Degenerative aortic valve disease (DAVD) represents the most prevalent valvular ailment among the elderly population, which significantly impacts their physical well-being and potentially poses a lethal risk. Currently, the underlying mechanisms of DAVD remain incompletely understood. While the progression of this disease has traditionally been attributed to degenerative processes associated with aging, numerous recent studies have revealed that heart valve calcification may represent a response of valve tissue to a specific initiating factor, involving the interaction of various genes and signaling pathways. This calcification process is further influenced by a range of factors, including genetic predispositions, environmental exposures, metabolic factors, and hemodynamic considerations. Based on the identification of its biomarkers, potential innovative therapeutic targets are proposed for the treatment of this complex condition. The present article primarily delves into the underlying pathophysiological mechanisms and advancements in diagnostic and therapeutic modalities pertaining to this malady.

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent worldwide due to aging and comorbidities. Epicardial adipose tissue (EAT), favored by diabetes and obesity, was shown to contribute to HFpEF pathophysiology and is an emerging therapeutic target. This study explored the relationship between ventricular EAT measured by cardiovascular magnetic resonance (CMR), metabolic factors, and imaging characteristics in controls, pre-HF patients, and HFpEF patients.

Patients from a Belgian cohort enrolled from December 2015 to June 2017 were categorized by HF stage: pre-HF (n = 16), HFpEF (n = 104) and compared to matched controls (n = 26) and to pre-HF (n = 191) from the Beta3-LVH cohort. Biventricular EAT volume was measured in end-diastolic short-axis cine stacks. In the Belgian cohort, associations between EAT, HF stage, and various biological and imaging markers were explored. The clinical endpoint was a composite of mortality or first HF hospitalization in the HFpEF group.

EAT significantly differed between groups, with higher values in HFpEF patients compared to pre-HF and controls (72.4 ± 20.8ml/m2vs. 55.0 ± 11.8ml/m2 and 48 ± 8.9ml/m2, p < 0.001) from the Belgian cohort and to pre-HF (52.0 ± 15.0 ml/m2, p < 0.001) from the Beta3-LVH cohort. Subsequent analyses focused on the Belgian cohort. In contrast to atrial fibrillation, diabetes prevalence and body mass index (BMI) did not differ between pre-HF and HFpEF patients. Multivariable logistic regression and random forest classification identified EAT, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and H2FPEF score as strong markers of HFpEF status. EAT was significantly correlated with H2FPEF score (r = 0.41, p = 0.003), BMI (r = 0.30, p < 0.001), high-sensitive troponin T (r = 0.41, p < 0.001), NT-proBNP (r = 0.37, p < 0.001), soluble suppression of tumorigenicity-2 (sST2) (r = 0.30, p < 0.001), E/e' ratio (r = 0.33, p < 0.001), and left ventricular global longitudinal strain (r = 0.35, p < 0.001). In HFpEF patients, diabetes, ischemic cardiomyopathy, and elevated sST2 were independently associated with elevated EAT. In contrast with diabetes and BMI, increased EAT was not associated with prognosis.

EAT assessed by CMR was significantly higher in HFpEF patients compared to controls and pre-HF patients, irrespective of diabetes and BMI. EAT was moderately associated with HFpEF status. HFpEF patients with elevated EAT exhibited a marked diabetic, ischemic, and inflammatory profile, highlighting the potential role of drugs targeting EAT.

Characterization of Heart Failure With Preserved Ejection Fraction; Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure (Beta3_LVH).

ClinicalTrials.gov. Identifier: NCT03197350; NCT02599480.

Anthracyclines are widely used in cancer treatment, yet their potential for anthracycline-induced cardiotoxicity (AIC) limits their clinical utility. Despite the significant anatomical relevance of pericardial adipose tissue (PeAT) to cardiovascular disease, its response to anthracycline exposure remains poorly understood.

