<?xml version="1.0" encoding="UTF-8" standalone="no"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="review-article">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cardiovasc. Med.</journal-id>
<journal-title>Frontiers in Cardiovascular Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cardiovasc. Med.</abbrev-journal-title>
<issn pub-type="epub">2297-055X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcvm.2021.695952</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cardiovascular Medicine</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Heart Failure Syndrome With Preserved Ejection Fraction Is a Metabolic Cluster of Non-resolving Inflammation in Obesity</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Tourki</surname> <given-names>Bochra</given-names></name>
<uri xlink:href="http://loop.frontiersin.org/people/1402400/overview"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Halade</surname> <given-names>Ganesh V.</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/196092/overview"/>
</contrib>
</contrib-group>
<aff><institution>Division of Cardiovascular Sciences, Department of Medicine, The University of South Florida</institution>, <addr-line>Tampa, FL</addr-line>, <country>United States</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Lisandra de Castro Br&#x000E1;s, East Carolina University, United States</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Rushita Bagchi, University of Colorado Anschutz Medical Campus, United States; Andriy Yabluchanskiy, University of Oklahoma Health Sciences Center, United States</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Ganesh V. Halade <email>ghalade&#x00040;usf.edu</email></corresp>
<fn fn-type="other" id="fn001"><p>This article was submitted to Cardiovascular Biologics and Regenerative Medicine, a section of the journal Frontiers in Cardiovascular Medicine</p></fn></author-notes>
<pub-date pub-type="epub">
<day>02</day>
<month>08</month>
<year>2021</year>
</pub-date>
<pub-date pub-type="collection">
<year>2021</year>
</pub-date>
<volume>8</volume>
<elocation-id>695952</elocation-id>
<history>
<date date-type="received">
<day>15</day>
<month>04</month>
<year>2021</year>
</date>
<date date-type="accepted">
<day>08</day>
<month>06</month>
<year>2021</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2021 Tourki and Halade.</copyright-statement>
<copyright-year>2021</copyright-year>
<copyright-holder>Tourki and Halade</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<abstract><p>Heart failure with preserved ejection fraction (HFpEF) is an emerging disease with signs of nonresolving inflammation, endothelial dysfunction, and multiorgan defects. Moreover, based on the clinical signs and symptoms and the rise of the obesity epidemic, the number of patients developing HFpEF is increasing. From recent molecular and cellular studies, it becomes evident that HFpEF is not a single and homogenous disease but a cluster of heterogeneous pathophysiology with aging at the base of the pyramid. Obesity superimposed on aging drives the number of inflammatory pathways that intersect with metabolic dysfunction and suboptimal inflammation. Here, we compiled information on obesity-directed macrophage dysfunction that coincide with metabolic defects. Obesity-associated proinflammatory stimuli facilitates heart and interorgan inflammation in HFpEF. Furthermore, diversified mechanisms that drive heart failure urge the need of studying pervasive and unresolved inflammation in animal models to understand HFpEF. A broad and system-based approach will help to study major translational aspects of HFpEF, since no single animal model recapitulates all signs of differential HFpEF stages in the clinical setting. Here, we covered experimental models that target HFpEF and emphasized the advances observed with formyl peptide 2 (FPR2) receptor, a prime sensor that is important in inflammation-resolution signaling. Dysfunction of FPR2 led to the development of spontaneous obesity, impaired macrophage function, and triggered kidney fibrosis, providing evidence of multiorgan defects in HFpEF in an obesogenic aging experimental model.</p>
</abstract>
<kwd-group>
<kwd>HFPEF</kwd>
<kwd>immune metabolism</kwd>
<kwd>endothelial dysfunction</kwd>
<kwd>macrophages</kwd>
<kwd>obesity</kwd>
</kwd-group>
<contract-sponsor id="cn001">National Heart, Lung, and Blood Institute<named-content content-type="fundref-id">10.13039/100000050</named-content></contract-sponsor>
<counts>
<fig-count count="3"/>
<table-count count="1"/>
<equation-count count="0"/>
<ref-count count="120"/>
<page-count count="11"/>
<word-count count="8736"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1">
<title>Evolution of Multidimensional Metabolic Heart Failure Within the Obesity Epidemic</title>
<p>Obesity serves as an incubator for many cardiometabolic and cardiorenal defects. Hypertension, insulin resistance, diabetes, and dysplasia are major metabolic diseases that are strongly linked to obesity. The prevalence of metabolic defects is exponentially rising parallel to the trend of obesity epidemic (<xref ref-type="bibr" rid="B1">1</xref>). Epidemiological reports indicate the development of metabolic syndrome that is documented based on body mass with fat localization in intra-abdominal sites, including ectopic fat in the liver, pancreas, and heart (<xref ref-type="bibr" rid="B2">2</xref>).</p>
<p>In this minireview, first, we highlight inflammation-mediated pathogenesis in the emerging heart failure with preserved ejection fraction (HFpEF) syndrome. Second, we cover the concept of non-resolving and multiorgan chronic inflammation with an updated list of experimental animal models of HFpEF syndrome.</p>
<p>In the last five decades, epidemiological and systemic research helped in clarifying that obesity is closely associated with multiple changes in the structure and function of the heart of obese individuals. Clinicians and scientists described HF as a pathological remodeling of left ventricle (LV) cardiomyocytes. This remodeling is a result of heart adaptation to blood hemodynamics along with the increase in fat mass accumulation. With the advances in ultrasound and magnetic resonance imaging techniques, a clear evolution of LV shape remodeling was observed ranging from one-dimensional view to multidimensional subtypes of HF with specific nomenclature that reflects the corresponding remodeling (<xref ref-type="fig" rid="F1">Figure 1</xref>). Furthermore, in extreme obesity, the main contributors of end-stage HF are dysfunction of the right ventricle as well as prominent diastolic dysfunction with LV stiffness, lung edema, and low-grade and suboptimal systemic inflammation.</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>Evolution of one-dimensional to multidimensional view of cardiovascular disease and heart failure. <bold>(A)</bold> One-dimensional view of heart failure (HF). Classically, HF emerges in a homogenous population based on geometry, structure, and function. The progress from being a phenotypically normal to abnormal structure accompanied with a decrease or increase in the (cardiomyocyte) heart size due to eccentric or concentric remodeling or following ischemic injury with dilation of the chambers and wall-thinning effect. HF specifically with preserved ejection fraction evolves from one-dimensional view to multidimensional view. <bold>(B)</bold> Metabolic defects directed the multidimensional view of heart failure with preserved ejection fraction (HFpEF). Heterogeneous metabolic comorbidities are a primary confounder in HFpEF patients like obesity, hypertension, kidney dysfunction, diabetes, aging, etc. The complexity of the HFpEF syndrome resulted in cardiometabolic and cardiorenal defects with signs of suboptimal inflammation without any current treatment.</p></caption>
<graphic xlink:href="fcvm-08-695952-g0001.tif"/>
</fig>
<p>From the one-dimensional perspective, HF is classified into three types based on geometry metamorphosis of the LV: (1) atrophy of the heart (contractile dysfunction), (2) concentric hypertrophy of the LV (thick wall), and (3) eccentric hypertrophy of the LV (thin wall) or ischemia-induced wall thinning. However, some rare cases of cardiac angiosarcoma can also lead to HF (<xref ref-type="bibr" rid="B3">3</xref>, <xref ref-type="bibr" rid="B4">4</xref>). This report emphasizes the evolution of HFpEF syndrome due to possible obesity-directed metabolic defects and multiorgan inflammation.</p>
<sec>
<title>Atrophy of the Heart</title>
<p>Atrophy of the aging heart is a consequence of sarcopenic heart remodeling following muscle wasting. In the elderly, the size of a tissue or organ decreases due to cellular shrinkage (<xref ref-type="bibr" rid="B5">5</xref>). The prevalence of sarcopenia in chronic HF patients amounts to up to 20% and may progress into cardiac cachexia. Muscle wasting is a strong predictor of frailty and reduced survival in HF patients (<xref ref-type="bibr" rid="B6">6</xref>). Basically, heart atrophy can lead to reduced cardiac workload; however, complex inflammatory disease can result also in heart atrophy (<xref ref-type="bibr" rid="B7">7</xref>). Cardiac dysfunction is the outcome of the molecular changes resulting from cardiac atrophy and fibrosis (<xref ref-type="bibr" rid="B8">8</xref>). Molecular and cellular signaling pathways that underlie heart atrophy are not fully understood. However, some putative mechanisms for cardiac atrophy were observed in cancer patients (<xref ref-type="bibr" rid="B9">9</xref>). In some cases, atrophy of the heart can also be observed as a consequence of oncological drug treatments. Experimental and clinical studies showed that anthracycline chemotherapeutics, such as doxorubicin, induced heart atrophy in patients and mice (<xref ref-type="bibr" rid="B10">10</xref>). Mice treated with doxorubicin developed myocardial fibrosis, displayed splenic contraction, increased myocyte apoptosis, and impaired pumping of the heart (<xref ref-type="bibr" rid="B11">11</xref>). This latter has been connected to the release of myostatin by the atrophic heart muscle, which induces muscle wasting in HF (<xref ref-type="bibr" rid="B12">12</xref>).</p>
<p>Cardiac atrophy can occur not only in pathological conditions (<xref ref-type="bibr" rid="B13">13</xref>) but also after prolonged horizontal bed rest that may occur after short-term space flights, due to a decrease in unload volume to less activity or to the impact of microgravity in astronauts (<xref ref-type="bibr" rid="B14">14</xref>). Recent clinical studies are trying to better understand the paradigm of how the heart shrinks, to become atrophic, but increases its strength as observed with exercise (<xref ref-type="bibr" rid="B15">15</xref>).</p>
</sec>
<sec>
<title>Hypertrophy of the Heart</title>
<p>Enlargement of the left ventricle (LV) is an adaptive process that evolves into maladaptive remodeling, which has long been recognized as one of the prime dysfunction mechanisms leading to HF. The heart is an extremely plastic organ and changes its geometry to compensate for either pressure or volume overload, normally resulting from exercise or obesity-related mechanical impact. This compensation has often been viewed as a feedback loop (<xref ref-type="bibr" rid="B16">16</xref>). Concentric hypertrophy, which develops in pressure overload, normalizes wall stress. However, eccentric hypertrophy that develops in volume overload as a result of ischemic insult allows for an increase in total stroke volume leading to defective physiological regulation (<xref ref-type="bibr" rid="B17">17</xref>). Therefore, ejection fraction (EF) as a measurement of the heart capability of pushing out the blood to the organs has emerged as a clinically useful phenotypic marker, indicative of unique pathophysiological mechanisms (<xref ref-type="bibr" rid="B18">18</xref>) and, most importantly, as tangible response to therapies (<xref ref-type="bibr" rid="B19">19</xref>). As selection and classification criteria, patients with EF &#x02264;40% are classified as HF with reduced EF; however, when EF is &#x02265;50%, patients are diagnosed with preserved EF (<xref ref-type="bibr" rid="B20">20</xref>, <xref ref-type="bibr" rid="B21">21</xref>). In simplified terms, there is no &#x0201C;single&#x0201D; straightforward clear cause or trigger of HF in patients. Several cellular and molecular pathways have been observed as direct or indirect consequence of the development or/and aggravation of the disease depending on the diverse root cause for HF (<xref ref-type="bibr" rid="B22">22</xref>). Due to sedentary lifestyle and lack of physical activity, different signs of HF are caused by defective fatty acid oxidation signaling and metabolic syndrome in the setting of obesity. At the molecular level, most observed changes in signaling pathways in cardiac hypertrophy relate to the decrease in PI3K&#x02013;Akt signaling thereby inhibiting eNOS activation and its downstream signaling, which is reflected by endothelial dysfunction (<xref ref-type="bibr" rid="B23">23</xref>). Another common observed metabolism disturbance is the increase in PPAR&#x003B1; activity, which simulates a cascade of transcriptional coactivators, such as peroxisome proliferator-activated receptor-&#x003B1; coactivator (PGC-1&#x003B1;) and peroxisome proliferator-activated receptor-&#x003B2; coactivator (PGC-1&#x003B2;), that form active transcriptional complexes with CREB-binding protein (CBP/p300) and steroid receptor coactivator 1 (SRC-1) (<xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B25">25</xref>). Another cellular and molecular consequence of excess of fatty acid flux in HF patients is the increase in free radical production (<xref ref-type="bibr" rid="B26">26</xref>).</p>
<sec>
<title>Heart Failure With Reduced Ejection Fraction</title>
