Journal of Obesity & Metabolic Syndrome

Search

Article

J Obes Metab Syndr 2023; 32(4): 322-329

Published online December 30, 2023 https://doi.org/10.7570/jomes23042

Copyright © Korean Society for the Study of Obesity.

An Overview of the Mechanism behind Excessive Volume of Pericardial Fat in Heart Failure

Sandeep Karna, Ki-Woon Kang *

Division of Cardiology, Cardiovascular Arrhythmia Center, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea

Correspondence to:
Ki-Woon Kang
https://orcid.org/0000-0002-1361-0022
Division of Cardiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea
Tel: +82-2-6299-2871
Fax: +82-2-6299-2871
E-mail: kwkang0115@gmail.com

Received: July 3, 2023; Reviewed : September 11, 2023; Accepted: October 11, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Heart failure (HF) is a clinical syndrome characterized by myocardial dysfunction leading to inefficient blood filling or ejection. Regardless of the etiology, various mechanisms, including adipokine hypersecretion, proinflammatory cytokines, stem cell proliferation, oxidative stress, hyperglycemic toxicity, and autonomic nervous system dysregulation in the pericardial fat (PCF), contribute to the development of HF. PCF has been directly associated with cardiovascular disease, and an increased PCF volume is associated with HF. The PCF acts as neuroendocrine tissue that is closely linked to myocardial function and acts as an energy reservoir. This review aims to summarize each mechanism associated with PCF in HF.

Keywords: Heart disease, Heart failure, Fat

The heart is predominantly surrounded by pericardial fat (PCF), including epicardial adipose tissue (EAT),1-3 and PCF has metabolic roles such as lipid storage, secretion of endocrine factors, and release of fatty acids.4,5 Under physiological conditions, EAT provides mechanical, biochemical, and thermogenic cardioprotective effects; under pathological conditions, EAT can locally secrete proinflammatory cytokines through paracrine pathways and can impact cardiovascular disease.6 In addition, EAT, also a metabolically active endocrine organ, can modulate cardiac structure and produce numerous harmful effects like atherosclerosis, activation of proinflammatory cytokines, atherogenic changes in monocytes and endothelial cells, cardiomyopathy, and modulation of intrinsic autonomic nerve activity.7 PCF has been directly associated with cardiovascular outcomes and risk factors due to its direct effects on the myocardium, and an increased PCF volume is associated with myocardial dysfunction in heart failure (HF).8-11 PCF has attracted the attention of physicians in relation to cardiovascular disease because it covers the heart’s surface and surrounds the adventitia of the coronary arteries. Therefore, a positive correlation exists between PCF volume and severity of cardiovascular disease.12 This review summarizes the basic science of the association of HF with PCF (Fig. 1).

Adipokines, including specific cytokines, play a role in obesity and its associated co-morbidities. The PCF (including EAT) secretes hormones, cytokines, growth factors, vasodilators, and other substances that function as important signaling molecules.13,14 These compounds contribute to the development of metabolic syndromes, including cardiovascular diseases. Leptin, which was discovered in 1994, was the first identified adipokine.15 Adiponectin, another member of the adipokine family, has a role in glucose regulation and fatty acid oxidation.16,17 Proinflammatory cytokines inhibit lipoprotein lipase in adipocytes, leading to insulin resistance and secretion of circulating free fatty acids.18 Insulin resistance is also associated with oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines, and inappropriate activation of the renin-angiotensin II-aldosterone system and the sympathetic nervous system. Insulin resistance is a major factor in the development of HF.19

Leptin

Leptin is an important hormone in weight regulation and energy homeostasis.20 It acts on the central nervous system to regulate appetite and directly or indirectly affects cardiovascular functions.21,22 Leptin is primarily produced by adipose tissue, but it is also secreted by other tissues, such as the skeletal muscles, placenta, gastric mucosa, and heart.23,24 Its main role is regulating energy balance and cell metabolism and controlling inflammatory and immune responses. Leptin is secreted from the PCF and is crucial in maintaining homeostasis in the cardiovascular system.25 The signaling of leptin involves various pathways, including Janus kinase, signal transducers and activators of transcription, insulin receptor substrate, phosphatidylinositol 3 kinase, mitogen-activated protein kinase, and extracellular signal-regulated protein kinase.20 Elevated leptin often is found in obese individuals, and this increase can be associated with leptin resistance, which can lead to cardiac dysfunction and HF.25 Studies have shown that elevated leptin level is associated with an increased risk of HF in men without preexisting coronary heart disease independent of body mass index and other potential mediators.26

