Pathophysiology Of Heart Failure With Preserved Ejection Fraction Research Articles

GLP-1 receptor agonists as promising anti-inflammatory agents in heart failure with preserved ejection fraction.

Heart Failure with Preserved Ejection Fraction (HFpEF) represents a significant challenge in modern cardiovascular medicine, characterized by diastolic dysfunction and a chronic pro-inflammatory milieu. The high prevalence of comorbidities such as diabetes, visceral obesity, and aging, which contribute to systemic inflammation, plays a pivotal role in the pathogenesis and progression of HFpEF. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs), a class of glucose-lowering drugs, have demonstrated a wide range of pleiotropic effects that extend beyond glycaemic control. These effects include the reduction of inflammation and oxidative stress, vasodilation, decreased arterial stiffness, and a reduction in myocardial fibrosis-key factors in the pathophysiology of HFpEF. Recent evidence from the STEP-HFpEF and STEP-HFpEF-DM trials provides the first robust data supporting the efficacy of GLP-1 RAs, specifically semaglutide, in improving the quality of life in obese patients with HFpEF. These trials also demonstrated a significant reduction in C-Reactive Protein (CRP) levels, reinforcing the hypothesis that suppressing the pro-inflammatory state may yield substantial clinical benefits in this patient population. These findings suggest that GLP-1 RAs could play a crucial role in the management of HFpEF, particularly in patients with obesity, by targeting the underlying inflammatory processes and contributing to better overall cardiovascular outcomes.

Commonalities of platelet dysfunction in heart failure with preserved ejection fraction and underlying comorbidities.

Heart failure with preserved ejection fraction (HFpEF) is characterized by a lack of a specific targeted treatment and a complex, partially unexplored pathophysiology. Common comorbidities associated with HFpEF are hypertension, atrial fibrillation, obesity and diabetes. These comorbidities, combined with advanced age, play a crucial role in the initiation and development of the disease through the promotion of systemic inflammation and consequent changes in cardiac phenotype. In this context, we suggest platelets as important players due to their emerging role in vascular inflammation. This review provides an overview of the role of platelets in HFpEF and its associated comorbidities, including hypertension, atrial fibrillation, obesity and diabetes mellitus, as well as the impact of age and sex on platelet function. These major HFpEF-associated comorbidities present alterations in platelet behaviour and in features linked to platelet size, content and reactivity. The resulting dysfunctional platelets can contribute to further increase inflammation, oxidative stress and endothelial dysfunction, suggesting an active role of these cells in the initiation and progression of HFpEF. Recent evidence shows that reduced platelet count and elevated mean platelet volume are associated with worsening heart failure in HFpEF patients. However, the specific mechanisms by which platelets contribute to HFpEF development and progression are still largely unexplored, with only a few studies investigating platelet function in HFpEF. We discuss the limited yet significant body of research investigating platelet function in HFpEF, emphasizing the need for more comprehensive studies. Additionally, we explore the potential mechanisms through which platelets may influence HFpEF, such as their interactions with the vascular endothelium and the secretion of bioactive molecules like cytokines, chemokines and RNA molecules. These interactions and secretions may play a role in modulating vascular inflammation and contributing to the pathophysiological landscape of HFpEF. The review underscores the necessity for future research to elucidate the precise contributions of platelets to HFpEF, aiming to potentially identify novel therapeutic targets and improve patient outcomes. The evidence presented herein supports the hypothesis that platelets are not merely passive bystanders but active participants in the pathophysiology of HFpEF and its comorbidities.

Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction.

The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.

Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization.

