Coronary microvascular dysfunction (CMD) has been proposed as a major mechanism and a potential therapeutic target for diabetic cardiomyopathy (DbCM); however, it has not been fully investigated in a clinical setting. The angiography-derived index of microcirculatory resistance (AMR) is a novel non-invasive measurement of CMD that exhibits promising clinical applications.

AMR was measured in hospitalized patients with DbCM and in control patients. The incidence, clinical characteristics, risk factors, and effects of pharmacological interventions on CMD were investigated.

AMR was significantly higher in patients who met the DbCM-2B diagnostic criteria. The independent risk factors for abnormal AMR included diabetes, body mass index (BMI), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP). Patients with elevated NT-pro-BNP had high AMR, and those grouped by medication indicated that ACEI/ARB, sacubitril/valsartan, and trimetazidine might lower AMR in patients with elevated NT-pro-BNP.

The DbCM-2B diagnostic criteria demonstrated a strong correlation with CMD. ACEI/ARB, sacubitril/valsartan, and trimetazidine might improve CMD in patients with DbCM.

Inflammatory conditions such as obesity and diabetes are linked to intermediate/non-classical monocyte activation, contributing to left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF).

To investigate whether circulating monocyte subtypes and their activity are associated with the presence LVDD and HFpEF.

We analyzed peripheral blood mononuclear cells (PBMCs) from 73 patients with or without LVDD/HFpEF. Cytokine secretion was measured post-stimulation, and gene expression was assessed via RNA sequencing. Monocyte subtypes were characterized using flow cytometry, and macrophage polarization was evaluated. We also examined the relationship between immunological markers and echocardiographic indicators of LVDD.

Among the participants, 24 were controls, 23 had LVDD, and 26 had HFpEF. PBMCs from LVDD patients secreted significantly less Interleukin-6 compared to controls (2053 ± 708 pg/mL vs 12,273 ± 3357 pg/mL, p = 0.008). RNA sequencing indicated increased estrogen receptor pathway activity in LVDD. HFpEF patients exhibited a 1.5-fold increase in intermediate monocytes and a significant rise in non-classical monocytes compared to controls. Stimulated macrophages from LVDD and HFpEF patients showed less CD206/CD80 expression, indicating a shift towards M2-macrophage polarization. Notably, higher non-classical monocyte counts correlated with lower E' septal velocity, suggesting an association with diastolic impairment (β = -0.15, p = 0.041).

LVDD and HFpEF are associated with a shift towards non-classical monocyte subtypes and higher numbers of non-classical monocytes are associated with signs of diastolic impairment. These findings highlight the importance of the inflammatory component in LVDD and HFpEF.

The prognosis of Heart failure with preserved ejection fraction (HFpEF) is significantly impacted by the existence and severity of comorbidities. Recent studies highlight the right ventricle (RV) as a crucial player in heart failure pathophysiology. However, there are still gaps in understanding how right ventricular dysfunction (RVD) affects long-term outcomes in patients with heart failure with preserved ejection fraction (HFpEF).

In this systematic review and meta-analysis, a comprehensive search was conducted to identify studies investigating RVD as the predictor of the composite outcome of All-cause death, cardiac death, and hospitalization for HF in patients with HFpEF published until October 2024. RVD was defined as the deviation of at least one measurement of RV function from the recommended normal range based on modality and the normal ranges established in each study. Time and survival probability were extracted for each Group (HFpEF patients with and without RVD) in each of the Kaplan-Meier curves. Individual patient data were reconstructed by processing the extracted time points, survival probabilities, and the number of patients at risk in a two-stage approach. The restricted mean survival time (RMST) was also calculated as the area under the survival curve for each group.

Seven studies met the inclusion criteria, comprising 1936 individuals, of which 555 patients had RVD. The pooled prevalence of RVD among HFpEF was 41.2% (95% CI: 36.5; 45.9). Patients with RVD had a significantly higher risk of adverse outcomes compared to those without RVD, with an HR of 2.28 (95% CI, 1.95; 2.68, p-value < 0.001) in the eight-year follow-up after the RVD diagnosis. The one-year landmark analysis revealed that the majority of the event-free survival disparity between patients with RVD and those without arises from the first year after an RVD diagnosis. Patients with RVD also had shorter event-free survival. (ΔRMST = -2.127 years, 95% CI, -2.383; -1.872, p-value < 0.001).

The development of RVD in HFpEF is linked to significantly increased composite outcomes of all-cause death and HF hospitalization and shorter event-free survival.

Heart failure (HF) with preserved ejection fraction (HFpEF) poses significant diagnostic challenges due to its complex aetiology and overlapping symptoms with other HF types. The heterogeneity of HFpEF, compounded by frequent comorbidities, complicates diagnosis. This study aimed to enhance HFpEF prediction through a two-phase approach: a simplified risk score and a decision tree model.

In Phase 1, an 8-point risk score based on accessible clinical parameters was developed. In Phase 2, we conducted comprehensive predictive modelling using decision tree analysis. Data from 560 HF patients were analysed. It achieved an accuracy of 63.13% (sensitivity: 62.87%, specificity: 54.24%). In Phase 2, a decision tree model using broader clinical variables improved accuracy to 73.04% (sensitivity: 53.89%, specificity: 81.17%).

This dual framework provides tools for both quick screening and detailed risk stratification in various clinical settings.

Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.

This study examined the ratio of erythrocyte distribution width (RDW) to albumin concentration (RAR) and all-cause, cardiovascular disease (CVD), and cancer mortality in the hypertension population, focusing on the role of inflammatory markers as mediators.

