CoChat
Sign Up
Cited by 62Cardiovascular Disease and AdiposityCardiovascular Function and Risk FactorsHeart Failure Treatment and Management

Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes

Open access
Salvatore, Teresa, Galiero, Raffaele, Caturano, Alfredo, Vetrano, Erica, Rinaldi, Luca, Coviello, Francesca, Di Martino, Anna, Albanese, Gaetana +5 more·2022·Biomolecules
DOI 10.3390/biom12020176PMC PMC8961672
Open this paper in CoChat — free accountOpen PDF

Abstract

Cardiovascular (CV) disease and heart failure (HF) are the leading cause of mortality in type 2 diabetes (T2DM), a metabolic disease which represents a fast-growing health challenge worldwide. Specifically, T2DM induces a cluster of systemic metabolic and non-metabolic signaling which may promote myocardium derangements such as inflammation, fibrosis, and myocyte stiffness, which represent the hallmarks of heart failure with preserved ejection fraction (HFpEF). On the other hand, several observational studies have reported that patients with T2DM have an abnormally enlarged and biologically transformed epicardial adipose tissue (EAT) compared with non-diabetic controls. This expanded EAT not only causes a mechanical constriction of the diastolic filling but is also a source of pro-inflammatory mediators capable of causing inflammation, microcirculatory dysfunction and fibrosis of the underlying myocardium, thus impairing the relaxability of the left ventricle and increasing its filling pressure. In addition to representing a potential CV risk factor, emerging evidence shows that EAT may guide the therapeutic decision in diabetic patients as drugs such as metformin, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is), have been associated with attenuation of EAT enlargement.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review proposes that dysregulated epicardial adipose tissue (EAT) links diabetes to heart failure with preserved ejection fraction (HFpEF) through mechanical, metabolic, paracrine, and vasocrine mechanisms, making EAT a potential risk marker and therapeutic target. It summarizes evidence that several glucose- and lipid-lowering therapies, especially SGLT2 inhibitors, can reduce EAT.

Key findings

  • Diabetes is associated with expanded EAT: a meta-analysis of 13 studies including 1102 diabetic patients and 813 healthy subjects found significantly higher EAT in diabetes irrespective of T1DM/T2DM, BMI, or measurement technique; EAT thickness is almost double in metabolic syndrome versus controls.
  • Enlarged, biologically transformed EAT may promote HFpEF via mechanical constriction, fatty acid overfeeding/myocardial steatosis, and secretion of leptin, TNF-α, IL-6, IL-1b, and resistin with reduced adiponectin, leading to inflammation, coronary microvascular dysfunction, fibrosis, and increased LV filling pressure/stiffness. Diabetes accounts for about 45% of HFpEF patients, and 30% of HFpEF patients have both obesity and T2DM; diastolic dysfunction can be detected in 75% of asymptomatic T2DM patients.
  • Therapeutic studies report EAT reduction with metformin in small studies; liraglutide reduced EAT thickness by 29% at 3 months and 36% at 6 months; semaglutide/dulaglutide reduced EAT by about 20% after 12 weeks; dapagliflozin reduced EAT by 20% versus 8% body weight change at week 24; PCSK9 inhibitors reduced EAT thickness by 20% after 6 months; statins produced a 7% mean decrease after 6–8 months.
  • In EMPEROR-Preserved, empagliflozin lowered the composite of CV death and HF hospitalization by 21% and HF hospitalization by 29% over a median of 26.2 months, independent of diabetes status.

Methods

  • Design: narrative review; the authors state they aim to highlight available evidence that EAT may couple diabetes and HFpEF and respond to fat-targeted therapies.
  • Data/sample: no original dataset; the paper synthesizes cited human observational studies, meta-analyses, randomized trials, animal models, and in vitro studies, including a table of glucose-lowering drug effects on EAT.
  • Main analysis: narrative synthesis of pathophysiological mechanisms and therapeutic evidence; no systematic search strategy, formal meta-analysis, or risk-of-bias assessment is described.

Limitations

  • Paper-stated: HFpEF lacks effective treatments beyond lifestyle optimization and symptomatic diuretics; knowledge gaps remain about whether manipulating EAT improves outcomes; a robust, low-operator-dependence method for EAT quantification is needed; metformin evidence is doubtful and requires a dedicated placebo-controlled trial with EAT measurement; heterogeneity between studies on pharmacologic EAT reduction is significant.
  • Evident from the text: this is a narrative review without a described systematic search or quality appraisal; many cited EAT studies are small, observational, or pilot studies, and some drug findings are discordant (e.g., liraglutide and empagliflozin failed to reduce EAT in some trials), so causality and class effects remain uncertain.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/biom12020176

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 165 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    EAT may act as a possible intermediary coupling diabetes and HFpEF.

    “In this review, we want to highlight the available evidence indicating that EAT may act as a possible intermediary coupling diabetes and HFpEF, and that it may positively respond to fat targeted therapies.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Human EAT is richer in saturated fatty acids and poorer in unsaturated ones compared with subcutaneous adipose tissue.

    “Compared with subcutaneous adipose tissue (SAT), human EAT is richer in saturated fatty acids (FAs) and poorer in unsaturated ones [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Pezeshkian, 2009, Fatty acid composition of epicardial and subcutaneous human adipose tissue, Metab. Syndr. Relat. Disord. source

      Not checked in the free run.

  • Premisecitation

    Diabetic patients often exhibit an abnormally expanded EAT, usually in association with obesity and metabolic syndrome in both T2DM and T1DM.

    “On the other hand, diabetic patients often exhibit an abnormally expanded EAT, usually in association with obesity and metabolic syndrome in both T2DM and T1DM [19,20,21,22].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Iacobellis, 2008, Relationship of epicardial fat thickness and fasting glucose, Int. J. Cardiol. source

      Not checked in the free run.