Metabolic substrate utilization in HFpEF (heart failure with preserved ejection fraction), the leading cause of heart failure worldwide, is pivotal to syndrome pathogenesis and yet remains ill defined. Under resting conditions, oxidation of free fatty acids (FFA) is the predominant energy source of the heart, supporting its unremitting contractile activity. In the context of disease-related stress, however, a shift toward greater reliance on glucose occurs. In the setting of obesity or diabetes, major contributors to HFpEF pathophysiology, the shift in metabolic substrate use toward glucose is impaired, sometimes attributed to the lower oxygen requirement of glucose oxidation versus fat metabolism. This notion, however, has never been tested conclusively. Furthermore, whereas oxygen demand increases in the setting of increased afterload, myocardial oxygen availability remains adequate for fatty acid oxidation (FAO). Therefore, a "preference" for glucose has been proposed. Pyruvate dehydrogenase complex (PDC) is the rate-limiting enzyme linking glycolysis to the TCA cycle. As PDK4 (PDC kinase 4) is up-regulated in HFpEF, we over-expressed PDK4 in cardiomyocytes, ensuring that PDC is phosphorylated and thereby inhibited. This leads to diminished use of pyruvate as energy substrate, mimicking the decline in glucose oxidation in HFpEF. Importantly, distinct from HFpEF-associated obesity, this model positioned us to abrogate the load-induced shift to glucose utilization in the absence of systemic high fat conditions. As expected, PDK4 transgenic mice manifested normal cardiac performance at baseline. However, they manifested a rapid and severe decline in contractile performance when challenged with modest increases in afterload triggered either by L-NAME or surgical transverse aortic constriction (TAC). This decline in function was not accompanied by an exacerbation of the myocardial hypertrophic growth response. Surprisingly, metabolic flux analysis revealed that, after TAC, fractional FAO decreased, even when glucose/pyruvate utilization was clamped at very low levels. Additionally, proteins involved in the transport and oxidation of FFA were paradoxically downregulated after TAC regardless of genotype. These data demonstrate that cardiomyocytes in a setting in which glucose utilization is robustly diminished and prevented from increasing do not compensate for the deficit in glucose utilization by up-regulating FFA use.

Proteomics Identify Clinical Phenotypes and Predict Functional Outcomes in Heart Failure With Preserved Ejection Fraction: Insights From VITALITY-HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that may emerge from overlapping systemic processes associated with comorbidities. We assessed whether unique clusters of circulating proteins are associated with specific clinical characteristics and functional status at baseline and follow-up in a well-phenotyped cohort of patients with HFpEF. We evaluated 368 proteins associated with cardiovascular disease and inflammation in prerandomization blood samples from 763 VITALITY-HFpEF (Vericiguat to Improve Physical Functioning in Daily Living Activities of Patients With HFpEF) participants who had a left ventricular ejection fraction ≥45% and a heart failure decompensation event within 6 months. Proteins were clustered, and their associations with clinical characteristics, baseline, and 24-week functional outcomes (Kansas City Cardiomyopathy Questionnaire Physical Limitation Score, 6-minute walk distance [6MWD], and Fried frailty phenotype) were estimated with linear regression. Elastic net regression was used to derive a proteomic summary composite to predict changes in 24-week functional outcomes. Four unique protein clusters were identified, containing 24, 66, 197, and 81 proteins. At baseline, 2 protein clusters with the hub proteins caspase-3 and Dickkopf-related protein 1 were associated with increased frailty, whereas the cluster with tumor necrosis factor receptor 1 as a hub protein was associated with lower Kansas City Cardiomyopathy Questionnaire Physical Limitation Score and shorter 6MWD. By contrast, the cluster with protein C as a hub protein was associated with less frailty and longer a 6MWD. The 24-week increase in 6MWD was negatively correlated with the protein cluster with caspase-3; the protein C cluster was correlated with less frailty at 24 weeks. The baseline proteomic summary composite predicted observed changes in Kansas City Cardiomyopathy Questionnaire Physical Limitation Score and 6MWD at 24 weeks (r=0.42 and 0.30; P<0.001 for both). Proteomics differentiate specific baseline functional traits associated with HFpEF and may facilitate phenotyping in a heterogeneous disease. These proteins also provide insights into the diverse pathophysiology of HFpEF and which patients may improve functional status during follow-up. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03547583.

Pathophysiological insights into HFpEF from studies of human cardiac tissue.