Adiponectin

Adiponectin is an adipokine protein and hormone that exerts various effects on metabolic processes; it is mainly known for its insulin-sensitizing and anti-inflammatory effects.17,27 Although the PCF is the primary site of production, adiponectin is also secreted by cardiomyocytes and connective tissue cells within the heart. Adiponectin is crucial in several metabolic processes, including promoting fatty acid oxidation, inhibiting glucose production in the liver, increasing insulin release from the pancreas, and promoting fat storage in subcutaneous fat pads.17 In humans, the plasma concentration of adiponectin typically ranges from 5 to 30 µg/mL.2,28 The adiponectin concentration tends to increase gradually with increasing severity of cardiovascular diseases, including HF.29 Kistorp et al.30 reported that high plasma level of adiponectin could serve as an independent predictor of mortality in HF, and adiponectin may have implications for the prognosis and outcome of HF (Fig. 2).

Overall, leptin and adiponectin play a significant role in metabolic regulation, insulin sensitivity, and inflammation. Their involvement in cardiovascular disease, particularly HF, suggests their potential as biomarkers and therapeutic targets for cardiovascular conditions.

Proinflammatory cytokines

Proinflammatory cytokines are low-molecular-weight proteins that have a crucial role in immune and inflammatory reactions. They are involved in various physiological and pathological processes, including recruiting immune cells to inflammatory sites and stimulating cell division, proliferation, and differentiation.31 In HF, proinflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-6, and IL-18, are activated and released into the surrounding tissue as part of the inflammatory response. These cytokines can directly affect the structure and function of cardiomyocytes.32 Circulating and intracardiac levels of proinflammatory cytokines have been reported to be elevated in HF.33,34 The presence of these cytokines is associated with the progression of HF. The mechanisms by which proinflammatory cytokines contribute to the progression of HF include cardiac myocyte hypertrophy, contractile dysfunction, cardiac myocyte apoptosis, and extracellular matrix remodeling.32 These effects of proinflammatory cytokines on cardiomyocytes and cardiac tissue contribute to the development and progression of HF (Fig. 2).

Adipose-derived stem cells (ADSCs) were first discovered by Zuk et al.35 in 2001 and are a type of mesenchymal stem cell. These cells can differentiate into various cell types found in the cardiovascular system, including cardiomyocytes, endothelial cells, and vascular smooth muscle cells.36 One of the significant characteristics of ADSCs is their secretion of various protective factors and signaling molecules. These compounds include vascular endothelial growth factor, hepatocyte growth factor, insulin-like growth factor-1, various types of mRNAs, and cytokines. These factors have multiple functions, such as promoting angiogenesis, reducing inflammation, and supporting cell survival and regeneration. This type of stem cell can secrete these factors to modulate signaling pathways in neighboring cells and to contribute to tissue repair and regeneration36 and has the unique property of being able to replace, repair, and regenerate dead or damaged cells in various tissue. They can integrate into the existing tissue and differentiate into specific cell types to restore functionality. However, an excessive volume of PCF can have detrimental effects on various signaling pathways, including those generating reactive oxygen species (ROS). The generation of ROS can induce apoptosis in ADSCs, potentially limiting their regenerative capability. Managing oxidative stress and maintaining proper mitochondrial function are essential for the survival and functionality of ADSCs.37

Oxidative stress refers to an imbalance between the production of ROS and the antioxidant defense mechanism. ROS are generated within the cellular environment through various sources, including mitochondria during oxidative phosphorylation, nicotinamide-adenine dinucleotide phosphate (NADPH), xanthine oxidase (XO), and uncoupled nitric oxide (NO) synthase.38 ROS are highly reactive oxygenated biochemical species that include superoxides (O2−), hydroxyl radicals, and nonradicals capable of generating free radicals like hydrogen peroxide. Excessive generation of ROS can lead to cellular dysfunction, lipid and protein peroxidation, DNA damage, irreversible cell damage, and cell death. These processes contribute to the development of various pathological cardiovascular conditions.38