Data from NHANES (1999-2018) were analyzed, linking National Death Index (NDI) records to mortality outcomes through December 31, 2019. A weighted sampling design categorized participants into three RAR groups. Cox regression models adjusted for demographic and clinical variables assessed the association between RAR and mortality outcomes. Mediation analyses explored the mediating role of the systemic Inflammatory response index (SIRI) and neutrophil-to-lymphocyte ratio (NLR).

Among 26,935 participants with a median follow-up of 102 months and 6,007 deaths, elevated RAR was associated with increased risks of all-cause mortality (HR = 1.83, 95% CI: 1.76-1.90), cardiovascular disease mortality (HR = 1.81, 95% CI: 1.68-1.95), and cancer mortality (HR = 1.70, 95% CI: 1.55-1.86). Segmented regression showed a nonlinear relationship between RAR and all-cause mortality, cardiovascular mortality, and cancer mortality, and the threshold effect results showed a fold value of 4.10, with a greater HR when RAR < 4.10. Mediation analysis revealed that SIRI and NLR mediated the relationship between RAR and all-cause mortality by 8.12% and 6.00%, respectively.

In hypertensive populations, higher RAR values are associated with increased all-cause mortality, cardiovascular mortality, and cancer mortality. Inflammation partially mediates the relationship between RAR and all-cause mortality.

Over the past few decades, the rising burden of metabolic disease, including type 2 diabetes, prediabetes, obesity, and metabolic dysfunction-associated steatotic liver disease, has corresponded with fundamental shifts in the landscape of heart failure (HF) epidemiology, including the rising prevalence of HF with preserved ejection fraction. It has become increasingly important to understand the role of extracardiac contributors and interorgan communication in the pathophysiology and phenotypic heterogeneity of HF. Whereas traditional epidemiological strategies have separately examined individual contributions of specific comorbidities to HF risk, these approaches may not capture the shared mechanisms and more complex, bidirectional relationships between cardiac and noncardiac comorbidities. In this review, we highlight the cardiac, kidney, liver, and metabolism multiorgan interactions and pathways that complicate HF development and progression and propose research strategies to further understand HF in the context of multiple organ disease. This includes evolving epidemiological approaches such as multiomics and machine learning which may better capture common underlying mechanisms and interorgan crosstalk. We review existing preclinical models of HF and how they have enhanced our understanding of the role of multiorgan disease in the development of HF subtypes. We suggest recommendations as to how clinical practice across multiple specialties should screen for and manage multiorgan involvement in HF. Finally, recognizing the advent of novel combinatorial therapeutic agents that may have multiple indications across the cardiac-kidney-liver metabolism continuum, we review the current clinical trials landscape. We specifically highlight a pressing need for the design of more inclusive trials that examine the contributions of multimorbidity and incorporate multiorgan end points, which we propose may lead to outcomes that are evermore clinically relevant today.

The liver and heart are closely interconnected organs, and their bidirectional interaction plays a central role in cardiometabolic disease. In this review, we summarize current evidence linking liver dysfunction-particularly metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and cirrhosis-with an increased risk of heart failure and other cardiovascular diseases. We discuss how these liver conditions contribute to cardiac remodeling, systemic inflammation, and hemodynamic stress and how cardiac dysfunction in turn impairs liver perfusion and promotes hepatic injury. Particular attention is given to the molecular mediators of liver-heart communication, including hepatokines and cardiokines, as well as the emerging role of advanced research methodologies, including omics integration, proximity labeling, and organ-on-chip platforms, that are redefining our understanding of interorgan cross talk. By integrating mechanistic insights with translational tools, this review aims to support the development of multiorgan therapeutic strategies for cardiometabolic disease.

Cardiovascular diseases including atherosclerosis and heart failure, arise from the intricate interplay of metabolic, immune, and neural dysregulation within vascular and cardiac tissues: This review focuses on integrating recent advances in metabolic and immune crosstalk of the cardiac vasculature that affects cardiometabolic health and disease progression. Coronary and lymphatic endothelial cells regulate cardiac metabolism, and their dysfunction is linked to cardiovascular diseases. Lymphatics maintain tissue homeostasis, including clearing metabolic waste, lipids, and immune cells, and their maladaptation in metabolic diseases worsens outcomes. Altered vascular endothelial metabolism in heart failure drives immune-mediated inflammation, fibrosis, and adverse cardiac remodeling. Concurrently, artery tertiary lymphoid organs formed in the adventitia of advanced atherosclerotic arteries, serve as pivotal neuroimmune hubs, coordinating local immunity through T and B cell activation and neurovascular signaling via artery-brain circuits. T cells within plaques and artery tertiary lymphoid organs undergo clonal expansion as a result of peripheral tolerance breakdown, with proinflammatory CD4+ and CD8+ subsets amplifying atherosclerosis, effects further shaped by systemic immune activation. Therapeutic strategies targeting endothelial cell metabolism, lymphatic dysfunction, neuroimmune crosstalk, and T cell plasticity hold promise for integrated cardiovascular disease management.

