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Aim: Left ventricular (LV) global longitudinal strain (GLS) may detect subtle abnormalities in myocardial contractility among individuals with normal LV ejection fraction (LVEF). However, the prognostic implications of GLS among healthy, community‐dwelling adults is not well‐established. Methods and results: Overall, 2234 community‐dwelling adults (56% women, 47% Black) with LVEF ≥50% without a history of cardiovascular disease (CVD) from the Dallas Heart Study who underwent cardiac magnetic resonance (CMR) with GLS assessed by feature tracking CMR (FT‐CMR) were included. The association of GLS with the risk of incident major adverse cardiovascular events (MACE; composite of incident myocardial infarction, incident heart failure [HF], hospitalization for atrial fibrillation, coronary revascularization, and all‐cause death), and incident HF or death were assessed with adjusted Cox proportional hazards models. A total of 309 participants (13.8%) had MACE during a median follow‐up duration of 17 years. Participants with the worst GLS (Q4) were more likely male and of the Black race with a history of tobacco use and diabetes with lower LVEF, higher LV end‐diastolic volume, and higher LV mass index. Cumulative incidence of MACE was higher among participants with worse (Q4 vs. Q1) GLS (20.4% vs. 9.0%). In multivariable‐adjusted Cox models that included clinical characteristics, cardiac biomarkers and baseline LVEF, worse GLS (Q4 vs. Q1) was associated with a significantly higher risk of MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.07–2.24, p = 0.02) and incident HF or death (HR 1.57, 95% CI 1.03–2.38, p = 0.04). Conclusions: Impaired LV GLS assessed by FT‐CMR among adults free of cardiovascular disease is associated with a higher risk of incident MACE and incident HF or death independent of cardiovascular risk factors, cardiac biomarkers and LVEF. [ABSTRACT FROM AUTHOR]

This article discusses the results of a post-hoc analysis of the VERTIS CV trial, which examined the effects of the medication ertugliflozin on the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease. The study found that ertugliflozin significantly reduced the risk of first HHF in the overall cohort of participants. However, the treatment effect was more pronounced in individuals with a pre-trial ejection fraction (EF) of less than 45% and attenuated in those with an EF greater than 60%. These findings contribute to the understanding of the efficacy of SGLT2 inhibitors in reducing the risk of HHF across different EF ranges. [Extracted from the article]

This article discusses the complexity of exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a common symptom of HFpEF and is associated with a poor quality of life and increased risk of adverse outcomes. The article highlights a study that characterizes the haemodynamic profiles of HFpEF patients and identifies four clinically defined phenogroups: cardiometabolic, left atrial myopathy, pulmonary vascular disease, and vascular stiffening. The study findings reveal distinct exercise haemodynamic impairments across these phenogroups and provide insights into the physiologic basis of disease progression. The article suggests that personalized treatment approaches based on these phenogroups may improve exercise capacity and quality of life for HFpEF patients. [Extracted from the article]

This article discusses the challenges in diagnosing heart failure with preserved ejection fraction (HFpEF) and the potential of artificial intelligence (AI) and natural language processing (NLP) to improve diagnosis. HFpEF is difficult to diagnose and often underdiagnosed, leading to missed opportunities for treatment and management. The study by Wu et al. applied NLP to a database of patients with a clinical diagnosis of heart failure and found a significant disparity in the diagnosis rates of HFpEF. NLP can aid clinicians in identifying high-risk patients and prompt further investigation for accurate diagnosis and personalized treatment. The incorporation of AI and NLP into HFpEF detection shows promise for enhancing diagnosis, monitoring disease progression, and tailoring treatment regimens. However, further research, validation, and ethical considerations are needed for the full integration of AI and NLP into clinical practice. [Extracted from the article]