Heart failure with preserved ejection fraction (HFpEF) is a major, worldwide health-care problem. Few therapies for HFpEF exist because the pathophysiology of this condition is poorly defined and, increasingly, postulated to be diverse. Although perturbations in other organs contribute to the clinical profile in HFpEF, altered cardiac structure, function or both are the primary causes of this heart failure syndrome. Therefore, studying myocardial tissue is fundamental to improve pathophysiological insights and therapeutic discovery in HFpEF. Most studies of myocardial changes in HFpEF have relied on cardiac tissue from animal models without (or with limited) confirmatory studies in human cardiac tissue. Animal models of HFpEF have evolved based on theoretical HFpEF aetiologies, but these models might not reflect the complex pathophysiology of human HFpEF. The focus of this Review is the pathophysiological insights gained from studies of human HFpEF myocardium. We outline the rationale for these studies, the challenges and opportunities in obtaining myocardial tissue from patients with HFpEF and relevant comparator groups, the analytical approaches, the pathophysiological insights gained to date and the remaining knowledge gaps. Our objective is to provide a roadmap for future studies of cardiac tissue from diverse cohorts of patients with HFpEF, coupling discovery biology with measures to account for pathophysiological diversity.

Racial Differences in Age-Related Changes in Left Ventricular Structural and Functional Echocardiographic Measurements Among Healthy Japanese and American Participants - A Subanalysis of the World Alliance Society of Echocardiography Normal Values Study.

Age-related changes in left ventricular (LV) structure and function lower the threshold for the onset of heart failure with preserved ejection fraction (HFpEF). LV parameters change also with race; however, the racial differences in age-related changes in LV parameters with and without adjustment for body mass index (BMI), heart rate (HR), and blood pressure (BP) remain unclear. We performed a subanalysis of the World Alliance Society of Echocardiography Normal Values Study, an international cross-sectional study that examined normal echocardiographic values in 15 countries. The age-related changes in 2-dimensional echocardiographic derived parameters including LV size, systolic function, and mass, were compared between healthy Japanese (n=227) and healthy White (n=98) and Black (n=69) American participants. In men, age-related changes in all parameters did not differ significantly among races. However, compared with Japanese women, White American women had a smaller body surface area (BSA)-indexed LV volume, BSA-indexed LV internal dimension at end-systole, BSA-indexed LV stroke volume, and LV mass index to BSA, and a larger LV ejection fraction with age, even after adjusting for BMI, HR, and BP. Age-related changes in LV structure and function, which are important for the pathophysiology of HFpEF, may differ by race. Therefore, future studies examining echocardiographic reference values for each age group in each race are needed.

Systematic review and meta-analysis to predict mortality in heart failure with preserved ejection fraction: Development and validation of the HF-DANAS score.

The morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) continue to increase with the accelerating global aging process. During the past decade, the pathophysiology, diagnostic methods, and prognostic prediction of HFpEF have been revolutionized, resulting in new and effective management strategies. Dynamic prognostic assessment facilitates systematic clinical management of patients, and the aim of this study was to investigate the risk factors for mortality in patients with HFpEF and to develop a risk prediction assessment model. Data for the derivation cohort were obtained from three databases, PubMed, Embase, and Cochrane. The validation cohort was obtained from the Chinese Heart Failure Center database. The β-coefficient was calculated based on the risk ratio (RR) and 95% confidence intervals (CI) corresponding to each risk factor to construct a mortality risk assessment model. A total of 30 studies were included in the meta-analysis: 22 prospective cohort studies and 8 retrospective cohort studies, including 34196 HFpEF patients. Seven predictors of all-cause mortality in HFpEF patients were derived. Considering the need for feasibility in clinical practice, we performed subgroup and sensitivity analyses and determined the following cutoff values: age>75years (RR: 2.07, 95% CI: 1.83-2.35; P<0.001), male sex (RR: 1.36, 95% CI: 1.17-1.59; P<0.001), DM (RR: 1.23, 95% CI: 1.11-1.36; P<0.001), anaemia (RR: 1.53, 95% CI: 1.41-1.67; P<0.001), albumin concentration<3.2g/dL (RR: 1.29, 95% CI: 1.14-1.47; P<0.001), AF (RR: 1.27, 95% CI: 1.12-1.43; P<0.001), and NYHA class III/IV (RR: 1.63, 95% CI: 1.43-1.87; P<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for this model was 71.3% (95% CI: 0.696-0.736), with an optimal cut-off value of 10.75. The sensitivity and specificity were 0.778 and 0.566, respectively. According to this risk score, we divided patients into three risk classes (low, moderate, and high risk), the numbers of patients who died by the end of the 1-year follow-up were 23 (1.87%), 82 (5.62%), and 382 (15.52%) in these three groups, and the 5-year mortality rates were 9.82%, 20.68%, and 43.28%, respectively. This study developed an HF-DANAS scoring system for the HFpEF mortality risk containing seven predictors, providing clinicians with a simple assessment tool that can help improve clinical management.