<p>Even though LV geometry is at the center of heart remodeling in HF, the LV EF is taking over on clinical classification of HFrEF or HFpEF (<xref ref-type="bibr" rid="B27">27</xref>). Both forms of heart pathology are well-established and explained in previous reviews. Multiple original reports described the morphologic and the hemodynamic differences in animal models (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B29">29</xref>) and clinical settings (<xref ref-type="bibr" rid="B17">17</xref>, <xref ref-type="bibr" rid="B30">30</xref>, <xref ref-type="bibr" rid="B31">31</xref>). The etiology of HFrEF is associated mostly with idiopathic dilated cardiomyopathy (DCM) and ischemic insult, resulting in systolic dysfunction of the heart (<xref ref-type="bibr" rid="B32">32</xref>). However, diastolic dysfunction is linked to HFpEF pathology (<xref ref-type="bibr" rid="B33">33</xref>). Commonly, HFrEF is a result of ischemic insult due to myocardial infarction (MI) caused by artery occlusion with signs of plaque formation. The plaque formation is an accumulation of lipid, especially cholesterol, infiltration of monocyte/macrophages, proliferation of smooth muscle cells, and accumulation of connective tissue components, thereby, forming a thrombus. This phenomena of atherogenesis depict a complicated stage of atheroprogression in the presence of inflammatory milieu as reported in obesity (<xref ref-type="bibr" rid="B34">34</xref>). After thrombosis, NO release is impaired, or there is a decrease in NO-(cGMP) signaling bioavailability to the cardiomyocytes. The decrease in NO is believed to be ultimately related to low-grade systemic inflammation and reduced cardiac perfusion (<xref ref-type="bibr" rid="B35">35</xref>&#x02013;<xref ref-type="bibr" rid="B37">37</xref>). Despite the progress in the treatment of HFrEF (<xref ref-type="bibr" rid="B38">38</xref>), the initial point that leads to the development and progression of HFrEF is still convoluted, and more information is needed to understand the genesis of the disease (<xref ref-type="bibr" rid="B39">39</xref>, <xref ref-type="bibr" rid="B40">40</xref>). From a metabolic point of view, abnormalities in myocardial energy metabolism in HFrEF have been reported but remain unclear due to the large number of metabolites/lipid mediators that control cardiac bioenergetics (<xref ref-type="bibr" rid="B41">41</xref>). At the cellular level, the disruption of electrical activity is present in both patients and animal models due to abnormalities in fat quality/quantity intake, sodium, and potassium channels on the myocardial membrane, which can lead to arrhythmias as well as cellular calcium dysregulation and altered calcium kinetics, thereby, leading to pathological heart contraction (<xref ref-type="bibr" rid="B42">42</xref>&#x02013;<xref ref-type="bibr" rid="B45">45</xref>).</p>
</sec>
<sec>
<title>Heart Failure With Preserved Ejection Fraction</title>
<p>Technically, if the EF is preserved, evidence of altered cardiac structure and function should be sought to provide further objective evidence toward HF syndrome. At the functional level, Doppler echocardiographic evidence of diastolic dysfunction is appearing as a digital biopsy. This is reflected in echocardiography by slow ventricular relaxation and increased diastolic stiffness or elevated left atrial pressure, which is common in HFpEF (<xref ref-type="bibr" rid="B27">27</xref>) with multiple cardiometabolic defects (<xref ref-type="bibr" rid="B46">46</xref>); however, clear targets and their molecular mechanisms remain to be identified.</p>
<p>In the USA, more than 50% of HF patients have HFpEF with primary signs of obesity and heterogeneous metabolic syndrome (hypertension, insulin resistance, diabetes, and hyperlipidemia) (<xref ref-type="bibr" rid="B35">35</xref>, <xref ref-type="bibr" rid="B47">47</xref>). In other words, the progress in the understanding of HF syndrome is not only based on structure/function of the heart but also includes heterogeneous arms of lifestyle-related triggers that promote HFpEF syndrome. As the etiology of HF syndrome is based on comorbidities and risk factors like aging, obesity, hypertension, and diabetes, the term multidimensional approaches needs to be considered in the development of preclinical HFpEF model and clinical treatment strategy (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B48">48</xref>).</p>
</sec>
</sec>
</sec>
<sec id="s2">
<title>Heart Failure Syndrome</title>
<p>HFrEF and HFpEF are end-stage disease pathologies with many confounding and overarching metabolic defects, thus, termed here as heart failure syndrome rather than disease. The pathophysiology of HFpEF is multifaceted signatures and heterogeneous, complex, and progressive. The increasing prevalence of HFpEF patients with aging and obesity defines a burden on healthcare systems (<xref ref-type="bibr" rid="B49">49</xref>). In the current clinical practice, HFpEF is reported as single disease abnormalities with LV diastolic dysfunction, chronotropic incompetence, and arterial stiffening (<xref ref-type="bibr" rid="B35">35</xref>). However, obesity or metabolic syndrome-driven endothelial dysfunction appeared as strongly related to HFpEF syndrome with multiorgan inflammation. Currently, obesity and inflammation are not considered as an epiphenomenon or prominent comorbidities for HFpEF but are intimately linked to its pathogenesis with progressive advancement (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B50">50</xref>, <xref ref-type="bibr" rid="B51">51</xref>). To recapitulate multiorgan etiologies, the development of accurate animal models is critical for the development of HFpEF targets (<xref ref-type="table" rid="T1">Table 1</xref>).</p>
<table-wrap position="float" id="T1">
<label>Table 1</label>
<caption><p>List of current heart failure with preserved ejection fraction (HFpEF) animal models with coexistence of metabolic phenotype.</p></caption>
<table frame="hsides" rules="groups">
<thead><tr>
<th valign="top" align="left"><bold>Animal model</bold></th>
<th valign="top" align="left"><bold>Phenotype</bold></th>
<th valign="top" align="left"><bold>References</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">FPR2KO</td>
<td valign="top" align="left">&#x02713; Obesity<break/> &#x02713; Cardiac dysfunction<break/> &#x02713; Aging<break/> &#x02713; Renal dysfunction<break/> &#x02713; Systemic inflammation<break/> &#x02713; Immunometabolism dysfunction Hypertension?<break/> Diabetes?</td>
<td valign="top" align="left">Mouse (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B52">52</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">HFD&#x0002B;L-NAME</td>
<td valign="top" align="left">&#x02713; Obesity<break/> &#x02713; Hypertensive stress<break/> &#x02713; Systemic inflammation<break/> &#x02713; Cardiac dysfunction<break/> &#x02713; Hypertension<break/> Aging?<break/> Renal dysfunction?<break/> Immunometabolism dysfunction?</td>
<td valign="top" align="left">Mouse (<xref ref-type="bibr" rid="B53">53</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">Ob/ob or db/db</td>
<td valign="top" align="left">&#x02713; Obesity<break/> &#x02713; Diabetes phenotype<break/> Aging?<break/> Renal dysfunction?<break/> Systemic inflammation?<break/> Immunometabolism dysfunction?</td>
<td valign="top" align="left">Mouse (<xref ref-type="bibr" rid="B54">54</xref>, <xref ref-type="bibr" rid="B55">55</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">ZF/ZDF</td>
<td valign="top" align="left">&#x02713; Obesity<break/> &#x02713; Diabetes phenotype<break/> Cardiac dysfunction?<break/> Renal dysfunction?<break/> Aging?<break/> Systemic inflammation?<break/> Immunometabolism dysfunction?</td>
<td valign="top" align="left">Rat (<xref ref-type="bibr" rid="B56">56</xref>, <xref ref-type="bibr" rid="B57">57</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">SKO</td>
<td valign="top" align="left">&#x02713; Diabetes phenotype<break/> &#x02713; Cardiomegaly<break/> &#x02713; Cardiac dysfunction<break/> Aging?<break/> Obesity?<break/> Hypertension?<break/> Immunometabolism dysfunction?</td>
<td valign="top" align="left">Mouse (<xref ref-type="bibr" rid="B58">58</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">Dahl salt-sensitive and ZSF1 models</td>
<td valign="top" align="left">&#x02713; Obesity<break/> &#x02713; Aging<break/> &#x02713; Hypertension<break/> &#x02713; Metabolism dysfunction<break/> &#x02713; Cardiac dysfunction<break/> Systemic inflammation?<break/> Renal dysfunction?</td>
<td valign="top" align="left">Rat (<xref ref-type="bibr" rid="B59">59</xref>)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><italic>(<bold>v</bold>) indicates experimental animal model that recapitulate HFpEF aspects. (?) indicates that the experimental animal model has not been studied for the indicated aspect. FPR2KO, formyl peptide receptor 2 knock out; Ob/Ob, obese mouse; db/db, db gene knock out, responsible for leptin receptor; ZF/ZDF, Zucker fatty/Zucker diabetic fatty; SKO, seipin knock out; ZSF1, Zucker spontaneously fatty hypertensive heart failure F1 hybrid</italic>.</p>
</table-wrap-foot>
</table-wrap>
<sec>
<title>Sterile Inflammation Resolution in Cardiac Repair and Suboptimal Inflammation in Heart Failure With Preserved Ejection Fraction</title>
<p>In response to an ischemic event, unresolved inflammation after cardiac injury is one of the common causal contributors in HFrEF (<xref ref-type="bibr" rid="B60">60</xref>). In the last two decades with high incidence of metabolic defects, it has been proven that inflammatory markers and array of cytokines may improve HF risk stratification and are considered predictors of HFpEF incident (<xref ref-type="bibr" rid="B61">61</xref>, <xref ref-type="bibr" rid="B62">62</xref>). To date, different studies are ongoing to understand the cellular and molecular mechanisms by which the inflammatory response ends up in sustained inflammation that triggers unresolved inflammation leading to HFpEF. Recent preclinical studies in mice dissect the macrophage&#x00027;s role in HFpEF therapy and open up previously unexplored treatment options (<xref ref-type="bibr" rid="B63">63</xref>). Post-MI, macrophage temporal expression during the initiation of inflammation is a critical determinant of cardiac repair. However, we must note that progression and resolution of inflammation are overlapping and active processes aimed to control undesirable long-term inflammation. These overlapping processes are a hallmark of macrophage function and characterized by the production of the specialized proresolving mediator (SPM) biosynthesis. A recent report suggests that the deletion of resolution sensor ALX/FPR2 develop age-related obesity and diastolic dysfunction in mice with HFpEF (<xref ref-type="fig" rid="F2">Figure 2</xref>) (<xref ref-type="bibr" rid="B52">52</xref>). After cardiac injury, ALX/FPR2 null mice induced macrophage dysfunction thereby lowering SPMs biosynthesis in the infarcted myocardium with defective activation of leukocytes in the spleen and heart (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B52">52</xref>). Thus, macrophages are key in SPM biosynthesis from one side to resolve inflammation but also perform as master regulators during inflammation if they are pre- or overactivated before cardiac injury. Over the years, the dichotomy of M1/M2 macrophage spectrum is limited to describe macrophage function and amalgam of these key players required for myocardium homeostasis (<xref ref-type="bibr" rid="B64">64</xref>). During the resolution phase, reparative (M2) macrophages secrete high levels of TGF&#x003B2;1, which drives the transcription of alpha smooth muscle actin (&#x003B1;-SMA) in the resident fibroblasts. Hence, it leads to the stiffness of the heart due to increased fibrosis, which reduces diastolic relaxation if it is over sustained (<xref ref-type="bibr" rid="B65">65</xref>). The explanation of macrophage dysfunction is described by many reports as pointing once inflammation is activated; a crosstalk is initiated between leukocytes, especially macrophage, and different types of cells such as endothelial and fibroblast cells, in a paracrine relationship. After cardiac injury, the crosstalk of activated macrophages and fibroblasts is necessary for ECM generation and reparative scar formation indicative of safe clearance of inflammation (<xref ref-type="bibr" rid="B66">66</xref>, <xref ref-type="bibr" rid="B67">67</xref>). These findings emphasize the macrophage role in physiological or pathological inflammation in the development of HFpEF especially the source of a ripple or stream effect in the disease pathogenesis depending on the time, the location, and the milieu.</p>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption><p>Resolvin D1 and lipoxin receptor-deficient mice (FPR2/ALXKO) complement the criteria of HFpEF with profound age-associated endothelial dysfunction and inflammation in the spleen, heart, and kidneys with signs of chronic inflammation. <bold>(A)</bold> Left panel indicates the heterogeneous, multidimensional, and multiorgan metabolic defects that contribute to HFpEF. <bold>(B)</bold> Right panel indicates the dysfunction of the resolution receptor FPR2/ALX in mice that develops spontaneous obesity with diastolic dysfunction along with limited changes in systolic function when obesity is superimposed on aging as signs of preserved ejection fraction. Suboptimal inflammation indicated with profound activation of IL1&#x003B2; gene expression in the heart, kidneys, and lungs in FPR2/ALXKO mice exemplifies the age-associated cardiac strain dysfunction, myocardium dissynchronicity, and amplified inflammation. &#x0002A;<italic>p</italic> &#x0003C; 0.05 compared to control WT group.</p></caption>
<graphic xlink:href="fcvm-08-695952-g0002.tif"/>
</fig>
<p>The other side of HFpEF is systemic inflammation and is an inherent phenotype in HFpEF patients. In clinical trials, in a group of patients with HF, it was confirmed that TNFR 2 plasma levels were significantly associated with the degree of diastolic dysfunction in patients with HFpEF but not HFrEF (<xref ref-type="bibr" rid="B68">68</xref>, <xref ref-type="bibr" rid="B69">69</xref>). Besides myocardium inflammation, several cell types and tissues could contribute to systemic inflammation in patients with chronic HF as leukocytes and tissue macrophages and endothelial cells (<xref ref-type="bibr" rid="B70">70</xref>). The precise root cause of multiorgan inflammation is unclear, however, postulated from the intrinsic lifestyle factors such as imbalanced diet, sleep, and activity. Whether inflammation is a cause or consequence in the progression of the disease is still under investigation. Recent reports indicate that abdominal obesity is associated with an increased risk of all-cause mortality in patients with HFpEF (93). Aging, hypertension, diabetes, kidney, and endothelial dysfunction are a cluster of non-cardiac metabolic risk factors that are causal contributors to suboptimal inflammation with consequent HFpEF and further mortality in HFpEF patients (<xref ref-type="bibr" rid="B71">71</xref>, <xref ref-type="bibr" rid="B72">72</xref>). Based on these facts, it is becoming clear that the presence of suboptimal or low-grade inflammation related to metabolic defects is behind the delay or worsening the start/progression of resolution of inflammation in HF. The sensor of resolution of inflammation as FPR2 receptors and SPMs were partially studied in experimental models of obesity superimposed on aging or &#x0201C;obesogenic aging.&#x0201D; However, Toll-like receptor (TLR) pathways have not been studied in animal models with multiple risk factors. TLRs are one of the main innate immune receptors that serve as mediators of sterile inflammatory conditions (<xref ref-type="bibr" rid="B73">73</xref>, <xref ref-type="bibr" rid="B74">74</xref>). Activated immune cells release damage-associated molecular patterns (DAMPS) that activate cardiomyocytes that switch on to TLR4-mediated cardiac apoptosis (<xref ref-type="bibr" rid="B75">75</xref>).</p>
