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.

Overweight and obesity are major risk factors for heart failure (HF), contributing to its development through metabolic, neurohormonal, haemodynamic, and inflammatory alterations. While overweight/obesity increases the risk of developing HF, its impact on patient outcomes remains complex. The "obesity paradox" suggests that a higher BMI may be associated with improved survival in patients with established HF. However, recent GLP-1 receptor agonist (GLP-1 RA) trials suggest that intentional weight loss positively influences outcomes in overweight/obese patients with HF. This seemingly contradictory evidence highlights the need for a deeper understanding of the mechanisms linking adiposity to HF outcomes. A more precise characterization of adiposity phenotypes using alternative and accurate measures of pathological fat accumulation is crucial in identifying individuals who may benefit most from anti-obesity treatments. In this context, recent research underscores the role of epicardial adipose tissue (EAT) in HF pathophysiology, as it directly influences cardiac function and structure through inflammatory, metabolic, and mechanical effects. This narrative review summarises current evidence on the impact of weight loss on HF outcomes, focusing on recent GLP-1 RA trial results. Additionally, it highlights epidemiological and molecular data supporting EAT as a novel adiposity measure that might allow refining patient selection for pharmacological weight-loss treatments. Finally, it emphasizes the need for future research to identify causal pathways linking alternative measures of visceral fat accumulation to HF outcomes. These efforts will be essential in optimizing the benefits of novel weight-loss treatments, ensuring effective and individualized therapeutic strategies for overweight or obese patients with HF.

Diabetic cardiomyopathy is a unique cardiomyopathy that is common in diabetic patients, and it is also a diabetic complication for which no effective treatment is currently available. Moreover, relevant studies have revealed that a link exists between type 2 diabetes and heart failure and that abnormal thickening of EAT is inextricably linked to the development of diabetic heart failure. Numerous clinical studies have demonstrated that EAT is implicated in the pathophysiologic process of diabetic myocardial disease. In this overview, we will introduce the physiology, pathophysiology of the disease and potential therapeutic strategies, knowledge gaps, and future directions of the role of epicardial adipose tissue in type 2 diabetes mellitus and heart failure to promote the development of novel therapeutic approaches to improve the prognosis of patients with diabetic cardiomyopathy.

Epicardial adipose tissue (EAT) is thought to have a deleterious effect on the progression of myocardial disease; the extracellular volume (ECV) fraction has been validated by histology to correlate with adverse myocardial remodeling. The aim of this study was to investigate the prognostic value of EAT volume index (EATVI) and ECV in patients with hypertrophic cardiomyopathy (HCM).

ECV and EAT were measured using cardiac magnetic resonance (CMR) imaging in 201 subjects with HCM. All patients were followed up prospectively. Major adverse cardiovascular events (MACEs) were categorized into primary and secondary endpoint events. The primary endpoint was a composite of cardiac death, heart transplant, and cardiopulmonary resuscitation following syncope. The secondary endpoint was defined as rehospitalization for heart failure (HF).

After 26±16 months of follow-up, 43 patients experienced MACEs (14 patients experienced a primary endpoint, and 29 patients experienced a secondary endpoint). Patients suffering from MACEs had significantly higher ECV and EATVI (p<0.001). After adjustment for body mass index (BMI), EATVI showed a significant correlation with ECV (r=0.424, p<0.001) among HCM patients. In the Kaplan-Meier analysis, the incidence of MACE was significantly higher in patients with increased ECV (p<0.001) and higher EATVI (p<0.001). In multivariate Cox regression analysis, ECV (HR=1.12, p<0.001) and EATVI (HR=1.31, p<0.001) were significantly associated with MACEs.

In patients with HCM, ECV and EATVI measured by CMR are strong predictors of MACEs and improve risk stratification.

Extracellular volume fraction and epicardial adipose tissue are associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy and can improve their risk stratification.

Diastolic dysfunction and alterations in cardiac geometry are early indicators of diabetic cardiomyopathy. However, the association between cardiac changes across the glucose continuum and the contribution of epicardial adipose tissue (EAT) to these changes has not yet been investigated.

In this study, we aimed to investigate the EAT on cardiac diastolic function and structural alterations along the diabetic continuum using cardiac magnetic resonance imaging (CMRI).

We enrolled individuals who were categorized into groups based on glucose tolerance status. Left ventricular structure and diastolic function were assessed using echocardiography and CMRI to determine the EAT, intramyocardial fat, and associated parameters. Multivariable logistic regression models were also used.