Abstract Tu042: Fatty Acid Dysregulation Drives Cardio-Hepatic Crosstalk in Heart Failure with Preserved Ejection Fraction (HFpEF)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome that accounts for nearly half of all heart failure cases world-wide. The pathophysiological mechanisms underlying HFpEF include a variety of extracardiac abnormalities such as metabolic derangements, arterial hypertension, and microvascular endothelial dysfunction, that all drive left ventricular remodeling and dysfunction. The phenotypic diversity presented in HFpEF involves functional and structural changes in several organs including the liver. As a highly vascularized organ, the liver is highly sensitive to any hemodynamic changes in the heart and clinical studies have established the presence of liver injury in HFpEF patients. However, there is limited evidence of this relationship in preclinical mouse models, thereby hindering the exploration of the pathological mechanisms linking the two organs. Cardio-hepatic interactions are poorly understood yet play a critical role in the pathophysiology of HFpEF where aberrant metabolic signaling pathways such as insulin resistance, inflammation and oxidative stress significantly contribute to disease progression and further perpetuate a vicious cycle of cardio-hepatic deterioration. Hypothesis: With limited preclinical data in the field, we sought to elucidate the potential pathophysiological mechanisms driving cardio-hepatic crosstalk in HFpEF. Methods: We used a two-hit preclinical mouse model that recapitulates cardiometabolic HFpEF to characterize the coexistence of cardiac and hepatic dysfunction in HFpEF. Male mice were kept on the HFpEF model for 15 weeks and subjected to echocardiography, glucose tolerance tests, histopathology, and multi-omics analyses. Results: We report that markers of HFpEF severity such as diastolic dysfunction and left ventricular hypertrophy, significantly correlated with hepatic injury and dysfunction that exacerbated metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Impaired energy substrate utilization due to fatty acid dysregulation was a major mechanism underlying cardio-hepatic crosstalk in HFpEF. Conclusion: Our findings highlight fatty acid metabolism as a potential target to mitigate inter-organ dysfunction in HFpEF, representing a promising opportunity to create new treatment paradigms and drive positive outcomes in HFpEF.

Abstract Or108: The role of SARM1 in regulation of immune response in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is an unmet medical need. Recent studies have shown that HFpEF is associated with immune dysregulation and decline in nicotinamide adenine dinucleotide (NAD + ) levels. However, the molecular mechanisms linking these factors in HFpEF are not completely understood. Sterile alpha and TIR motif-containing 1 (SARM1) is a NAD + consuming enzyme that may regulate immune response and NAD + metabolism. Here, we investigated the role of SARM1 in HFpEF pathophysiology. We utilized a two-hit diet model to induce HFpEF in mice (HFpEF diet: high-fat diet and L-NAME). Wild-type (WT) mice on HFpEF diet showed progressive decline in diastolic function (e.g. decreased E’/A’, increased relaxation time, IVRT) at 5- and 15-week, associated with unchanged systolic function and increased cardiac hypertrophy. Despite decline in NAD + levels as previously reported in HFpEF hearts, qPCR analysis showed no significant differences in the expression of enzymes involved in NAD + biosynthesis including the salvage, Preiss-Handler and de novo pathways. We employed RNA-sequencing to identify cardiac gene signatures that are associated with HFpEF. Gene ontology analysis showed activation of various immune pathways in HFpEF hearts. Using flow cytometry analysis, we observed around 66% increase in total leukocytes (CD45+) number, along with infiltration of both T cells (CD3+ CD4+/CD8+) and myeloid cell populations (CD11b+) in HFpEF hearts. To understand the role of SARM1 in HFpEF pathogenesis, we subjected global SARM1 knock out (KO) mice to HFpEF diet. SARM1 KO hearts had improved diastolic function and reduced hypertrophy after 15-week HFpEF diet. RNA-sequencing of SARM1 KO-HFpEF hearts showed downregulations of transcripts in immune activation pathways, compared to WT-HFpEF hearts. In summary, our findings suggest that SARM1 may regulate immune activation pathways and promote HFpEF pathogenesis. We plan to determine the intricate relationships between immune dysregulation, metabolic stress, and cardiac dysfunction in HFpEF pathogenesis. The future direction may identify potential avenues for targeted therapeutic interventions aimed at modulating immune responses for HFpEF.