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Sex differences in long‐term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow‐up following an index HF hospitalization event. Methods and results: Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines‐Heart Failure registry with available 5‐year follow‐up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5‐year follow‐up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41–49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5‐year follow‐up, males and females had comparably poor survival post‐discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age‐ and sex‐matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65‐69 years). In adjusted analysis, females (vs. males) had a lower risk of 5‐year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87–0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85–0.89; pinteraction[sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5‐year follow‐up (aHR 1.06, 95% CI 1.04–1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07–1.14; pinteraction[sex*HF subtype] = 0.001). Conclusions: While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age‐ and sex‐matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology of HF, many issues remain including residual risk despite therapy, understanding the pathophysiology and phenotypes of patients with HF and preserved ejection fraction, and the challenges related to integrating a large amount of disparate information available for risk stratification and management of these patients. Risk prediction algorithms based on artificial intelligence (AI) may have superior predictive ability compared to traditional methods in certain instances. AI algorithms can play a pivotal role in the evolution of HF care by facilitating clinical decision making to overcome various challenges such as allocation of treatment to patients who are at highest risk or are more likely to benefit from therapies, prediction of adverse outcomes, and early identification of patients with subclinical disease or worsening HF. With the ability to integrate and synthesize large amounts of data with multidimensional interactions, AI algorithms can supply information with which physicians can improve their ability to make timely and better decisions. In this review, we provide an overview of the AI algorithms that have been developed for establishing early diagnosis of HF, phenotyping HF with preserved ejection fraction, and stratifying HF disease severity. This review also discusses the challenges in clinical deployment of AI algorithms in HF, and the potential path forward for developing future novel learning‐based algorithms to improve HF care. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF. [ABSTRACT FROM AUTHOR]

Background Individuals with diabetes have a high frailty burden and increased risk of heart failure (HF). In this study, we evaluated the association of baseline and longitudinal changes in frailty with risk of HF and its subtypes: HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Methods Participants (age: 45–76 years) of the Look AHEAD trial without prevalent HF were included. The frailty index (FI) was used to assess frailty burden using a 35-variable deficit model. The association between baseline and longitudinal changes (1- and 4-year follow-up) in FI with risk of overall HF, HFpEF (ejection fraction [EF] ≥ 50%), and HFrEF (EF < 50%) independent of other risk factors and cardiorespiratory fitness was assessed using adjusted Cox models. Results The study included 5 100 participants with type 2 diabetes mellitus, of which 257 developed HF. In adjusted analysis, higher frailty burden was significantly associated with a greater risk of overall HF. Among HF subtypes, higher baseline FI was significantly associated with risk of HFpEF (hazard ratio [HR] [95% CI] per 1- SD higher FI: 1.37 [1.15–1.63]) but not HFrEF (HR [95% CI]: 1.19 [0.96–1.46]) after adjustment for potential confounders, including traditional HF risk factors. Among participants with repeat measures of FI at 1- and 4-year follow-up, an increase in frailty burden was associated with a higher risk of HFpEF (HR [95% CI] per 1- SD increase in FI at 4 years: 1.78 [1.35–2.34]) but not HFrEF after adjustment for other confounders. Conclusions Among individuals with type 2 diabetes mellitus, higher baseline frailty and worsening frailty burden over time were independently associated with higher risk of HF, particularly HFpEF after adjustment for other confounders. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the impact of obstructive coronary artery disease (CAD) in patients with acute decompensated heart failure (ADHF), and examine potential differences in prognostic utility for heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). Methods and results: The Atherosclerosis Risk in Communities study conducted hospital surveillance of ADHF from 2005 to 2014. Obstructive CAD was defined as ≥50% or ≥75% stenosis, respectively, for the left main and other major epicardial arteries. Adjusted associations between obstructive CAD and 30‐, 60‐, and 90‐day mortality were analysed. A total of 934 (4146 weighted) patients admitted with ADHF (mean age 72 years, 46% women, 30% Black, 30% HFpEF) had available angiography (61% performed in hospital). Obstructive CAD was more prevalent with HFrEF than HFpEF, whether at the left main (15% vs. 11%), left anterior descending (LAD) (48% vs. 30%), left circumflex (37% vs. 32%), right coronary (42% vs. 32%), or multiple coronary arteries (45% vs. 33%). In‐hospital revascularization was performed in 25% and 22% of patients with HFrEF and HFpEF, respectively. Obstructive CAD was associated with higher adjusted mortality, particularly with left main or LAD involvement, and had a more pronounced association with 90‐day mortality in HFrEF (odds ratio [OR] 2.77; 95% confidence interval [CI] 1.53–5.02) than HFpEF (OR 0.94; 95% CI 0.36–2.41) (p‐interaction = 0.05). Conclusion: Patients hospitalized with ADHF and coexisting obstructive CAD have higher short‐term mortality, warranting the need for effective interventions and secondary prevention. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure, but its etiology is poorly understood. Clonal hematopoiesis (CH) has been shown to promote atherosclerosis and heart failure with reduced ejection fraction, but whether and how CH may promote HFpEF is less well understood. We screened for CH in 109 HFpEF patients at UTSW and identified CH in 25% of patients, as compared with 19% of age/gender-matched controls. The most frequent mutation was in TET2 (63%), and notably 42% of patients with TET2-mutated CH harbored two TET2 mutations. In contrast, mutations in DNMT3A, classically the most frequent mutation in age-associated CH, were present at a much lower rate (30%). To test if TET2-mutated CH promotes HFpEF, we used a mouse model in which a high-fat diet and nitric oxide synthase inhibition by L-NAME recapitulate the clinical features of HFpEF (Nature 2019;568:351). We transplanted pIpC-treated bone marrow from Mx1-Cre;Tet2fl/fl mice or Cre-negative Tet2fl/fl control mice into wild-type mice, and six weeks later we induced HFpEF for 12 weeks. Consistent with our clinical observations, we discovered that recipients of Tet2-null hematopoietic cells exhibited significantly worse diastolic dysfunction. This effect was dependent on the NLRP3 inflammasome and was specific to loss of Tet2, while mice transplanted with Dnmt3a-null bone marrow did not manifest a worse HFpEF phenotype. Additionally, bulk and single-cell transcriptomic analyses revealed that HFpEF induction led to an expansion in the heart of Spp1+ macrophages, which exhibit both pro-inflammatory and pro-fibrotic features, which was exacerbated in the setting of CH. In sum, TET2-mutated CH is common in patients with HFpEF and drives disease pathogenesis in an allele-specific manner. These findings establish a rationale for targeting CH to treat or prevent HFpEF. [ABSTRACT FROM AUTHOR]