Male New Zealand White rabbits (n=17) received weekly doxorubicin injections and underwent magnetic resonance imaging (MRI) scans biweekly for 10 weeks. PeAT volumes (total, left paraventricular, right paraventricular) were measured together with ventricular function. Histopathological evaluations were also conducted. A mixed linear model identified the earliest timeframe for detectable changes in PeAT volume and left ventricular function. Total PeAT volume decreased from the 6th week (1.17±0.06, P<0.05) and continued to decrease until the 8th week (0.96±0.06, P<0.05) and left paraventricular adipose tissue volume decreased significantly, but no changes were observed in right paraventricular adipose tissue volume. The volume of PeAT exhibited a positive correlation with left ventricular ejection fraction (LVEF) (r=0.43, P<0.05), which declined below 50% by the 8th week, and a negative correlation with myocardial cell injury scores (r=-0.595, P<0.05).

Anthracycline administration led to an early reduction in PeAT volume, particularly in the left paraventricular region, detectable by MRI as early as the 6th week. Changes in PeAT volume preceded alterations in LVEF and were associated with declines in cardiac function and myocardial cell damage.

Cardiovascular effects of obesity may be driven, in part, by the distribution of fat. More recently, epicardial adipose tissue (EAT) has gained recognition as an adverse visceral fat impacting cardiac dysfunction in heart failure with preserved ejection fraction (HFpEF).

EAT can be identified and measured using several non-invasive imaging techniques, including transthoracic echocardiography, computed tomography, and cardiac magnetic resonance. The presence of EAT is associated with increased risk of HFpEF and worse clinical outcomes among patients with established HFpEF, independent of total adiposity. EAT may serve a pivotal role in the pathogenesis of HFpEF by worsening volume distribution, enhancing pericardial restraint and ventricular interaction, worsening right ventricular dysfunction, and diminishing exercise tolerance. No large trials have tested the effects of reducing fat in specific areas of the body on cardiovascular outcomes, but some studies that followed people in communities and trials over time have suggested that drug and non-drug treatments that lower EAT could improve the risk factors for heart problems in patients with HFpEF. Further understanding the role that pathogenic fat depots play in HFpEF incidence and progression may provide future therapeutic targets in treating the obese-HFpEF phenotype.

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).

Although the epidemic of atherosclerosis has slowed down in industrialized nations, it has increased in speed and severity in developing countries. The worldwide expanding incidence and prevalence of obesity, insulin resistance, and diabetes mellitus may be among the most important drivers of this trend, and the role of visceral adipose tissue as a promoter of atherosclerosis has come under intense scrutiny. Epicardial adipose tissue (EAT) is embryologically similar to the visceral fat in the intraperitoneal space. Both adipose compartments are capable of secreting numerous pro-atherosclerotic cytokines and have been shown to promote inflammation in patients with dysmetabolic syndromes and in patients with established coronary artery disease. The adverse cardiovascular effects of EAT extend to influencing the development of atrial fibrillation and heart failure, mostly with preserved ejection fraction, through a combination of inflammatory, pro-fibrotic, and pro-arrhythmogenic pathways. In this work we provide an overview of the current understanding of the role of EAT in the development of several cardiovascular conditions as well as some of the therapeutic advances in the field.

Pulmonary hypertension associated with left heart disease (PH-LHD) represents the most prevalent form of pulmonary hypertension; however, being lacks precise and effective treatment strategies. Recent clinical studies have indicated a positive correlation between the volume of pericardiac adipose tissue (PAT) and the severity of PH-LHD. Nonetheless, there is a paucity of research characterizing PAT phenotypes in PH-LHD disease models. This study aimed to elucidate the gene-level characteristics of PAT in PH-LHD through RNA sequencing and targeted metabolomic analysis of PAT in order to identify potential therapeutic targets for PH-LHD by modulating PAT. This study developed a mouse model of PH-LHD through cardiac overload combined with metabolic syndrome and verified that PAT volume and adipocyte size were significantly increased in PH-LHD mice. We used RNA sequencing to reveal that DEGs in PAT were primarily enriched in fatty acid metabolism pathways. Then, real-time PCR showed no significant differences in the mRNA expression of inflammatory markers or adipocytokines; however, genes of fatty acid synthesis (Fasn, Acaca, and Scd1) and fatty acid decomposition (Ehhadh, Acot4, and Pdk1) significantly changed between the two groups. Consistently, targeted metabolomic analysis showed levels of most types of medium- and long-chain fatty acids substantially reduced in PAT, suggesting that PAT in PH-LHD mice exhibits suppressed fatty acid de novo synthesis and enhanced fatty acid breakdown, resulting in impaired fatty acid storage. These findings highlight the potential of targeting PAT fatty acid synthesis and metabolism pathways as a novel therapeutic approach for PH-LHD.