    • cites [20] Cakici, 2013, Relation of epicardial fat thickness with carotid intima-media thickness in patients with type 2 diabetes mellitus, Int. J. Endocrinol.

      Not checked in the free run.

    • cites [21] Wang, 2009, Increased epicardial adipose tissue (EAT) volume in type 2 diabetes mellitus and association with metabolic syndrome and severity of coronary atherosclerosis, Clin. Endocrinol. source

      Not checked in the free run.

    • cites [22] Momesso, 2011, Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome, Diabetes Res. Clin. Pract. source

      Not checked in the free run.

  • Interpretationreasoning

    EAT may positively respond to fat-targeted therapies.

    “In this review, we want to highlight the available evidence indicating that EAT may act as a possible intermediary coupling diabetes and HFpEF, and that it may positively respond to fat targeted therapies.”
    Quote in the paperSubstantial claim
  • Premisereasoning

    EAT contributes to heart physiology by mechanical, metabolic, thermogenic, and paracrine/vasocrine mechanisms.

    “EAT may contribute to heart physiology by mechanical, metabolic, thermogenic, and paracrine/vasocrine mechanisms.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 62

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    T2DM increases the incidence of HF up to more than double with respect to non-affected individuals, and this complication may develop independently of coronary artery disease and associated risk factors.

    “Since the report of the Framingham Heart study, type 2 diabetes (T2DM) has been known to increase the incidence of HF up to more than double with respect to non-affected individuals, with the growing awareness that this complication may develop independently of coronary artery disease (CAD) and associated risk factors [8,9,10,11].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [8] Kannel, 1979, Diabetes and cardiovascular disease. The Framingham study, JAMA source

      Not checked in the free run.

    • cites [9] Nichols, 2001, Congestive heart failure in type 2 diabetes: Prevalence, incidence, and risk factors, Diabetes Care source

      Not checked in the free run.

    • cites [10] Cas, 2015, Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure, JACC Heart Fail. source

      Not checked in the free run.

    • cites [11] Lehrke, 2017, Diabetes Mellitus and Heart Failure, Am. J. Cardiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EAT exerts mechanical protection of coronary arteries from excessive distortion and compression during contraction of neighbouring myocardium.

    “Due to its spatial distribution, EAT exerts mechanical protection of coronary arteries from excessive distortion and compression during the contraction of neighbouring myocardium [29,30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Szasz, 2012, Perivascular adipose tissue: More than just structural support, Clin. Sci. source

      Not checked in the free run.

    • cites [30] Iacobellis, 2015, Local and systemic effects of the multifaceted epicardial adipose tissue depot, Nat. Rev. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT is located under the visceral pericardium in anatomical continuity with the myocardium and is supplied by branches of coronary arteries with a shared microcirculation that facilitates direct crosstalk with the myocardium.

    “Otherwise, EAT is located under the visceral pericardium in anatomical continuity with the myocardium and is embriologically derived, as mesenteric and omental fat, from the brown adipose tissue (BAT) of splanchnic mesoderm. Importantly, EAT is supplied by branches of coronary arteries with a shared microcirculation that facilitate a direct crosstalk with the myocardium [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Iacobellis, 2009, Epicardial and pericardial fat: Close, but very different, Obesity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diabetes markedly increases the development, morbidity and mortality of HFpEF.

    “Diabetes markedly increases the development, morbidity and mortality of HF with preserved ejection fraction (HFpEF), showing a particularly close link with this clinical entity [14,15].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Mentz, 2014, Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction, J. Am. Coll. Cardiol. source

      Not checked in the free run.

    • cites [15] Sandesara, 2018, The Prognostic Significance of Diabetes and Microvascular Complications in Patients with Heart Failure with Preserved Ejection Fraction, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an autopsy study of patients with ante mortem diagnosis of HFpEF, the myocardium morphology was featured by severe hypertrophy, microvascular rarefaction, and fibrosis.

    “In an autopsy study in patients with ante mortem diagnosis of HFpEF, the myocardium morphology was featured by severe hypertrophy, microvascular rarefaction, and fibrosis [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Mohammed, 2015, Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired bioavailability of nitric oxide impairs its downstream cGMP protein kinase G (PKG) pathway in cardiomyocytes, which become hypertrophied and stiffened.

    “As a result, the impaired bioavailability in nitric oxide impairs its downstream cGMP protein kinase G (PKG) pathway in cardiomyocytes which become hypertrophied and stiffened [65,67].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Paulus, 2015, Clinical diabetic cardiomyopathy: A two-faced disease with restrictive and dilated phenotypes, Eur. Heart J. source

      Not checked in the free run.

    • cites [67] Paulus, 2013, A Novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under physiological conditions, EAT secretes adiponectin, which nourishes the myocardium contributing to FAs combustion, and exerts protective actions against hypertrophy stimuli for cardiomyocytes and against inflammation and fibrosis of myocardium and coronary arteries.

    “Under physiological conditions, EAT secretes the adiponectin, an adipocyte-derived adaptive adipokine that nourishes the myocardium contributing to FAs combustion, and exerts a series of protective actions against hypertrophy stimuli for cardiomyocytes and against inflammation and fibrosis of myocardium and coronary arteries [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Packer, 2018, Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In diabetic subjects, EAT adipocyte size is significantly larger than in non-diabetic subjects, and both SAT and EAT have a predominantly inflammatory profile.

    “In a bioptical study comparing SAT and EAT among subjects with or without diabetes, adipocyte size in EAT was significantly larger in diabetic than non-diabetic subjects, and both SAT and EAT were featured in diabetic group by a predominantly inflammatory profile [62].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Bambace, 2014, Inflammatory profile in subcutaneous and epicardial adipose tissue in men with and without diabetes, Heart Vessel. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT adiposity is associated with alterations of myocardial function in T2DM people and may be a predictor of diastolic dysfunction in newly diagnosed patients.