The cardiopulmonary vasculature and its associated endothelial cells (ECs) play an essential role in sustaining life by ensuring the delivery of oxygen and nutrients. Beyond these foundational functions, ECs serve as key regulators of immune responses. Recent advances in single-cell RNA sequencing have revealed that the cardiopulmonary vasculature is composed of diverse EC subpopulations, some of which exhibit specialized immunomodulatory properties. Evidence for immunomodulation includes distinct expression profiles associated with antigen presentation, cytokine secretion, immune cell recruitment, translocation, and clearance - functions critical for maintaining homeostasis in the heart and lungs. In cardiopulmonary diseases, ECs undergo substantial transcriptional reprogramming, leading to a shift from homeostasis to an activated state marked by heightened immunomodulatory activity. This transformation has highlighted the critical role for ECs in disease pathogenesis and their potential as future therapy targets. This Review emphasizes the diverse functions of ECs in the heart and lungs, particularly adaptive and maladaptive immunoregulatory roles in cardiopulmonary health and disease.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have shown promising effects on heart failure (HF) outcomes, particularly in phenotype-specific populations. However, their impact on cardiac structure and function in HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) remains unclear.

Medline, Cochrane Library, and Scopus were queried through December 2024 for primary and secondary analyses of randomized controlled trials comparing GLP-1RA with placebo in HF patients. Outcomes included changes in left ventricular ejection fraction (LVEF), end-diastolic volume (LVEDV), end-systolic volume (LVESV), global longitudinal strain (GLS), left ventricular mass, left atrial volume (LAV), and NT-proBNP levels. Random-effects models were used to calculate weighted mean differences (WMDs) or hazard ratios (HRs).

Six trials (n = 1,195) were included, with three each evaluating HFpEF and HFrEF populations. In patients with HFpEF, GLP-1RA significantly reduced the LV mass (WMD: -8.6 g; 95% CI: -14.6, -2.6; p = 0.005) and LAV (WMD: -5.4 ml; 95% CI: -8.8, -2.0; p = 0.002) and lowered NT-proBNP concentration throughout (HR: 0.85; 95% CI: 0.8, 0.9; p < 0.001). A decrease in LAV was observed in the HFrEF population (WMD: -5.4 ml [95% CI: -8.8, -2.0]; p = 0.002). However, no significant improvements were observed in LVEF, LVEDV, LVESV, or GLS. There were significant differences between HFpEF and HFrEF for LVEDV (p = 0.01) and LVESV (p = 0.04).

GLP-1RA demonstrated phenotype-specific benefits, improving structural remodeling in HFpEF but showing limited effects in HFrEF. These findings highlight the importance of targeted therapeutic strategies based on HF phenotypes. Further research is warranted to elucidate underlying mechanisms and optimize patient selection.

Cardiac autonomic dysfunction is associated with heart failure (HF). Reduced heart rate recovery (HRR) indicates impaired parasympathetic reactivation after physical activity. Heart rate recovery 60 seconds after peak effort (HRR60) is linked to autonomic dysfunction, but data on its relevance across HF phenotypes are scarce. This study aimed to identify clinical determinants of HRR60 in an HF cohort and assess its relationship with clinical outcomes.

Data from the MyoVasc study (NCT04064450; N=3289) were analyzed. Participants underwent standardized clinical phenotyping including cardiopulmonary exercise testing. HRR60 was defined as the heart rate decline 60 seconds after exercise termination. Clinical determinants of HRR60 were evaluated using multivariate regression, whereas Cox regression analyses assessed all-cause death and worsening of HF.

The analysis sample comprised 1289 individuals (median age, 66.0 [interquartile range {IQR}, 58.0-73.0] years, 30.4% women) ranging from stage B to stage C/D according to the universal definition of HF. Age, sex, smoking, obesity, peripheral artery disease, and chronic kidney disease were identified as determinants of HRR60. HRR60 showed a strong association with all-cause death (hazard ratio [HR]HRR60 [10 bpm], 1.56 [95% CI, 1.32-1.85]; P<0.0001) and worsening of HF (HRHRR60 [10 bpm], 1.36 [95% CI, 1.10-1.69]; P=0.0052) independent of age, sex, and clinical profile. Sensitivity analysis showed a stronger association with worsening HF in HF with preserved left ventricular ejection fraction (Pinteraction=0.027).

HRR60 was associated with clinical outcome in chronic HF. Because it showed a stronger association with outcomes in HF with preserved ejection fraction, future research should consider phenotype-specific differences.

Heart failure with preserved ejection fraction (HFpEF), marked by cardiac diastolic dysfunction, contributes to half of all heart failure cases globally and poses a significant public health challenge. Effective therapies for HFpEF are rare, largely due to its complex and heterogeneous pathophysiology, which often involves multiple comorbidities. Berberine (BBR), an isoquinoline alkaloid, has demonstrated beneficial effects on multiple metabolic and cardiovascular disorders; however, its impact on cardiac diastolic dysfunction in HFpEF remains poorly understood. In this study, we utilized a rat model of HFpEF induced by a sustained high-fat/high-sucrose (HFHS) diet to explore the impact and mechanisms of BBR on diastolic dysfunction. The results revealed that BBR administration effectively alleviated cardiac diastolic dysfunction and alleviated extracardiac comorbidities, including increased weight, impaired glucose tolerance, hypercholesterolemia and hypertension, in rats fed an HFHS diet. Furthermore, BBR mitigated myocardial inflammation, oxidative stress, microvascular endothelial dysfunction, and notably restored the disturbed NO-cGMP-PKG pathway. Additionally, BBR reduced myocardial fibrosis and inhibited the abnormally activated TGF-β/Smads signaling. Moreover, BBR attenuated the systemic inflammation and corrected immune dysregulation in an HFHS diet-fed rats. Our study suggests that BBR exhibits multi-beneficial effects in the prevention and management of HFpEF, demonstrating its potential as a holistic therapeutic candidate for HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent among individuals with obesity, primarily due to metabolic dysfunction and structural cardiac remodeling. This review explores the emerging therapeutic role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing HFpEF in obese populations.