NO is an essential biochemical molecule involved in normal cardiovascular homeostasis. It has a role in cardiac function, coronary vasodilatation, modulation of cardiac contractile function, and inhibition of platelet and neutrophil adhesion and activation.39 NO also acts as an antioxidant by inhibiting the activity of the enzymes XO and NADPH oxidase, and it helps maintain the homeostatic balance between O2− and NO in the body.39 However, increased level of peroxynitrite, a reaction product of NO and O2−, can compromise the physiological functions and bioavailability of NO. ROS directly influence contractile function in the heart by modifying proteins involved in calcium handling. For example, ROS can modify critical –SH groups on the ryanodine receptor to increase the probability of calcium release from intracellular stores. ROS can also suppress the L-type calcium channel current and interact with Ca2+ ATPase, inhibiting calcium uptake into intracellular stores. These interactions disrupt calcium homeostasis, which is crucial for proper cardiac function.40-42 Numerous scientists and clinicians have reported that HF is associated with excessive generation of ROS.43-45 Landmesser and Drexler46 also reported that oxidative stress could cause endothelial dysfunction in HF, contributing to impaired vascular function.

Insulin is a powerful hormone that exerts diverse effects depending on the cell type. Its primary metabolic functions include stimulating glucose uptake in skeletal muscles and adipocytes, promoting glycogen synthesis in skeletal muscles, suppressing hepatic glucose production, and inhibiting lipolysis in adipocytes.47 Insulin resistance refers to a condition in which the biological effect of insulin is lower than expected, either clinically or experimentally. Impaired responsiveness to insulin occurs in insulin resistance, leading to increased lipid synthesis in hepatocytes and enhanced lipolysis in adipocytes, and results in elevated levels of circulating fatty acids and triglycerides.48

Insulin resistance is associated with alterations of the left ventricular structure and function.49 Cardiac insulin resistance is directly related to systemic insulin resistance due to the metabolic and endocrine overload of insulin.49 Factors such as oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines/cytokines, and inappropriate activation of the renin-angiotensin II-aldosterone axis contribute to the development of cardiac insulin resistance.19 This condition leads to metabolic inflexibility, impaired calcium handling, mitochondrial dysfunction, dysregulated myocardial-endothelial interactions, energy deficiency, impaired diastolic dysfunction, myocardial cell death, and cardiac fibrosis.19

Insulin resistance severely affects cardiac function, including coronary heart disease, cardiorenal syndrome, hypertension, diabetic cardiomyopathy, and obesity cardiomyopathy.50-52 The development of these conditions is associated with increased circulating levels of nutrients, oxidative stress, and alterations in the neurohumoral and cytokine balance, which have been considered a risk factor for HF.19,53 Clinical studies have shown that insulin resistance predicts the development of HF, indicating a strong association between insulin resistance and HF.50

The cardiac autonomic nervous system contains the ganglion plexus located in the EAT pads of the PCF. These fat pads play a role in sympathetic and parasympathetic innervation in the heart.54 In adjacent cardiac myocytes, the neurotransmitter acetylcholine activates a specific M2 subtype known as muscarinic acetylcholine receptors. Activation of these receptors leads to stimulation of G protein-gated K+ channels, resulting in hyperpolarization of the cardiomyocytes through a cholinergic potassium hyperpolarizing current (IKACh). This process inhibits the synthesis and signaling of the second messenger cyclic 3',5'-adenosine monophosphate. It counteracts the intracellular Ca2+ elevation produced by activation of β-adrenergic receptors during cardiac sympathetic hyperexcitation. Dysregulation of this balance between sympathetic and parasympathetic activity can contribute to development and progression of HF.55 An increased PCF volume is closely associated with dysregulation of autonomic nervous activity, which can lead to increased risk of HF and mortality. Furthermore, EAT, which is located in the PCF, has 5.6-fold higher catecholamine level compared with subcutaneous adipose tissue. In HF, there is increased biosynthetic activity of catecholamines in the EAT, which is likely due to the increased volume of EAT that contains a large number of adipocytes that synthesize catecholamines.56 Dysregulation of the autonomic nervous activity and the increased presence of catecholamines in the PCF contribute to the pathophysiology of HF and can further exacerbate the sympathetic hyperexcitation in HF and have implications for disease progression and outcomes. Understanding the role of PCF in cardiac autonomic regulation and the production of catecholamines provides insights into potential therapeutic targets for HF (Fig. 2).