<p>HFrEF patients are prone to pathogen-directed systemic inflammation like sepsis (<xref ref-type="bibr" rid="B76">76</xref>). There are some contradicting clinical reports suggesting that obesity can prevent mortality rate in septic patients with chronic heart failure (CHF) (<xref ref-type="bibr" rid="B77">77</xref>) with limited supportive evidence and explanation. The paradigm is how obesity influences the immune response of septic patients, by increasing the whole proinflammatory response, but at the same time improving survival rate (<xref ref-type="bibr" rid="B78">78</xref>). One common explanation of this outcome is that lipid mediators/metabolites act as scavengers in circulatory blood and bind to endotoxins/leukocyte receptors and perform as antagonists (<xref ref-type="bibr" rid="B79">79</xref>). Future prospective studies should quantify adipose tissue at or before sepsis diagnosis to accurately identify true association between obesity and septic HF etiology (<xref ref-type="bibr" rid="B80">80</xref>). The presence of suboptimal inflammation plays a pivotal role in the initiation/progression of the disease. From this perspective, here, we emphasized the evolution of HFpEF from the concept of one-dimensional to multidimensional view where suboptimal inflammation serves as the hallmark in HFpEF progression due to the cluster of metabolic defects.</p>
</sec>
<sec>
<title>Immune Metabolism and Macrophage Dysfunction</title>
<p>Based on the integrative function of leukocytes and metabolism, we discovered that splenic leukocytes dysregulation due to obesity or age-related unresolved inflammation is a primary mechanism of HFpEF in obesogenic aging. Immune cells, particularly leukocytes, operate for the resolution of inflammation and tissue repair. Cardiac injury site operates in the inflammation-resolution program with a supply of necessary energy nutrients and oxygen demand to accomplish processes of phagocytosis and microbial killing (<xref ref-type="bibr" rid="B81">81</xref>, <xref ref-type="bibr" rid="B82">82</xref>). At the cellular level, if there is a metabolic defect, the phagocytosis mechanism would be certainly affected, which is common in obesity (<xref ref-type="bibr" rid="B83">83</xref>), in addition to the fact that changes in nutritional status impact immune cell metabolism and function due to Treg cells, which induces a significant shift in immune cell populations and cytokine production toward a proinflammatory state (<xref ref-type="bibr" rid="B84">84</xref>). Recent data showed that a resolution sensor FPR2/ALX plays a central role in metabolic homeostasis interaction with immune metabolism. Intriguingly, FPR2/ALX is essential for safe clearance of inflammation postcardiac injury (<xref ref-type="bibr" rid="B85">85</xref>, <xref ref-type="bibr" rid="B86">86</xref>). In fact, FPR2/ALX receptor agonists lipoxins and resolvins, known as specialized proresolving mediators, decreased after ischemia in resolution receptor-deficient mice. In addition, the pharmacological inhibition of FPR2/ALX by WRW4 impaired leukocyte recruitment and elicited non-resolving inflammation in acute HF by limiting leukocyte mobilization to the injured site (<xref ref-type="bibr" rid="B87">87</xref>). Furthermore, in the absence of ischemic injury, young and aging mice show signs of metabolic defects after deletion of the FPR2/ALX receptor (<xref ref-type="fig" rid="F2">Figure 2</xref>). Moreover, the immune response coordination of the leukocyte reservoir from the spleen to the heart (splenocardiac axis) was disrupted in these mice because of macrophage dysfunction (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B52">52</xref>). Recent reports indicate that infiltrating macrophages undergo metabolic re-programming in cardiac repair process to increase oxidative phosphorylation post-MI (<xref ref-type="bibr" rid="B88">88</xref>&#x02013;<xref ref-type="bibr" rid="B90">90</xref>). Increased oxidative phosphorylation in addition to fatty acid synthesis and oxidation is a signature of reparative (M2) phenotype (<xref ref-type="bibr" rid="B91">91</xref>). In the clinical setting, HF failure is marked with the presence of unresolved inflammation after MI with multiple risk factors. This notion regained interest in the last three decades after the discovery of the resolution of inflammation concept where elevated levels of tumor necrosis factor-&#x003B1; (TNF-&#x003B1;) were observed in HFpEF patients (<xref ref-type="bibr" rid="B92">92</xref>). As a therapeutic approach, blockade of the inflammatory cytokines and chemokines turned out as a negative outcome in the clinical settings. However, modulating the fate map of leukocytes, particularly macrophages, representing up to 50% of all cell types within the hypertrophic obese adipose tissue of mice and humans, appear to be potentially successful procedures (<xref ref-type="bibr" rid="B93">93</xref>&#x02013;<xref ref-type="bibr" rid="B96">96</xref>). Over the years, there has been a growing recognition on how initiation, activation, and programming of the immune cell lead to the on/off of the inflammatory response in cardiac tissue repair. Since immune cell activation and its phenotypes are related to the metabolism, studies are focusing in defining the metabolic plasticity of immune cells after an injury. Research reflects the complexity of immune-metabolic signaling, networks, and the cellular and molecular events that can determine either the return to homeostasis or failure of the heart. The impact of metabolic disturbance, due to obesity with defective immune metabolism, misalign the activation of immune cells by enabling them to access the extracellular environment. From one side, in obese mice, the fat mass alters the integrity of the architecture of the immune tissue, thereby, impacting leukocyte roles postcardiac injury (<xref ref-type="bibr" rid="B97">97</xref>, <xref ref-type="bibr" rid="B98">98</xref>). From another side, emerging evidence shows that activation of the immune response in the setting of obesity is activated through free fatty acid (FFA) metabolic signals by different molecular signaling pathways leading to stimulation of critical inflammatory signaling cascades (<xref ref-type="bibr" rid="B99">99</xref>). In fact, <italic>in vivo</italic> studies have shown that increasing plasma FFA levels activate NF-&#x003BA;B in human skeletal muscle, which leads to an increased expression of proinflammatory cytokines and elevated circulating levels of MCP-1 (<xref ref-type="bibr" rid="B100">100</xref>). Also, circulating FFAs impair insulin sensitivity through binding to the plasma membrane receptor Toll-like receptor 4 (TLR4) in tissues of obese animals, resulting in the activation of signaling proteins, such as inhibitor of nuclear factor-&#x003BA;B (I&#x003BA;B) kinase (IKK), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase (MAPK), that negatively dysregulate the metabolic axis of macrophage polarization favoring chronic inflammation (<xref ref-type="bibr" rid="B101">101</xref>, <xref ref-type="bibr" rid="B102">102</xref>). Overall, physiological studies strongly support a reciprocal relationship between the FFAs and respective receptors (FFARs) that helps in regulating the metabolic&#x02013;inflammatory axis in HFpEF.</p>
</sec>
<sec>
<title>Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction</title>
<p>Chronic inflammation is strongly linked to endothelial dysfunction (<xref ref-type="bibr" rid="B103">103</xref>, <xref ref-type="bibr" rid="B104">104</xref>), since inflammatory signals activate the endothelial cells and fibroblasts resulting in subsequent concentric cardiac remodeling and dysfunction (<xref ref-type="bibr" rid="B105">105</xref>). Endothelial dysfunction is portrayed as one of the cellular mechanisms underlying HFpEF syndrome. In fact, the decline in endothelial NO bioavailability is observed in 90% of patients with HFpEF along with the decrease in intracellular cGMP and protein kinase G activity kinases that contribute to LV filling pressures and triggers the delay of myocardial relaxation (<xref ref-type="bibr" rid="B106">106</xref>, <xref ref-type="bibr" rid="B107">107</xref>). Recent studies observed that the microvascular endothelial dysfunction is primed essentially by activated macrophages due to suboptimal inflammation (<xref ref-type="bibr" rid="B52">52</xref>, <xref ref-type="bibr" rid="B108">108</xref>, <xref ref-type="bibr" rid="B109">109</xref>). In obese animal models, targeting CCR2 helps to avoid accumulation of macrophages in the vascular wall thereby reducing endothelial dysfunction and oxidative stress (<xref ref-type="bibr" rid="B109">109</xref>, <xref ref-type="bibr" rid="B110">110</xref>). Moreover, in experimental model of aging, it has been reported that endothelial senescence and inflammation are associated through the senescence-associated secretory phenotype. Age-related inflammation contribute to the development of HFpEF early stage marked by hemodynamic and structural changes evolving to a typical HFpEF phenotype (<xref ref-type="bibr" rid="B111">111</xref>). Besides aging and inflammation inducing endothelial dysfunction, the deficiency of protease-activated receptor 2 (PAR2) is associated with extracellular matrix remodeling, which might be an alternative contributor to HFpEF pathophysiology (<xref ref-type="bibr" rid="B112">112</xref>). In addition, emerging explanation for endothelial dysfunction in HFpEF is the endothelial metabolic reprogramming. Recently, it has been shown that the impairment of silent mating type information regulation 2 homolog (SIRT3)-mediated endothelial cell metabolism may lead to a disruption of communications between myocyte adjacent cells and coronary microvascular rarefaction (<xref ref-type="bibr" rid="B113">113</xref>). In this context, a model of cardiac metabolic disorder due to the dysfunction of ALX receptor, essential for the resolution of inflammation in cardiac repair (<xref ref-type="bibr" rid="B114">114</xref>), shows a pronounced cardiorenal endothelial dysfunction in the mice along with diastolic dysfunction and preserved EF (<xref ref-type="bibr" rid="B52">52</xref>) (<xref ref-type="fig" rid="F2">Figure 2</xref>). In an age-related study, ALX/FPR2KO mice decreased protein and gene expressions of eNOS and CD31 in the heart and kidneys with lower distribution of both endothelial markers in tissues compared with age-matched controls (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B52">52</xref>). In addition, recent findings highlighted an improved endothelial function in Zucker spontaneously fatty hypertensive heart failure F1 hybrid (ZSF1) obese rats, a recent model qualifying for HFpEF studies including hypertension and diabetes. In this study, supplementation of the NAD<sup>&#x0002B;</sup> precursor nicotinamide (NAM) elicited an antihypertensive effect correlated with improved endothelial function, as indicated by an enhanced vasodilatory response to acetylcholine in isolated aortic rings (<xref ref-type="bibr" rid="B59">59</xref>) (<xref ref-type="table" rid="T1">Table 1</xref>).</p>
</sec>
</sec>
<sec id="s3">
<title>Prevention and Treatment Perspective</title>
<p>The recent PARAGON clinical trial resulted in FDA approval to the Entresto drug, a sacubitril/valsartan combination, as the first treatment for HFpEF patients. However, due to the diversity and complexity of HFpEF patient phenotype, a large proportion of HFpEF patients will remain without meaningful treatment options considering the exclusion criteria in the actual treatment (<xref ref-type="bibr" rid="B115">115</xref>). This brings insights into the fundamental foundation for HFpEF treatment that remains supported by primary preventive treatment that focuses on lifestyle. As of today, no treatment is patient specific that target multiorgan and system-based approach due to heterogeneous pathology. Based on sedentary lifestyle, new terminology emerged termed as lifestyle-associated inflammatory diseases and their corresponding immune-stimulatory lifestyle-associated molecular patterns (LAMPs) (<xref ref-type="bibr" rid="B116">116</xref>). LAMPs are third generation after classical pathogen-associated molecular patterns (PAMPs) as lipopolysaccharide (LPS) or infection and damage-associated molecular patterns (DAMPs) as serum amyloid A or TLRs, known to induce inflammation-related disease. However, LAMPs impair the sterile inflammation due to our lifestyle-associated risk factors. As a self-choice avoiding known risk factors like sleep cycle regulation (<xref ref-type="bibr" rid="B117">117</xref>) (respecting body clock), diet/nutrient [healthy food with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) food intake], and exercise (<xref ref-type="bibr" rid="B118">118</xref>) (maintaining active lifestyle) might entail a balanced metabolism and help in delaying the inevitable decline in various body systems and physiological processes of aging. For total health, it is obvious to avoid or limit smoking (both passive and active smoke), and control psychological stress and alcohol intake (<xref ref-type="fig" rid="F3">Figure 3</xref>). Thus, third-generation novel LAMPs are manageable and should be considered strongly to reduce the burden of prevalence of HFpEF in obesogenic aging (<xref ref-type="bibr" rid="B119">119</xref>, <xref ref-type="bibr" rid="B120">120</xref>). Molecular and cellular mechanism of LAMPs is warranted after extensive research on PAMPs and DAMPs.</p>
<fig id="F3" position="float">
<label>Figure 3</label>
<caption><p>Fundamental and lifestyle-associated prime factors that control inflammation (left arm of figure) in contrast to risk factors that drive suboptimal inflammation in HFpEF and integration with lifestyle-associated molecular patterns (LAMPs). The main four aspects of daily life to consider as prime strategy for prevention of HFpEF (diet/nutrient, sleep/wake up rhythm, exercise, and choice of active life and limited sedentary lifestyle). Adoption of optimal age-related lifestyle would be helpful to balance the genesis of LAMPs in cardiovascular disease that will help to limit the progression to heart failure.</p></caption>
<graphic xlink:href="fcvm-08-695952-g0003.tif"/>
</fig>
</sec>
<sec sec-type="conclusions" id="s4">
<title>Conclusion</title>
<p>Like every area of life sciences, change is not permanent, and likewise, the HF pathophysiology evolved from one-dimensional homogenous pathology to heterogeneous multiorgan dysfunction particularly in obesity/metabolic syndrome superimposed on aging. From a prevention perspective, primary focus on diet/nutrition intake (quality/quantity), sleep&#x02013;wake up cycle (circadian rhythm), and physical activity (exercise/sedentary lifestyle) are key determinants of total health and specifically for cardiovascular health (<xref ref-type="fig" rid="F3">Figure 3</xref>). Recent ongoing clinical trials for HFpEF are targeting metabolic diseases like type 2 diabetes/insulin resistance/hyperglycemia with improvement in cardiovascular outcome that underline the strength of metabolic disorder and HF-related suboptimal inflammation. However, the major missing point in HFpEF is the multitude of phenotypes in HF syndrome of which half of the patients are either obese or aging or both, which make the clinical cases deeply complicated; thus, innovative animal model and treatment strategy are extensively warranted to study lifestyle-associated molecular patterns (LAMPs).</p>
</sec>
<sec id="s5">
<title>Author Contributions</title>
<p>GH conceptualized the outline, edited the multiple drafts, prepared/edited the figures, and approved for submission. BT prepared the first draft and re-edited after the input from GH. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec sec-type="COI-statement" id="conf1">