In a study of 370 patients (209 normal glucose tolerance, 82 prediabetes, 79 diabetes), those with prediabetes and diabetes showed increased heart dimensions and diastolic dysfunction, including the ratio of early mitral inflow velocity to mitral annular early diastolic velocity (7.9 ± 0.51 vs 8.5 ± 0.64 vs 10.0 ± 0.93, P = .010), left atrial volume index (28.21 ± 14.7 vs 33.2 ± 12.8 vs 37.4 ± 8.2 mL/m2, P < .001), and left ventricular peak filling rate (4.46 ± 1.75 vs 3.61 ± 1.55 vs 3.20 ± 1.30 mL/s, P < .001). EAT significantly increased in prediabetes and diabetes (26.3 ± 1.16 vs 31.3 ± 1.83 vs 33.9 ± 1.9 gm, P = .001), while intramyocardial fat did not differ significantly. Prediabetes altered heart geometry but not diastolic function (odds ratio [OR] 1.22 [1.02-1.83], P = .012; and 1.70 [0.79-3.68], P = .135). Diabetes significantly affected both heart structure and diastolic function (OR 1.42 [1.11-1.97], P = .032; and 2.56 [1.03-5.40], P = .034) after adjusting for covariates.

Elevated EAT was observed in patients with prediabetes and is associated with adverse alterations in cardiac structure and diastolic function, potentially serving as an underlying mechanism for the early onset of diabetic cardiomyopathy.

Heart failure with preserved ejection fraction (HFpEF) is a growing global health problem characterized by high morbidity and mortality, with limited effective therapies available. Obesity significantly influences haemodynamic and structural changes in the myocardium and vasculature, primarily through the accumulation and action of visceral adipose tissue. Particularly, epicardial adipose tissue (EAT) contributes to HFpEF through inflammation and lipotoxic infiltration of the myocardium. However, the precise signalling pathways leading to diastolic stiffness in HFpEF require further elucidation. This review explores the dynamic role of EAT in health and disease. Drawing upon insights from studies in other conditions, we discuss potential EAT-mediated inflammatory pathways in HFpEF and how they may contribute to functional and structural myocardial and endothelial derangements, including intramyocardial lipid infiltration, fibrosis, endothelial dysfunction, cardiomyocyte stiffening, and left ventricular hypertrophy. Lastly, we propose potential targets for novel therapeutic avenues.

Heart failure (HF) is a significant global health issue, categorized by left ventricular ejection fraction, being either reduced (HFrEF < 0.40) or preserved (HFpEF > 0.50), or in the middle of this range. Although the overall incidence of HF remains stable, HFpEF cases are increasing, representing about 50% of all HF cases. Outcomes for HFpEF are similar to those for HFrEF, leading to substantial health-care resource use. Despite extensive research over the past 2 decades, the prognosis and mortality rates for HFpEF remain high. A key feature of HFpEF is exercise intolerance, characterized by severe exertional dyspnea and fatigue, which significantly impacts quality of life. The underlying mechanisms of exercise intolerance are not fully understood due to the complex pathophysiology and multisystem involvement. Obesity is a common comorbidity in HFpEF, especially in North America, leading to worsening symptoms, hemodynamics, and mortality rates. Increased adiposity leads to inflammation, hypertension, dyslipidemia, and insulin resistance, and impairing cardiac, vascular, pulmonary, and skeletal muscle function. Therefore, managing obesity is crucial in treating HFpEF. In this review we explore the pathophysiologic mechanisms of HFpEF, emphasizing obesity's role, and we discuss current management strategies while identifying areas needing further research.

Cardiovascular diseases (CVDs) remain a global health concern, prompting ongoing research into novel contributors to their pathogenesis. Due to the proximity of the coronary arteries and the myocardium in epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT), these tissues have emerged as key areas of interest for their potential influence on cardiac function and vascular health. This review synthesizes current research on the physiological and biological characteristics of EAT and PAT, exploring their composition and clinical measurement approaches. The roles of EAT and PAT in coronary artery disease (CAD), atrial fibrillation, and heart failure are discussed, and the contributions of EAT and PAT to these cardiovascular conditions are highlighted alongside their potential as therapeutic targets.

Metabolic dysfunction-associated steatotic liver disease (MASLD), defined by steatotic liver disease (SLD) and cardiometabolic factors, is increasing in prevalence, but its association with heart failure (HF) is unclear.

Patients with SLD without a history of HF from 2006 to 2021 were retrospectively included and were classified into MASLD and non-MASLD groups that were followed longitudinally. The primary outcome was the new development of HF, which was sub-classified by echocardiography. Multivariable and propensity score matching analyses were conducted to adjust for confounding factors. Overall, 26 676 patients with SLD were included, with a median age of 51 years and 71% classified as MASLD. During a median follow-up of 6 years, 429 (1.61%) patients developed HF, and 76% were HF with preserved ejection fraction (HFpEF). The risk of HF was significantly higher in patients with MASLD than in those without (sub-distribution hazard ratio [SHR] 2.59, 95% confidence interval [CI] 1.84-3.64) after adjustment of competing mortality. There was a dose-dependent increase in HF risks in patients with more cardiometabolic risk factors (SHR 1.12, 95% CI 1.04-1.22). MASLD was also associated with higher risk of HF-related hospitalization (SHR 2.30, 95% CI 1.31-4.04) and specifically, the risk of HFpEF (SHR 1.91, 95% CI 1.27-2.86). In propensity score-matched cohorts, MASLD was also associated with a 2.52-fold higher risk of HF.