Epicardial adipose tissue (EAT), a unique fat depot surrounding the heart, plays a multifaceted role in glucose and lipid metabolism, thermogenesis, and the secretion of bioactive molecules that influence cardiac structure and function. Its proximity to the myocardium allows it to contribute directly to CVDs, including coronary artery disease, arrhythmias, and heart failure. In particular, excessive EAT has emerged as a significant factor in heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure, especially in individuals with obesity and diabetes. Traditional metrics like body mass index (BMI) fail to capture the complexities of visceral fat, as patients with similar BMIs can exhibit varying CVD risks. EAT accumulation induces mechanical stress and fosters a pro-inflammatory and fibrotic environment, driving cardiac remodeling and dysfunction. Pharmacological modulation of EAT has shown promise in delivering cardiometabolic benefits. Recent advancements in diabetes therapies, such as SGLT2 inhibitors and GLP-1 receptor agonists, and antilipidemic drugs have demonstrated their potential in reducing pro-inflammatory cytokine production and improving glucose regulation, which directly influences EAT. These discoveries suggest that EAT could be a significant therapeutic target, though further investigation is necessary to elucidate its role in HFpEF and other CVDs. Recent advances have identified the prokineticin/PKR1 signaling pathway as pivotal in EAT development and remodeling. This pathway regulates epicardial progenitor cells (EPDCs), promoting angiogenesis while reducing EAT accumulation and metabolic stress on the heart, particularly under high-calorie conditions. Prokineticin, acting through its receptor PKR1, limits visceral adipose tissue growth, enhances insulin sensitivity, and offers cardioprotection by reducing oxidative stress and activating cellular survival pathways. In this review, we provide a comprehensive analysis of EAT's role in CVDs, explore novel therapeutic strategies targeting EAT, and highlight the potential of prokineticin signaling as a promising treatment for HFpEF, obesity, and diabetes.

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.

Epicardial adiposity has been positively associated with visceral adipose tissue (VAT). Few studies have examined the association between cardiorespiratory fitness (CRF) and epicardial adiposity. Furthermore, whether this relationship was independent of VAT remains unexplored. Our purpose was to investigate the contribution of VAT in the relationships between CRF, physical activity (PA) and epicardial adipose tissue (EAT) in asymptomatic women and men.

We examined the associations between EAT and VAT measured by magnetic resonance imaging, CRF measured by cardiopulmonary exercise testing, and PA assessed using pedometers and a 3-day PA journal in 239 apparently healthy adults (43 % women). Participants were compared according to EAT tertiles and CRF level in both sexes. Participants with the highest EAT level presented more VAT (p < 0.001), lower CRF (p < 0.01), and a more deteriorated cardiometabolic health score (p < 0.01) than those with the lowest EAT level. CRF was negatively associated with EAT in both sexes (p < 0.01). No significant relationship was found with PA (p = NS). Stepwise multivariable regression analyses showed that VAT explained most of the variance in EAT in women and men. Mediation analyses confirmed that VAT was a mediator of the association between CRF and EAT in both sexes.

In women and men, VAT appears as a major mediator of the association between CRF and EAT thereby suggesting that managing VAT by improving CRF could help in the prevention of cardiometabolic disorders related to excess EAT.

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney disease Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6 months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.

Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.