<title>Conflict of Interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s6">
<title>Publisher&#x00027;s Note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
</body>
<back>
<ack><p>The authors would like to acknowledge the Servier Medical Art library for some figures presented in this review.</p>
</ack>
<ref-list>
<title>References</title>
<ref id="B1">
<label>1.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ward</surname> <given-names>ZJ</given-names></name> <name><surname>Bleich</surname> <given-names>SN</given-names></name> <name><surname>Cradock</surname> <given-names>AL</given-names></name> <name><surname>Barrett</surname> <given-names>JL</given-names></name> <name><surname>Giles</surname> <given-names>CM</given-names></name> <name><surname>Flax</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Projected U.S. state-level prevalence of adult obesity and severe obesity</article-title>. <source>N Engl J Med.</source> (<year>2019</year>) <volume>381</volume>:<fpage>2440</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1056/NEJMsa1909301</pub-id><pub-id pub-id-type="pmid">31851800</pub-id></citation></ref>
<ref id="B2">
<label>2.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Han</surname> <given-names>TS</given-names></name> <name><surname>Lean</surname> <given-names>ME</given-names></name></person-group>. <article-title>A clinical perspective of obesity, metabolic syndrome and cardiovascular disease</article-title>. <source>JRSM Cardiovasc Dis.</source> (<year>2016</year>) <volume>5</volume>:<fpage>2048004016633371</fpage>. <pub-id pub-id-type="doi">10.1177/2048004016633371</pub-id><pub-id pub-id-type="pmid">26998259</pub-id></citation></ref>
<ref id="B3">
<label>3.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Patel</surname> <given-names>SD</given-names></name> <name><surname>Peterson</surname> <given-names>A</given-names></name> <name><surname>Bartczak</surname> <given-names>A</given-names></name> <name><surname>Lee</surname> <given-names>S</given-names></name> <name><surname>Chojnowski</surname> <given-names>S</given-names></name> <name><surname>Gajewski</surname> <given-names>P</given-names></name> <etal/></person-group>. <article-title>Primary cardiac angiosarcoma&#x02014;a review</article-title>. <source>Med Sci Monit.</source> (<year>2014</year>) <volume>20</volume>:<fpage>103</fpage>&#x02013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.12659/MSM.889875</pub-id></citation></ref>
<ref id="B4">
<label>4.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pazhenkottil</surname> <given-names>AP</given-names></name> <name><surname>Bode</surname> <given-names>PK</given-names></name></person-group>. <article-title>Angiosarcoma Involving the Heart</article-title>. <source>N Engl J Med.</source> (<year>2020</year>) <volume>382</volume>:<fpage>855</fpage>. <pub-id pub-id-type="doi">10.1056/NEJMicm1910259</pub-id></citation></ref>
<ref id="B5">
<label>5.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Larsson</surname> <given-names>L</given-names></name> <name><surname>Degens</surname> <given-names>H</given-names></name> <name><surname>Li</surname> <given-names>M</given-names></name> <name><surname>Salviati</surname> <given-names>L</given-names></name> <name><surname>Lee</surname> <given-names>YI</given-names></name> <name><surname>Thompson</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>Sarcopenia: aging-related loss of muscle mass and function</article-title>. <source>Physiol Rev.</source> (<year>2019</year>) <volume>99</volume>:<fpage>427</fpage>&#x02013;<lpage>511</lpage>. <pub-id pub-id-type="doi">10.1152/physrev.00061.2017</pub-id><pub-id pub-id-type="pmid">30427277</pub-id></citation></ref>
<ref id="B6">
<label>6.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lena</surname> <given-names>A</given-names></name> <name><surname>Anker</surname> <given-names>MS</given-names></name> <name><surname>Springer</surname> <given-names>J</given-names></name></person-group>. <article-title>Muscle wasting and sarcopenia in heart failure-the current state of science</article-title>. <source>Int J Mol Sci.</source> (<year>2020</year>) <volume>21</volume>:<fpage>6549</fpage>. <pub-id pub-id-type="doi">10.3390/ijms21186549</pub-id><pub-id pub-id-type="pmid">32911600</pub-id></citation></ref>
<ref id="B7">
<label>7.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lavine</surname> <given-names>KJ</given-names></name> <name><surname>Sierra</surname> <given-names>OL</given-names></name></person-group>. <article-title>Skeletal muscle inflammation and atrophy in heart failure</article-title>. <source>Heart Fail Rev.</source> (<year>2017</year>) <volume>22</volume>:<fpage>179</fpage>&#x02013;<lpage>89</lpage>. <pub-id pub-id-type="doi">10.1007/s10741-016-9593-0</pub-id><pub-id pub-id-type="pmid">28091823</pub-id></citation></ref>
<ref id="B8">
<label>8.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cardinale</surname> <given-names>D</given-names></name> <name><surname>Colombo</surname> <given-names>A</given-names></name> <name><surname>Lamantia</surname> <given-names>G</given-names></name> <name><surname>Colombo</surname> <given-names>N</given-names></name> <name><surname>Civelli</surname> <given-names>M</given-names></name> <name><surname>De Giacomi</surname> <given-names>G</given-names></name> <etal/></person-group>. <article-title>Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy</article-title>. <source>J Am Coll Cardiol.</source> (<year>2010</year>) <volume>55</volume>:<fpage>213</fpage>&#x02013;<lpage>20</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2009.03.095</pub-id><pub-id pub-id-type="pmid">20117401</pub-id></citation></ref>
<ref id="B9">
<label>9.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sweeney</surname> <given-names>M</given-names></name> <name><surname>Yiu</surname> <given-names>A</given-names></name> <name><surname>Lyon</surname> <given-names>AR</given-names></name></person-group>. <article-title>Cardiac atrophy and heart failure in cancer</article-title>. <source>Card Fail Rev.</source> (<year>2017</year>) <volume>3</volume>:<fpage>62</fpage>&#x02013;<lpage>5</lpage>. <pub-id pub-id-type="doi">10.15420/cfr.2017:3:2</pub-id><pub-id pub-id-type="pmid">28785478</pub-id></citation></ref>
<ref id="B10">
<label>10.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Willis</surname> <given-names>MS</given-names></name> <name><surname>Parry</surname> <given-names>TL</given-names></name> <name><surname>Brown</surname> <given-names>DI</given-names></name> <name><surname>Mota</surname> <given-names>RI</given-names></name> <name><surname>Huang</surname> <given-names>W</given-names></name> <name><surname>Beak</surname> <given-names>JY</given-names></name> <etal/></person-group>. <article-title>Doxorubicin exposure causes subacute cardiac atrophy dependent on the striated muscle-specific ubiquitin ligase MuRF1</article-title>. <source>Circ Heart Fail.</source> (<year>2019</year>) <volume>12</volume>:<fpage>e005234</fpage>. <pub-id pub-id-type="doi">10.1161/CIRCHEARTFAILURE.118.005234</pub-id><pub-id pub-id-type="pmid">30871347</pub-id></citation></ref>
<ref id="B11">
<label>11.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Jadapalli</surname> <given-names>JK</given-names></name> <name><surname>Wright</surname> <given-names>GW</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Sherwani</surname> <given-names>MA</given-names></name> <name><surname>Sonkar</surname> <given-names>R</given-names></name> <name><surname>Yusuf</surname> <given-names>N</given-names></name> <etal/></person-group>. <article-title>Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium</article-title>. <source>Am J Physiol Heart Circ Physiol.</source> (<year>2018</year>) <volume>315</volume>:<fpage>H1091</fpage>&#x02013;<lpage>h1100</lpage>. <pub-id pub-id-type="doi">10.1152/ajpheart.00290.2018</pub-id><pub-id pub-id-type="pmid">30074834</pub-id></citation></ref>
<ref id="B12">
<label>12.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Heineke</surname> <given-names>J</given-names></name> <name><surname>Auger-Messier</surname> <given-names>M</given-names></name> <name><surname>Xu</surname> <given-names>J</given-names></name> <name><surname>Sargent</surname> <given-names>M</given-names></name> <name><surname>York</surname> <given-names>A</given-names></name> <name><surname>Welle</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure</article-title>. <source>Circulation.</source> (<year>2010</year>) <volume>121</volume>:<fpage>419</fpage>&#x02013;<lpage>25</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.109.882068</pub-id><pub-id pub-id-type="pmid">20065166</pub-id></citation></ref>
<ref id="B13">
<label>13.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hellerstein</surname> <given-names>HK</given-names></name> <name><surname>Santiago-Stevenson</surname> <given-names>D</given-names></name></person-group>. <article-title>Atrophy of the heart; a correlative study of 85 proved cases</article-title>. <source>Circulation.</source> (<year>1950</year>) <volume>1</volume>:<fpage>93</fpage>&#x02013;<lpage>26</lpage> illust. <pub-id pub-id-type="doi">10.1161/01.CIR.1.1.93</pub-id><pub-id pub-id-type="pmid">15401199</pub-id></citation></ref>
<ref id="B14">
<label>14.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Perhonen</surname> <given-names>MA</given-names></name> <name><surname>Franco</surname> <given-names>F</given-names></name> <name><surname>Lane</surname> <given-names>LD</given-names></name> <name><surname>Buckey</surname> <given-names>JC</given-names></name> <name><surname>Blomqvist</surname> <given-names>CG</given-names></name> <name><surname>Zerwekh</surname> <given-names>JE</given-names></name> <etal/></person-group>. <article-title>Cardiac atrophy after bed rest and spaceflight</article-title>. <source>J Appl Physiol.</source> (<year>1985</year>). (<year>2001</year>) <volume>91</volume>:<fpage>645</fpage>&#x02013;<lpage>53</lpage>. <pub-id pub-id-type="doi">10.1152/jappl.2001.91.2.645</pub-id><pub-id pub-id-type="pmid">16467397</pub-id></citation></ref>
<ref id="B15">
<label>15.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Baskin</surname> <given-names>KK</given-names></name> <name><surname>Taegtmeyer</surname> <given-names>H</given-names></name></person-group>. <article-title>Taking pressure off the heart: the ins and outs of atrophic remodelling</article-title>. <source>Cardiovasc Res.</source> (<year>2011</year>) <volume>90</volume>:<fpage>243</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1093/cvr/cvr060</pub-id><pub-id pub-id-type="pmid">21354996</pub-id></citation></ref>
<ref id="B16">
<label>16.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lehrer</surname> <given-names>P</given-names></name> <name><surname>Eddie</surname> <given-names>D</given-names></name></person-group>. <article-title>Dynamic processes in regulation and some implications for biofeedback and biobehavioral interventions</article-title>. <source>Appl Psychophysiol Biofeedback.</source> (<year>2013</year>) <volume>38</volume>:<fpage>143</fpage>&#x02013;<lpage>55</lpage>. <pub-id pub-id-type="doi">10.1007/s10484-013-9217-6</pub-id><pub-id pub-id-type="pmid">23572244</pub-id></citation></ref>
<ref id="B17">
<label>17.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Carabello</surname> <given-names>BA</given-names></name></person-group>. <article-title>Concentric versus eccentric remodeling</article-title>. <source>J Card Fail.</source> (<year>2002</year>) <volume>8</volume>:<fpage>S258</fpage>&#x02013;<lpage>63</lpage>. <pub-id pub-id-type="doi">10.1054/jcaf.2002.129250</pub-id></citation></ref>
<ref id="B18">
<label>18.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Borlaug</surname> <given-names>BA</given-names></name> <name><surname>Redfield</surname> <given-names>MM</given-names></name></person-group>. <article-title>Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum</article-title>. <source>Circulation.</source> (<year>2011</year>) <volume>123</volume>:<fpage>2006</fpage>&#x02013;<lpage>13</lpage>; discussion 2014. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.110.954388</pub-id><pub-id pub-id-type="pmid">21555723</pub-id></citation></ref>
<ref id="B19">
<label>19.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Redfield</surname> <given-names>MM</given-names></name></person-group>. <article-title>Heart failure with preserved ejection fraction</article-title>. <source>N Engl J Med.</source> (<year>2016</year>) <volume>375</volume>:<fpage>1868</fpage>&#x02013;<lpage>77</lpage>. <pub-id pub-id-type="doi">10.1056/NEJMcp1511175</pub-id></citation></ref>
<ref id="B20">
<label>20.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ponikowski</surname> <given-names>P</given-names></name> <name><surname>Voors</surname> <given-names>AA</given-names></name> <name><surname>Anker</surname> <given-names>SD</given-names></name> <name><surname>Bueno</surname> <given-names>H</given-names></name> <name><surname>Cleland</surname> <given-names>JGF</given-names></name> <name><surname>Coats</surname> <given-names>AJS</given-names></name> <etal/></person-group>. <article-title>2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC</article-title>. <source>Eur Heart J.</source> (<year>2016</year>) <volume>37</volume>:<fpage>2129</fpage>&#x02013;<lpage>200</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehw128</pub-id><pub-id pub-id-type="pmid">27207191</pub-id></citation></ref>
<ref id="B21">
<label>21.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yancy</surname> <given-names>CW</given-names></name> <name><surname>Jessup</surname> <given-names>M</given-names></name> <name><surname>Bozkurt</surname> <given-names>B</given-names></name> <name><surname>Butler</surname> <given-names>J</given-names></name> <name><surname>Casey</surname> <given-names>DE</given-names> <suffix>Jr</suffix></name> <name><surname>Colvin</surname> <given-names>MM</given-names></name> <etal/></person-group>. <article-title>2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America</article-title>. <source>Circulation.</source> (<year>2017</year>) <volume>136</volume>:<fpage>e137</fpage>&#x02013;<lpage>e161</lpage>. <pub-id pub-id-type="doi">10.1161/CIR.0000000000000509</pub-id><pub-id pub-id-type="pmid">28461259</pub-id></citation></ref>
<ref id="B22">
<label>22.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shah</surname> <given-names>MS</given-names></name> <name><surname>Brownlee</surname> <given-names>M</given-names></name></person-group>. <article-title>Molecular and cellular mechanisms of cardiovascular disorders in diabetes</article-title>. <source>Circ Res.</source> (<year>2016</year>) <volume>118</volume>:<fpage>1808</fpage>&#x02013;<lpage>29</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.116.306923</pub-id><pub-id pub-id-type="pmid">27230643</pub-id></citation></ref>
<ref id="B23">