In patients with SLD, those with MASLD show a higher risk of HF, specifically HFpEF. Future studies are warranted to validate the association between HF and MASLD.

Obesity is a known risk factor for heart failure with preserved ejection fraction (HFpEF) and is considered a distinct phenotype with more concentric remodeling. Epicardial adipose tissue (EAT) is also increased in obesity-related HFpEF and is associated with adverse events.

The cardiac magnetic resonance (CMR) substudy of the SUMMIT trial aimed to examine the effects of tirzepatide on cardiac structure and function with the underlying hypothesis that it would reduce left ventricular (LV) mass and EAT in obesity-related HFpEF.

A total of 175 patients with obesity-related HFpEF from the parent study of tirzepatide (2.5 mg subcutaneously weekly, increasing to a maximum of 15 mg weekly) or matching placebo underwent CMR at baseline, which consisted of multiplanar cine imaging. A total of 106 patients completed the CMR and had adequate image quality for analysis of LV and left atrial structure and function and paracardiac (epicardial plus pericardial) adipose tissue at both baseline and 52 weeks. The prespecified primary endpoint of this substudy was between-group changes in LV mass.

LV mass decreased by 11 g (95% CI: -19 to -4 g) in the treated group (n = 50) when corrected for placebo (n = 56) (P = 0.004). Paracardiac adipose tissue decreased in the treated group by 45 mL (95% CI: -69 to -22 mL) when corrected for placebo (P < 0.001). The change in LV mass in the treated group correlated with changes in body weight (P < 0.02) and tended to correlate with changes in waist circumference and blood pressure (P = 0.06 for both). The LV mass change also correlated with changes in LV end-diastolic volume and left atrial end-diastolic and end-systolic volumes (P < 0.03 for all).

The CMR substudy of the SUMMIT trial demonstrated that tirzepatide therapy in obesity-related HFpEF led to reduced LV mass and paracardiac adipose tissue as compared with placebo, and the change in LV mass paralleled weight loss. These physiologic changes may contribute to the reduction in heart failure events seen in the main SUMMIT trial. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial; NCT04847557).

Heart failure with preserved ejection fraction (HFpEF) represents a major clinical challenge with rising global prevalence. Women have a nearly double lifetime risk of developing HFpEF compared to heart failure with reduced ejection fraction (HFrEF). In HFpEF, sex differences emerge both in how traditional cardiovascular risk factors (such as hypertension, obesity, and diabetes) affect cardiac function and through distinct pathophysiological mechanisms triggered by sex-specific events like menopause and adverse pregnancy outcomes. These patterns influence not only disease development, but also therapeutic responses, necessitating sex-specific approaches to treatment. This review aims to synthesize existing knowledge regarding HFpEF in women including traditional and sex-specific risk factors, pathophysiology, presentation, and therapies, while outlining important knowledge gaps that warrant further investigation. The impact of HFpEF spans a woman's entire lifespan, requiring prevention and management strategies tailored to different life stages. While understanding of sex-based differences in HFpEF has improved, significant knowledge gaps persist. Through examination of current evidence and challenges, this review highlights promising opportunities for innovative research, therapeutic development, and clinical care approaches that could transform the management of HFpEF in women.

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were managed in isolation. However, emerging evidence reveals that these disorders share overlapping pathophysiological mechanisms and treatment strategies. In 2023, the American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, recognizing the interconnected roles of the heart, kidneys, and metabolic system. Yet, this model omits the liver-a critical organ impacted by metabolic dysfunction. MASLD, which can progress to metabolic dysfunction-associated steatohepatitis (MASH), is closely tied to insulin resistance and obesity, contributing directly to cardiovascular and renal impairment. Notably, MASLD is bidirectionally associated with the development and progression of CKM syndrome. As a result, we introduce an expanded framework-the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome-to more comprehensively capture the broader inter-organ dynamics. We provide guidance for an integrated diagnostic approach aimed at halting progression to advanced stages and preventing further organ damage. In addition, we highlight advances in medical management that target shared pathophysiological pathways, offering benefits across multiple organ systems. Viewing these conditions as an integrated whole, rather than as discrete entities, and incorporating the liver into this framework fosters a more holistic management strategy and offers a promising path to addressing the cardiometabolic pandemic.

Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN-induced kinase 1 (PINK1) and peroxiredoxin-2 (Prdx2) in HFpEF pathogenesis remain unclear.

This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.

In vivo, PINK1-knockout mice and cardiac-specific PINK1-overexpressing transgenic mice were used to establish an HFpEF mouse model via a high-fat diet and L-NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved.

We determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N-terminal region (amino acids 1-133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid-induced apoptosis through the c-Jun amino-terminal kinase (JNK) and mitogen-activated protein kinase (p38) pathways, whereas siRNA-mediated Prdx2 knockdown abolished the protective effect of PINK1.

PINK1 alleviates lipotoxicity-induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.

Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF. Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate cardiomyocyte apoptosis by modulating the JNK and p38 pathways, thereby alleviating myocardial lipotoxicity and improving HFpEF cardiac function. Our studies offer valuable insights, opening avenues for the development of innovative therapeutic strategies in the prevention and treatment of HFpEF.

Hereditary transthyretin amyloidosis (ATTRv) is a hereditary disease that affects multiple bodily systems. Although sonography generally reveals enlargement of nerves in the limbs, the brachial plexus, and vagus nerve, the clinical significance of these findings remains unclear.

We performed sonographic measurements of the median nerve, cervical spinal nerves at the C5-C7 level, and the vagus nerve in patients with ATTRv and healthy controls. Clinical profiles and cardiac and gastrointestinal examination results were also collected for linear regression analysis.

We recruited 47 patients with ATTRv (males/females: 34/13, age: 65.6 ± 5.3 years). The sampled segments were all significantly larger than those of the controls. In the clinical profiles, the sum of the Z scores of the neck triangle nerves (cervical spinal nerves and vagus nerve) and of all nerves (cervical spinal nerves, vagus nerve, and median nerve at the wrist) significantly correlated with the familial amyloid polyneuropathy stage, onset of autonomic nervous system (ANS) symptoms, and autonomic symptom scores. On cardiac examinations, several ultrasonography and magnetic resonance imaging parameters (primarily those that reflect heart volume) were found to be significantly correlated with the sum of the Z scores of the cervical spinal nerves but not with the Z score of the vagus nerve. In gastrointestinal evaluation, the cross-sectional area of the vagus nerve was correlated with gastric emptying time parameters on scintigraphy.

Neck triangle nerve enlargement on sonography correlated with parameters related to ANS dysfunction, indicating that nerve enlargement observed on ultrasonography may serve as a potential surrogate biomarker of ATTRv.

Epicardial adipose tissue (EAT) is a fat depot covering the heart. No physical barrier separates EAT from the myocardium, so EAT can easily affect the underlying cardiac muscle. EAT can participate in the development and progression of heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). In healthy humans, excess EAT is associated with impaired cardiac function and worse outcomes. In HFpEF, this trend continues: EAT amount is usually increased, and excess EAT correlates with worse function/outcomes. However, in HFrEF, the opposite is true: reduced EAT amount correlates with worse cardiac function/outcomes. Surprisingly, although EAT has beneficial effects on cardiac function, it aggravates ventricular arrhythmias. Here, we dissect these phenomena, trying to explain these paradoxical findings to find a target for novel heart failure therapies aimed at EAT rather than the myocardium itself. However, the success of this approach depends on a thorough understanding of interactions between EAT and the myocardium.

Epicardial adipose tissue is a unique visceral adipose tissue depot that plays a crucial role in myocardial metabolism. Epicardial adipose tissue is a major source of energy and free fatty acids for the adjacent myocardium. However, under pathological conditions, epicardial fat can affect the heart through the excessive and abnormal influx of lipids. The cardio-lipotoxicity of the epicardial adipose tissue is complex and involves different pathways, such as increased inflammation, the infiltration of lipid intermediates such as diacylglycerol and ceramides, mitochondrial dysfunction, and oxidative stress, ultimately leading to cardiomyocyte dysfunction and coronary artery ischemia. These changes can contribute to the pathogenesis of various cardio-metabolic diseases including atrial fibrillation, coronary artery disease, heart failure, and obstructive sleep apnea. Hence, the role of the cardio-lipotoxicity of epicardial fat and its clinical implications are discussed in this 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.

Epicardial adipose tissue (EAT) is a unique fat depot located between the myocardium and the visceral layer of pericardium. It can be further subdivided into pericoronary (PCAT), periatrial (PAAT) and periventricular adipose tissue (PVentAT), each of them exhibiting specific characteristics and association with the underlying tissue. Since no physical barrier separates EAT from the myocardium, this fat tissue can easily interact with the underlying cardiac structure. EAT can be visualized using various imaging modalities. Computed tomography provides not only information on EAT volume, but also on its density. Indeed, EAT density reflected by the recently developed fat attenuation index (FAI) is emerging as a useful index of PCAT inflammation, PAAT inflammation and fibrosis, while the relevance of density of PVentAT is much less known. The emerging data indicates that FAI can be an important diagnostic and prognostic tool in both coronary artery disease and atrial fibrillation. Future studies will demonstrate if it also could be used as a marker of efficacy of therapies and whether FAI PVentAT could indicate ventricular pathologies, such as heart failure. The aim of the review is to present computed tomography derived FAI as an important tool both to study and better understand the epicardial fat and as a potential predictive marker in cardiovascular disorders.

Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of HF cases, with no effective treatments. The ZSF1-obese rat model recapitulates numerous clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and LV diastolic dysfunction. Here, we utilized a systems-biology approach to define the early metabolic and transcriptional signatures to gain mechanistic insight into the pathways contributing to HFpEF development.

Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14w of age for extensive physiological phenotyping and LV tissue harvesting for unbiased metabolomics, RNA-sequencing, and assessment of mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes contributing to HFpEF pathology, versus hypertension + metabolic syndrome.

ZSF1-obese rats displayed numerous clinical features of HFpEF. Comparison of ZSF1-lean vs WKY (i.e., hypertension-exclusive effects) revealed metabolic remodeling suggestive of increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by the upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and cellular metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of nearly all catabolic pathways contributing to energy production, manifesting in a marked decrease in the energetic state (i.e., reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Mitochondrial function was also impaired as demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling.

Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential target for intervention.

Obesity is an ongoing pandemic and is associated with the development of heart failure (HF), and especially HF with preserved ejection fraction. The definition of obesity is currently based on anthropometric measurements but neglects the location and molecular properties of excess fat. Important depots associated with HF development are subcutaneous adipose tissue and visceral adipose tissue, both located in the abdominal region, and epicardial adipose tissue (EAT) surrounding the myocardium. However, mechanisms linking these different adipose tissue depots to HF development are incompletely understood. EAT in particular is of great interest because of its close proximity to the heart. In this review, we therefore focus on the characteristics of different adipose tissue depots and their response to obesity. In addition, we evaluate how different mechanisms associated with EAT expansion potentially contribute to HF and in particular HF with preserved ejection fraction development.

Studies have reported the association of epicardial adipose tissue (EAT) with cardiac structure and function as well as exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF), yielding inconsistent results. We aimed to conduct a meta-analysis of studies on the association of EAT with cardiac structure and function and exercise capacity in HFpEF patients.

We searched studies examining the association of EAT quantified by echocardiography, computed tomography, or magnetic resonance imaging (MRI) with cardiac structure and function or exercise capacity in HFpEF patients through PubMed, Web of Science, and Scopus. In cases of significant heterogeneity (I2 > 50 %), data were pooled using a random-effects model; otherwise, a fixed-effects model was used. We identified five echocardiography studies (n = 825) and six MRI studies (n = 562), but found no computed tomography studies. In the echocardiography studies, EAT thickness correlated positively with left ventricular (LV) mass (P random  < 0.01) and negatively with LV global longitudinal strain (P random  < 0.01) and peak exercise oxygen uptake (P fix  < 0.001). In the MRI studies, EAT volume correlated positively with LV mass (P fix  < 0.01), left atrial volume (P fix  < 0.001), and the ratio of LV early diastolic mitral inflow to early diastolic mitral annular velocity (E/e'; P random  < 0.01) and negatively with LV ejection fraction (P fix  < 0.01) and LV global longitudinal strain (P fix  < 0.001).

Our meta-analysis indicates a potential association of increased EAT with altered cardiac structure and function and exercise intolerance in HFpEF patients. However, our meta-analysis included only two or three studies for each outcome and thus further studies are necessary to confirm our findings.

Background: The role of epicardial adipose tissue (EAT) in heart failure with preserved ejection fraction (HFpEF) remains to be defined. Methods: A consecutive series of outpatients with chronic heart failure-heart failure with reduced ejection fraction (HFrEF) and HFpEF and/or diastolic dysfunction-had EAT assessed by echocardiographic measurement and related to indices of cardiac structure and function. Results: Epicardial fat thickness was significantly (p < 0.05) greater in HFpEF (N = 141) with a mean of 6.7 ± 1.6 mm compared with a mean of 5.1 ± 1.0 mm in HFrEF (n = 40). After adjusting for the relationship with BMI, in HFpEF, epicardial fat was significantly (p < 0.05) negatively correlated with left ventricular internal diameter end diastole (LVIDd), left ventricular internal diameter end systole (LVIDs), left ventricular (LV) end-diastolic volume (EDV) index, lateral e', septal e', right atrial (RA) volume index, and hemoglobin (Hgb). The association with Hgb was no longer significant after adjusting for the effect of age. HFpEF was associated with smaller LVIDd, LVIDs, LV EDV indexes, and left atrial (LA) and RA volume indexes. Conclusions: Epicardial fat is significantly (p < 0.05) greater in HFpEF than HFrEF. Epicardial fat is associated with smaller cardiac chamber sizes in HFpEF suggesting that epicardial fat acts as a constraint to cardiac dilation.

Obesity is a common comorbidity among patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), with the strongest pathophysiologic link of obesity being seen for HFpEF. Lifestyle measures are the cornerstone of weight loss management, but sustainability is a challenge, and there are limited efficacy data in the heart failure (HF) population. Bariatric surgery has moderate efficacy and safety data for patients with preoperative HF or left ventricular dysfunction and has been associated with reductions in HF hospitalizations and medium-term mortality. Antiobesity medications historically carried concerns for cardiovascular adverse effects, but the safety and weight loss efficacy seen in general population trials of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide/GLP-1 agonists are highly encouraging. Although there are safety concerns regarding GLP-1 agonists in advanced HFrEF, trials of the GLP-1 agonist semaglutide for treatment of obesity have confirmed safety and efficacy in patients with HFpEF.