Recent clinical trials, including the STEP-HFpEF and SUMMIT studies, have shown that GLP-1 RAs such as semaglutide and tirzepatide significantly reduce body weight (13.3% and 13.9%, respectively), enhance exercise capacity (increases of 21.5m and 26m in 6-minute walk distance), and improve quality of life (19.5 and 16.6-point increases in KCCQ-CSS scores). Additionally, both agents demonstrated marked reductions in systemic inflammation, with C-reactive protein levels decreasing by 38.8% and 43.5%, respectively. GLP-1 RAs represent a promising class of agents targeting the cardiometabolic axis in HFpEF, offering meaningful improvements in functional capacity and symptom burden among obese patients. However, current evidence is limited by short trial durations, lack of population diversity, and insufficient long-term data. Future research should focus on more inclusive cohorts and extended outcomes such as hospitalization rates and cardiovascular events to fully define the long-term safety and efficacy of GLP-1 RAs in HFpEF management.

Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca2+ signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca2+ level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca2+-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. This comprehensive review aims to elucidate the intricate mechanisms by which inflammation contributes to the development and progression of HF. The review synthesizes current research on the involvement of both innate and adaptive immune responses in HF, highlighting the roles of cytokines, chemokines, and other inflammatory mediators. Recent studies have demonstrated that chronic inflammation, driven by factors such as oxidative stress, neurohormonal activation, and metabolic disturbances, leads to adverse cardiac remodeling and impaired myocardial function. The review explores how systemic inflammation, characterized by elevated levels of inflammatory biomarkers like C-reactive protein (CRP) and interleukin-6 (IL-6), correlates with HF severity and outcomes. Additionally, it discusses the impact of comorbid conditions such as diabetes, obesity, and hypertension on inflammatory pathways and HF risk. The review also delves into the therapeutic implications of targeting inflammation in HF. Despite mixed results from early clinical trials, emerging evidence suggests that anti-inflammatory therapies offer benefits in specific HF phenotypes. The potential of novel therapeutic strategies, including the use of biologics and small molecule inhibitors, is examined in the context of their ability to modulate inflammatory responses and improve clinical outcomes.

Obesity leads to both heart failure with a preserved ejection fraction (HFpEF) and to chronic kidney disease (CKD); CKD may both influence the clinical course of obesity-related HFpEF; and incretin-based drugs may influence renal function.

This analysis had dual objectives: 1) to evaluate the influence of CKD on the clinical responses to tirzepatide in patients with obesity-related HFpEF; and 2) to investigate the complexity of tirzepatide-related changes in renal function. For both objectives, we focused on discrepancies between creatinine-based and cystatin C-based estimates of the estimated glomerular filtration rate (eGFR).

The SUMMIT trial randomly assigned 731 patients with HFpEF and a body mass index ≥30 kg/m2, who were enriched for participants with CKD. Patients received either placebo or tirzepatide for a median of 104 weeks and were followed for cardiovascular death or worsening heart failure events and for changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) after 52 weeks. Because of the confounding produced by obesity and changes in muscle mass, eGFR was assessed at randomization and after 12, 24, and 52 weeks by both creatinine-based and cystatin C-based formulae.

Patients with CKD (based on creatinine or cystatin C) had greater severity of heart failure, as reflected by: 1) worse functional class, KCCQ-CSS scores, and 6-minute walk distance; 2) higher levels of NT-proBNP and cardiac troponin T; and 3) a 2-fold increase in the risk of worsening heart failure events. CKD did not influence the effect of tirzepatide to reduce the relative risk of major adverse heart failure events and to improve KCCQ-CSS, quality of life, and functional capacity, but the absolute risk reduction in the primary events was numerically greater in patients with CKD. Regarding renal function assessments, baseline eGFR-cystatin C was consistently ≈9 mL/min/1.73 m2 lower than that eGFR-creatinine, with significant individual variance. Furthermore, tirzepatide increased eGFR at 52 weeks, assessed by both creatinine-based and cystatin C-based formulae, but with considerable discordance in individual patients. Tirzepatide produced a decline in eGFR at 12 weeks with eGFR-creatinine (but not eGFR-cystatin C), and it led to an improvement in eGFR at 52 weeks in all patients (when assessed by cystatin C), but only in patients with CKD (when assessed by eGFR-creatinine).

The triad of obesity, HFpEF, and CKD identifies patients with considerable functional impairment and an unfavorable prognosis, who nevertheless respond favorably to tirzepatide. Long-term tirzepatide improves renal function (both by cystatin C and creatinine), but the measurement of eGFR in patients with obesity receiving incretin-based drugs is likely to be skewed by the effects of fat and muscle mass (and by changes in body composition) on the synthesis of both cystatin C and creatinine. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial; NCT04847557).