    “Importantly, EAT adiposity is associated with alterations of myocardial function in T2DM people and may be a predictor of diastolic dysfunction in new diagnosed patients [60,61].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Christensen, 2019, Epicardial and pericardial adipose tissues are associated with reduced diastolic and systolic function in type 2 diabetes, Diabetes Obes. Metab. source

      Not checked in the free run.

    • cites [61] Kazlauskaite, 2010, Predictors of diastolic dysfunction among minority patients with newly diagnosed type 2 diabetes, Diabetes Res. Clin. Pract. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These two phenotypes are not successive stages of diabetic cardiomyopathy, but two pictures that independently may evolve to HFrEF or HFpEF.

    “These two phenotypes are not successive stages of diabetic cardiomyopathy, but two pictures that independently may evolve to HFrEF or HFpEF, respectively [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Paulus, 2015, Clinical diabetic cardiomyopathy: A two-faced disease with restrictive and dilated phenotypes, Eur. Heart J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diabetic cardiomyopathy may clinically manifest as eccentric LV dilatation impairing systolic function or as restrictive concentric LV remodeling determining diastolic dysfunction.

    “Diabetic cardiomyopathy may clinically manifest as a condition of eccentric left ventricle (LV) dilatation impairing systolic function, as classically described, or as a restrictive concentric LV remodeling determining diastolic dysfunction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Paulus, 2015, Clinical diabetic cardiomyopathy: A two-faced disease with restrictive and dilated phenotypes, Eur. Heart J. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    An enlarged and biologically transformed EAT loses its physiological protective role and acquires lipotoxic effects through excess FFA release, leading to abnormal lipid deposition and fatty infiltration in the myocardium.

    “This is what can happen when an enlarged and biologically transformed EAT coats the heart, thus losing its physiological protective role, and acquiring lipotoxic effects throughout an excess FFa release, which leads to abnormal lipid deposition and fatty infiltration in the myocardium [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Iacobellis, 2019, Epicardial adipose tissue feeding and overfeeding the heart, Nutrition source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT provides FAs directly to myocardium at times of high energy demand and implements local triacylglycerol storage as request decreases.

    “To that end, EAT provides FAs directly to myocardium at times of high energy demand and implements the local triacylglycerol storage as request decreases [34,35].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Burgeiro, 2016, Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [35] Nagy, 2017, Clinical importance of epicardial adipose tissue, Arch. Med. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT thickness is almost double in individuals with metabolic syndrome compared to controls, with a significant correlation with each component of syndrome.

    “It has been calculated that EAT thickness is almost double in individuals with metabolic syndrome compared to controls, with a significant correlation with each component of syndrome [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Rabkin, 2014, The relationship between epicardial fat and indices of obesity and the metabolic syndrome: A systematic review and meta-analysis, Metab. Syndr. Relat. Disord. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several pathophysiological mechanisms associated with diabetes may contribute to diabetic cardiomyopathy: oxidative stress, inflammation, impaired mitochondrial energetics, altered intracellular calcium handling, and increased neuro-humoral activation, determining myocardial inflammation, hypertrophy, fibrosis, and coronary microvascular disease.

    “Several pathophysiological mechanisms associated with diabetes may contribute to this entity, namely oxidative stress, inflammation, impaired mitochondrial energetics, altered intracellular calcium handling, and increased neuro-humoral activation, that all together determine myocardial inflammation, hypertrophy, fibrosis, and coronary microvascular disease [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Salvatore, 2021, The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms, Front. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT is an extremely active endocrine organ producing adipocytokines involved in thermogenesis, lipid and glucose metabolism, and pro-inflammatory and anti-inflammatory response.

    “EAT is an extremely active endocrine organ producing adipocytokines, not only ones involved in thermogenesis and regulation of lipid and glucose metabolism, but even those capable of both pro-inflammatory and anti-inflammatory response”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Iacobellis, 2005, Epicardial adipose tissue: Anatomic, biomolecular and clinical relationships with the heart, Nat. Clin. Pract. Cardiovasc. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT has a unique transcriptome enriched in genes involved in coagulation, endothelial function, phospholipase activity, apoptosis, and immune signaling, and a secretome that may be influenced by environmental, epigenetic, and genetic factors.

    “EAT has a unique transcriptome enriched in genes involved in coagulation, endothelial function, phospholipase activity, apoptosis, and immune signaling, and a secretome that may be influenced by environmental, epigenetic, and genetic factors [43,44,45].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] McAninch, 2015, Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease, Obesity source

      Not checked in the free run.

    • cites [44] Camarena, 2017, Novel atherogenic pathways from the differential transcriptome analysis of diabetic epicardial adipose, tissue, Nutr. Metab. Cardiovasc. Dis. source

      Not checked in the free run.

    • cites [45] Ansaldo, 2019, Epicardial adipose tissue and cardiovascular diseases, Int. J. Cardiol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    HFpEF may be considered an inflammatory cardiometabolic disease in which comorbidities involving a systemic inflammatory condition induce oxidative stress and endothelial dysfunction in the coronary microvascular endothelium.

    “According to a paradigm suggested by Paulus and Tschöpe almost a decade ago, HFpEF may be considered an inflammatory cardiometabolic disease in which comorbidities involving a systemic inflammatory condition induce oxidative stress and endothelial dysfunction in the coronary microvascular endothelium.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Excess fat surrounding the coronary arteries causes inflammation and accelerated atherosclerosis at this level, acting in a paracrine manner, contributing to CAD-related HF.