The global prevalence of obesity has escalated into a formidable health challenge intricately linked with the risk of developing cardiac diastolic disfunction and heart failure with preserved ejection fraction (HFpEF). Abnormal fat distribution is potentially strongly associated with an increased risk of cardiac diastolic dysfunction, and we aimed to scrutinize and elucidate the correlation between them.

Following the Cochrane Handbook and PRISMA 2020 guidelines, we systematically reviewed the literature from PubMed, Embase, and Web of Science. We focused on studies reporting the mean and standard deviation (SD) of abnormal fat in HFpEF or cardiac diastolic dysfunction patients and the Pearson/Spearman correlation coefficients for the relationship between abnormal fat distribution and the risk of developing cardiac diastolic dysfunction. Data were standardized to the standard mean difference (SMD) and Fisher's z value for meta-analysis.

After progressive filtering and selection, 63 studies (43,113 participants) were included in the quantitative analyses. Abnormal fat distribution was significantly greater in participants with cardiac diastolic dysfunction than in controls [SMD 0.88 (0.69, 1.08)], especially in epicardial adipose tissue [SMD 0.99 (0.73, 1.25)]. Abnormal fat distribution was significantly correlated with the risk of developing cardiac diastolic dysfunction [E/E': 0.23 (0.18, 0.27), global longitudinal strain: r=-0.11 (-0.24, 0.02)]. Meta-regression revealed sample size as a potential heterogeneous source, and subgroup analyses revealed a stronger association between abnormal fat distribution and the risk of developing cardiac diastolic dysfunction in the overweight and obese population.

Abnormal fat distribution was significantly associated with the risk of developing cardiac diastolic dysfunction.

CRD42024543774.

This study aimed to identify the impact of increased epicardial adipose tissue (EAT) and its regional distribution on cardiac function in patients with diastolic dysfunction.

Sixty-eight patients with exertional dyspnoea (New York Heart Association ≥II), preserved ejection fraction (≥50%), and diastolic dysfunction (E/e' ≥ 8) underwent rest and stress right heart catheterization, transthoracic echocardiography, and cardiovascular magnetic resonance (CMR). EAT volumes were depicted from CMR short-axis stacks. First, the impact of increased EAT above the median was investigated. Second, the association of ventricular and atrial EAT with myocardial deformation at rest and during exercise stress was analysed in a multivariable regression analysis. Patients with high EAT had higher HFA-PEFF and H2FPEFF scores as well as N-terminal prohormone of brain natriuretic peptide levels (all P < 0.048). They were diagnosed with manifest heart failure with preserved ejection fraction (HFpEF) more frequently (low EAT: 37% vs. high EAT: 64%; P = 0.029) and had signs of adverse remodelling indicated by higher T1 times (P < 0.001). No differences in biventricular volumetry and left ventricular mass (all P > 0.074) were observed. Patients with high EAT had impaired atrial strain at rest and during exercise stress, and impaired ventricular strain during exercise stress. Regionally increased EAT was independently associated with functional impairment of the adjacent chambers.

Patients with diastolic dysfunction and increased EAT show more pronounced signs of diastolic functional failure and adverse structural remodelling. Despite similar morphological characteristics, patients with high EAT show significant cardiac functional impairment, in particular in the atria. Our results indicate that regionally increased EAT directly induces atrial functional failure, which represents a distinct pathophysiological feature in HFpEF.

The association between obesity and some cardiovascular complications such as heart failure (HF) is well established, and drugs affecting adiposity are supposed to be promising treatments for these conditions. The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antidiabetic drugs showing benefits in patients with HF, despite the underlying mechanisms have not been completely understood yet. SGLT2i are supposed to promote systemic effects, such as triglycerides mobilization, through the enhancement of fibroblast growth factor-21 (FGF-21) activity. So, in this study, we evaluated the effects of dapagliflozin treatment on FGF-21 and related receptors (FGF-Rs) gene expression and on lipid content in myocardial tissue in an animal model of genetically induced obesity to unravel possible metabolic mechanisms accounting for the cardioprotection of SGLT2i.

Six-week-old C57BL/6J wild-type mice and B6.V-LEP (ob/ob) mice were randomly assigned to the control or treatment group (14 animals/group). Treatment was based on the administration of dapagliflozin 0.15 mg/kg/day for 4 weeks. The gene expression of FGF-21 and related receptors (FGF-R1, FGF-R3, FGF-R4, and β-klotho co-receptor) was assessed at baseline and after treatment by real-time PCR. Similarly, cardiac triglycerides concentration was measured in the control group and treated animals.

At baseline, FGF-21 mRNA expression in the heart did not differ between lean and obese ob/ob mice. Dapagliflozin administration significantly increased heart FGF-21 gene expression, but only in ob/ob mice (p < 0.005). Consistently, when measuring the amount of triglycerides in the cardiac tissue, SGLT2i treatment reduced the lipid content in obese ob/ob mice, while no significant effects were observed in treated lean animals (p < 0.001). The overall expression of the FGF-21 receptors was only minimally affected by dapagliflozin treatment both in obese ob/ob mice and in lean controls.