Excessive deposition of PCF, particularly in the form of epicardial and pericardial adipocytes, can have detrimental effects on the heart and contribute to the development of HF. Managing body weight and reducing excess adipose tissue deposition,57 including PCF, may be important for preventing or managing HF.

Study concept and design: KWK; acquisition of data: KWK; analysis and interpretation of data: SK and KKW; drafting of the manuscript: SK and KKW; critical revision of the manuscript: KWK; statistical analysis: KWK; obtained funding: KWK; administrative, technical, or material support: KWK; and study supervision: KWK.

Fig. 1. A basic perspective of heart failure associated with pericardial fat. TNF-α, tumor necrosis factor α; IL, interleukin; ROS, reactive oxygen species; cAMP, cyclic 3',5'-adenosine monophosphate.
Fig. 2. Various biological mechanisms that present as excessive volume of pericardial fat (including epicardial fat) that may lead to heart failure. NE, norepinephrine; SNS, sympathetic nervous system; Ach, acetylcholine; PNS, peripheral nervous system; PCF, pericardial fat; EAT, epicardial fat; cAMP, cyclic 3',5'-adenosine monophosphate; βAR, β-adrenergic receptor; IKACh, cholinergic potassium hyperpolarizing current; GIRK, G protein-gated K+ channel; M2mAChR, muscarinic acetylcholine receptor.
  1. Ouwens DM, Sell H, Greulich S, Eckel J. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med 2010;14:2223-34.
    Pubmed KoreaMed CrossRef
  2. Sacks HS, Fain JN. Human epicardial adipose tissue: a review. Am Heart J 2007;153:907-17.
    Pubmed CrossRef
  3. Corradi D, Maestri R, Callegari S, Pastori P, Goldoni M, Luong TV, et al. The ventricular epicardial fat is related to the myocardial mass in normal, ischemic and hypertrophic hearts. Cardiovasc Pathol 2004;13:313-6.
    Pubmed CrossRef
  4. Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 2015;11:363-71.
    Pubmed CrossRef
  5. Cherian S, Lopaschuk GD, Carvalho E. Cellular cross-talk between epicardial adipose tissue and myocardium in relation to the pathogenesis of cardiovascular disease. Am J Physiol Endocrinol Metab 2012;303:E937-49.
    Pubmed CrossRef
  6. Iacobellis G, Bianco AC. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab 2011;22:450-7.
    Pubmed KoreaMed CrossRef
  7. Gaborit B, Abdesselam I, Dutour A. Epicardial fat: more than just an "epi" phenomenon? Horm Metab Res 2013;45:991-1001.
    Pubmed CrossRef
  8. Ding J, Kritchevsky SB, Harris TB, Burke GL, Detrano RC, Szklo M, et al. The association of pericardial fat with calcified coronary plaque. Obesity (Silver Spring) 2008;16:1914-9.
    Pubmed KoreaMed CrossRef
  9. Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M, et al. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 2009;90:499-504.
    Pubmed KoreaMed CrossRef
  10. Shah RV, Anderson A, Ding J, Budoff M, Rider O, Petersen SE, et al. Pericardial, but not hepatic, fat by CT is associated with cv outcomes and structure: the multi-ethnic study of atherosclerosis. JACC Cardiovasc Imaging 2017;10:1016-27.
    Pubmed KoreaMed CrossRef
  11. Kenchaiah S, Ding J, Carr JJ, Allison MA, Budoff MJ, Tracy RP, et al. Pericardial fat and the risk of heart failure. J Am Coll Cardiol 2021;77:2638-52.
    Pubmed KoreaMed CrossRef
  12. Yamada H, Sata M. Role of pericardial fat: the good, the bad and the ugly. J Cardiol 2015;65:2-4.
    Pubmed CrossRef
  13. Lehr S, Hartwig S, Sell H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin Appl 2012;6:91-101.
    Pubmed CrossRef