Abstract Mo103: Aberrant Trans- and De- Nitrosylation Underpins Nitrosative Stress in Cardiometabolic HFpEF

Background: Heart failure with preserved ejection fraction (HFpEF) is among the leading causes of cardiovascular mortality and morbidity. Recent reports suggest excessive myocardial protein S-nitrosylation (-SNO), a hallmark of nitrosative stress, contributes to HFpEF pathophysiology. However, the role of transnitrosylases, enzymes that induce protein-SNO, or denitrosylases, enzymes that eliminate protein-SNO, have not been investigated in the context of HFpEF. Research Questions and Goals: We sought to investigate the regulation of protein nitrosylation dynamics in a rat model of cardiometabolic HFpEF. Methods: Echocardiographic assessment, invasive hemodynamic measurements, and exercise testing were conducted in WKY or ZSF1 obese (Ob) rats to evaluate HFpEF severity. Nitric oxide (NO) bioavailability and protein-SNO levels were determined in the heart tissue. Endothelial-dependent vascular reactivity was assayed to further evaluate NO signaling. In parallel, single-cell (sc) RNA sequencing was performed to determine the transcriptional changes in trans- and denitrosylases, as well as NO synthases. Results: We observed progressive deterioration in LV diastolic function (significantly elevated E/e’ and LV end-diastolic pressure) and exercise performance in ZSF1 Ob when compared to WKY controls. Notably, ZSF1 Ob rats exhibited an age-dependent elevation in protein-SNO levels, despite significant reduction in NO bioavailability and signaling. Targeted sc transcriptomic analysis revealed significantly elevated expression of transnitrosylases such as hemoglobin subunit α and β in cardiomyocytes, endothelial cells, and cardiac fibroblasts from ZSF1 Ob hearts. In contrast, significantly reduced expression of denitrosylases such as thioredoxin 2 was found in the ZSF1 Ob cardiomyocytes. No change was observed in expression of NO synthases (nNOS, iNOS, eNOS). Conclusion: Herein, we demonstrate a profound disconnect between insufficient NO bioavailability and nitrosative stress in ZSF1 Ob rat model of HFpEF. Our data suggests the pathological accumulation of nitroso - proteins, may be attributed in part to the derangement of transnitrosylases and denitrosylases expression. Restoration of physiological protein nitrosylation dynamics may represent a novel therapeutic approach for HFpEF, and warrants further investigation.