    “Basically, it may concur to the development of a CAD-related HF, because the excess of fat surrounding the coronary arteries causes inflammation and accelerated atherosclerosis at this level, acting in a paracrine manner.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Sinha, 2016, Epicardial Adipose Tissue Thickness and Its Association With the Presence and Severity of Coronary Artery Disease in Clinical Setting: A Cross-Sectional Observational Study, J. Clin. Med. Res. source

      Not checked in the free run.

    • cites [84] Rodenbeck, 2017, Epicardial Adipose Tissue Removal Potentiates Outward Remodeling and Arrests Coronary Atherogenesis, Ann. Thorac. Surg. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In TOPCAT, three phenogroups were identified, one of which represented by 'Obese, diabetic with advanced symptoms'; these subjects exhibited the worst overall prognosis and the highest levels of biomarkers of TNF-α mediated inflammation.

    “In a recent study in participants of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial), three phenogroups were identified, one of which represented by “Obese, diabetic with advanced symptoms”. These subjects exhibited the worst overall prognosis and the highest levels of biomarkers of TNF-α mediated inflammation [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Cohen, 2020, Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone, JACC Heart Fail. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    About 45% of people suffering from HFpEF have diabetes, with a significantly increasing proportion in those with new-onset HFpEF.

    “In the past decade, HFpEF has taken on great importance in individuals with diabetes who represent about 45% of people suffering from this type of HF, with a significantly increasing proportion in those with new-onset HFpEF [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Xu, 2016, Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: Findings from Get With The Guidelines-Heart Failure registry, Am. Heart J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The secretion pattern of EAT is considerably different from SAT and PAT, and in diabetic compared to non-diabetic individuals.

    “The study also demonstrated that the secretion pattern of EAT was considerably different from SAT and PAT, and in diabetic compared to non-diabetic individuals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Greulich, 2012, Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both morbidity and long-term mortality of HFpEF are greatly worsened by a coexisting diabetes, and this adverse outcome cannot be offset by effective treatments.

    “Both morbidity and long-term mortality of HFpEF are greatly worsened by a coexisting diabetes and this adverse outcome cannot be offset by effective treatments [71,76].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] McHugh, 2019, Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review, J. Am. Coll. Cardiol. source

      Not checked in the free run.

    • cites [76] Aguilar, 2010, Comparison of patients with heart failure and preserved left ventricular ejection fraction among those with versus without diabetes mellitus, Am. J. Cardiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Thirty percent of HFpEF patients have both obesity and T2DM, and this prevalence is expected to grow worldwide.

    “Thirty percent of HFpEF patients have both obesity and T2DM, and this prevalence is expected to grow worldwide due to the pandemic of these diseases, as well as the longer life expectancy [74,75].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Lam, 2011, Epidemiology and clinical course of heart failure with preserved ejection fraction, Eur. J. Heart Fail. source

      Not checked in the free run.

    • cites [75] Petrie, 2018, Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology, Eur. J. Heart Fail. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both inflammation and microvasculopathy promote cardiac fibrosis with the contribution of mesenchymal stem cells of the epicardium that can migrate into myocardium, where they can mature into fibroblasts.

    “Both inflammation and microvasculopathy promote cardiac fibrosis with the contribution of mesenchymal stem cells of the epicardium that can migrate into myocardium, where they can mature into fibroblasts [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Saifi, 2019, Myocardial regeneration: Role of epicardium and implicated genes, Mol. Biol. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The essence of HFpEF pathophysiology is the increase of LV filling pressure, meaning that the heart can adequately pump the blood at expense of an elevation of cardiac filling pressures that, if disproportionate during exercise or at rest, are responsible of dyspnea.

    “Even if the diastolic dysfunction is the hemodynamic feature of HFpEF, the essence of its pathophysiology is the increase of LV filling pressure, meaning that the heart can adequately pump the blood at expense of an elevation of cardiac filling pressures that, if disproportionate during exercise or at rest, are responsible of dyspnea [102,103].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Borlaug, 2020, Evaluation and management of heart failure with preserved ejection fraction, Nat. Rev. Cardiol. source

      Not checked in the free run.

    • cites [103] Youn, 2021, Pathophysiology of Heart Failure with Preserved Ejection Fraction, Heart Fail. Clin. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Myocardial damage induced by systemic inflammation is perpetrated by a pathologic EAT that adversely affects structure and function, intensifying cardiac inflammation, coronary microvascular dysfunction, and pro-fibrotic mechanisms, the pathologic hallmarks of HFpEF.

    “As a consequence, the myocardial damage induced by systemic inflammation is perpetrated by a pathologic EAT that adversely affects structure and function intensifying cardiac inflammation, coronary microvascular dysfunction, and pro-fibrotic mechanisms, the pathologic hallmarks of HFpEF [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Shah, 2016, Inflammation in Heart Failure With Preserved Ejection Fraction: Time to Put Out the Fire, JACC Heart Fail. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin adversely affects calcium handling in cardiomyocytes so as to impair myocardial relaxation, stimulates the synthesis of collagen inducing cardiac fibrosis by increasing aldosterone secretion, and enhances sodium tubular reabsorption.

    “Moreover, leptin adversely affects calcium handling in cardiomyocytes so as to impair myocardial relaxation, stimulates the synthesis of collagen inducing cardiac fibrosis by increasing aldosterone secretion, and enhances the sodium tubular reabsorption [95,96,97].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [95] Na, 2007, Upregulation of leptin pathway correlates with abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure and reversal by CPU86017, Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie source

      Not checked in the free run.

    • cites [96] Huby, 2015, Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis, Circulation source

      Not checked in the free run.

    • cites [97] Marciniak, 2006, Time-dependent transition from H2O2-extracellular signal-regulated kinase- to O2-nitric oxide-dependent mechanisms in the stimulatory effect of leptin on renal Na+/K+/-ATPase in the rat, Clin. Exp. Pharmacol. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The final result is a decreased ventricular compliance which presents with impairment in relaxation or increase in stiffness of LV.