Background/Objectives: Heart failure (HF) with preserved ejection fraction (HFpEF) poses a diagnostic challenge, as it lacks a definitive hallmark beyond preserved left ventricular (LV)EF. This retrospective study aims to analyze the demographic and clinical characteristics of HFpEF patients within a real-world hospital cohort, with a particular focus on obesity and associated comorbidities. Methods: A total of 4019 patients who underwent echocardiography in 2020-2021 at a university hospital were screened for HFpEF. After stringent manual verification, 219 patients fulfilled the European Society of Cardiology (ESC) criteria for HFpEF. Demographic, clinical, and comorbidity data were analyzed and stratified by body mass index (BMI) categories and sex distribution. Results: Among the 219 HFpEF patients, 71.3% were classified as pre-obese or obese. Hypertension (93.6%), atrial fibrillation (74.3%), and obesity were common in the cohort, while sex distribution was balanced. Edema was more prevalent among obese patients, though HFpEF severity, as reflected by New York Heart Association (NYHA) classification and natriuretic peptide levels, did not differ significantly across BMI groups. Medical treatment patterns varied with BMI, with obese patients more frequently receiving diuretics, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and angiotensin receptor blockers (ARB). No significant differences were observed between male and female patients in terms of HFpEF severity markers. Conclusions: Obesity is a predominant feature in HFpEF and is associated with a high burden of comorbidities. However, sex does not appear to influence HFpEF severity in this cohort. These findings underscore the need for targeted therapeutic strategies in obese HFpEF patients.

Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester.

Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background were challenged with high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester for 9 weeks (n=6-10).

Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e' (42.8 versus 21.5, P=1.2×10-10), E/A (2.3 versus 1.4, P=4.1×10-2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10-3), and myocardial fibrosis (P=2.3×10-2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10-3) and a 38.8% reduction in glutathione:GSSG (P=2.6×10-2) among Nnt+/+ mice after high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis.

Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.

Cardiovascular disease (CVD) is the leading cause of death in developed countries worldwide, often manifesting in the form of heart failure (HF). Recent successful clinical outcomes of anti-inflammatory therapies in HF patients have greatly boosted interest in basic and translational research on the role of inflammation in development of HF. In this review, we discuss recent and ongoing therapies targeting inflammation in CVD/HF, including broad-spectrum anti-inflammatory drugs, supplements, and biologicals such as canakinumab and anakinra. We also discuss the growing body of literature supporting off-target/anti-inflammatory actions of mainline CVD/HF agents, including guideline-directed medical therapy (GDMT) drugs that target the neurohormonal axis, and statins. We discuss therapeutics that target autoimmune mechanisms, and their implications for treating patients with autoimmune diseases with HF or at-risk of developing HF. We also discuss recent evidence for vaccines in modulating the immune response during HF. We conclude that despite the wealth of knowledge gained in the past decade, the therapeutic efficacy of anti-inflammatory therapy is driven by many biological and logistical factors that vary from patient to patient. Furthermore, more studies are needed to understand the adaptive/autoimmune component of HF, particularly in women and patients with pre-existing autoimmune disease. As the number of patients with HF patients who suffer from obesity, diabetes, or autoimmune disease continues to grow, our understanding of inflammation must continue to evolve to reflect these underlying co-morbidities.

This study investigates the therapeutic mechanisms of Qiliqiangxin (QLQX) capsules in treating Heart Failure with Preserved Ejection Fraction (HFpEF). The study aims to understand how QLQX impacts cardiac function and underlying molecular pathways.

HFpEF was induced in a rat model through unilateral nephrectomy, DOCA pellet implantation, and a high-salt diet. Cardiac function was assessed via M-mode imaging and Doppler flow measurements, focusing on key parameters like ejection fraction and diastolic function. A network pharmacology approach identified active QLQX components and potential targets, followed by comprehensive multi-omics analyses-including transcriptomics, proteomics, and metabolomics-to uncover the molecular mechanisms modulated by QLQX. Quantitative RT-PCR was employed to measure mRNA levels of key cardiac markers, providing further insights into QLQX's impact on cardiac remodeling.

QLQX treatment significantly improved cardiac function, with notable enhancements in ejection fraction and left ventricular diastolic function. Network pharmacology revealed 530 potential targets of QLQX, with 38 overlapping HFpEF targets. Key pathways identified include cGMP-PKG, adrenergic signaling, and calcium signaling. Transcriptomic analysis showed significant gene expression changes related to inflammation, energy metabolism, and myocardial remodeling, which were reversed by QLQX. Proteomic analysis identified 401 differentially expressed proteins, enriched in pathways such as cGMP-PKG and NF-κB signaling. Metabolomic profiling highlighted the role of lipid metabolism and adrenergic signaling in HFpEF, which were normalized by QLQX. In vivo validation confirmed the involvement of the cGMP-PKG pathway, with increased serum NO and cGMP levels, improved endothelial function, and reduced pro-fibrotic markers following QLQX treatment.

QLQX exerts multifaceted therapeutic effects on HFpEF by modulating gene expression, protein function, and metabolic pathways, particularly through the cGMP-PKG signaling pathway. These findings support QLQX as a promising therapeutic intervention for HFpEF, offering improvements in cardiac function and reversing pathological changes at multiple molecular levels.

To examine the effects of fluctuations in fasting blood glucose (FBG) levels on left ventricular function in patients with T2DM and coronary microcirculation dysfunction (CMD).

A total of 290 patients with T2DM who received glucose-lowering therapy during hospitalization and were subsequently followed up for 18 months at the First Affiliated Hospital of Harbin Medical University, were enrolled in this study. 135 were diagnosed with CMD and were assigned to the CMD group, whereas 155 patients without CMD were allocated to the non-CMD group. The fasting blood glucose coefficient of variation (FBG-CV) was calculated for all participants. The CMD group was further stratified into three subgroups based on their FBG-CV values: CMD1 (FBG-CV > 25%), CMD2 (FBG-CV 15% ~ 25%), and CMD3 (FBG-CV < 15%). The left ventricular function, assessed by left ventricular ejection fraction (LVEF) and the E/e' ratio, was compared within each group before and after the follow-up period. This study was registered in the Chinese Clinical Trial Register, ChiCTR-ORC-16009800.