  14. Zorena K, Jachimowicz-Duda O, Slezak D, Robakowska M, Mrugacz M. Adipokines and obesity: potential link to metabolic disorders and chronic complications. Int J Mol Sci 2020;21:3570.
    Pubmed KoreaMed CrossRef
  15. Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, Lago F, et al. Adipokines: biofactors from white adipose tissue: a complex hub among inflammation, metabolism, and immunity. Biofactors 2011;37:413-20.
    Pubmed CrossRef
  16. Ghoshal K, Chatterjee T, Chowdhury S, Sengupta S, Bhattacharyya M. Adiponectin genetic variant and expression coupled with lipid peroxidation reveal new signatures in diabetic dyslipidemia. Biochem Genet 2021;59:781-98.
    Pubmed CrossRef
  17. Ghoshal K, Bhattacharyya M. Adiponectin: probe of the molecular paradigm associating diabetes and obesity. World J Diabetes 2015;6:151-66.
    Pubmed KoreaMed CrossRef
  18. Jager J, Gremeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, et al. Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis. Diabetes 2010;59:61-70.
    Pubmed KoreaMed CrossRef
  19. Aroor AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin 2012;8:609-17.
    Pubmed KoreaMed CrossRef
  20. Kang KW, Ok M, Lee SK. Leptin as a key between obesity and cardiovascular disease. J Obes Metab Syndr 2020;29:248-59.
    Pubmed KoreaMed CrossRef
  21. Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000;62:413-37.
    Pubmed CrossRef
  22. Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: response to therapeutic interventions. Circulation 2008;117:3238-49.
    Pubmed KoreaMed CrossRef
  23. Zhao S, Kusminski CM, Scherer PE. Adiponectin, leptin and cardiovascular disorders. Circ Res 2021;128:136-49.
    Pubmed KoreaMed CrossRef
  24. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998;393:684-8.
    Pubmed CrossRef
  25. Poetsch MS, Strano A, Guan K. Role of leptin in cardiovascular diseases. Front Endocrinol (Lausanne) 2020;11:354.
    Pubmed KoreaMed CrossRef
  26. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Obesity and risk of incident heart failure in older men with and without pre-existing coronary heart disease: does leptin have a role? J Am Coll Cardiol 2011;58:1870-7.
    Pubmed CrossRef
  27. Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003;148:293-300.
    Pubmed CrossRef
  28. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286-9.
    Pubmed CrossRef
  29. Mado H, Szczurek W, Gasior M, Szygula-Jurkiewicz B. Adiponectin in heart failure. Future Cardiol 2021;17:757-64.
    Pubmed CrossRef
  30. Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, et al. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation 2005;112:1756-62.
    Pubmed CrossRef
  31. Oppenheim JJ. Cytokines: past, present, and future. Int J Hematol 2001;74:3-8.
    Pubmed CrossRef
  32. Hedayat M, Mahmoudi MJ, Rose NR, Rezaei N. Proinflammatory cytokines in heart failure: double-edged swords. Heart Fail Rev 2010;15:543-62.
    Pubmed CrossRef
  33. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002;91:988-98.
    Pubmed CrossRef
  34. Ueland T, Gullestad L, Nymo SH, Yndestad A, Aukrust P, Askevold ET. Inflammatory cytokines as biomarkers in heart failure. Clin Chim Acta 2015;443:71-7.
    Pubmed CrossRef
  35. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211-28.
    Pubmed CrossRef
  36. Ma T, Sun J, Zhao Z, Lei W, Chen Y, Wang X, et al. A brief review: adipose-derived stem cells and their therapeutic potential in cardiovascular diseases. Stem Cell Res Ther 2017;8:124.
    Pubmed KoreaMed CrossRef
