clearance did not differ between patient groups., Conclusions: Hypovitaminosis D is prevalent amongst AA residing in Memphis, with or without HF. Elevations in serum PTH in keeping with secondary hyperparathyroidism are only found in AA with decompensated HF, where hypovitaminosis D and other factors are contributory.

Heart failure is thought to be more common and of greater severity in African-Americans (AAs). Potential mechanisms remain uncertain. The importance of micronutrient deficiencies in the pathophysiologic expression of congestive heart failure (CHF) in AAs remains to be explored, including hypovitaminosis D, which can promote secondary hyperparathyroidism (SHPT), together with hypozincemia and hyposelenemia, the 2 most crucial trace minerals integral to diverse biologic functions. Serum parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), Zn, and Se were monitored in 30 AAs hospitalized during June through December 2005, with decompensated failure and reduced ejection fraction (EF) (<35%) of predominantly nonischemic origin treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), furosemide, and spironolactone. Based on their symptomatic status before hospitalization, 15 patients were stratified as having protracted (>or=4 weeks) CHF, whereas 15 patients had short-term (1-2 weeks) CHF. These hospitalized patients were compared with 10 AA outpatients with stable, similarly treated compensated failure and comparable EF, and 9 AA normal volunteers without cardiovascular disease. Serum PTH was elevated in all patients with protracted CHF and in 60% of patients with short-term CHF, but not in compensated patients or normal volunteers. However, serum 25(OH)D was reduced in all patients with >or=4 weeks and 80% with either 1-2 weeks CHF or compensated failure compared with volunteers. Serum Zn was below normal in 11 of 15 patients with protracted CHF, in 8 of 15 patients with shorter duration CHF, and in 5 of 10 patients with compensated failure. Serum Se was reduced in all patients with >or=4 weeks, 60% with short-term CHF, and 90% of compensated patients. Concomitant to hypovitaminosis D, hypozincemia, and hyposelenemia, SHPT is a covariant of CHF in housebound AAs.

Objective: We previously noted secondary hyperparathyroidism (SHPT) in African-American patients hospitalized during February, 2005 with either untreated or treated congestive heart failure (CHF) due to ischemic or idiopathic cardiomyopathy. Herein, we hypothesized that housebound African-American patients hospitalized during the period of June 1 through August 31, 2005, with CHF would have SHPT and hypovitaminosis D., Methods: Twenty-five African-American patients with an ejection fraction (EF) less than 35% due to ischemic or dilated (idiopathic) cardiomyopathy were monitored: 20 were hospitalized with CHF, stratified on historical grounds as of 4 weeks' or longer duration or of 1 to 2 weeks' duration in 11 and 9 patients, respectively, despite medical care that included furosemide; serum parathyroid hormone (PTH) and 25(OH)D at the time of admission in these patients were compared to five asymptomatic outpatients seen during the summer with stable, compensated failure., Results: Serum PTH was elevated (127 +/- 13; 82-243 pg/mL) in all patients with CHF of 4 weeks' or longer duration (normal, 12-65 pg/mL) and was elevated in three of nine patients (59 +/- 8; 18-99 pg/mL) with CHF of 1 to 2 weeks' duration. Ionized hypocalcemia (1.09 +/- 0.03 and 1.08 +/- 0.02 mmol/L; normal, 1.12-1.30) and hypomagnesemia (0.47 +/- 0.02 and 0.46 +/- 0.03 mmol/L; normal, 0.53-0.67) were respectively found in long- or short-duration CHF. No compensated patient had elevated PTH (42 +/- 5; 17-53). Hypovitaminosis D (< or =30 ng/mL) was universally present in patients with CHF of 4 weeks' or longer duration (15.1 +/- 1.4; 7.0-23.8 ng/mL) and was also prevalent in the other groups (20.3 +/- 5.1, 7.0-54.1 ng/mL in CHF of 1 to 2 weeks' duration and 23.1 +/- 4.9; 17.2-42.7 ng/mL in compensated failure)., Conclusions: In African-American patients with CHF, hypovitaminosis D, aldosteronism, and loop diuretic treatment each exaggerate Ca and Mg losses to stress a fragile Ca balance leading to ionized hypocalcemia and hypomagnesemia with SHPT.

Purpose: The management of chronic cardiac failure, a salt-sensitive state, frequently includes administration of a loop diuretic to enhance urinary Na excretion. We hypothesized that a period of timed semirecumbency (vis-à-vis upright posture) would enhance the natriuresis that accompanies oral furosemide dosing in patients with compensated cardiac failure., Methods: Four ambulatory patients with compensated chronic cardiac failure (NYHA Class III) of ischemic and nonischemic origin and systolic dysfunction (ejection fraction <35%), who were receiving a stable regimen of oral furosemide and angiotensin-converting enzyme inhibitor, were enrolled into the study. In the institution's Clinical Research Center, we monitored and compared urine flow rate (mL/min) and Na excretion rate (mEq/hr) in each patient in response to two different protocols. Protocol 1 consisted of an initial 90-minute period of bedrest followed by the patient's oral furosemide dose and 180 minutes of upright activity and a subsequent 90-minute period of bedrest. Protocol 2 was similar, with the exception that furosemide dosing was given after upright activity and immediately prior to the second period of bedrest., Results: With each patient serving as his or her own control, both urine flow rate and urinary Na excretion rate were markedly increased when furosemide was given prior to bedrest as compared to its dosing prior to upright activity., Conclusions: In patients with compensated chronic cardiac failure, the natriuresis that accompanies oral furosemide dosing is enhanced when given just prior to a period of timed semirecumbency. This approach represents a more optimal use of this loop diuretic in patients with compensated heart failure.

Rationale & Objective: Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Study Design: Prospective cohort study. Settings & Participants: A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Exposure: Baseline plasma FGF23. Outcomes: Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF] ≥ 50%), HF with reduced EF (HFrEF, EF