    “The final result is a decreased ventricular compliance which presents with impairment in relaxation or increase in stiffness of LV.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    An EAT enlarged and biologically transformed by diabetes and/or obesity may transfer intrinsic injury towards the heart already damaged by the same systemic metabolic disorders.

    “More interestingly, according to a suggestive and convincing pathophysiological reconstruction formulated by some experts, an EAT enlarged and biologically transformed by diabetes and/or obesity, may transfer intrinsic injury towards the heart already damaged by the same systemic metabolic disorders.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Packer, 2018, Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium, J. Am. Coll. Cardiol. source

      Not checked in the free run.

    • cites [90] Patel, 2017, Epicardial adipose tissue as a metabolic transducer: Role in heart failure and coronary artery disease, Heart Fail. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HFpEF is a heterogeneous syndrome characterized by a frequent association with multiple comorbidities (mainly diabetes and obesity), a complex pathophysiology, and a variegate clinical expression with different phenotypes.

    “HFpEF is a heterogeneous syndrome characterized by a frequent association with multiple comorbidities (mainly diabetes and obesity), a complex pathophysiology originating from the interplay of cardiac and extracardiac abnormalities, and a consequent variegate clinical expression with different phenotypes [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] McHugh, 2019, Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with hypertension and/or T1DM, an impaired coronary flow reserve is associated with diastolic dysfunction and with amount of ventricular EAT.

    “As evidence, in patients with hypertension and/or T1DM, an impaired coronary flow reserve has been associated with diastolic dysfunction, and, more recently, with amount of ventricular EAT [98,99].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] Galderisi, 2002, Coronary flow reserve and myocardial diastolic dysfunction in arterial hypertension, Am. J. Cardiol. source

      Not checked in the free run.

    • cites [99] Kirkwood, 2004, Sympathetic dysfunction in type 1 diabetes: Association with impaired myocardial blood flow reserve and diastolic dysfunction, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In systemic disorders such as T2DM and obesity, the adipocytes within the epicardium take on the features of white adipose tissue, overfilled with lipids and prone to lipolysis, releasing an excess of FAs.

    “In systemic disorders such as T2DM and obesity, the adipocytes within the epicardium take on the features of white adipose tissue (WAT), namely they are overfilled with lipids and prone to lipolysis, releasing an excess of FAs [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Iacobellis, 2019, Epicardial adipose tissue feeding and overfeeding the heart, Nutrition source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diastolic dysfunction can develop early in T2DM course and be detected in 75% of asymptomatic patients, with a prevalence and severity that increase across the whole spectrum of glucose dysregulation from prediabetes to diabetes.

    “A diastolic dysfunction can develop early in T2DM course and be detected in 75% of asymptomatic patients, with a prevalence and a severity that increase across the whole spectrum of glucose dysregulation from prediabetes to diabetes [79,80].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Boyer, 2004, Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus, Am. J. Cardiol. source

      Not checked in the free run.

    • cites [80] Stahrenberg, 2010, Association of glucose metabolism with diastolic function along the diabetic continuum, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EAT expansion is associated with intramyocardial accumulation of triglycerides in severely obese subjects, and intramyocardial fat is correlated with LV diastolic dysfunction.

    “In studies using proton magnetic resonance spectroscopy, EAT expansion was associated with intramyocardial accumulation of triglycerides in severely obese subjects and intramyocardial fat was correlated with LV diastolic dysfunction [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Gaborit, 2012, Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: Relationship to metabolic profile, cardiac function and visceral fat, Int. J. Obes. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In T2DM and obesity, the adipocytes of expanded EAT release large amounts of FAs that trigger macrophage infiltration and secretion of pro-inflammatory adipocytokines including leptin, TNF-α, IL-6, IL-1b and resistin; simultaneously, the production of adiponectin diminishes.

    “In T2DM and obesity, the adipocytes of expanded EAT release large amounts of FAs that trigger macrophage infiltration and secretion of pro-inflammatory adipocytokines including leptin, TNF-α, IL-6, IL-1b and resistin. Simultaneously, the production of adiponectin diminishes [18,91].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Packer, 2018, Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium, J. Am. Coll. Cardiol. source

      Not checked in the free run.

    • cites [91] Grant, 2015, Adipose tissue as an immunological organ, Obesity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sitagliptin or liraglutide as add-on therapy in overweight/obese T2DM inadequately controlled on metformin significantly reduce EAT after six months, whereas no such result is detected in metformin groups.

    “Recently, two randomized trials evaluating EAT changes induced after six months by sitagliptin or liraglutide as add-on therapy in overweight/obese T2DM individuals inadequately controlled on metformin monotherapy showed that both incretin-based therapies significantly reduced EAT, whereas no such result was detected in the metformin groups [122,123].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [122] Paoli, 2016, Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: A pilot study, Endocrine source

      Not checked in the free run.

    • cites [123] Iacobellis, 2017, Liraglutide causes large and rapid epicardial fat reduction, Obesity source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PPAR-γ is implicated in attenuation of inflammation and oxidative stress determined by adiponectin in LPS-induced inhibition of pre-adipocyte differentiation.

    “The PPAR-γ has been implicated in the attenuation of inflammation and oxidative stress determined by adiponectin in LPS-induced inhibition of pre-adipocyte differentiation [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Yang, 2019, PPAR γ/Nnat/NF-κB Axis Involved in Promoting Effects of Adiponectin on Preadipocyte Differentiation, Mediat. Inflamm. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin up-regulates fat oxidation-related enzyme in liver, UCP-1 in brown adipose tissue, and UCP-3 in skeletal muscle, supporting a possible mechanism of enhanced fat oxidation.