Background: Supervised aerobic exercise training (ET) is recommended for stable outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). Frailty, a syndrome characterized by increased vulnerability and decreased physiologic reserve, is common in patients with HFrEF and associated with a higher risk of adverse outcomes. The effect modification of baseline frailty on the efficacy of aerobic ET in HFrEF is not known.Methods: Stable outpatients with HFrEF randomized to aerobic ET versus usual care in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were included. Baseline frailty was estimated using the Rockwood frailty index (FI), a deficit accumulation-based model of frailty assessment; participants with FI scores >0.21 were identified as frail. Multivariable Cox proportional hazard models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether frailty modified the treatment effect of aerobic ET on the primary composite end point (all-cause hospitalization or mortality), secondary end points (composite of cardiovascular death or cardiovascular hospitalization, and cardiovascular death or HF hospitalization), and Kansas City Cardiomyopathy Questionnaire score. Separate models were constructed for continuous (FI) and categorical (frail versus not frail) measures of frailty.Results: Among 2130 study participants (age, 59±13 years; 28% women), 1266 (59%) were characterized as frail (FI>0.21). Baseline frailty burden significantly modified the treatment effect of aerobic ET (P interaction: FI × treatment arm=0.02; frail status [frail versus nonfrail] × treatment arm=0.04) with a lower risk of primary end point in frail (hazard ratio [HR], 0.83 [95% CI, 0.72-0.95]) but not nonfrail (HR, 1.04 [95% CI, 0.87-1.25]) participants. The favorable effect of aerobic ET among frail participants was driven by a significant reduction in the risk of all-cause hospitalization (HR, 0.84 [95% CI, 0.72-0.99]). The treatment effect of aerobic ET on all-cause mortality and other secondary endpoints was not different between frail and nonfrail patients (P interaction>0.1 for each). Aerobic ET was associated with a nominally greater improvement in Kansas City Cardiomyopathy Questionnaire scores at 3 months among frail versus nonfrail participants without a significant treatment interaction by frailty status (P interaction>0.2).Conclusions: Among patients with chronic stable HFrEF, baseline frailty modified the treatment effect of aerobic ET with a greater reduction in the risk of all-cause hospitalization but not mortality. [ABSTRACT FROM AUTHOR]