  37. Jee MK, Kim JH, Han YM, Jung SJ, Kang KS, Kim DW, et al. DHP-derivative and low oxygen tension effectively induces human adipose stromal cell reprogramming. PLoS One 2010;5:e9026.
    Pubmed KoreaMed CrossRef
  38. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol 2011;301:H2181-90.
    Pubmed CrossRef
  39. Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 2007;49:241-8.
    Pubmed CrossRef
  40. Kawakami M, Okabe E. Superoxide anion radical-triggered Ca2+ release from cardiac sarcoplasmic reticulum through ryanodine receptor Ca2+ channel. Mol Pharmacol 1998;53:497-503.
    Pubmed CrossRef
  41. Fearon IM, Palmer AC, Balmforth AJ, Ball SG, Varadi G, Peers C. Modulation of recombinant human cardiac L-type Ca2+ channel alpha1C subunits by redox agents and hypoxia. J Physiol 1999;514(Pt 3):629-37.
    Pubmed KoreaMed CrossRef
  42. Xu KY, Zweier JL, Becker LC. Hydroxyl radical inhibits sarcoplasmic reticulum Ca(2+)-ATPase function by direct attack on the ATP binding site. Circ Res 1997;80:76-81.
    Pubmed CrossRef
  43. Ruffolo RR Jr, Feuerstein GZ. Neurohormonal activation, oxygen free radicals, and apoptosis in the pathogenesis of congestive heart failure. J Cardiovasc Pharmacol 1998;32 Suppl 1:S22-30.
    CrossRef
  44. Belch JJ, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J 1991;65:245-8.
    Pubmed KoreaMed CrossRef
  45. Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 1996;148:291-300.
  46. Landmesser U, Drexler H. The clinical significance of endothelial dysfunction. Curr Opin Cardiol 2005;20:547-51.
    Pubmed CrossRef
  47. Janus A, Szahidewicz-Krupska E, Mazur G, Doroszko A. Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders. Mediators Inflamm 2016;2016:3634948.
    Pubmed KoreaMed CrossRef
  48. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuniga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol 2018;17:122.
    Pubmed KoreaMed CrossRef
  49. Fujii S. Insulin resistance and heart failure: underlying molecular mechanisms and potential pharmacological solutions. J Cardiovasc Pharmacol 2013;62:379-80.
    Pubmed CrossRef
  50. Horwich TB, Fonarow GC. Glucose, obesity, metabolic syndrome, and diabetes relevance to incidence of heart failure. J Am Coll Cardiol 2010;55:283-93.
    Pubmed KoreaMed CrossRef
  51. Wong C, Marwick TH. Obesity cardiomyopathy: pathogenesis and pathophysiology. Nat Clin Pract Cardiovasc Med 2007;4:436-43.
    Pubmed CrossRef
  52. Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol 2008;51:93-102.
    Pubmed CrossRef
  53. Norton C, Georgiopoulou VV, Kalogeropoulos AP, Butler J. Epidemiology and cost of advanced heart failure. Prog Cardiovasc Dis 2011;54:78-85.
    Pubmed CrossRef
  54. Shivkumar K, Ajijola OA, Anand I, Armour JA, Chen PS, Esler M, et al. Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol 2016;594:3911-54.
    Pubmed KoreaMed CrossRef
  55. Pollard CM, Desimine VL, Wertz SL, Perez A, Parker BM, Maning J, et al. Deletion of osteopontin enhances β2-adrenergic receptor-dependent anti-fibrotic signaling in cardiomyocytes. Int J Mol Sci 2019;20:1396.
    Pubmed KoreaMed CrossRef
  56. Parisi V, Rengo G, Perrone-Filardi P, Pagano G, Femminella GD, Paolillo S, et al. Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure. Circ Res 2016;118:1244-53.
    Pubmed CrossRef
  57. Meister BM, Hong SG, Shin J, Rath M, Sayoc J, Park JY. Healthy versus unhealthy adipose tissue expansion: the role of exercise. J Obes Metab Syndr 2022;31:37-50.
    Pubmed KoreaMed CrossRef