    “Moreover, an up-regulation of fat oxidation-related enzyme in the liver, of UCP-1 in the brown adipose tissue, and of UCP-3 in the skeletal muscle were found to support a possible mechanism of enhancement of fat oxidation [156].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Tokubuchi, I., Tajiri, Y., Iwata, S., Hara, K., Wada, N., Hashinaga, T., Nakayama, H., Mifune, H., and Yamada, K. (2017). Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS ONE, 12. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CMR imaging revealed more prevalent fibrosis in HFpEF subjects than in control subjects, and the HFpEF group was associated with adverse outcomes.

    “Cardiac magnetic resonance (CMR) imaging revealed more prevalent fibrosis in HFpEF subjects than in control subjects, and the first group was associated with adverse outcomes [105,106].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [105] Kanagala, 2019, Relationship Between Focal and Diffuse Fibrosis Assessed by CMR and Clinical Outcomes in Heart Failure with Preserved Ejection Fraction, JACC Cardiovasc. Imaging source

      Not checked in the free run.

    • cites [106] Roy, 2018, Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction, J. Cardiovasc. Magn. Reson. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Statins reduce HFpEF morbidity and mortality, and this benefit might depend in part on EAT and systemic inflammation reduction, not on the effect on diabetes.

    “Several studies support a reduction of HFpEF morbidity and mortality induced by statins, a benefit that might depend in part on EAT and systemic inflammation reduction, and not on the effect on diabetes [148,149].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [148] Alehagen, 2015, Association between Use of Statins and Mortality in Patients with Heart Failure and Ejection Fraction of ≥50%, Circ. Heart Fail. source

      Not checked in the free run.

    • cites [149] Anker, 2019, Association of statin use and clinical outcomes in heart failure patients: A systematic review and meta-analysis, Lipids Health Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both lipid and glucose-lowering agents independently reduce EAT mass, although with significant heterogeneity between studies.

    “Particularly, both lipid and glucose-lowering agents independently reduce EAT mass, although with a significant heterogeneity between studies [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Launbo, 2021, Targeting epicardial adipose tissue with exercise, diet, bariatric surgery or pharmaceutical interventions: A systematic review and meta-analysis, Obes. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CMR offers potential multiple evaluations of underlying myocardial ischemia, storage diseases like amyloidosis, intramyocardial triacylglycerol accumulation, and diffuse myocardial fibrosis, in addition to the evaluation of systo-diastolic function and myocardial work.

    “Apart from being radiation-free, this technique offers potential multiple evaluations of underlying myocardial ischemia, storage diseases like amyloidosis, intramyocardial triacylglycerol accumulation, and diffuse myocardial fibrosis, in addition to the evaluation of systo-diastolic function and myocardial work [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Elsanhoury, 2021, Epicardial Fat Expansion in Diabetic and Obese Patients with Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype, Front. Cardiovasc. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atorvastatin and simvastatin/ezetimibe induce similar improvements in cholesterol profiles and a 7% mean decrease of EAT after six to eight months, with a more pronounced effect for atorvastatin.

    “In a cohort study, atorvastatin and simvastatin/ezetimibe induced similar improvements in cholesterol profiles and a 7% mean decrease of EAT after six to eight-month follow-up, with an effect significantly more pronounced for atorvastatin [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Park, 2010, Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: Comparison of atorvastatin with simvastatin/ezetimibe, J. Cardiovasc. Ultrasound. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings indicate inferiority of metformin used alone, but do not exclude a synergistic effect on EAT change with the added glucose-lowering drug.

    “These findings are indicative of the inferiority of metformin used alone, even in the absense of a comparison with placebo, but do not exclude a synergistic effect on EAT change with the added glucose-lowering drug.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CMR is considered the gold standard method for EAT quantification, validated even in animal models for research purposes.

    “CMR is considered the gold standard method for EAT quantification, validated even in animal models for research purposes [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Kessels, 2006, Epicardial adipose tissue imaged by magnetic resonance imaging: An important risk marker of cardiovascular disease, Heart source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, statins have a significantly higher anti-inflammatory effect on EAT compared to SAT, supporting a direct action on EAT metabolic activity and pro-inflammatory cytokine secretome.

    “Interestingly, the in vitro examination in the same study showed a significantly higher anti-inflammatory effect on EAT compared to SAT, supporting the hypothesis of a direct action of these drugs on EAT metabolic activity and pro-inflammatory cytokine secretome (IL-1b, IL-1ra, IL-2, IL4, IL-6, IL-8, IL-12, basic Fibroblast Growth Factor (FGF), Eotaxin, Granulocyte-Colony Stimulating Factor (G-CSF”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Parisi, 2019, Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue, Int. J. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The measurability of EAT by non-invasive imaging techniques may allow its use as a tool for prediction of cardiometabolic risk and a modifiable therapeutic target.

    “The great clinical implication associated with epicardial fat resides in its measurability by non-invasive imaging techniques which may allow its use as a tool for prediction of cardiometabolic risk and a modifiable therapeutic target [107].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Iacobellis, 2007, Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome, Curr. Pharm. Des. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Benefit in HFpEF may be obtained through control of associated morbidities and risk factors, mainly by implementation of a healthy lifestyle including smoking cessation, weight reduction, exercise, and healthy diet.

    “Benefit may be obtained through control of associated morbidities and risk factors, mainly by implementation of a healthy lifestyle including smoking cessation, weight reduction, exercise, and healthy diet [115].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Cilia, 2017, Heart Failure With Preserved Ejection Fraction: Prevention and Management, Am. J. Lifestyle Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Metformin treatment is associated with lower mortality in people with HFpEF and amelioration of cardiac functional parameters in patients with mild forms of HF, mainly HFpEF.