Lower lean body mass associated with reduced cardiovascular reserve at rest and peak exercise in women but not men may underlie sex differences in heart failure with preserved ejection fraction (Diaz-Canestro et al.). [ABSTRACT FROM AUTHOR]

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the association between prefrailty and the risk of heart failure (HF) among older adults. Design, setting, and participants: This prospective, community‐based cohort study included participants from the Atherosclerotic Risk in Communities study who underwent detailed frailty assessment using Fried Criteria and physical function assessment using the Short Performance Physical Battery (SPPB) score. Individuals with prevalent HF and frailty were excluded. Main outcomes and measures: Adjusted association between prefrailty (vs robust), physical function measures (SPPB score, grip strength, and gait speed), and incident HF (overall and HF subtypes, HF with reduced [HFrEF, EF < 50%] and preserved ejection fraction [HFpEF]) were assessed using Cox proportional hazards models. Results: Among 5210 participants (mean age 75 years, 58% women), 2565 (49.2%) were identified as prefrail. In cross‐sectional analysis, prefrail individuals had a higher burden of chronic myocardial injury (troponin, Std β = 0.08 [0.05–0.10]) and neurohormonal stress (NT‐ProBNP, Std β = 0.03 [0.02–0.05]) after adjustment for potential confounders. Over a median follow‐up of 4.6 years, there were 232 (4.5%) HF events (HFrEF: 102; HFpEF: 97). Prefrailty was associated with an increased risk of HF after adjusting for potential clinical confounders and cardiac biomarkers (aHR [95% CI] = 1.65 [1.24–2.20]). Among HF subtypes, prefrailty was associated with an increased risk of HFpEF but not HFrEF (aHR [95% CI] = 1.73 [1.11–2.70] and 1.38 [0.90–2.10], respectively). A lower SPPB score was also associated with an increased risk of overall HF and HFpEF, but not HFrEF. Among individual components, increased gait speed were associated with a lower risk of HFpEF, but not HFrEF. Conclusions and relevance: Subtle abnormalities in physiological reserve (prefrailty) and impairment in physical function (SPPB) were both significantly associated with a higher risk of incident HF, particularly HFpEF. These findings highlight the potential role of routine assessment of geriatric syndromes for early identification of HF risk. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Obesity increases with age, is disproportionately prevalent in black populations, and is associated with heart failure with preserved ejection fraction (HFpEF). An "obesity paradox," or improved survival with obesity, has been reported in patients with HFpEF. The aim of this study was to examine whether racial differences exist in the temporal trends and outcomes associated with obesity among older patients with HFpEF. DESIGN: Community surveillance of acute decompensated heart failure (ADHF) hospitalizations, sampled by stratified design from 2005 to 2014. SETTING: Atherosclerosis Risk in Communities Study (NC, MS, MD, MN). PARTICIPANTS: A total of 10,147 weighted hospitalizations for ADHF (64% female, 74% white, mean age 77 years), with ejection fraction ≥50%. MEASUREMENTS: ADHF classified by physician review, HFpEF defined by ejection fraction ≥50%. Body mass index (BMI) calculated from weight at hospital discharge. Obesity defined by BMI ≥30 kg/m2, class III obesity by BMI ≥40 kg/m2. RESULTS: When aggregated across 2005–2014, the mean BMI was higher for black compared to white patients (34 vs 30 kg/m2; P <.0001), as was prevalence of obesity (56% vs 43%; P <.0001) and class III obesity (24% vs 13%; P <.0001). Over time, the annual mean BMI and prevalence of class III obesity remained stable for black patients, but steadily increased for white patients, with annual rates statistically differing by race (P‐interaction =.04 and P =.03, respectively). For both races, a U‐shaped adjusted mortality risk was observed across BMI categories, with the highest risk among patients with a BMI ≥40 kg/m2. CONCLUSION: Black patients were disproportionately burdened by obesity in this decade‐long community surveillance of older hospitalized patients with HFpEF. However, temporal increases in mean BMI and class III obesity prevalence among white patients narrowed the racial difference in recent years. For both races, the worst survival was observed with class III obesity. Effective strategies are needed to manage obesity in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Initiating HF therapies traditionally involves starting 1 to 3 medications (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, -blocker, mineralocorticoid receptor antagonist) at low doses, followed by methodical uptitration. Furthermore, observations from the SCD-HeFT trial (Sudden Cardiac Death in Heart Failure) demonstrated early improvements in left ventricular ejection fraction recorded within 3 to 7 months of treatment initiation in 67% of patients treated with -blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Keywords: evidence-based practice; heart failure; heart failure, systolic; practice guidelines as topic EN evidence-based practice heart failure heart failure, systolic practice guidelines as topic 276 278 3 07/25/22 20220726 NES 220726 Heart failure (HF) is the leading cause of hospitalization among older adults and a major cause of morbidity and mortality. [Extracted from the article]