<label>23.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>van Heerebeek</surname> <given-names>L</given-names></name> <name><surname>Franssen</surname> <given-names>CPM</given-names></name> <name><surname>Hamdani</surname> <given-names>N</given-names></name> <name><surname>Verheugt</surname> <given-names>FWA</given-names></name> <name><surname>Somsen</surname> <given-names>GA</given-names></name> <name><surname>Paulus</surname> <given-names>WJ</given-names></name></person-group>. <article-title>Molecular and cellular basis for diastolic dysfunction</article-title>. <source>Curr Heart Fail Rep.</source> (<year>2012</year>) <volume>9</volume>:<fpage>293</fpage>&#x02013;<lpage>302</lpage>. <pub-id pub-id-type="doi">10.1007/s11897-012-0109-5</pub-id><pub-id pub-id-type="pmid">24464932</pub-id></citation></ref>
<ref id="B24">
<label>24.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Osorio</surname> <given-names>JC</given-names></name> <name><surname>Stanley</surname> <given-names>WC</given-names></name> <name><surname>Linke</surname> <given-names>A</given-names></name> <name><surname>Castellari</surname> <given-names>M</given-names></name> <name><surname>Diep</surname> <given-names>QN</given-names></name> <name><surname>Panchal</surname> <given-names>AR</given-names></name> <etal/></person-group>. <article-title>Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure</article-title>. <source>Circulation.</source> (<year>2002</year>) <volume>106</volume>:<fpage>606</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1161/01.CIR.0000023531.22727.C1</pub-id><pub-id pub-id-type="pmid">12147544</pub-id></citation></ref>
<ref id="B25">
<label>25.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Barger</surname> <given-names>PM</given-names></name> <name><surname>Brandt</surname> <given-names>JM</given-names></name> <name><surname>Leone</surname> <given-names>TC</given-names></name> <name><surname>Weinheimer</surname> <given-names>CJ</given-names></name> <name><surname>Kelly</surname> <given-names>DP</given-names></name></person-group>. <article-title>Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth</article-title>. <source>J Clin Invest.</source> (<year>2000</year>) <volume>105</volume>:<fpage>1723</fpage>&#x02013;<lpage>30</lpage>. <pub-id pub-id-type="doi">10.1172/JCI9056</pub-id><pub-id pub-id-type="pmid">10862787</pub-id></citation></ref>
<ref id="B26">
<label>26.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bugger</surname> <given-names>H</given-names></name> <name><surname>Schwarzer</surname> <given-names>M</given-names></name> <name><surname>Chen</surname> <given-names>D</given-names></name> <name><surname>Schrepper</surname> <given-names>A</given-names></name> <name><surname>Amorim</surname> <given-names>PA</given-names></name> <name><surname>Schoepe</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure</article-title>. <source>Cardiovasc Res.</source> (<year>2010</year>) <volume>85</volume>:<fpage>376</fpage>&#x02013;<lpage>84</lpage>. <pub-id pub-id-type="doi">10.1093/cvr/cvp344</pub-id><pub-id pub-id-type="pmid">19843514</pub-id></citation></ref>
<ref id="B27">
<label>27.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nauta</surname> <given-names>JF</given-names></name> <name><surname>Hummel</surname> <given-names>YM</given-names></name> <name><surname>Tromp</surname> <given-names>J</given-names></name> <name><surname>Ouwerkerk</surname> <given-names>W</given-names></name> <name><surname>van der Meer</surname> <given-names>P</given-names></name> <name><surname>Jin</surname> <given-names>X</given-names></name> <etal/></person-group>. <article-title>Concentric vs. eccentric remodelling in heart failure with reduced ejection fraction: clinical characteristics, pathophysiology and response to treatment</article-title>. <source>Eur J Heart Fail.</source> (<year>2019</year>) <volume>22</volume>:<fpage>1147</fpage>&#x02013;<lpage>55</lpage>. <pub-id pub-id-type="doi">10.1002/ejhf.1632</pub-id><pub-id pub-id-type="pmid">31713324</pub-id></citation></ref>
<ref id="B28">
<label>28.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tourki</surname> <given-names>B</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Pullen</surname> <given-names>AB</given-names></name> <name><surname>Norris</surname> <given-names>PC</given-names></name> <name><surname>Patel</surname> <given-names>N</given-names></name> <name><surname>Arora</surname> <given-names>P</given-names></name> <etal/></person-group>. <article-title>Lack of resolution sensor drives age-related cardiometabolic and cardiorenal defects and impedes inflammation-resolution in heart failure</article-title>. <source>Mol Metab.</source> (<year>2019</year>) <volume>31</volume>:<fpage>138</fpage>&#x02013;<lpage>49</lpage>. <pub-id pub-id-type="doi">10.1016/j.molmet.2019.10.008</pub-id><pub-id pub-id-type="pmid">31918915</pub-id></citation></ref>
<ref id="B29">
<label>29.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Concei&#x000E7;&#x000E3;o</surname> <given-names>G</given-names></name> <name><surname>Heinonen</surname> <given-names>I</given-names></name> <name><surname>Louren&#x000E7;o</surname> <given-names>AP</given-names></name> <name><surname>Duncker</surname> <given-names>DJ</given-names></name> <name><surname>Falc&#x000E3;o-Pires</surname> <given-names>I</given-names></name></person-group>. <article-title>Animal models of heart failure with preserved ejection fraction</article-title>. <source>Neth Heart J.</source> (<year>2016</year>) <volume>24</volume>:<fpage>275</fpage>&#x02013;<lpage>86</lpage>. <pub-id pub-id-type="doi">10.1007/s12471-016-0815-9</pub-id><pub-id pub-id-type="pmid">33350094</pub-id></citation></ref>
<ref id="B30">
<label>30.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kehat</surname> <given-names>I</given-names></name> <name><surname>Molkentin</surname> <given-names>JD</given-names></name></person-group>. <article-title>Molecular pathways underlying cardiac remodeling during pathophysiological stimulation</article-title>. <source>Circulation.</source> (<year>2010</year>) <volume>122</volume>:<fpage>2727</fpage>&#x02013;<lpage>35</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.110.942268</pub-id><pub-id pub-id-type="pmid">21173361</pub-id></citation></ref>
<ref id="B31">
<label>31.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nanayakkara</surname> <given-names>S</given-names></name> <name><surname>Haykowsky</surname> <given-names>M</given-names></name> <name><surname>Mariani</surname> <given-names>J</given-names></name> <name><surname>Van Empel</surname> <given-names>V</given-names></name> <name><surname>Maeder</surname> <given-names>MT</given-names></name> <name><surname>Vizi</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Hemodynamic profile of patients with heart failure and preserved ejection fraction vary by age</article-title>. <source>J Am Heart Assoc.</source> (<year>2017</year>) <volume>6</volume>:<fpage>e005434</fpage>. <pub-id pub-id-type="doi">10.1161/JAHA.116.005434</pub-id><pub-id pub-id-type="pmid">28939710</pub-id></citation></ref>
<ref id="B32">
<label>32.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Reed</surname> <given-names>BN</given-names></name> <name><surname>Sueta</surname> <given-names>CA</given-names></name></person-group>. <article-title>A practical guide for the treatment of symptomatic heart failure with reduced ejection fraction (HFrEF)</article-title>. <source>Curr Cardiol Rev.</source> (<year>2015</year>) <volume>11</volume>:<fpage>23</fpage>&#x02013;<lpage>32</lpage>. <pub-id pub-id-type="doi">10.2174/1574884708666131117125508</pub-id><pub-id pub-id-type="pmid">24251455</pub-id></citation></ref>
<ref id="B33">
<label>33.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Komamura</surname> <given-names>K</given-names></name></person-group>. <article-title>Similarities and differences between the pathogenesis and pathophysiology of diastolic and systolic heart failure</article-title>. <source>Cardiol Res Pract.</source> (<year>2013</year>) <volume>2013</volume>:<fpage>824135</fpage>. <pub-id pub-id-type="doi">10.1155/2013/824135</pub-id><pub-id pub-id-type="pmid">24459600</pub-id></citation></ref>
<ref id="B34">
<label>34.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Halade</surname> <given-names>GV</given-names></name></person-group>. <article-title>Gravin gravitates atherogenesis to atheroprogression in the obesogenic setting</article-title>. <source>Am J Physiol Heart Circ Physiol.</source> (<year>2019</year>) <volume>317</volume>:<fpage>H790</fpage>&#x02013;<lpage>h792</lpage>. <pub-id pub-id-type="doi">10.1152/ajpheart.00508.2019</pub-id><pub-id pub-id-type="pmid">31518153</pub-id></citation></ref>
<ref id="B35">
<label>35.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pfeffer</surname> <given-names>MA</given-names></name> <name><surname>Shah</surname> <given-names>AM</given-names></name> <name><surname>Borlaug</surname> <given-names>BA</given-names></name></person-group>. <article-title>Heart failure with preserved ejection fraction in perspective</article-title>. <source>Circ Res.</source> (<year>2019</year>) <volume>124</volume>:<fpage>1598</fpage>&#x02013;<lpage>617</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.119.313572</pub-id></citation></ref>
<ref id="B36">
<label>36.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rech</surname> <given-names>M</given-names></name> <name><surname>Barandiaran Aizpurua</surname> <given-names>A</given-names></name> <name><surname>van Empel</surname> <given-names>V</given-names></name> <name><surname>van Bilsen</surname> <given-names>M</given-names></name> <name><surname>Schroen</surname> <given-names>B</given-names></name></person-group>. <article-title>Pathophysiological understanding of HFpEF: microRNAs as part of the puzzle</article-title>. <source>Cardiovasc Res.</source> (<year>2018</year>) <volume>114</volume>:<fpage>782</fpage>&#x02013;<lpage>93</lpage>. <pub-id pub-id-type="doi">10.1093/cvr/cvy049</pub-id><pub-id pub-id-type="pmid">29462282</pub-id></citation></ref>
<ref id="B37">
<label>37.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Paulus</surname> <given-names>WJ</given-names></name> <name><surname>Tschope</surname> <given-names>C</given-names></name></person-group>. <article-title>A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation</article-title>. <source>J Am Coll Cardiol.</source> (<year>2013</year>) <volume>62</volume>:<fpage>263</fpage>&#x02013;<lpage>71</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2013.02.092</pub-id><pub-id pub-id-type="pmid">23684677</pub-id></citation></ref>
<ref id="B38">
<label>38.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Butler</surname> <given-names>J</given-names></name> <name><surname>Anker</surname> <given-names>SD</given-names></name> <name><surname>Packer</surname> <given-names>M</given-names></name></person-group>. <article-title>Redefining heart failure with a reduced ejection fraction</article-title>. <source>JAMA.</source> (<year>2019</year>) <volume>322</volume>:<fpage>1761</fpage>&#x02013;<lpage>2</lpage>. <pub-id pub-id-type="doi">10.1001/jama.2019.15600</pub-id><pub-id pub-id-type="pmid">31517955</pub-id></citation></ref>
<ref id="B39">
<label>39.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bloom</surname> <given-names>MW</given-names></name> <name><surname>Greenberg</surname> <given-names>B</given-names></name> <name><surname>Jaarsma</surname> <given-names>T</given-names></name> <name><surname>Januzzi</surname> <given-names>JL</given-names></name> <name><surname>Lam</surname> <given-names>CSP</given-names></name> <name><surname>Maggioni</surname> <given-names>AP</given-names></name> <etal/></person-group>. <article-title>Heart failure with reduced ejection fraction</article-title>. <source>Nat Rev Dis Primers.</source> (<year>2017</year>) <volume>3</volume>:<fpage>17058</fpage>. <pub-id pub-id-type="doi">10.1038/nrdp.2017.58</pub-id></citation></ref>
<ref id="B40">
<label>40.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tschope</surname> <given-names>C</given-names></name> <name><surname>Kherad</surname> <given-names>B</given-names></name> <name><surname>Klein</surname> <given-names>O</given-names></name> <name><surname>Lipp</surname> <given-names>A</given-names></name> <name><surname>Blaschke</surname> <given-names>F</given-names></name> <name><surname>Gutterman</surname> <given-names>D</given-names></name> <etal/></person-group>., <article-title>Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond</article-title>. <source>Eur J Heart Fail.</source> (<year>2019</year>) <volume>21</volume>:<fpage>14</fpage>&#x02013;<lpage>22</lpage>. <pub-id pub-id-type="doi">10.1002/ejhf.1349</pub-id><pub-id pub-id-type="pmid">30485591</pub-id></citation></ref>
<ref id="B41">
<label>41.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chatham</surname> <given-names>JC</given-names></name> <name><surname>Young</surname> <given-names>ME</given-names></name></person-group>. <article-title>Metabolic remodeling in the hypertrophic heart: fuel for thought</article-title>. <source>Circ Res.</source> (<year>2012</year>) <volume>111</volume>:<fpage>666</fpage>&#x02013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.112.277392</pub-id><pub-id pub-id-type="pmid">22935530</pub-id></citation></ref>
<ref id="B42">
<label>42.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lund</surname> <given-names>LH</given-names></name> <name><surname>Jurga</surname> <given-names>J</given-names></name> <name><surname>Edner</surname> <given-names>M</given-names></name> <name><surname>Benson</surname> <given-names>L</given-names></name> <name><surname>Dahlstrom</surname> <given-names>U</given-names></name> <name><surname>Linde</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Prevalence, correlates, and prognostic significance of QRS prolongation in heart failure with reduced and preserved ejection fraction</article-title>. <source>Eur Heart J.</source> (<year>2013</year>) <volume>34</volume>:<fpage>529</fpage>&#x02013;<lpage>39</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehs305</pub-id><pub-id pub-id-type="pmid">23041499</pub-id></citation></ref>
<ref id="B43">
<label>43.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Spannbauer</surname> <given-names>A</given-names></name> <name><surname>Traxler</surname> <given-names>D</given-names></name> <name><surname>Zlabinger</surname> <given-names>K</given-names></name> <name><surname>Gugerell</surname> <given-names>A</given-names></name> <name><surname>Winkler</surname> <given-names>J</given-names></name> <name><surname>Mester-Tonczar</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Large animal models of heart failure with reduced ejection fraction (HFrEF)</article-title>. <source>Front Cardiovasc Med.</source> (<year>2019</year>) <volume>6</volume>:<fpage>117</fpage>. <pub-id pub-id-type="doi">10.3389/fcvm.2019.00117</pub-id><pub-id pub-id-type="pmid">31475161</pub-id></citation></ref>
<ref id="B44">
<label>44.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Ingle</surname> <given-names>KA</given-names></name> <name><surname>Kachman</surname> <given-names>M</given-names></name> <name><surname>Baum</surname> <given-names>H</given-names></name> <name><surname>Shanmugam</surname> <given-names>G</given-names></name> <name><surname>Rajasekaran</surname> <given-names>NS</given-names></name> <etal/></person-group>. <article-title>Excess omega-6 fatty acids influx in aging drives metabolic dysregulation, electrocardiographic alterations, and low-grade chronic inflammation</article-title>. <source>Am J Physiol Heart Circ Physiol.</source> (<year>2018</year>) <volume>314</volume>:<fpage>H160</fpage>&#x02013;<lpage>h169</lpage>. <pub-id pub-id-type="doi">10.1152/ajpheart.00297.2017</pub-id><pub-id pub-id-type="pmid">28986357</pub-id></citation></ref>