Computed tomography (CT)-derived Epicardial Adipose Tissue (EAT) is linked to cardiovascular disease outcomes. However, its role in patients undergoing Transcatheter Aortic Valve Replacement (TAVR) and the interplay with aortic stenosis (AS) cardiac damage (CD) remains unexplored. We aim to investigate the relationship between EAT characteristics, AS CD, and all-cause mortality. We retrospectively included consecutive patients who underwent CT-TAVR followed by TAVR. EAT volume and density were estimated using a deep-learning platform and CD was assessed using echocardiography. Patients were classified according to low/high EAT volume and density. All-cause mortality at 4 years was compared using Kaplan-Meier and Cox regression analyses. A total of 666 patients (median age 81 [74-86] years; 54% female) were included. After a median follow-up of 1.28 (IQR 0.53-2.57) years, 11.7% (n = 77) of patients died. The EAT volume (p = 0.017) decreased, and density increased (p < 0.001) with worsening AS CD. Patients with low EAT volume (< 49cm3) and high density (≥-86 HU) had higher all-cause mortality (log-rank p = 0.02 and p = 0.01, respectively), even when adjusted for age, sex, and clinical characteristics (HR 1.71, p = 0.02 and HR 1.73, p = 0.03, respectively). When CD was added to the model, low EAT volume (HR 1.67 p = 0.03) and CD stages 3 and 4 (HR 3.14, p = 0.03) remained associated with all-cause mortality. In patients with AS undergoing TAVR, CT-derived low EAT volume, and high density were independently associated with increased 4-year mortality and worse CD stage. Only EAT volume remained associated when adjusted for CD.

This study aims to investigate the relationship between epicardial adipose tissue (EAT) and left atrial function in patients with preserved ejection fraction heart failure (HFpEF).

We conducted a cross-sectional study involving 113 patients diagnosed with HFpEF and 48 control subjects without heart failure. Echocardiography was performed to assess EAT thickness and left atrial function was quantified using Autostrain left atrium (LA), including left atrial strain during reservoir phase (LASr), left atrial strain during conduit phase (LAScd), and left atrial strain during contraction phase (LASct). Clinical and biochemical parameters were correlated with EAT and LA strain using regression analyses and generating receiver operating characteristic (ROC) curves for left atrial strain parameters.

EAT thickness was significantly greater in the HFpEF group (8.0 ± 1.0 mm) compared to the control group (5.0 ± 0.7 mm). HFpEF group exhibited poorer left ventricle diastolic function, indicated by lower e' velocity, E/A ratio, and higher E/e' values. Left atrial strain parameters, including LASr (22.4 ± 9.1%), LAScd (11.9 ± 6.9%), and LASct (10.5 ± 3.9%), were all lower in the HFpEF. EAT thickness was positively correlated with NT-proBNP, triglycerides, and fasting blood glucose. Multivariate analysis revealed significant associations between EAT and LA strain parameters even after adjusting for potential confounders. ROC curve analysis indicated that LASr had the highest diagnostic accuracy for HFpEF. Additionally, left atrial strain parameters were strongly correlated with left ventricular diastolic function.

Patients with HFpEF exhibit increased EAT thickness and reduced left atrial function. The thickening of EAT is associated with a decrease in left atrial strain. LA strain, particularly LASr, may serve as a sensitive indicator for early detection of left ventricular diastolic dysfunction in HFpEF.

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

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various phenotypes, and obesity is one of the most common and clinically relevant phenotypes of HFpEF. Obesity contributes to HFpEF through multiple mechanisms, including sodium retention, neurohormonal dysregulation, altered energy substrate metabolism, expansion of visceral adipose tissue, and low-grade systemic inflammation. Glucagon-like peptide-1 (GLP-1) is a hormone in the incretin family. It is produced by specialized cells called neuroendocrine L cells located in the distal ileum and colon. GLP-1 reduces blood glucose levels by promoting glucose-dependent insulin secretion from pancreatic β cells, suppressing glucagon release from pancreatic α cells, and blocking hepatic gluconeogenesis. Recent evidence suggests that GLP-1 receptor agonists (GLP-1 RAs) can significantly improve physical activity limitations and exercise capacity in obese patients with HFpEF. The possible cardioprotective mechanisms of GLP-1 RAs include reducing epicardial fat tissue thickness, preventing activation of the renin-angiotensin-aldosterone system, improving myocardial energy metabolism, reducing systemic inflammation and cardiac oxidative stress, and delaying the progression of atherosclerosis. This review examines the impact of obesity on the underlying mechanisms of HFpEF, summarizes the trial data on cardiovascular outcomes of GLP-1 RAs in patients with type 2 diabetes mellitus, and highlights the potential cardioprotective mechanisms of GLP-1 RAs to give a pathophysiological and clinical rationale for using GLP-1 RAs in obese HFpEF patients.