Abstract Tu081: T-tubule microdomains promote protective mitophagy in failing hearts

Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of all HF incidence, yet with limited therapeutic options. Although poorly understood, a key pathophysiology of HFpEF includes mitochondrial dysfunction and increased oxidative stress. We recently identified that abnormal remodeling of the cardiomyocyte t-tubule microdomains organized by the scaffolding protein cardiac bridging integrator 1 (cBIN1) contributes to HFpEF progression in db/db mice with type 2 diabetes, which can be rescued by cBIN1 gene therapy. In db/db mice, cBIN1 gene therapy (2x10 12 vg/kg) rescues HFpEF by normalizing t-tubule microdomains. With transmission electron microscopy imaging, here we report that t-tubule cBIN1-microdomains are in close proximity to mitochondria and can correct abnormal mitochondrial accumulation in db/db cardiomyocytes (Figure 1A-B). Oroboros and seahorse analysis indicates that reduced mitochondrial calcium retention, elevated oxidative stress, and impaired oxygen consumption in diabetic cardiomyocytes can be normalized by cBIN1 therapy (Figure 1C-E). Furthermore, proteomics analysis indicates accumulation of mitochondrial proteins in db/db cardiomyocytes can be reversed by the therapy. cBIN1-normalized mitochondrial number, proteomics, and function in db/db cardiomyocytes are associated with activation of LC3 but not changes in PGC1a, indicating increased mitophagy by the therapy. Mechanistic exploration in rat myoblast H9C2 cells indicates that FCCP stress induces mitophagy as evidenced by elevated LC3II/I ratio, which is further accumulated with autophagic flux blockade with chloroquine. Knockdown of BIN1 results in further accumulation of LC3II/I in FCCP-stressed cells (Figure 1F with quantification in the bar graph below), which is abolished by chloroquine. These data indicate that cBIN1 promotes protective mitophagy in diabetic failing hearts, suggesting its therapeutic potential for HFpEF in general.

Abstract Tu056: A Two-Hit HFpEF-like Mouse Model with Accelerated Disease Onset

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with multiple co-morbidities and has limited therapeutic options. To better understand the underlying mechanisms and develop novel therapies, it is important to focus on development of pre-clinical models that mimic the multi-factorial nature of HFpEF. Goal &amp; Methodology: We aimed to develop a mouse HFpEF model by incorporating unfavourable metabolic axis, in db/db mice carrying mutation in lectin receptor, with Ang-II induced impaired hemodynamic conditions. Briefly, we infused Angiotensin II (Ang II, 1500 ng/kg/min) subcutaneously in 12-week-old wild type (WT) and db/db mice for 4 weeks (Fig 1). SGLT2 inhibitor (SGLT2i) was used as a pharmacological intervention. Results: The db/db + Ang II mice showed impaired diastolic function reflected by increase in E/A, E/e’ and global longitudinal strain. This increase was not observed in the db/db + Ang II mice upon treatment with SGLT2i. The ejection fraction was preserved across all groups. Interestingly, db/db + Ang II group did not develop cardiac hypertrophy &amp; fibrosis as indicated by unchanged LV mass, picosirius red staining and unaltered expression of Nppa, Nppb &amp; Acta2 transcripts. Investigation of lipid metabolism showed reduction of fatty acid synthase in db/db (+/-Ang II) groups in comparison to WT animals. Also, phosphorylation of ATP citrate lyase in db/db + Ang II group was diminished compared to db/db animals. Among the glucose metabolism markers, lactate dehydrogenase and pyruvate dehydrogenase showed decreasing trend in all groups compared to WT group. Conclusion: The present mouse model recapitulates metabolic and hemodynamic aspects of HFpEF pathophysiology. Our model is useful for basic research as well as quick evaluation of targets and assets focused on cardiac metabolism with the advantage of faster disease onset and clinically relevant echocardiographic endpoints.

Exercise training for patients with heart failure and preserved ejection fraction. A narrative review.

Heart failure with preserved ejection fraction (HFpEF) remains a significant global health challenge, accounting for up to 50% of all heart failure cases and predominantly affecting the elderly and women. Despite advancements in therapeutic strategies, HFpEF's complexity poses substantial challenges in management, particularly due to its high comorbidity burden, including renal failure, atrial fibrillation, and obesity, among others. These comorbidities not only complicate the pathophysiology of HFpEF but also exacerbate its symptoms, necessitating a personalized approach to treatment focused on comorbidity management and symptom alleviation. In heart failure with reduced ejection fraction, exercise training (ET) was effective in improving exercise tolerance, quality of life, and reducing hospitalizations. However, the efficacy of ET in HFpEF patients remains less understood, with limited studies showing mixed results. Exercise intolerance is a key symptom in HFpEF patients, and it has a multifactorial origin since both central and peripheral oxygen mechanisms of transport and utilization are often compromised. Recent evidence underscores the potential of supervised ET in enhancing exercise tolerance and quality of life among HFpEF patients; however, the literature remains sparse and predominantly consists of small-scale studies. This review highlights the critical role of exercise intolerance in HFpEF and synthesizes current knowledge on the benefits of ET. It also calls for a deeper understanding and further research into exercise-based interventions and their underlying mechanisms, emphasizing the need for larger, well-designed studies to evaluate the effectiveness of ET in improving outcomes for HFpEF patients.