<ref id="B45">
<label>45.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halade</surname> <given-names>GV</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Ingle</surname> <given-names>KA</given-names></name></person-group>. <article-title>Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology</article-title>. <source>Am J Physiol Heart Circ Physiol.</source> (<year>2018</year>) <volume>314</volume>:<fpage>H255</fpage>&#x02013;<lpage>h267</lpage>. <pub-id pub-id-type="doi">10.1152/ajpheart.00528.2017</pub-id><pub-id pub-id-type="pmid">29101178</pub-id></citation></ref>
<ref id="B46">
<label>46.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Samson</surname> <given-names>R</given-names></name> <name><surname>Jaiswal</surname> <given-names>A</given-names></name> <name><surname>Ennezat</surname> <given-names>PV</given-names></name> <name><surname>Cassidy</surname> <given-names>M</given-names></name> <name><surname>Le Jemtel</surname> <given-names>TH</given-names></name></person-group>. <article-title>Clinical phenotypes in heart failure with preserved ejection fraction</article-title>. <source>J Am Heart Assoc.</source> (<year>2016</year>) <volume>5</volume>: <pub-id pub-id-type="doi">10.1161/JAHA.115.002477</pub-id></citation></ref>
<ref id="B47">
<label>47.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Dunlay</surname> <given-names>SM</given-names></name> <name><surname>Roger</surname> <given-names>VL</given-names></name> <name><surname>Redfield</surname> <given-names>MM</given-names></name></person-group>. <article-title>Epidemiology of heart failure with preserved ejection fraction</article-title>. <source>Nat Rev Cardiol.</source> (<year>2017</year>) <volume>14</volume>:<fpage>591</fpage>&#x02013;<lpage>602</lpage>. <pub-id pub-id-type="doi">10.1038/nrcardio.2017.65</pub-id></citation></ref>
<ref id="B48">
<label>48.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gevaert</surname> <given-names>AB</given-names></name> <name><surname>Boen</surname> <given-names>JRA</given-names></name> <name><surname>Segers</surname> <given-names>VF</given-names></name> <name><surname>Van Craenenbroeck</surname> <given-names>EM</given-names></name></person-group>. <article-title>Heart failure with preserved ejection fraction: a review of cardiac and noncardiac pathophysiology</article-title>. <source>Front Physiol.</source> (<year>2019</year>) <volume>10</volume>:<fpage>638</fpage>. <pub-id pub-id-type="doi">10.3389/fphys.2019.00638</pub-id><pub-id pub-id-type="pmid">31191343</pub-id></citation></ref>
<ref id="B49">
<label>49.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Suzuki</surname> <given-names>S</given-names></name> <name><surname>Yoshihisa</surname> <given-names>A</given-names></name> <name><surname>Sato</surname> <given-names>Y</given-names></name> <name><surname>Kanno</surname> <given-names>Y</given-names></name> <name><surname>Watanabe</surname> <given-names>S</given-names></name> <name><surname>Abe</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Clinical significance of get with the guidelines-heart failure risk score in patients with chronic heart failure after hospitalization</article-title>. <source>J Am Heart Assoc.</source> (<year>2018</year>) <volume>7</volume>:<fpage>e008316</fpage>. <pub-id pub-id-type="doi">10.1161/JAHA.117.008316</pub-id><pub-id pub-id-type="pmid">30371158</pub-id></citation></ref>
<ref id="B50">
<label>50.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kitzman</surname> <given-names>DW</given-names></name> <name><surname>Shah</surname> <given-names>SJ</given-names></name></person-group>. <article-title>The HFpEF obesity phenotype: the elephant in the room</article-title>. <source>J Am Coll Cardiol.</source> (<year>2016</year>) <volume>68</volume>:<fpage>200</fpage>&#x02013;<lpage>3</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2016.05.019</pub-id><pub-id pub-id-type="pmid">27386774</pub-id></citation></ref>
<ref id="B51">
<label>51.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Glezeva</surname> <given-names>N</given-names></name> <name><surname>Baugh</surname> <given-names>JA</given-names></name></person-group>. <article-title>Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target</article-title>. <source>Heart Fail Rev.</source> (<year>2014</year>) <volume>19</volume>:<fpage>681</fpage>&#x02013;<lpage>94</lpage>. <pub-id pub-id-type="doi">10.1007/s10741-013-9405-8</pub-id><pub-id pub-id-type="pmid">24005868</pub-id></citation></ref>
<ref id="B52">
<label>52.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tourki</surname> <given-names>B</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Shaikh</surname> <given-names>SR</given-names></name> <name><surname>Leroy</surname> <given-names>X</given-names></name> <name><surname>Serhan</surname> <given-names>CN</given-names></name> <name><surname>Halade</surname> <given-names>GV</given-names></name></person-group>. <article-title>Deficit of resolution receptor magnifies inflammatory leukocyte directed cardiorenal and endothelial dysfunction with signs of cardiomyopathy of obesity</article-title>. <source>Faseb J.</source> (<year>2020</year>) <volume>34</volume>:<fpage>10560</fpage>&#x02013;<lpage>73</lpage>. <pub-id pub-id-type="doi">10.1096/fj.202000495RR</pub-id><pub-id pub-id-type="pmid">32543720</pub-id></citation></ref>
<ref id="B53">
<label>53.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schiattarella</surname> <given-names>GG</given-names></name> <name><surname>Altamirano</surname> <given-names>F</given-names></name> <name><surname>Tong</surname> <given-names>D</given-names></name> <name><surname>French</surname> <given-names>KM</given-names></name> <name><surname>Villalobos</surname> <given-names>E</given-names></name> <name><surname>Kim</surname> <given-names>SY</given-names></name> <etal/></person-group>. <article-title>Nitrosative stress drives heart failure with preserved ejection fraction</article-title>. <source>Nature.</source> (<year>2019</year>) <volume>568</volume>:<fpage>351</fpage>&#x02013;<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1038/s41586-019-1100-z</pub-id><pub-id pub-id-type="pmid">30971818</pub-id></citation></ref>
<ref id="B54">
<label>54.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hall</surname> <given-names>ME</given-names></name> <name><surname>Maready</surname> <given-names>MW</given-names></name> <name><surname>Hall</surname> <given-names>JE</given-names></name> <name><surname>Stec</surname> <given-names>DE</given-names></name></person-group>. <article-title>Rescue of cardiac leptin receptors in db/db mice prevents myocardial triglyceride accumulation</article-title>. <source>Am J Physiol Endocrinol Metab.</source> (<year>2014</year>) <volume>307</volume>:<fpage>E316</fpage>&#x02013;<lpage>E325</lpage>. <pub-id pub-id-type="doi">10.1152/ajpendo.00005.2014</pub-id><pub-id pub-id-type="pmid">24939734</pub-id></citation></ref>
<ref id="B55">
<label>55.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shimada</surname> <given-names>YJ</given-names></name></person-group>. <article-title>Is leptin protective against heart failure with preserved ejection fraction? A complex interrelationship among leptin, obesity, and left ventricular hypertrophy</article-title>. <source>Hypertens Res.</source> (<year>2019</year>) <volume>42</volume>:<fpage>141</fpage>&#x02013;<lpage>2</lpage>. <pub-id pub-id-type="doi">10.1038/s41440-018-0135-0</pub-id><pub-id pub-id-type="pmid">30420723</pub-id></citation></ref>
<ref id="B56">
<label>56.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Clark</surname> <given-names>JB</given-names></name> <name><surname>Palmer</surname> <given-names>CJ</given-names></name> <name><surname>Shaw</surname> <given-names>WN</given-names></name></person-group>. <article-title>The diabetic Zucker fatty rat</article-title>. <source>Proc Soc Exp Biol Med.</source> (<year>1983</year>) <volume>173</volume>:<fpage>68</fpage>&#x02013;<lpage>75</lpage>. <pub-id pub-id-type="doi">10.3181/00379727-173-41611</pub-id></citation></ref>
<ref id="B57">
<label>57.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Franssen</surname> <given-names>C</given-names></name> <name><surname>Chen</surname> <given-names>S</given-names></name> <name><surname>Unger</surname> <given-names>A</given-names></name> <name><surname>Korkmaz</surname> <given-names>HI</given-names></name> <name><surname>De Keulenaer</surname> <given-names>GW</given-names></name> <name><surname>Tsch&#x000F6;pe</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction</article-title>. <source>JACC Heart Fail.</source> (<year>2016</year>) <volume>4</volume>:<fpage>312</fpage>&#x02013;<lpage>24</lpage>. <pub-id pub-id-type="doi">10.1016/j.jchf.2015.10.007</pub-id><pub-id pub-id-type="pmid">26682792</pub-id></citation></ref>
<ref id="B58">
<label>58.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bai</surname> <given-names>B</given-names></name> <name><surname>Yang</surname> <given-names>W</given-names></name> <name><surname>Fu</surname> <given-names>Y</given-names></name> <name><surname>Foon</surname> <given-names>HL</given-names></name> <name><surname>Tay</surname> <given-names>WT</given-names></name> <name><surname>Yang</surname> <given-names>K</given-names></name> <etal/></person-group>. <article-title>Seipin knockout mice develop heart failure with preserved ejection fraction</article-title>. <source>JACC Basic Transl Sci.</source> (<year>2019</year>) <volume>4</volume>:<fpage>924</fpage>&#x02013;<lpage>37</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacbts.2019.07.008</pub-id><pub-id pub-id-type="pmid">31909301</pub-id></citation></ref>
<ref id="B59">
<label>59.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Abdellatif</surname> <given-names>M</given-names></name> <name><surname>Trummer-Herbst</surname> <given-names>V</given-names></name> <name><surname>Koser</surname> <given-names>F</given-names></name> <name><surname>Durand</surname> <given-names>S</given-names></name> <name><surname>Ad&#x000E3;o</surname> <given-names>R</given-names></name> <name><surname>Vasques-N&#x000F3;voa</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Nicotinamide for the treatment of heart failure with preserved ejection fraction</article-title>. <source>Sci Transl Med.</source> (<year>2021</year>) <volume>13</volume>:<fpage>eabd7064</fpage>. <pub-id pub-id-type="doi">10.1126/scitranslmed.abd7064</pub-id><pub-id pub-id-type="pmid">33568522</pub-id></citation></ref>
<ref id="B60">
<label>60.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Riehle</surname> <given-names>C</given-names></name> <name><surname>Bauersachs</surname> <given-names>J</given-names></name></person-group>. <article-title>Key inflammatory mechanisms underlying heart failure</article-title>. <source>Herz.</source> (<year>2019</year>) <volume>44</volume>:<fpage>96</fpage>&#x02013;<lpage>106</lpage>. <pub-id pub-id-type="doi">10.1007/s00059-019-4785-8</pub-id><pub-id pub-id-type="pmid">30715565</pub-id></citation></ref>
<ref id="B61">
<label>61.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kalogeropoulos</surname> <given-names>A</given-names></name> <name><surname>Georgiopoulou</surname> <given-names>V</given-names></name> <name><surname>Psaty</surname> <given-names>BM</given-names></name> <name><surname>Rodondi</surname> <given-names>N</given-names></name> <name><surname>Smith</surname> <given-names>AL</given-names></name> <name><surname>Harrison</surname> <given-names>DG</given-names></name> <etal/></person-group>. <article-title>Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study</article-title>. <source>J Am Coll Cardiol.</source> (<year>2010</year>) <volume>55</volume>:<fpage>2129</fpage>&#x02013;<lpage>37</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2009.12.045</pub-id><pub-id pub-id-type="pmid">20447537</pub-id></citation></ref>
<ref id="B62">
<label>62.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname> <given-names>CK</given-names></name> <name><surname>Su</surname> <given-names>MM</given-names></name> <name><surname>Wu</surname> <given-names>YF</given-names></name> <name><surname>Hwang</surname> <given-names>JJ</given-names></name> <name><surname>Lin</surname> <given-names>LY</given-names></name></person-group>. <article-title>Combination of plasma biomarkers and clinical data for the detection of myocardial fibrosis or aggravation of heart failure symptoms in heart failure with preserved ejection fraction patients</article-title>. <source>J Clin Med.</source> (<year>2018</year>) <volume>7</volume>:<fpage>427</fpage>. <pub-id pub-id-type="doi">10.3390/jcm7110427</pub-id><pub-id pub-id-type="pmid">30413105</pub-id></citation></ref>
<ref id="B63">
<label>63.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hulsmans</surname> <given-names>M</given-names></name> <name><surname>Sager</surname> <given-names>HB</given-names></name> <name><surname>Roh</surname> <given-names>JD</given-names></name> <name><surname>Valero-Munoz</surname> <given-names>M</given-names></name> <name><surname>Houstis</surname> <given-names>NE</given-names></name> <name><surname>Iwamoto</surname> <given-names>Y</given-names></name> <etal/></person-group>. <article-title>Cardiac macrophages promote diastolic dysfunction</article-title>. <source>J Exp Med.</source> (<year>2018</year>) <volume>215</volume>:<fpage>423</fpage>&#x02013;<lpage>40</lpage>. <pub-id pub-id-type="doi">10.1084/jem.20171274</pub-id><pub-id pub-id-type="pmid">29493572</pub-id></citation></ref>
<ref id="B64">
<label>64.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nahrendorf</surname> <given-names>M</given-names></name> <name><surname>Swirski</surname> <given-names>FK</given-names></name></person-group>. <article-title>Abandoning M1/M2 for a network model of macrophage function</article-title>. <source>Circ Res.</source> (<year>2016</year>) <volume>119</volume>:<fpage>414</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.116.309194</pub-id><pub-id pub-id-type="pmid">27458196</pub-id></citation></ref>
<ref id="B65">
<label>65.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>O&#x00027;Rourke</surname> <given-names>SA</given-names></name> <name><surname>Dunne</surname> <given-names>A</given-names></name> <name><surname>Monaghan</surname> <given-names>MG</given-names></name></person-group>. <article-title>The role of macrophages in the infarcted myocardium: orchestrators of ECM remodeling</article-title>. <source>Front Cardiovasc Med.</source> (<year>2019</year>) <volume>6</volume>:<fpage>101</fpage>. <pub-id pub-id-type="doi">10.3389/fcvm.2019.00101</pub-id><pub-id pub-id-type="pmid">31417911</pub-id></citation></ref>
<ref id="B66">
<label>66.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ma</surname> <given-names>Y</given-names></name> <name><surname>Mouton</surname> <given-names>AJ</given-names></name> <name><surname>Lindsey</surname> <given-names>ML</given-names></name></person-group>. <article-title>Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction</article-title>. <source>Transl Res.</source> (<year>2018</year>) <volume>191</volume>:<fpage>15</fpage>&#x02013;<lpage>28</lpage>. <pub-id pub-id-type="doi">10.1016/j.trsl.2017.10.001</pub-id><pub-id pub-id-type="pmid">29106912</pub-id></citation></ref>