Aims: Non‐alcoholic fatty liver disease leads to progressive liver fibrosis and appears to be a frequent co‐morbid disease in heart failure with preserved ejection fraction (HFpEF). It is well known that liver fibrosis severity predicts future liver‐related morbidity and mortality, but its impact on outcomes in patients with HFpEF remains unknown. This analysis aimed to describe the prevalence of liver fibrosis, as assessed using surrogate biomarkers, in patients with HFpEF and the association of such biomarkers in predicting clinical outcomes in these patients. Methods and results: Patients with HFpEF from TOPCAT Americas were included in the analysis. The non‐alcoholic fatty liver disease fibrosis score (NFS) and fibrosis‐4 (FIB‐4) scores were calculated using a combination of clinical characteristics and laboratory parameters. Risk of advanced fibrosis was classified as low, intermediate, and high. For the 1423 with sufficient data, we used Cox regression analysis to test the association between the risk of fibrosis severity and the combined primary endpoint of all cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Advanced fibrosis, as determined by high fibrosis scores, was present in 37.57% by the NFS and 8.02% by the FIB‐4. Higher risk of advanced hepatic fibrosis was associated with older age. In unadjusted models, the risk of advanced fibrosis was associated with the primary cardiovascular outcome [NFS high vs. low, hazard ratio (HR) 1.709 (95% confidence interval, CI 1.238–2.358, P = 0.0011) and FIB‐4 high vs. low, HR 1.561 (95% CI 1.139–2.140, P = 0.0056)]. After multivariable adjustment, this association was diminished [NFS high vs. low, HR 1.349 (95% CI 0.938–1.939, P = 0.1064) and FIB‐4 high vs. low, HR 1.415 (95% CI 0.995–2.010, P = 0.0531)]. Conclusions: Our study suggests that advanced liver fibrosis, as estimated by fibrosis risk scores, may not be uncommon in patients with HFpEF, and there appears to be a limited independent association between liver fibrosis risk scores and clinical outcomes related to heart failure events. [ABSTRACT FROM AUTHOR]

Aims Methods Conclusions Compared with those without obesity, patients with obesity‐related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4‐dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity‐related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose.We describe the rationale and design of HuMAIN‐HFpEF, a Phase 2a randomized, double‐blind, placebo‐controlled, dose‐titration, parallel‐group trial in patients with obesity‐related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials.HuMAIN will test a promising novel agent for obesity‐related HFpEF. [ABSTRACT FROM AUTHOR]

B This article refers to 'Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction' by S.J. Shah I et al i ., published in this issue on pages 1541-1551. b Heart failure with preserved ejection fraction (HFpEF) is growing in prevalence and associated with a high burden of morbidity, mortality, and poor quality of life.1,2 HFpEF is common in older adults and particularly among women, with more than 80% of new-onset heart failure among octogenarian women being due to HFpEF.3 Development of HFpEF involves a complex interplay of multiple pathophysiologic impairments, including adverse physiologic consequences of adiposity, increased comorbidity burden, accelerated decline in exercise capacity with aging, up-regulation of inflammatory pathways, and sarcopenia, that culminates in decreased aerobic physiologic reserve and symptoms of clinical heart failure.2,4-7 Patients with HFpEF have a similar high burden of functional impairment, frailty, and poor quality of life as patients with heart failure with reduced ejection fraction.7-9 Exercise intolerance, characterized by reduced exercise capacity and symptoms of fatigue and dyspnoea with usual daily activities, is one the most common manifestations of HFpEF. Patients with HFpEF have 30-40% lower exercise capacity than healthy age- and sex-matched controls and often perform activities of daily living using near maximal aerobic effort.10-12 Exercise intolerance is associated with higher risk of hospitalization, death, and poor quality of life in HFpEF.12,13 Thus, exercise intolerance and low aerobic capacity are meaningful endpoints that should be targeted for developing effective therapies to improve this patient-centred outcome. Improving exercise tolerance and quality of life in heart failure with preserved ejection fraction - time to think outside the heart. [Extracted from the article]