After the end of follow-up, the E/e' ratio in CMD1 was significantly higher than that in CMD2 and CMD3 (14.35 vs 8.57; p < 0.01; 14.35 vs 6.61; p < 0.01), and the E/e' ratio in CMD2 was significantly higher than that in CMD3 (8.57 vs 6.61; p < 0.01). Compared to the baseline measurements, the E/e' ratio in CMD1 showed a significant increase after an average 17.8 months of follow up (14.35 vs 8.44; p < 0.001). We found elevated E/e' ratio was associated with an increased FBG-CV level (odds ratio [OR]: 2.571; 95% CI 1.819-3.634; p < 0.001). In multivariate logistic analysis, course of diabetes (OR:1.062; 1.016-1.11; P = 0.007) and CMD (OR:2.231; 1.303-3.819; P = 0.003), were significantly associated with elevated E/e' ratio, while oral stains drugs (OR = 0.412 95% CI 0.237-0.715; P = 0.002) and insulin injections (OR = 0.536 95% CI 0.311-0.924; P = 0.025) behaved as a protective factor.

Our study clarified the association between FBG-CV levels and the E/e' ratio in a prospective cohort study. In T2DM patients with CMD, FBG-CV > 25% may adversely affect left ventricular diastolic function, whereas an optimal FBG-CV is considered to be less than 15%.

Obesity and inflammation have been associated with an increased incidence of heart failure (HF) and death. However, until recent years, no therapy directed towards reducing inflammation and reducing obesity has been shown to reduce those adverse outcomes. Over the past few years, a few small studies have suggested that improving obesity-and in even smaller studies, reducing inflammation-may help improve HF severity, congestion, quality of life, and possibly outcomes. Larger studies that are being planned and executed, which will report their results within the next 2-3 years, should help further clarify the effects of weight and inflammation reduction in patients with HF.

Pericoronary fat attenuation index (FAI) assessed on computed tomography is associated with the inflammation of the pericoronary artery.

This study aimed to investigate whether pericoronary FAI predicts hospitalization for heart failure with preserved ejection fraction (HFpEF).

This retrospective single-center study included 1,196 consecutive patients who underwent clinically indicated coronary computed tomography angiography (CCTA) and transthoracic echocardiography. We assessed the FAI of proximal 40-mm segments for each major epicardial coronary vessel. The primary outcome was the incidence of hospitalization for HFpEF. Patients were divided into groups based on the optimal cutoff value for predicting hospitalization for HFpEF by receiver operating characteristic curve analysis.

During a median follow-up of 4.3 years, 29 hospitalizations for HFpEF occurred. Multivariable Cox regression analysis revealed that a left anterior descending artery (LAD)-FAI ≥-63.4 HU and a left circumflex artery-FAI ≥-61.6 HU were significantly associated with hospitalization for HF after adjustment for age and sex (HR: 4.8; 95% CI: 2.1-10.8 and HR: 4.5; 95% CI: 2.1-9.4, respectively). The addition of LAD-FAI >-63.4 HU to a model incorporating other risk factors, including hypertension, estimated glomerular filtration rate <60 mL/min/1.73 m2, and significant stenosis on CCTA, increased the C-statistic for predicting hospitalization for HFpEF from 0.646 to 0.750 (P = 0.010).

LAD- and left circumflex artery-FAI can predict hospitalization for HFpEF in patients undergoing clinically indicated CCTA. Pericoronary inflammation may be useful for identifying patients at high risk of developing HFpEF.

Microvascular function, particularly of the plantar foot, reflects overall vascular health and is influenced by physiological oscillators such as heart rate, respiratory, myogenic, and neurogenic rhythms. Slow deep breathing modulates autonomic nervous system activity and affects peripheral microcirculation. This study investigates the effects of slow deep breathing on plantar foot perfusion using photoplethysmography imaging (PPGI).

Twenty healthy young adults participated in a four-stage protocol: baseline, deep breathing test (DBT), and two recovery stages (REST1 and REST2). PPGI was used to measure changes in plantar foot perfusion, focusing on energy, amplitude, and phase synchronization within frequency bands corresponding to key physiological oscillators. Time-frequency analyses and advanced signal processing were applied to assess these parameters.

Significant increases in energy were observed in all frequency bands during DBT, with slow frequency oscillators (SFOs) maintaining elevated activity up to 5 min after DBT. Amplitude analysis revealed a significant decrease in the first and second harmonic components of the heart rate signals during DBT. Phase synchronization between medial and lateral foot regions improved for respiratory, myogenic, and neurogenic frequency bands during DBT, with myogenic synchronization persisting for up to 2.5 min after DBT.

Slow deep breathing enhances microvascular perfusion and synchronizes autonomic oscillators in healthy individuals. PPGI proved effective in capturing these dynamics, indicating its potential as a non-invasive tool for assessing autonomic and microvascular function. Future research should explore its applicability in detecting early autonomic or vascular dysfunction in clinical populations.

Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals.