    “These results might account for the lower mortality in metformin-treated people with HFpEF reported in a systematic review and meta-regression analysis, and for the amelioration of cardiac functional parameters possibly observed in patients with mild forms of HF, mainly HFpEF, no history of CV events, and after a long-time chronic treatment [159].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Halabi, 2020, Metformin treatment in heart failure with preserved ejection fraction: A systematic review and meta-regression analysis, Cardiovasc. Diabetol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The relationship between change in BMI and change in EAT is significant for diet, less apparent for bariatric surgery, and virtually absent for exercise.

    “A study comparing these three weight loss strategies reports that the relationship between change in BMI and change in EAT is significant for diet, less apparent for bariatric surgery, and virtually absent for exercise [146].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Rabkin, 2015, Comparison of reducing epicardial fat by exercise, diet or bariatric surgery weight loss strategies: A systematic review and meta-analysis, Obes. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Statins decrease EAT attenuation at CCT, a marker of inflammation, independently of LDL-cholesterol lowering intensity, but have a neutral effect on subcutaneous fat.

    “In a more recent study, statins induced over time and independently of intensity of LDL-cholesterol lowering, a decrease in the attenuation of EAT at CCT considered a marker of inflammation, but a neutral effect on subcutaneous fat [151].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Raggi, 2019, Statins Reduce Epicardial Adipose Tissue Attenuation Independent of Lipid Lowering: A Potential Pleiotropic Effect, J. Am. Heart Assoc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise has no effect on BMI, but may reduce EAT and waist circumference.

    “A recent systematic review and meta-analysis reports that exercise has no effect on BMI, but may reduce EAT and waist circumference [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Colonetti, 2021, Effect of exercise on epicardial adipose tissue in adults: A systematic review and meta-analyses, Heart Fail. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Echocardiography is limited by a high dependency on operator expertise and a linear measurement at a single location, which fails to take account for the site variability of epicardial fat thickness.

    “While rapid, relatively inexpensive, and widely available, this technique is limited by a high dependency on operator expertise and a linear measurement at a single location, which fails to take account for the site variability of epicardial fat thickness [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Iacobellis, 2003, Epicardial fat from echocardiography: A new method for visceral adipose tissue prediction, Obes. Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Metformin may exert beneficial effects on body weight and fat composition, as well as extra metabolic ancillary effects.

    “Metformin, the most widely prescribed drug to treat T2DM, especially when associated with obesity, may exert beneficial effects on body weight and fat composition, as well as extra metabolic ancillary effects that are clinically very interesting [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Morgillo, 2017, Results of the safety run-in part of the METAL (METformin in Advanced Lung cancer) study: A multicentre, open-label phase I-II study of metformin with erlotinib in second-line therapy of patients with stage IV non-small-cell lung cancer, ESMO Open. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EAT may be evaluated on positron emission tomography/CCT to associate anatomical data and functional information.

    “To associate anatomical data and functional information, EAT may be evaluated on positron emission tomography/CCT [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Janik, 2010, Epicardial adipose tissue volume and coronary artery calcium to predict myocardial ischemia on positron emission tomography-computed tomography studies, J. Nucl. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pioglitazone in CAD patients with T2DM or metabolic syndrome increases PPARγ in SAT and selectively reduces expression of IL-1β, IL-1Ra and IL-10 in EAT, and IL-10 in SAT, irrespective of other clinical variables.

    “The treatment with pioglitazone in CAD patients with T2DM or metabolic syndrome, was shown to increase PPARγ in SAT and to selectively reduce the expression of IL-1β, IL-1Ra and IL-10 in EAT, and of IL-10 in SAT, irrespective of other clinical variables (weight, BMI, waist, fasting blood glucose, A1C, HOMA-IR, ACE inhibitors, angiotensin receptor blockers, statins, aspirin, and metformin) [120].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Sacks, 2011, Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: Changes associated with pioglitazone, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liraglutide on top of metformin reduces EAT thickness by 29% at 3 months and 36% at 6 months in T2DM patients, with no change in those remaining on metformin.

    “However, other authors underline that the cardio-metabolic advantage offered by liraglutide may be the substantial and rapid reduction of EAT thickness (29% at 3 months and 36% at 6 months), a result observed in a study with T2DM patients randomized to liraglutide on top of metformin versus metformin alone. In those remaining on metformin no change in EAT thickness was registered [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Iacobellis, 2017, Liraglutide causes large and rapid epicardial fat reduction, Obesity source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Liraglutide primarily reduces SAT but fails to decrease visceral, hepatic, myocardial or epicardial fat.

    “One recent placebo-controlled trial study reports that liraglutide primarily reduced SAT, but failed to decrease visceral, hepatic, myocardial or epicardial fat [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Bizino, 2020, Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: A pre-specified secondary study on ectopic fat accumulation, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thiazolidinediones (pioglitazone and rosiglitazone) are PPAR-γ agonists that may cause weight gain with a favorable shift in fat distribution from VAT to SAT in T2DM patients.

    “Thiazolidinediones (pioglitazone and rosiglitazone) are PPAR-γ agonists that, administered to T2DM patients, may cause weight gain with a favorable shift in fat distribution from VAT to SAT [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Fonseca, 2003, Effect of thiazolidinediones on body weight in patients with diabetes mellitus, Am. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1R is present in adipose tissue with increased mRNA and protein expressions in visceral adipose depots, and it promotes pre-adipocyte differentiation and increases number of small adipocytes.

    “Earlier studies provided evidence that GLP-1R was present in adipose tissue with an increased mRNA and protein expressions in visceral adipose depots, and that it promoted pre-adipocyte differentiation and increased number of small adipocytes [174].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Vendrell, 2011, Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liraglutide promotes pre-adipocyte differentiation and inhibits FA synthase in adipose tissues from mice.