<ref id="B67">
<label>67.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lindsey</surname> <given-names>ML</given-names></name> <name><surname>Saucerman</surname> <given-names>JJ</given-names></name> <name><surname>DeLeon-Pennell</surname> <given-names>KY</given-names></name></person-group>. <article-title>Knowledge gaps to understanding cardiac macrophage polarization following myocardial infarction</article-title>. <source>Biochim Biophys Acta.</source> (<year>2016</year>) <volume>1862</volume>:<fpage>2288</fpage>&#x02013;<lpage>92</lpage>. <pub-id pub-id-type="doi">10.1016/j.bbadis.2016.05.013</pub-id><pub-id pub-id-type="pmid">27240543</pub-id></citation></ref>
<ref id="B68">
<label>68.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Dutka</surname> <given-names>M</given-names></name> <name><surname>Bobi&#x00144;ski</surname> <given-names>R</given-names></name> <name><surname>Ulman-W&#x00142;odarz</surname> <given-names>I</given-names></name> <name><surname>Hajduga</surname> <given-names>M</given-names></name> <name><surname>Bujok</surname> <given-names>J</given-names></name> <name><surname>Pajak</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Various aspects of inflammation in heart failure</article-title>. <source>Heart Fail Rev.</source> (<year>2020</year>) <volume>25</volume>:<fpage>537</fpage>&#x02013;<lpage>48</lpage>. <pub-id pub-id-type="doi">10.1007/s10741-019-09875-1</pub-id></citation></ref>
<ref id="B69">
<label>69.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Putko</surname> <given-names>BN</given-names></name> <name><surname>Wang</surname> <given-names>Z</given-names></name> <name><surname>Lo</surname> <given-names>J</given-names></name> <name><surname>Anderson</surname> <given-names>T</given-names></name> <name><surname>Becher</surname> <given-names>H</given-names></name> <name><surname>Dyck</surname> <given-names>JR</given-names></name> <etal/></person-group>. <article-title>Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology</article-title>. <source>PLoS ONE.</source> (<year>2014</year>) <volume>9</volume>:<fpage>e99495</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0099495</pub-id><pub-id pub-id-type="pmid">24923671</pub-id></citation></ref>
<ref id="B70">
<label>70.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Westermann</surname> <given-names>D</given-names></name> <name><surname>Lindner</surname> <given-names>D</given-names></name> <name><surname>Kasner</surname> <given-names>M</given-names></name> <name><surname>Zietsch</surname> <given-names>C</given-names></name> <name><surname>Savvatis</surname> <given-names>K</given-names></name> <name><surname>Escher</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction</article-title>. <source>Circ Heart Fail.</source> (<year>2011</year>) <volume>4</volume>:<fpage>44</fpage>&#x02013;<lpage>52</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCHEARTFAILURE.109.931451</pub-id><pub-id pub-id-type="pmid">21075869</pub-id></citation></ref>
<ref id="B71">
<label>71.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Walker</surname> <given-names>AMN</given-names></name> <name><surname>Drozd</surname> <given-names>M</given-names></name> <name><surname>Hall</surname> <given-names>M</given-names></name> <name><surname>Patel</surname> <given-names>PA</given-names></name> <name><surname>Paton</surname> <given-names>M</given-names></name> <name><surname>Lowry</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Prevalence and predictors of sepsis death in patients with chronic heart failure and reduced left ventricular ejection fraction</article-title>. <source>J Am Heart Assoc.</source> (<year>2018</year>) <volume>7</volume>:<fpage>e009684</fpage>. <pub-id pub-id-type="doi">10.1161/JAHA.118.009684</pub-id><pub-id pub-id-type="pmid">30371261</pub-id></citation></ref>
<ref id="B72">
<label>72.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Simmonds</surname> <given-names>SJ</given-names></name> <name><surname>Cuijpers</surname> <given-names>I</given-names></name> <name><surname>Heymans</surname> <given-names>S</given-names></name> <name><surname>Jones</surname> <given-names>EAV</given-names></name></person-group>. <article-title>Cellular and molecular differences between HFpEF and HFrEF: a step ahead in an improved pathological understanding</article-title>. <source>Cells.</source> (<year>2020</year>) <volume>9</volume>:<fpage>242</fpage>. <pub-id pub-id-type="doi">10.3390/cells9010242</pub-id><pub-id pub-id-type="pmid">31963679</pub-id></citation></ref>
<ref id="B73">
<label>73.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yndestad</surname> <given-names>A</given-names></name> <name><surname>Dam&#x000E5;s</surname> <given-names>JK</given-names></name> <name><surname>Oie</surname> <given-names>E</given-names></name> <name><surname>Ueland</surname> <given-names>T</given-names></name> <name><surname>Gullestad</surname> <given-names>L</given-names></name> <name><surname>Aukrust</surname> <given-names>P</given-names></name></person-group>. <article-title>Systemic inflammation in heart failure&#x02013;the whys and wherefores</article-title>. <source>Heart Fail Rev.</source> (<year>2006</year>) <volume>11</volume>:<fpage>83</fpage>&#x02013;<lpage>92</lpage>. <pub-id pub-id-type="doi">10.1007/s10741-006-9196-2</pub-id><pub-id pub-id-type="pmid">16819581</pub-id></citation></ref>
<ref id="B74">
<label>74.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zettel</surname> <given-names>K</given-names></name> <name><surname>Korff</surname> <given-names>S</given-names></name> <name><surname>Zamora</surname> <given-names>R</given-names></name> <name><surname>Morelli</surname> <given-names>AE</given-names></name> <name><surname>Darwiche</surname> <given-names>S</given-names></name> <name><surname>Loughran</surname> <given-names>PA</given-names></name> <etal/></person-group>. <article-title>Toll-like receptor 4 on both myeloid cells and dendritic cells is required for systemic inflammation and organ damage after hemorrhagic shock with tissue trauma in mice</article-title>. <source>Front Immunol.</source> (<year>2017</year>) <volume>8</volume>:<fpage>1672</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2017.01672</pub-id><pub-id pub-id-type="pmid">29234326</pub-id></citation></ref>
<ref id="B75">
<label>75.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>L</given-names></name> <name><surname>Wang</surname> <given-names>Y</given-names></name> <name><surname>Cao</surname> <given-names>ZY</given-names></name> <name><surname>Wang</surname> <given-names>MM</given-names></name> <name><surname>Liu</surname> <given-names>XM</given-names></name> <name><surname>Gao</surname> <given-names>T</given-names></name> <etal/></person-group>. <article-title>Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction</article-title>. <source>J Cell Mol Med.</source> (<year>2015</year>) <volume>19</volume>:<fpage>2728</fpage>&#x02013;<lpage>40</lpage>. <pub-id pub-id-type="doi">10.1111/jcmm.12659</pub-id><pub-id pub-id-type="pmid">26290459</pub-id></citation></ref>
<ref id="B76">
<label>76.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chebl</surname> <given-names>RB</given-names></name> <name><surname>Berbari</surname> <given-names>I</given-names></name> <name><surname>Safa</surname> <given-names>R</given-names></name> <name><surname>Shami</surname> <given-names>A</given-names></name> <name><surname>Sabra</surname> <given-names>M</given-names></name> <name><surname>Jamali</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Clinical outcome of septic patients with heart failure with preserved ejection fraction presenting to the emergency department of a tertiary hospital: a retrospective cohort study</article-title>. <source>Front Med.</source> (<year>2020</year>) <volume>7</volume>:<fpage>517999</fpage>. <pub-id pub-id-type="doi">10.3389/fmed.2020.517999</pub-id><pub-id pub-id-type="pmid">33195290</pub-id></citation></ref>
<ref id="B77">
<label>77.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pepper</surname> <given-names>DJ</given-names></name> <name><surname>Demirkale</surname> <given-names>CY</given-names></name> <name><surname>Sun</surname> <given-names>J</given-names></name> <name><surname>Rhee</surname> <given-names>C</given-names></name> <name><surname>Fram</surname> <given-names>D</given-names></name> <name><surname>Eichacker</surname> <given-names>P</given-names></name> <etal/></person-group>. <article-title>Does obesity protect against death in sepsis? a retrospective cohort study of 55,038 adult patients</article-title>. <source>Crit Care Med.</source> (<year>2019</year>) <volume>47</volume>:<fpage>643</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1097/CCM.0000000000003692</pub-id><pub-id pub-id-type="pmid">31415324</pub-id></citation></ref>
<ref id="B78">
<label>78.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kolyva</surname> <given-names>AS</given-names></name> <name><surname>Zolota</surname> <given-names>V</given-names></name> <name><surname>Mpatsoulis</surname> <given-names>D</given-names></name> <name><surname>Skroubis</surname> <given-names>G</given-names></name> <name><surname>Solomou</surname> <given-names>EE</given-names></name> <name><surname>Habeos</surname> <given-names>IG</given-names></name> <etal/></person-group>. <article-title>The role of obesity in the immune response during sepsis</article-title>. <source>Nutr Diabetes.</source> (<year>2014</year>) <volume>4</volume>:<fpage>e137</fpage>. <pub-id pub-id-type="doi">10.1038/nutd.2014.34</pub-id><pub-id pub-id-type="pmid">25244356</pub-id></citation></ref>
<ref id="B79">
<label>79.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tourki</surname> <given-names>B</given-names></name> <name><surname>Halade</surname> <given-names>GV</given-names></name></person-group>. <article-title>The failing of the obesity paradox in the failing heart</article-title>. <source>Am J Physiol Heart Circ Physiol.</source> (<year>2018</year>) <volume>315</volume>:<fpage>H1353</fpage>&#x02013;<lpage>5</lpage>. <pub-id pub-id-type="doi">10.1152/ajpheart.00496.2018</pub-id><pub-id pub-id-type="pmid">30074838</pub-id></citation></ref>
<ref id="B80">
<label>80.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Merx</surname> <given-names>MW</given-names></name> <name><surname>Weber</surname> <given-names>C</given-names></name></person-group>. <article-title>Sepsis and the heart</article-title>. <source>Circulation.</source> (<year>2007</year>) <volume>116</volume>:<fpage>793</fpage>&#x02013;<lpage>802</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.106.678359</pub-id></citation></ref>
<ref id="B81">
<label>81.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Borregaard</surname> <given-names>N</given-names></name> <name><surname>Herlin</surname> <given-names>T</given-names></name></person-group>. <article-title>Energy metabolism of human neutrophils during phagocytosis</article-title>. <source>J Clin Invest.</source> (<year>1982</year>) <volume>70</volume>:<fpage>550</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1172/JCI110647</pub-id><pub-id pub-id-type="pmid">7107894</pub-id></citation></ref>
<ref id="B82">
<label>82.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chandak</surname> <given-names>PG</given-names></name> <name><surname>Radovi&#x00107;</surname> <given-names>B</given-names></name> <name><surname>Aflaki</surname> <given-names>E</given-names></name> <name><surname>Kolb</surname> <given-names>D</given-names></name> <name><surname>Buchebner</surname> <given-names>M</given-names></name> <name><surname>Fr&#x000F6;hlich</surname> <given-names>E</given-names></name> <etal/></person-group>. <article-title>Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase<sup>&#x0002A;</sup></article-title>. <source>J Biol Chem.</source> (<year>2010</year>) <volume>285</volume>:<fpage>20192</fpage>&#x02013;<lpage>201</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.M110.107854</pub-id><pub-id pub-id-type="pmid">20424161</pub-id></citation></ref>
<ref id="B83">
<label>83.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Fortu&#x000F1;o</surname> <given-names>A</given-names></name> <name><surname>San</surname> <given-names>Jos&#x000E9; G</given-names></name> <name><surname>Moreno</surname> <given-names>MU</given-names></name> <name><surname>Beloqui</surname> <given-names>O</given-names></name> <name><surname>D&#x000ED;ez</surname> <given-names>J</given-names></name> <name><surname>Zalba</surname> <given-names>G</given-names></name></person-group>. <article-title>Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome</article-title>. <source>Diabetes.</source> (<year>2006</year>) <volume>55</volume>:<fpage>209</fpage>&#x02013;<lpage>15</lpage>. <pub-id pub-id-type="doi">10.2337/diabetes.55.01.06.db05-0751</pub-id><pub-id pub-id-type="pmid">16380495</pub-id></citation></ref>
<ref id="B84">
<label>84.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kern</surname> <given-names>PA</given-names></name> <name><surname>Saghizadeh</surname> <given-names>M</given-names></name> <name><surname>Ong</surname> <given-names>JM</given-names></name> <name><surname>Bosch</surname> <given-names>RJ</given-names></name> <name><surname>Deem</surname> <given-names>R</given-names></name> <name><surname>Simsolo</surname> <given-names>RB</given-names></name></person-group>. <article-title>The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase</article-title>. <source>J Clin Invest.</source> (<year>1995</year>) <volume>95</volume>:<fpage>2111</fpage>&#x02013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1172/JCI117899</pub-id><pub-id pub-id-type="pmid">7738178</pub-id></citation></ref>
<ref id="B85">
<label>85.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halade</surname> <given-names>GV</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Serhan</surname> <given-names>CN</given-names></name></person-group>. <article-title>Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure</article-title>. <source>Faseb J.</source> (<year>2018</year>) <volume>32</volume>:<fpage>3717</fpage>&#x02013;<lpage>29</lpage>. <pub-id pub-id-type="doi">10.1096/fj.201701173RR</pub-id><pub-id pub-id-type="pmid">29455574</pub-id></citation></ref>
<ref id="B86">
<label>86.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halade</surname> <given-names>GV</given-names></name> <name><surname>Dorbane</surname> <given-names>A</given-names></name> <name><surname>Ingle</surname> <given-names>KA</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Schmitter</surname> <given-names>JM</given-names></name> <name><surname>Rhourri-Frih</surname> <given-names>B</given-names></name></person-group>. <article-title>Comprehensive targeted and non-targeted lipidomics analyses in failing and non-failing heart</article-title>. <source>Anal Bioanal Chem.</source> (<year>2018</year>) <volume>410</volume>:<fpage>1965</fpage>&#x02013;<lpage>76</lpage>. <pub-id pub-id-type="doi">10.1007/s00216-018-0863-7</pub-id><pub-id pub-id-type="pmid">29411084</pub-id></citation></ref>