Dapagliflozin administration increases FGF-21gene expression and reduces triglyceride content in myocardial tissue of ob/ob mice, while no significant effect was observed in lean controls. These results might help understand the cardiometabolic effects of SGLT2i inducing increased FGF-21 synthesis while reducing lipid content in cardiomyocytes as a possible expression of the switch to different energy substrates. This mechanism could represent a potential target of SGLT2i in obesity-related heart diseases.

Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure.

26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed.

SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects.

Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

Heart failure (HF) management guidelines recommend individualized assessments based on HF phenotypes. Adiposity is a known risk factor for HF. Recently, there has been an increased interest in organ-specific adiposity, specifically the role of the epicardial adipose tissue (EAT), in HF risk. EAT is easily assessable through various imaging modalities and is anatomically and functionally connected to the myocardium. In pathological conditions, EAT secretes inflammatory cytokines, releases excessive fatty acids, and increases mechanical load on the myocardium, resulting in myocardial remodeling. EAT plays a pathophysiological role in characterizing both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In HFrEF, EAT volume is reduced, reflecting an impaired metabolic reservoir, whereas in HFpEF, the amount of EAT is associated with worse biomarker and hemodynamic profiles, indicating increased EAT activity. Studies have examined the possibility of therapeutically targeting EAT, and recent studies using sodium glucose cotransporter 2 inhibitors have shown potential in reducing EAT volume. However, further research is required to determine the clinical implications of reducing EAT activity in patients with HF.

Obesity has become a serious public health issue, significantly elevating the risk of various complications. It is a well-established contributor to Heart failure with preserved ejection fraction (HFpEF). Evaluating HFpEF in obesity is crucial. Epicardial adipose tissue (EAT) has emerged as a valuable tool for validating prognostic biomarkers and guiding treatment targets. Hence, assessing EAT is of paramount importance. Cardiovascular magnetic resonance (CMR) imaging is acknowledged as the gold standard for analyzing cardiac function and morphology. We hope to use CMR to assess EAT as a bioimaging marker to evaluate HFpEF in obese patients.

To assess the diagnostic utility of CMR for evaluating heart failure with preserved ejection fraction [HFpEF; left ventricular (LV) ejection fraction ≥ 50%] by measuring the epicardial adipose tissue (EAT) volumes and EAT mass in obese patients.

Sixty-two obese patients were divided into two groups for a case-control study based on whether or not they had heart failure with HFpEF. The two groups were defined as HFpEF+ and HFpEF-. LV geometry, global systolic function, EAT volumes and EAT mass of all subjects were obtained using cine magnetic resonance sequences.

Forty-five patients of HFpEF- group and seventeen patients of HFpEF+ group were included. LV mass index (g/m2) of HFpEF+ group was higher than HFpEF- group (P < 0.05). In HFpEF+ group, EAT volumes, EAT volume index, EAT mass, EAT mass index and the ratio of EAT/[left atrial (LA) left-right (LR) diameter] were higher compared to HFpEF- group (P < 0.05). In multivariate analysis, Higher EAT/LA LR diameter ratio was associated with higher odds ratio of HFpEF.

EAT/LA LR diameter ratio is highly associated with HFpEF in obese patients. It is plausible that there may be utility in CMR for assessing obese patients for HFpEF using EAT/LA LR diameter ratio as a diagnostic biomarker. Further prospective studies, are needed to validate these proof-of-concept findings.

The authors conducted transcardiac blood sampling in healthy subjects and subjects with heart failure with preserved ejection fraction (HFpEF) to compare cardiac metabolite and lipid substrate use. We demonstrate that fatty acids are less used by HFpEF hearts and that lipid extraction is influenced by hemodynamic factors including pulmonary pressures and cardiac index. The release of many products of protein catabolism is apparent in HFpEF compared to healthy myocardium. In subgroup analyses, differences in energy substrate use between female and male hearts were identified.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.

The aim of this retrospective study was to explore the diagnostic potential of various cardiac parameters in differentiating between heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-ranged and reduced ejection fraction (HFm + rEF), and to discern their relationship with normal cardiac function.

This research encompassed a comparative analysis of heart failure subtypes based on multiple indicators. Participants were categorized into HFm + rEF, HFpEF, and control groups. For each participant, we investigated indicators of left ventricular function (LVEDVi, LVESVi, and LVEF) and myocardial strain parameters (GLS, GCS, GRS). Additionally, quantitative tissue evaluation parameters including native T1, enhanced T1, and extracellular volume (ECV) were examined.For comprehensive diagnostic performance analysis, receiver operating characteristic (ROC) curve evaluations for each parameters were conducted.