Imaging and mechanisms of heart failure with preserved ejection fraction: a state-of-the-art review.

Understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has advanced rapidly over the past two decades. Currently, HFpEF is recognized as a heterogeneous syndrome, and there is a growing movement towards developing personalized treatments based on phenotype-guided strategies. Left ventricular dysfunction is a fundamental pathophysiological abnormality in HFpEF; however, recent evidence also highlights significant roles for the atria, right ventricle, pericardium, and extracardiac contributors. Imaging plays a central role in characterizing these complex and highly integrated domains of pathophysiology. This review focuses on established evidence, recent insights, and the challenges that need to be addressed concerning the pathophysiology of HFpEF, with a focus on imaging-based evaluations and opportunities for further research.

Nonpharmacological Approaches to Managing Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common subtype of heart failure marked by impaired left ventricular diastolic function and decreased myocardial compliance. Given the limited availability of evidence-based pharmacological treatments for HFpEF, there is a growing interest in nonpharmacological interventions as viable therapeutic alternatives. This review aims to explore the pathophysiology of HFpEF and present recent advancements in nonpharmacological management approaches, encompassing noninvasive therapies, invasive procedures and targeted treatments for comorbidities. An extensive literature review was undertaken to identify and synthesize emerging nonpharmacological treatment options for HFpEF, assessing their potential to enhance patient outcomes. Nonpharmacological strategies, such as vagus nerve stimulation, percutaneous pulmonary artery denervation, renal denervation, transcatheter insertion of atrial shunts and pericardial resection, demonstrate promising potential for alleviating HFpEF symptoms and improving patient prognosis. Moreover, addressing comorbidities, such as hypertension and diabetes, may offer additional therapeutic benefits. These cutting-edge techniques, in conjunction with well-established exercise therapies, pave the way for future research and clinical applications in the field. Nonpharmacological interventions hold promise for advancing HFpEF patient care and fostering a deeper understanding of these treatment approaches, which will facilitate new clinical applications and contribute to the development of more targeted therapies.

α-Adrenergic regulation of skeletal muscle blood flow during exercise in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70±6years, 3 female/4 male) and seven controls (CON) (66±3years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16%±4% vs. -26%±5%, HFpEF vs. CON; P<0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10W (16%±8% vs. 8%±5%; P<0.05). PHEN increased leg in HFpEF (10%±3%, 11%±6%, 15%±7% at 0, 5 and 10W; P<0.05) but not in controls (-1%±9%, -4%±2%, -1%±5%; P=0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest-PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6%±4%, -6%±6%, -7%±5% vs. -13%±6%, -17%±5%, -20%±5% at 0, 5 and 10W; P<0.05) and was positively related to LBF, leg oxygen delivery, leg , and the PHEN-induced increase in LBF (P<0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.

Sudden Cardiac Death Risk Stratification in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) poses a significant clinical challenge, with sudden cardiac death (SCD) emerging as one of the leading causes of mortality. Despite advancements in cardiovascular medicine, predicting and preventing SCD in HFpEF remains complex due to multifactorial pathophysiological mechanisms and patient heterogeneity. Unlike heart failure with reduced ejection fraction, where impaired contractility and ventricular remodeling predominate, HFpEF pathophysiology involves heavy burden of comorbidities such as hypertension, obesity, and diabetes. Diverse mechanisms, including diastolic dysfunction, microvascular abnormalities, and inflammation, also contribute to distinct disease and SCD risk profiles. Various parameters such as clinical factors and electrocardiogram features have been proposed in SCD risk assessment. Advanced imaging modalities and biomarkers offer promise in risk prediction, yet comprehensive risk stratification models specific to HFpEF ar0e lacking. This review offers recent evidence on SCD risk factors and discusses current therapeutic strategies aimed at reducing SCD risk in HFpEF.