In the forth visit of the STANISLAS family cohort, involving 1309 participants (mean age 48 ± 14 years; 48% male) from parent and children generations, we analysed the association of 32 HF-related proteins with non-invasively assessed VAC using pulse wave velocity (PWV)/global longitudinal strain (GLS) and arterial elastance (Ea)/ventricular end-systolic elastance (Ees). Among the 32 tested proteins, fatty acid-binding protein adipocyte 4, interleukin-6, growth differentiation factor 15, matrix metalloproteinase (MMP)-1, and MMP-9 and adrenomedullin were positively associated with PWV/GLS whereas transforming growth factor beta receptor type 3, MMP-2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were negatively associated. In multivariable models, only MMP-2 and NT-proBNP were significantly and inversely associated with PWV/GLS in the whole population and in the parent generation. Higher levels of NT-proBNP were also negatively associated with Ea/Ees in the whole cohort but this association did not persist in the parent subgroup.

Elevated MMP-2 and NT-proBNP levels correlate with better VAC (lower PWV/GLS), possibly indicating a compensatory cardiovascular response to regulate left ventricular pressure amidst cardiac remodelling and overload.

During exercise stress echocardiography (ESE), there are patients with normal left ventricular ejection fraction (LVEF) who paradoxically develop reduced LVEF during exercise despite absence of coronary artery disease (CAD) and a significant hypertensive response. This study sought to describe the clinical features and outcomes of this population.

Among ESEs performed between 2003 and 2022, patients without CAD by angiogram within 90 days of ESE and resting LVEF ≥50% with a ≥5% LVEF decrease during ESE were included. Outcomes assessed were all-cause mortality, heart failure (HF) hospitalization, and atrial fibrillation (AF). Kaplan-Meier and Cox regression methods were used to analyze time-to-event outcomes.

Among 213,643 ESE, 134 patients met the eligibility criteria. The mean age of the population was 66 ± 10 years, 76% were women, and 16% had AF at baseline. Mean LVEF was 58% ± 4% at rest and 43% ± 4% at peak stress. Stress ECG met the criteria for ischemia in 14% of these patients. The 10-year estimated incidence of HF hospitalization was 17.6% (95% CI, 9.0%-26.2%). Among the subgroup without AF at baseline, the 10-year estimated incidence of developing AF was 23.4% (95% CI, 13.4%-33.4%). The 10-year estimated incidence of all-cause mortality was 12.9% (95% CI, 5.5%-20.3%), with 89% of deaths occurring due to noncardiovascular causes.

Patients with exercise-induced reduction in LVEF in the absence of obstructive CAD have a high incidence of HF hospitalizations and AF. The underlying pathophysiology of this disease process needs to be further investigated.

Heart failure is a prevalent global health issue. Heart failure with preserved ejection fraction (HFpEF), which already represents half of all heart cases worldwide, is projected to further increase, driven by aging populations and rising cardiovascular risk factors. Effective therapies for HFpEF remain limited, particularly due to its pathophysiological heterogeneity and incomplete understanding of underlying pathomechanisms and implications. Coronary microvascular dysfunction (CMD), characterized by structural and functional changes in the coronary microcirculation, is increasingly recognized as a significant factor in HFpEF even though the exact nature of their causal relationship is still unclear. This review explores prevalence, prognostic implications, and potential therapeutic targets for CMD in HFpEF. CMD's role in HFpEF might involve impaired coronary blood flow regulation, leading to myocardial ischemia, impaired relaxation, and/or adverse remodeling. Vice versa, increased wall stress in patients with HFpEF might elevate coronary resistances, further worsening microvascular perfusion. Finally, abnormalities in substrate metabolism might cause both CMD and HFpEF. Current treatments, including pharmacotherapy and device-based therapies, show limited success, highlighting the need for more targeted approaches. New possible therapies, such as the coronary sinus reducer device, may show promise in improving myocardial perfusion and function. However, further large-scale studies are required to elucidate the mechanistic links between CMD and HFpEF and to develop specialized treatments for distinct heart failure phenotypes.

Heart failure is the leading cardiovascular cause of hospitalization with an increasing prevalence, especially in older patients. About 50% of patients with heart failure have preserved ventricular function, a form of heart failure that, until a few years ago, was orphaned by pharmacological treatments effective in reducing hospitalization and mortality. New trials, which have tested the use of gliflozins in patients with heart failure with preserved ejection fraction (HFpEF), have for the first time demonstrated their effectiveness in changing the natural history of this insidious and frequent form of heart failure. Therefore, diagnosing those patients early is crucial to provide the best treatment. Moreover, the diagnosis is influenced by the patient's comorbidities, and some HFpEF patients have symptoms common to other rare diseases that, if unrecognized, develop an unfavourable prognosis. This position paper aims to provide the clinician with a useful tool for diagnosing and treating patients with HFpEF, guiding the clinician towards the most appropriate diagnostic and therapeutic pathway.

Single ventricle congenital heart disease like hypoplastic left heart syndrome with a Fontan circulation constitutes, the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20% to 50%. We investigated the mechanisms leading to Fontan failure to identify novel therapeutic targets.

Blood was collected from patients with hypoplastic left heart syndrome post-Fontan and controls (n=6/group). Plasma microvesicles were isolated, and proteomics assessed using data-independent acquisition mass spectroscopy. Dysregulated proteins with a fold change >1.5 or ≤1.5, P<0.05, were evaluated using the Database for Annotation, Visualization, and Integrated Discovery and Ingenuity pathway analysis. Correlation of highly dysregulated proteins was assessed with New York Heart Association class, right ventricular fractional area change, oxygen saturation, and hemoglobin.