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) has been suggested to play paradoxical roles in patients with heart failure. The role of EAT in dilated cardiomyopathy (DCM) patients remains unclear. We aimed to assess the associations between the dynamic changes EAT and left ventricular reverse remodeling (LVRR) in DCM patients based on baseline and follow-up CMR.

In this prospective study, we consecutive enrolled DCM patients with baseline and follow-up cardiac magnetic resonance (CMR) examinations. All participating patients underwent 1-2 years of guideline-directed medical therapy (GDMT) at follow-up. The EAT was measured as pericardial and epicardial fat thickness, and paracardial fat volume, while the abdominal adiposity was measured in terms of subcutaneous and visceral fat thickness. The univariable and multivariable logistic regression analyses were performed to evaluate the associations of changes in abdominal and epicardial adiposities with the presence of LVRR.

A total of 232 patients (mean age, 45.7 ± 15.1 years, 157 male) at baseline were enrolled. After a period of GDMT with a median duration of 15.5 months (interquartile range, 12.5-19.1 months) all participants underwent follow-up CMR with the same standardized protocol. Patients who reached LVRR showed a significant increment in EAT parameters compared to those who did not. After adjusting for age, sex, and delta changes of body mass index (BMI), the increment of pericardial fat thickness (odds ratio [OR]: 1.53; 95% confidence interval [CI]: 1.27 to 1.83; p < 0.001), epicardial fat thickness (OR: 2.10; 95% CI: 1.68 to 2.63; p < 0.001), and paracardial fat volume (OR: 1.01; 95% CI: 1.01 to 1.02; p = 0.001) were significantly associated with LVRR.

In DCM patients, the CMR-derived EAT parameters increased after 1-2 years of GDMT and significantly correlated with improved ventricular structure and function, independent of changes in BMI and abdominal adiposity, which may indicate the potential protective role of EAT in DCM patients.

URL: https://www.

gov ; Unique identifier: ChiCTR1800017058.

Epicardial adipose tissue (EAT) accumulation is thought to play a role in the pathophysiology of heart failure (HF) with mid-range ejection fraction and HF with preserved ejection fraction, but its effect on outcome is unknown.

A total of 692 patients with HF with mid-range ejection fraction or HF with preserved ejection fraction who underwent cardiovascular magnetic resonance at 2 medical centers in China between October 2016 and October 2022 were included in this study. EAT volume and extracellular volume were calculated using cardiovascular magnetic resonance. The main outcome was the composite of all-cause mortality and first HF hospitalization. Of 692 participants, 41.3% were women. The mean age, body mass index, left ventricular ejection fraction, and EAT volume were 57.0 years, 27.2 kg/m2, 50.0%, and 67.1 mL/m2, respectively. During a median follow-up of 34 months, 169 patients (24.4%) died or were hospitalized for HF. EAT volume exhibited a strong unadjusted association with the composite outcome (hazard ratio per 1 mL/m2 [HR], 1.57 [95% CI, 1.40-1.76], P<0.001). After fully adjusting, EAT remained associated with the outcome (HR, 1.62 [95% CI, 1.42-1.86], P<0.001). We constructed a baseline multivariable model including comorbidities, New York Heart Association functional class, extracellular volume, age, body mass index, left ventricular ejection fraction, and N-terminal pro-brain natriuretic peptide. Addition of EAT volume to the baseline multivariable model significantly improved model performance (C statistic improvement: 0.711-0.760; P<0.001).

EAT accumulation is associated with an adverse prognosis in patients with HF with mid-range ejection fraction and those with HF with preserved ejection fraction. In addition, EAT provides incremental prognostic value beyond left ventricular ejection fraction and New York Heart Association class.

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.

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.