Deeper insights into heart failure with preserved ejection fraction through rna-sequencing of circulating endothelial cells - advanced protocol establishment enables complete transcriptome analysis

Abstract Funding Acknowledgements None. Heart failure with preserved ejection fraction (HFpEF) continues to pose a significant challenge with a bleak prognosis and a rising incidence, particularly among the aging population in Western countries. An in-depth comprehension of cellular-level pathogenesis, with a specific emphasis on the pivotal role of cellular senescence in endothelial dysfunction, is imperative for the evolution of innovative therapeutic interventions. Many previous approaches to investigate the genesis of HFpEF are based only on HFpEF-mouse models, which cannot directly be transferred to humans. The isolation of circulating endothelial cells from peripheral blood samples represents a more translatable, feasible, less invasive way to study endothelial dysfunction, a central component of HFpEF-pathogenesis, in human material for the identification of new therapeutical targets. This study focuses on establishing a new protocol for isolating circulating endothelial cells (CEC) in HFpEF patients to address endothelial dysfunction and pinpoint novel therapeutic targets through a comprehensive whole transcriptome analysis. Methodologically, CEC isolation from whole blood samples was achieved using a newly established Fluorescence-Activated Cell Sorting (FACS) panel. HFpEF patients were recruited based on their HFA-PEFF score, with non-diseased controls comprising both young and old subjects meticulously matched for sex and age. Subsequently, the isolated CECs were subjected to transcriptome analysis. Our new protocol is based on red blood cell lysis followed by magnetic cell sorting to deplete CD45+ cells. This is followed by staining with fluorescent-conjugated monoclonal antibodies. This FACS panel includes known endothelial-specific markers including CD11b- and CD45-, CD146+, CD34+ and CD31+ as well as DAPI- as a nucleus marker. The prepared CECs were sorted using FACS and a specially developed gating. We isolated the RNA in preparation for sequencing. Our protocol was validated by immunofluorescence staining of isolated CECs (markers: CD31, vWF, CD146, Phalloidin) and PCR analysis (markers: CD31, CD146 and vWF). In summary, we have successfully established a new, robust and highly targeted workflow for consistently isolating circulating endothelial cells from blood and performing RNA sequencing on the collected samples. This is a key advance towards a deeper understanding of the pathophysiology of HFpEF. The application of our methodology may enable the characterization of patients with HFpEF at the transcriptome level. The whole transcriptome analyses provide potential starting points for further in vitro and in vivo studies. As we extend our investigations to larger patient cohorts in the future, there is potential for the identification of novel therapeutic targets.

Semaglutide in Heart Failure With Preserved Ejection Fraction: Exploring Recent Evidence in Therapeutic Potential for the Obese Population.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent condition, particularly among the aging population in the United States, and is associated with significant challenges due to its complex pathophysiology and limited therapeutic options. Historically, few pharmacological therapies have successfully mitigated HFpEF, making the emergence of effective treatments particularly significant. This review evaluates recent evidence on the therapeutic potential of semaglutide for managing HFpEF, especially in the obese population. Results from the STEP-HFpEF and STEP-HFpEF DM trials demonstrate that semaglutide, a glucagon-like peptide-1 receptor agonist originally developed for type 2 diabetes but now also approved for obesity treatment, significantly improves clinical outcomes such as symptom scores, body weight, exercise capacity, and inflammation markers in the obese population suffering from HFpEF. These improvements are attributed to both the weight loss induced by semaglutide and its direct effects on the congestive pathophysiology of HFpEF. The efficacy of semaglutide offers new hope for addressing a condition that has long lacked effective pharmacological interventions.