The age of Fontan patients versus controls was 16.0±2.1 versus 15.3±2.2. Three of 6 Fontan patients were in New York Heart Association class II, and 3 of 6 were in New York Heart Association III/IV; 4 of 6 had Fontan-associated liver disease. Overall, 72 proteins were upregulated, and 187 proteins were downregulated in Fontan failure. Proteins upregulated in Fontan failure predicted cell death pathways (Solute carrier family 2, Angiotensinogen, CD14) and mitochondrial reactive oxygen species signaling (ATP5F1A, S100A8); downregulated proteins predicted impaired cell survival (tyrosine-protein kinase, endothelial growth factors) and mitochondrial antioxidant enzymes (GPX1, PRDX5) Increasing expression of the following proteins was associated with worsening New York Heart Association class, ventricular function and cyanosis: complement system (C1QA, r=0.91), mitochondrial reactive oxygen species generation (HSPD1, r=0.81; ATP5F1A, r=0.75), and cytoskeletal proteins (ANK1, r=0.63; ACTN1, r=0.76).

Proteins from circulating microvesicles from patients with hypoplastic left heart syndrome post-Fontan are mostly from the liver. While this pilot study is limited by its sample size and may not represent the broader Fontan population, the proteomic changes were associated with worsening heart failure and cyanosis, suggesting their potential utility as biomarkers.

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease (CVD) including heart failure (HF). However, little is known regarding the relative risks of HF subtypes such as HF with preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF) in RA compared with non-RA.

We identified patients with RA and matched non-RA comparators among participants consenting to broad research from two large academic centers. We identified incident HF and categorized HF subtypes based on EF closest to the HF incident date. Covariates included age, sex, and established CVD risk factors. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident HF and HF subtypes.

We studied 1,445 patients with RA and 4,335 matched non-RA comparators (mean age 51.4 and 51.7 years, respectively; 78.7% female). HFpEF was the most common HF subtype in both groups (65% in RA vs 59% in non-RA). Patients with RA had an HR of 1.79 (95% confidence interval [CI] 1.38-2.32) for incident HF compared with those without RA after adjusting for CVD risk factors. Patients with RA had a higher rate of HFpEF (HR 1.99, 95% CI 1.43-2.77), but there was no statistical difference in the HFrEF rate (HR 1.45, 95% CI 0.81-2.60).

RA was associated with a higher rate of HF overall compared with non-RA, even after adjustment for established CVD risk factors. The elevated risk was driven by HFpEF, supporting a role for inflammation in HFpEF and highlighting potential opportunities to address this excess risk in RA.

Relationship between blood pressure (BP) control and left ventricular (LV) diastolic function in children with chronic kidney disease (CKD) is uncertain. The aim of this study is to investigate whether achieving lower BP yields a favourable impact on diastolic function.

We performed an exploratory analysis in the HOT-KID, a parallel group, open-label, multicentre, randomised, controlled trial (ISRCTN25006406). Children with CKD were randomised to standard (50th-75th percentile) or intensive (<40th percentile) standardised office systolic BP targets. Echocardiograms were performed at baseline and at follow-up visits. Diastolic function was assessed by early (E) and late mitral inflow (A) E/A ratio, mitral annular motion of myocardial relaxation (e') and atrial contraction (a') velocity, LV compliance of E/e' and e'/a' ratio, and left atrial volume index (LAVi) by a blinded observer.

There was a difference in the average annual rate of change in E/A ratio (difference in means -0·07 per year, 95% CI: -0·14 to -0·01), septal e' (difference in means -0·003 m/s per year, 95% CI: -0·005 to 0·001), and LAVi (difference in means 0·82 ml/m2 per year, 95% CI: 0·22-1·42) in the standard (n = 60) compared to the intensive treatment arm (n = 64). However, the average annual changes in all other diastolic function measures were similar between standard and intensive treatment groups. There was no difference for overall adverse events or serious adverse events between the two treatment groups.

Our exploratory analysis in a small, open label RCT suggests that achieving lower blood pressure may favourably impact some measures of LV diastolic function in children with CKD.

British Heart Foundation (PG/11/90/28,994); The authors MDS, PJC acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre and Clinical Research Facilities awards to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. There are no relationships with industry.

To evaluate the risk of heart failure (HF) in patients with immune-mediated inflammatory diseases (IMIDs) compared to the general population with and without diabetes mellitus (DM).

A population-based cohort study was conducted in patients with rheumatoid arthritis (RA), radiographic axial spondyloarthritis (r-axSpA), psoriatic arthritis, and psoriasis (PsO) in Ontario from 2011 until 2019. The study outcome was first hospitalization for HF. Incidence rates of HF were calculated for each cohort. Hazard ratios (HRs) for HF were calculated using Cox proportional hazard models. The etiology of HF was descriptively classified into mutually exclusive groups based on comorbidities during HF hospitalization.

A total of 243,061 patients with IMID, 748,517 with DM, and 8,278,934 non-IMID, non-DM controls were analyzed. The crude incidence rate for HF in IMID was 2.70 per 1000 person-years, with the highest rate in RA and lowest in r-axSpA. The risk of being hospitalized for HF was higher in IMID compared with non-IMID comparators (HR 1.34, 95% CI 1.30-1.38). This risk was highest among patients with RA (HR 1.61, 95% CI 1.54-1.68) and lowest in PsO (HR 1.09, 95% CI 1.03-1.15). In comparison, the risk of HF hospitalization in patients with DM was higher (HR 2.19, 95% CI 2.16-2.21). The most common antecedent comorbidity associated with HF in all patients with IMID was ischemic heart disease. In patients with IMID without DM, atrial fibrillation had a similar effect as ischemic heart disease.

The risk of HF hospitalization is increased in patients with IMID compared to the general population.