Heart failure (HF) is the predominant terminal stage and the leading cause of mortality in cardiac disease. Heart failure with preserved ejection fraction (HFpEF) affects roughly 50% of HF patients globally. Due to the global aging population, the prevalence, morbidity, and mortality of HFpEF have gradually increased. Epicardial adipose tissue (EAT), as a key visceral adipose tissue around the heart, affects cardiac diastolic function and exercise reserve capacity. EAT closely adheres to the myocardium and can produce inflammatory factors, neurotransmitters, and other factors through autocrine or paracrine mechanisms, affecting the heart function by inflammatory response, cardiac metabolism and energy supply, cardiomyocyte structure and electrical activity, and pericardial vascular function. Currently, research on the mechanism and treatment methods of HFpEF is constantly improving. EAT may play a multi-level impact on the occurrence and development of HFpEF. This review also summarizes the potential impact of EAT on the heart in HFpEF combined with other metabolism-related diseases such as obesity or diabetes over other obesity-related measures, such as body mass index (BMI) or other adipose tissue. Above all, this review comprehensively summarizes the potential mechanisms by which EAT may affect HFpEF. The objective is to enhance our comprehension and management of HFpEF. Future research should delve into the mechanistic relationship between EAT and HFpEF, and investigate interventions aimed at EAT to improve the prognosis of patients with HFpEF.

Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose.

We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials.

HuMAIN will test a promising novel agent for obesity-related HFpEF.

Epicardial adipose tissue (EAT) quantity is associated with poor cardiovascular outcomes. However, the quality of EAT may be of incremental prognostic value. Cardiac magnetic resonance (CMR) is the gold standard for tissue characterization but has never been applied for EAT quality assessment. We aimed to investigate EAT quality measured on CMR T1 mapping as a predictor of poor outcomes in an all-comer cohort.

We investigated the association of EAT area and EAT T1 times (EAT-T1) with a composite endpoint of nonfatal myocardial infarction, heart failure hospitalization, and all-cause death.

A total of 966 participants were included (47.2% female; mean age: 58.4 years) in this prospective observational CMR registry. Mean EAT area and EAT-T1 were 7.3 cm2 and 268 ms, respectively. On linear regression, EAT-T1 was not associated with markers of obesity, dyslipidemia, or comorbidities such as diabetes (p > 0.05 for all). During a follow-up of 57.7 months, a total of 280 (29.0%) events occurred. EAT-T1 was independently associated (adjusted hazard ratio per SD: 1.202; 95% CI: 1.022-1.413; p = 0.026) with the composite endpoint when adjusted for established clinical risk.

EAT quality (as assessed via CMR T1 times), but not EAT quantity, is independently associated with a composite endpoint of nonfatal myocardial infarction, heart failure hospitalization, and all-cause death.

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.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and has a prevalence that is expected to rise with the growing ageing population. HFpEF is associated with significant morbidity and mortality. Specific HFpEF risk factors include age, diabetes, hypertension, obesity and atrial fibrillation. Haemodynamic contributions to HFpEF include changes in left ventricular structure, diastolic and systolic dysfunction, left atrial myopathy, pulmonary hypertension, right ventricular dysfunction, chronotropic incompetence, and vascular dysfunction. Inflammation, fibrosis, impaired nitric oxide signalling, sarcomere dysfunction, and mitochondrial and metabolic defects contribute to the cellular and molecular changes observed in HFpEF. HFpEF impacts multiple organ systems beyond the heart, including the skeletal muscle, peripheral vasculature, lungs, kidneys and brain. The diagnosis of HFpEF can be made in individuals with signs and symptoms of heart failure with abnormality in natriuretic peptide levels or evidence of cardiopulmonary congestion, facilitated by the use of HFpEF risk scores and additional imaging and testing with the exclusion of HFpEF mimics. Management includes initiation of guideline-directed medical therapy and management of comorbidities. Given the significant impact of HFpEF on quality of life, future research efforts should include a particular focus on how patients can live better with this disease.