Background: Lifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.Methods: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.Results: We included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.Conclusions: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control. [ABSTRACT FROM AUTHOR]

Objectives To systematically examine the relative magnitude and predictors of responses to exercise training in older adult with heart failure ( HF) with reduced ejection fraction ( HFr EF), and preserved EF ( HFp EF). Design Secondary analysis of a randomized controlled trial. Setting Outpatient cardiac rehabilitation program. Participants Individuals with HF (24 HFrEF, 24 HFpEF) who underwent supervised exercise training. Measurements The study included individual-level data from the exercise training arms of a randomized controlled trial that evaluated the effect of 16 weeks of supervised moderate-intensity endurance exercise training in older adults with chronic, stable HFp EF and HFr EF. Changes in peak oxygen uptake ( VO2peak) in response to supervised training in individuals with HFp EF were compared with that of individuals with HFr EF. The significant clinical predictors of changes in VO2peak with exercise training were assessed using univariate and multivariate regression models. Results Training-related improvement in VO2peak was higher in participants with HFp EF than in those with HFr EF (change: 18.7 ± 17.6% vs −0.3 ± 15.4%, P < .001). In univariate analysis, echocardiographic abnormalities in left ventricular structure and function and lower body mass index were associated with blunted response of VO2peak with exercise training. In multivariate regression analysis using stepwise selection, submaximal exercise systolic blood pressure, and resting early deceleration time were independent predictors of change in VO2peak. Conclusion The change in VO2peak in response to endurance exercise training in older adults with HF differs significantly according to HF subtype, with greater VO2peak improvement in HFp EF than HFr EF. These results suggest that the current Centers for Medicare and Medicaid Services policy excluding individuals with HFp EF from reimbursement from cardiac rehabilitation may need to be revisited. [ABSTRACT FROM AUTHOR]

Abstract Background: Older patients with heart failure with preserved ejection fraction have severe exercise intolerance. Vitamin D may play a role in cardiovascular and skeletal muscle function, and may therefore be implicated in exercise intolerance in heart failure with preserved ejection fraction. However, there are few data on vitamin D status and its relationship to exercise capacity in heart failure with preserved ejection fraction patients. Methods: Plasma 25-hydroxyvitamin D (25[OH]D) and exercise capacity (peak oxygen consumption, [VO 2 ], 6-minute walk distance) were measured in 112 older heart failure with preserved ejection fraction patients (mean ± SD age = 70 ± 8 years) and 37 healthy age-matched controls. General linear models were used to compare 25(OH)D between heart failure with preserved ejection fraction patients and healthy controls, and to determine the cross-sectional association between 25(OH)D and exercise capacity. The association between 25(OH)D and left ventricular function was evaluated secondarily in heart failure with preserved ejection fraction patients. Results: 25(OH)D concentrations were significantly lower in heart failure with preserved ejection fraction vs healthy controls (11.4 ± 0.6 ng/mL vs 19.1 ± 2.1 ng/mL; P =.001, adjusted for age, race, sex, body mass index, season). More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency (<20 ng/mL) and 30% had frank 25(OH)D deficiency (<10 ng/mL). In heart failure with preserved ejection fraction patients, but not healthy controls, 25(OH)D was significantly correlated with peak VO 2 (r = 0.26; P = 0.007) and 6-minute walk distance (r = 0.34; P <.001). Conclusions: More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency, and 30% were frankly deficient. Lower 25(OH)D was associated with lower peak VO 2 and 6-minute walk distance in heart failure with preserved ejection fraction, suggesting that 25(OH)D insufficiency could contribute to exercise intolerance in this patient population. These findings provide the data and rationale for a future randomized trial designed to test the potential for vitamin D supplementation to improve exercise intolerance in heart failure with preserved ejection fraction. [ABSTRACT FROM AUTHOR]