    “Liraglutide was seen to promote pre-adipocytes differentiation and to inhibit FA synthase in adipose tissues from mice [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Chen, 2017, GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis, Cell Physiol. Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    12-week treatment with exenatide or liraglutide produces a mild yet significant reduction of EAT thickness, BMI, HbA1c and weight in T2DM patients, without difference between the two GLP-1RAs.

    “Previously, one study reported that a 12-week short term treatment either with exenatide or liraglutide, determined a mild yet significant reduction of EAT thickness, BMI, HbA1c and weight in a smaller group of T2DM patients without difference between the two GLP-1RAs [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Morano, 2015, Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonists on fat distribution in patients with type 2 diabetes mellitus: An ultrasonography study, Acta Diabetol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pioglitazone improves diastolic and systolic function in T2DM patients without clinical CV disease, and this amelioration is closely related to improved myocardial insulin sensitivity.

    “In a clinical study, treatment with pioglitazone in patients with T2DM without clinical CV disease improved both diastolic and systolic function assessed with CMR, and this amelioration was closely related to improved myocardial insulin sensitivity evaluated after euglycemic insulin clamp with PET [166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Clarke, 2017, Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liraglutide reduces LV filling pressure and improves diastolic function, parameters relevant for progression of diabetic cardiomyopathy and symptomatic HFpEF.

    “Among these, a study with liraglutide demonstrated a reduction in LV filling pressure and an improvement in diastolic function, both parameters relevant for progression of diabetic cardiomyopathy and symptomatic HFpEF [171].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Bizino, 2019, Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: Randomized placebo-controlled trial, Cardiovasc. Diabetol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weekly semaglutide or dulaglutide causes substantial (of the order of 20%) and dose-dependent reduction in EAT thickness after 12 weeks in T2DM and obesity, while no EAT reduction occurs in the control group taking metformin alone.

    “More recently, a controlled parallel study in 80 subjects with T2DM and obesity demonstrated that the weekly administration of semaglutide or dulaglutide, two long-acting GLP-1 RAs, caused a substantial (of the order of 20%) and dose-dependent reduction in EAT thickness after 12 weeks, while there was no EAT reduction in the control group taking metformin alone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Iacobellis, 2020, Effects of Semaglutide Versus Dulaglutide on Epicardial Fat Thickness in Subjects with Type 2 Diabetes and Obesity, J. Endocr. Soc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Seven trials have demonstrated superiority or almost non-inferiority of GLP-1 RAs for CV outcomes, indicating advantageous cardio-protective effects.

    “In recent years, seven trials have demonstrated their superiority or almost non-inferiority for CV outcomes, indicating advantageous cardio-protective effects [170].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Sheahan, 2020, An overview of GLP-1 agonists and recent cardiovascular outcomes trials, Postgrad. Med. J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exenatide reduces liver fat content and epicardial fat in obese patients with uncontrolled T2DM, not associated with significant HbA1c reduction but with significant relation with weight loss.

    “Similarly, in another trial using RM, in obese patients with uncontrolled T2DM, exenatide reduced liver fat content and epicardial fat, not associated with a significant HbA1c reduction, but with a significant relation with weight loss when compared with reference treatment (sulphonylureas or repaglinide alone or in combination with metformin) [127].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Dutour, 2016, Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: A prospective randomized clinical trial using magnetic resonance imaging and spectroscopy, Diabetes Obes. Metab. source

      Not checked in the free run.

68 of 68

  • The paper relies on this without support.

    HFpEF currently lacks effective treatments other than lifestyle optimization and symptomatic use of diuretics.

    “HFpEF at moment lacks effective treatments other than lifestyle optimization and symptomatic use of diuretics, as well as of studies demonstrating a therapeutic improvement in its prognosis.”

  • The paper relies on this without support.

    Reducing or modifying EAT will improve clinical outcomes in HFpEF.

    “EAT could be seen as an appealing therapeutic target to assess the efficacy of drugs that modulating epicardial adiposity may ameliorate, or better yet, prevent HFpEF.”

  • The paper relies on this without support.

    EAT is a crucial pathogenic factor for HFpEF.

    “In recent years, the recognition of EAT as a crucial pathogenic factor for HFpEF has increased the interest towards therapeutic strategies that target this fat depot.”

  • The paper relies on this without support.

    The effects of drugs on EAT thickness or volume are clinically meaningful for HFpEF.

    “The weight loss achieved by lifestyle modifications and by pharmacological and/or surgical interventions may have beneficial results.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conclusion says no study shows improved HFpEF prognosis

    Minor

    The conclusion says there are no studies demonstrating a therapeutic improvement in HFpEF prognosis, but the paper earlier describes an empagliflozin trial in HFpEF that found lower risks of cardiovascular death or heart-failure hospitalization.

1 of 1

The citation lists haven’t been fetched yet

References 227 · Cited by 62

Authors
Salvatore, T., Galiero, R., Caturano, A., Vetrano, E., Rinaldi, L., Coviello, F., Di Martino, A., Albanese, G., Colantuoni, S., Medicamento, G., Marfella, R., Sardu, C., & Sasso, F. C.
Affiliations
  • University of Campania "Luigi Vanvitelli" (IT)
  • Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy
Corresponding author
Sasso, Ferdinando Carlo
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2022-01-21
Volume
12
Issue
2
Pages
176
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom12020176
PMC
PMC8961672
OpenAlex
W4206952064
Cited by
62
References
227
Citations by year
2026: 5 · 2025: 15 · 2024: 23 · 2023: 11 · 2022: 8
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
epicardial adipose tissue, heart failure with preserved ejection fraction, type 2 diabetes, myocardial fibrosis, myocarditis, diastolic dysfunction, left ventricular filling pressure, metformin, GLP-1 receptor agonists, SGLT2 inhibitors, therapeutic target
MeSH terms
Adipose Tissue, Diabetes Mellitus, Type 2, Heart Failure, Humans, Microcirculation, Risk Factors, Stroke Volume

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review