Cardiovascular diseases (CVDs) remain a major global health challenge, leading to significant morbidity and mortality while straining healthcare systems. Despite progress in medical treatments for CVDs, their increasing prevalence calls for a shift towards more effective prevention strategies. Traditional preventive approaches have centered around lifestyle changes, risk factors management, and medication. However, the integration of imaging methods offers a novel dimension in early disease detection, risk assessment, and ongoing monitoring of at-risk individuals. Imaging techniques such as supra-aortic trunks ultrasound, echocardiography, cardiac magnetic resonance, and coronary computed tomography angiography have broadened our understanding of the anatomical and functional aspects of cardiovascular health. These techniques enable personalized prevention strategies by providing detailed insights into the cardiac and vascular states, significantly enhancing our ability to combat the progression of CVDs. This review focuses on amalgamating current findings, technological innovations, and the impact of integrating advanced imaging modalities into cardiovascular risk prevention, aiming to offer a comprehensive perspective on their potential to transform preventive cardiology.

Heart failure (HF) with improved ejection fraction (EF, HFimpEF) is a distinct HF subtype, characterized by left ventricular (LV) reverse remodeling and myocardial functional recovery. Multiple cardiometabolic factors are implicated in this process. Epicardial adipose tissue (EAT), emerging as an endocrine and paracrine organ, contributes to the onset and progression of HF. However, the relation between EAT and the incidence of HFimpEF is still unclear.

A total of 203 hospitalized HF patients with reduced EF (HFrEF, LVEF ≤ 40%) who underwent coronary CT angiography (CCTA) during index hospitalization were consecutively enrolled between November 2011 and December 2022. Routine follow-up and repeat echocardiograms were performed. The incidence of HFimpEF was defined as (1) an absolute LVEF improvement ≥ 10% and (2) a second LVEF > 40% (at least 3 months apart). EAT volume and density were semiautomatically quantified on non-enhanced series of CCTA scans.

During a median follow-up of 8.6 (4.9 ~ 13.3) months, 104 (51.2%) patients developed HFimpEF. Compared with HFrEF patients, HFimpEF patients had lower EAT volume (115.36 [IQR 87.08 ~ 154.78] mL vs. 169.67 [IQR 137.22 ~ 218.89] mL, P < 0.001) and higher EAT density (-74.92 ± 6.84 HU vs. -78.76 ± 6.28 HU, P < 0.001). Multivariate analysis showed lower EAT volume (OR: 0.885 [95%CI 0.822 ~ 0.947]) and higher density (OR: 1.845 [95%CI 1.023 ~ 3.437]) were both independently associated with the incidence of HFimpEF. Subgroup analysis revealed that the association between EAT properties and HFimpEF was not modified by HF etiology.

This study reveals that lower EAT volume and higher EAT density are associated with development of HFimpEF. Therapies targeted at reducing EAT quantity and improving its quality might provide favorable effects on myocardial recovery in HF patients.

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi-imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost-effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium-glucose co-transporter-2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF.

Epicardial adipose tissue (EAT) is associated with the development of cardiovascular disease and long-term survival. This study aimed to assess the characteristics of EAT according to the metabolic health and obesity status using low-dose chest computed tomography (CT).

A total of 1074 asymptomatic adults who underwent a medical health check-up were enrolled. Subjects were categorized into the following four groups according to the metabolic health and obesity status: metabolically healthy non-obese (MHNO); metabolically unhealthy non-obese (MUNO); metabolically healthy obese (MHO); and metabolically unhealthy obese (MUO). EAT on low-dose chest CT was measured by using automatic, quantitative measurement software.

MUO showed the highest EAT volume and lowest EAT radiodensity in comparison with MHNO (p < 0.001). The MUNO (n = 70), MHO (n = 259), and MUO (n = 231) groups had increased EAT volume (β [95 % CI], 37.65 [23.11,52.18], 56.79 [47.56,66.02], 84.85 [74.59,95.11] respectively, all p < 0.001), decreased EAT radiodensity (β [95 % CI], - 3.22 [- 4.59,- 1.85], - 4.48 [- 5.30,- 3.66], - 6.03 [- 6.90,- 5.16] respectively, all p < 0.001) in comparison with the MHNO (n = 514) group by using multivariable linear regression models.