HFm + rEF patients exhibited elevated LVEDVi and LVESVi and decreased LVEF compared to both HFpEF and control groups. Myocardial strain revealed significant reductions in GLS, GCS, and GRS for HFm + rEF patients compared to the other groups. HFpEF patients showed strain reductions relative to the control group. In cardiac magnetic resonance imaging (CMR) evaluations, HFm + rEF patients demonstrated heightened native T1 times and ECV fractions. Native T1 was particularly effective in distinguishing HFpEF from healthy subjects.

Native T1, ECV, and myocardial strain parameters have substantial diagnostic value in identifying HFpEF. Among them, native T1 displayed superior diagnostic efficiency relative to ECV, offering critical insights into early-stage HFpEF. These findings can play a pivotal role in refining clinical management and treatment strategies for heart failure patients.

The arrhythmogenic role of epicardial adipose tissue (EAT) in atrial arrhythmias is well established, but its effect on ventricular arrhythmias has been significantly less investigated. Since ventricular arrhythmias are thought to cause 75%-80% of cases of sudden cardiac death, this is not a trivial issue. We provide an overview of clinical data as well as experimental and molecular data linking EAT to ventricular arrhythmias, attempting to dissect possible mechanisms and indicate future directions of research and possible clinical implications. However, despite a wealth of data indicating the role of epicardial and intramyocardial fat in the induction and propagation of ventricular arrhythmias, unfortunately there is currently no direct evidence that indeed EAT triggers arrhythmia or can be a target for antiarrhythmic strategies.

Preclinical data strongly suggest that myocardial steatosis leads to adverse cardiac remodelling and left ventricular dysfunction. Using 1 H cardiac magnetic resonance spectroscopy, similar observations have been made across the spectrum of health and disease. The purpose of this brief review is to summarize these recent observations. We provide a brief overview of the determinants of myocardial triglyceride accumulation, summarize the current evidence that myocardial steatosis contributes to cardiac dysfunction, and identify opportunities for further research.

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.

Epicardial adipose tissue (EAT) is a metabolically highly active tissue modulating numerous pathophysiological processes. The aim of this study was to investigate the association between EAT thickness and endothelial function in patients with heart failure (HF) across the entire ejection fraction spectrum.

A total of 258 patients with HF with an ejection fraction across the entire spectrum [HF with reduced ejection fraction (HFrEF), n = 168, age 60.6 ± 11.2 years; HF with preserved ejection fraction (HFpEF), n = 50, mean age 65.1 ± 11.9 years; HF with mildly reduced ejection fraction (HFmrEF), n = 32, mean age 65 ± 12] were included. EAT was measured with transthoracic echocardiography. Vascular function was assessed with flicker-light-induced vasodilation of retinal arterioles (FIDart%) and flow-mediated dilatation (FMD%) in conduit arteries. Patients with HFrEF have less EAT compared with patients with HFpEF (4.2 ± 2 vs. 5.3 ± 2 mm, respectively, P < 0.001). Interestingly, EAT was significantly associated with impaired microvascular function (FIDart%; r = -0.213, P = 0.012) and FMD% (r = -0.186, P = 0.022), even after multivariate correction for confounding factors (age, body mass index, hypertension, and diabetes; standardized regression coefficient (SRC) = -0.184, P = 0.049 for FIDart% and SRC = -0.178, P = 0.043 for FMD%) in HFrEF but not in HFpEF.

Although less EAT is present in HFrEF than in HFpEF, only in HFrEF EAT is associated with vascular dysfunction. The diverging role of EAT in HF and its switch to a functionally deleterious tissue promoting HF progression provide the rationale to specifically target EAT, in particular in patients with reduced ejection fraction.

Existing evidence suggested that the role of epicardial adipose tissue (EAT) in heart failure with reduced and preserved ejection fraction (HFrEF/HFpEF) might be divergent. Here, we conducted a systematic review and meta-analysis to evaluate the association between EAT and HF. Several databases were searched from their inception to January 20, 2023. We calculated the standard mean difference (SMD) in EAT between the HF and control groups, as well as the correlation coefficient between EAT and left atrial (LA) and left ventricular (LV) function. This meta-analysis included 23 studies, involving 1563 HFrEF and 1351 HFpEF patients. Our findings indicated that EAT was significantly higher in HFpEF patients (SMD: 0.61, 95% CI: 0.27-0.94), but not in total HF or HFrEF patients compared to controls. In HFrEF, EAT was positively correlated with LVEF, LV end-diastolic volume index (LVEDVI), LA global longitudinal strain (LAGLS), and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-ProBNP). However, no significant relationship existed between EAT and LV mass index (LVMI) or LVGLS. For HFpEF, EAT correlated positively with LVMI, LVEDVI, LV end-systolic volume index (LVESVI), LA volume index (LAVI), cardiac troponin T, and extracellular volume (ECV), but negatively with LVGLS and LAGLS. EAT was shown to be higher in HFpEF, but not in HFrEF. Less EAT was linked with worse LA function but not worse LV function in HFrEF, while more EAT was associated with worse LA/LV function in HFpEF.