Both metabolic abnormalities and obesity were closely associated with EAT characteristics. Characteristics of EAT are similar in MHO and MUNO. This finding suggests that MHO is not a favorable condition in terms of cardiac health, as assessed by the characteristics of EAT. The combination of obesity and metabolically unhealthy status has a synergistic adverse effect on EAT. Measurement of EAT could be a useful imaging biomarker for evaluation of an individual's metabolic health/obesity status.

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.

Inflammation triggers atherosclerotic plaque rupture, leading to acute myocardial infarction (AMI). Following AMI, peri-coronary adipose tissue (PCAT) undergoes a transition from lipid-rich to hydrophilic characteristics due to vascular inflammation. This study investigates PCAT changes and neutrophil-to-lymphocyte ratio levels during AMI.

60 AMI patients undergoing coronary computed tomography angiography and angiography (Jan 2020-Jun 2022) were studied 60 age, gender, BMI-matched stable angina, and 60 non-coronary artery disease patients were included. Siemens VB20.0 measured PCAT-volume and fat attenuation index (FAI). Neutrophil-to-lymphocyte ratio levels were calculated by peripheral blood tests.

The PCAT volume and PCAT-FAI gradually increased across the control, stable angina, and AMI groups, with a corresponding gradual rise in NLR. NLR exhibited weak positive correlation with PCAT-FAI (r=0.35) and PCAT-volume (r=0.24). Multivariable logistic regression identified increased PCAT-volume, PCAT-FAI and neutrophil-to-lymphocyte ratio as possible independent AMI risk factors. No significant PCAT-volume difference was observed between infarct-related artery (IRA) and non-IRA for all three coronary arteries. Only PCAT-FAI around IRA-LAD was higher than non-IRA-LAD (-74.84±6.93 HU vs -79.04±8.68 HU). PCAT-FAI around culprit vessels in AMI was higher than corresponding lesion related vessel in SA. PCAT-volume around narrowed non-IRA in AMI was higher than that of corresponding LRV in SA. PCAT-FAI of narrowed non-IRA-LADs and non-IRA-LCXs in AMI were elevated compared to LADs (-78.46±8.56HU vs -83.13±8.34 HU) and LCXs (-73.83±10.63 HU vs -81.38±7.88 HU) of lesion related vessel in stable angina.

We found an association between AMI and inflammation in the coronary perivascular adipose tissue and systemic inflammatory response.

Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome, making it challenging to improve prognosis with pharmacotherapy. Obesity is one of the leading phenotypes of HFpEF, and its prevalence continues to grow worldwide. Consequently, obesity-targeted interventions have attracted attention as a novel treatment strategy for HFpEF.

The authors review the association between the pathogenesis of obesity and HFpEF and the potential for obesity-targeted pharmacotherapeutic strategies in HFpEF, together with the latest evidence. The literature search was conducted in PubMed up to April 2024.

The STEP HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) and SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trials recently demonstrated that the glucagon-like peptide 1 analogue, semaglutide, improves various aspects of clinical outcomes in obese HFpEF patients and significantly reduces cardiovascular and heart failure events in non-diabetic obese patients, along with a substantial weight loss. Future clinical trials with other incretin mimetics with more potent weight loss and sub-analyses of the SELECT trial may further emphasize the importance of the obesity phenotype-based approach in the treatment of HFpEF.

Cardiometabolic diseases (CMDs) are interrelated and multifactorial conditions, including arterial hypertension, type 2 diabetes, heart failure, coronary artery disease, and stroke. Due to the burden of cardiovascular morbidity and mortality associated with CMDs' increasing prevalence, there is a critical need for novel diagnostic and therapeutic strategies in their management. In clinical practice, innovative methods such as epicardial adipose tissue evaluation, ventricular-arterial coupling, and exercise tolerance studies could help to elucidate the multifaceted mechanisms associated with CMDs. Similarly, epigenetic changes involving noncoding RNAs, chromatin modulation, and cellular senescence could represent both novel biomarkers and targets for CMDs. Despite the promising data available, significant challenges remain in translating basic research findings into clinical practice, highlighting the need for further investigation into the complex pathophysiology underlying CMDs.