<ref id="B87">
<label>87.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Jadapalli</surname> <given-names>JK</given-names></name> <name><surname>Tourki</surname> <given-names>B</given-names></name> <name><surname>Halade</surname> <given-names>GV</given-names></name></person-group>. <article-title>Inhibition of FPR2 impaired leukocytes recruitment and elicited non-resolving inflammation in acute heart failure</article-title>. <source>Pharmacol Res.</source> (<year>2019</year>) <volume>146</volume>:<fpage>104295</fpage>. <pub-id pub-id-type="doi">10.1016/j.phrs.2019.104295</pub-id><pub-id pub-id-type="pmid">31216426</pub-id></citation></ref>
<ref id="B88">
<label>88.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mouton</surname> <given-names>AJ</given-names></name> <name><surname>DeLeon-Pennell</surname> <given-names>KY</given-names></name> <name><surname>Rivera Gonzalez</surname> <given-names>OJ</given-names></name> <name><surname>Flynn</surname> <given-names>ER</given-names></name> <name><surname>Freeman</surname> <given-names>TC</given-names></name> <name><surname>Saucerman</surname> <given-names>JJ</given-names></name> <etal/></person-group>. <article-title>Mapping macrophage polarization over the myocardial infarction time continuum</article-title>. <source>Basic Res Cardiol.</source> (<year>2018</year>) <volume>113</volume>:<fpage>26</fpage>. <pub-id pub-id-type="doi">10.1007/s00395-018-0686-x</pub-id><pub-id pub-id-type="pmid">29868933</pub-id></citation></ref>
<ref id="B89">
<label>89.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halade</surname> <given-names>GV</given-names></name> <name><surname>Norris</surname> <given-names>PC</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Serhan</surname> <given-names>CN</given-names></name> <name><surname>Ingle</surname> <given-names>KA</given-names></name></person-group>. <article-title>Splenic leukocytes define the resolution of inflammation in heart failure</article-title>. <source>Sci Signal.</source> (<year>2018</year>) <volume>11</volume>:<fpage>eaao1818</fpage>. <pub-id pub-id-type="doi">10.1126/scisignal.aao1818</pub-id><pub-id pub-id-type="pmid">29511119</pub-id></citation></ref>
<ref id="B90">
<label>90.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halade</surname> <given-names>GV</given-names></name> <name><surname>Tourki</surname> <given-names>B</given-names></name></person-group>. <article-title>Specialized pro-resolving mediators directs cardiac healing and repair with activation of inflammation and resolution program in heart failure</article-title>. <source>Adv Exp Med Biol.</source> (<year>2019</year>) <volume>1161</volume>:<fpage>45</fpage>&#x02013;<lpage>64</lpage>. <pub-id pub-id-type="doi">10.1007/978-3-030-21735-8_6</pub-id><pub-id pub-id-type="pmid">31562621</pub-id></citation></ref>
<ref id="B91">
<label>91.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Galvan-Pena</surname> <given-names>S</given-names></name> <name><surname>O&#x00027;Neill</surname> <given-names>LA</given-names></name></person-group>. <article-title>Metabolic reprograming in macrophage polarization</article-title>. <source>Front Immunol.</source> (<year>2014</year>) <volume>5</volume>:<fpage>420</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2014.00420</pub-id></citation></ref>
<ref id="B92">
<label>92.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Levine</surname> <given-names>B</given-names></name> <name><surname>Kalman</surname> <given-names>J</given-names></name> <name><surname>Mayer</surname> <given-names>L</given-names></name> <name><surname>Fillit</surname> <given-names>HM</given-names></name> <name><surname>Packer</surname> <given-names>M</given-names></name></person-group>. <article-title>Elevated circulating levels of tumor necrosis factor in severe chronic heart failure</article-title>. <source>N Engl J Med.</source> (<year>1990</year>) <volume>323</volume>:<fpage>236</fpage>&#x02013;<lpage>41</lpage>. <pub-id pub-id-type="doi">10.1056/NEJM199007263230405</pub-id><pub-id pub-id-type="pmid">2195340</pub-id></citation></ref>
<ref id="B93">
<label>93.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ferrante</surname> <given-names>AW</given-names> <suffix>Jr</suffix></name></person-group>. <article-title>The immune cells in adipose tissue</article-title>. <source>Diabetes Obes Metab.</source> (<year>2013</year>) <volume>15</volume> (<supplement>Suppl. 3</supplement>):<fpage>34</fpage>&#x02013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1111/dom.12154</pub-id></citation></ref>
<ref id="B94">
<label>94.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Weisberg</surname> <given-names>SP</given-names></name> <name><surname>McCann</surname> <given-names>D</given-names></name> <name><surname>Desai</surname> <given-names>M</given-names></name> <name><surname>Rosenbaum</surname> <given-names>M</given-names></name> <name><surname>Leibel</surname> <given-names>RL</given-names></name> <name><surname>Ferrante</surname> <given-names>AW</given-names> <suffix>Jr</suffix></name></person-group>. <article-title>Obesity is associated with macrophage accumulation in adipose tissue</article-title>. <source>J Clin Invest.</source> (<year>2003</year>) <volume>112</volume>:<fpage>1796</fpage>&#x02013;<lpage>808</lpage>. <pub-id pub-id-type="doi">10.1172/JCI200319246</pub-id><pub-id pub-id-type="pmid">14679176</pub-id></citation></ref>
<ref id="B95">
<label>95.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lumeng</surname> <given-names>CN</given-names></name> <name><surname>Bodzin</surname> <given-names>JL</given-names></name> <name><surname>Saltiel</surname> <given-names>AR</given-names></name></person-group>. <article-title>Obesity induces a phenotypic switch in adipose tissue macrophage polarization</article-title>. <source>J Clin Invest.</source> (<year>2007</year>) <volume>117</volume>:<fpage>175</fpage>&#x02013;<lpage>84</lpage>. <pub-id pub-id-type="doi">10.1172/JCI29881</pub-id><pub-id pub-id-type="pmid">17200717</pub-id></citation></ref>
<ref id="B96">
<label>96.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kraakman</surname> <given-names>MJ</given-names></name> <name><surname>Murphy</surname> <given-names>AJ</given-names></name> <name><surname>Jandeleit-Dahm</surname> <given-names>K</given-names></name> <name><surname>Kammoun</surname> <given-names>HL</given-names></name></person-group>. <article-title>Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function?</article-title> <source>Front Immunol.</source> (<year>2014</year>) <volume>5</volume>:<fpage>470</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2014.00470</pub-id><pub-id pub-id-type="pmid">25309549</pub-id></citation></ref>
<ref id="B97">
<label>97.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kanneganti</surname> <given-names>TD</given-names></name> <name><surname>Dixit</surname> <given-names>VD</given-names></name></person-group>. <article-title>Immunological complications of obesity</article-title>. <source>Nat Immunol.</source> (<year>2012</year>) <volume>13</volume>:<fpage>707</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1038/ni.2343</pub-id></citation></ref>
<ref id="B98">
<label>98.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname> <given-names>H</given-names></name> <name><surname>Youm</surname> <given-names>YH</given-names></name> <name><surname>Vandanmagsar</surname> <given-names>B</given-names></name> <name><surname>Rood</surname> <given-names>J</given-names></name> <name><surname>Kumar</surname> <given-names>KG</given-names></name> <name><surname>Butler</surname> <given-names>AA</given-names></name> <etal/></person-group>. <article-title>Obesity accelerates thymic aging</article-title>. <source>Blood.</source> (<year>2009</year>) <volume>114</volume>:<fpage>3803</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1182/blood-2009-03-213595</pub-id></citation></ref>
<ref id="B99">
<label>99.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ringseis</surname> <given-names>R</given-names></name> <name><surname>Eder</surname> <given-names>K</given-names></name> <name><surname>Mooren</surname> <given-names>FC</given-names></name> <name><surname>Kruger</surname> <given-names>K</given-names></name></person-group>. <article-title>Metabolic signals and innate immune activation in obesity and exercise</article-title>. <source>Exerc Immunol Rev.</source> (<year>2015</year>) <volume>21</volume>:<fpage>58</fpage>&#x02013;<lpage>68</lpage>. <pub-id pub-id-type="pmid">25825956</pub-id></citation></ref>
<ref id="B100">
<label>100.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Itani</surname> <given-names>SI</given-names></name> <name><surname>Ruderman</surname> <given-names>NB</given-names></name> <name><surname>Schmieder</surname> <given-names>F</given-names></name> <name><surname>Boden</surname> <given-names>G</given-names></name></person-group>. <article-title>Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha</article-title>. <source>Diabetes.</source> (<year>2002</year>) <volume>51</volume>:<fpage>2005</fpage>&#x02013;<lpage>11</lpage>. <pub-id pub-id-type="doi">10.2337/diabetes.51.7.2005</pub-id><pub-id pub-id-type="pmid">12086926</pub-id></citation></ref>
<ref id="B101">
<label>101.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ieronymaki</surname> <given-names>E</given-names></name> <name><surname>Theodorakis</surname> <given-names>EM</given-names></name> <name><surname>Lyroni</surname> <given-names>K</given-names></name> <name><surname>Vergadi</surname> <given-names>E</given-names></name> <name><surname>Lagoudaki</surname> <given-names>E</given-names></name> <name><surname>Al-Qahtani</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Insulin resistance in macrophages alters their metabolism and promotes an m2-like phenotype</article-title>. <source>J Immunol.</source> (<year>2019</year>) <volume>202</volume>:<fpage>1786</fpage>&#x02013;<lpage>97</lpage>. <pub-id pub-id-type="doi">10.4049/jimmunol.1800065</pub-id><pub-id pub-id-type="pmid">30718296</pub-id></citation></ref>
<ref id="B102">
<label>102.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kubota</surname> <given-names>T</given-names></name> <name><surname>Inoue</surname> <given-names>M</given-names></name> <name><surname>Kubota</surname> <given-names>N</given-names></name> <name><surname>Takamoto</surname> <given-names>I</given-names></name> <name><surname>Mineyama</surname> <given-names>T</given-names></name> <name><surname>Iwayama</surname> <given-names>K</given-names></name> <etal/></person-group>. <article-title>Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity</article-title>. <source>Nat Commun.</source> (<year>2018</year>) <volume>9</volume>:<fpage>4863</fpage>. <pub-id pub-id-type="doi">10.1038/s41467-018-07358-9</pub-id><pub-id pub-id-type="pmid">30451856</pub-id></citation></ref>
<ref id="B103">
<label>103.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Jambusaria</surname> <given-names>A</given-names></name> <name><surname>Hong</surname> <given-names>Z</given-names></name> <name><surname>Zhang</surname> <given-names>L</given-names></name> <name><surname>Srivastava</surname> <given-names>S</given-names></name> <name><surname>Jana</surname> <given-names>A</given-names></name> <name><surname>Toth</surname> <given-names>PT</given-names></name> <etal/></person-group>. <article-title>Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation</article-title>. <source>Elife.</source> (<year>2020</year>) <volume>9</volume>:<fpage>e51413</fpage>. <pub-id pub-id-type="doi">10.7554/eLife.51413</pub-id><pub-id pub-id-type="pmid">31944177</pub-id></citation></ref>
<ref id="B104">
<label>104.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tsch&#x000F6;pe</surname> <given-names>C</given-names></name> <name><surname>Van Linthout</surname> <given-names>S</given-names></name></person-group>. <article-title>New insights in (inter)cellular mechanisms by heart failure with preserved ejection fraction</article-title>. <source>Curr Heart Fail Rep.</source> (<year>2014</year>) <volume>11</volume>:<fpage>436</fpage>&#x02013;<lpage>44</lpage>. <pub-id pub-id-type="doi">10.1007/s11897-014-0219-3</pub-id><pub-id pub-id-type="pmid">25189801</pub-id></citation></ref>
<ref id="B105">
<label>105.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Murdoch</surname> <given-names>CE</given-names></name> <name><surname>Chaubey</surname> <given-names>S</given-names></name> <name><surname>Zeng</surname> <given-names>L</given-names></name> <name><surname>Yu</surname> <given-names>B</given-names></name> <name><surname>Ivetic</surname> <given-names>A</given-names></name> <name><surname>Walker</surname> <given-names>SJ</given-names></name> <etal/></person-group>. <article-title>Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition</article-title>. <source>J Am Coll Cardiol.</source> (<year>2014</year>) <volume>63</volume>:<fpage>2734</fpage>&#x02013;<lpage>41</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2014.02.572</pub-id><pub-id pub-id-type="pmid">24681145</pub-id></citation></ref>
<ref id="B106">
<label>106.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Reddy</surname> <given-names>YNV</given-names></name> <name><surname>Lewis</surname> <given-names>GD</given-names></name> <name><surname>Shah</surname> <given-names>SJ</given-names></name> <name><surname>LeWinter</surname> <given-names>M</given-names></name> <name><surname>Semigran</surname> <given-names>M</given-names></name> <name><surname>Davila-Roman</surname> <given-names>VG</given-names></name> <etal/></person-group>. <article-title>INDIE-HFpEF (inorganic nitrite delivery to improve exercise capacity in heart failure with preserved ejection fraction): rationale and design</article-title>. <source>Circ Heart Fail.</source> (<year>2017</year>) <volume>10</volume>:<fpage>e003862</fpage>. <pub-id pub-id-type="doi">10.1161/CIRCHEARTFAILURE.117.003862</pub-id><pub-id pub-id-type="pmid">28476756</pub-id></citation></ref>
<ref id="B107">
<label>107.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Borlaug</surname> <given-names>BA</given-names></name></person-group>. <article-title>The pathophysiology of heart failure with preserved ejection fraction</article-title>. <source>Nat Rev Cardiol.</source> (<year>2014</year>) <volume>11</volume>:<fpage>507</fpage>&#x02013;<lpage>15</lpage>. <pub-id pub-id-type="doi">10.1038/nrcardio.2014.83</pub-id></citation></ref>
<ref id="B108">
<label>108.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liao</surname> <given-names>X</given-names></name> <name><surname>Shen</surname> <given-names>Y</given-names></name> <name><surname>Zhang</surname> <given-names>R</given-names></name> <name><surname>Sugi</surname> <given-names>K</given-names></name> <name><surname>Vasudevan</surname> <given-names>NT</given-names></name> <name><surname>Alaiti</surname> <given-names>MA</given-names></name> <etal/></person-group>. <article-title>Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy</article-title>. <source>Proc Natl Acad Sci U S A.</source> (<year>2018</year>) <volume>115</volume>:<fpage>E4661</fpage>&#x02013;<lpage>e4669</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1720065115</pub-id><pub-id pub-id-type="pmid">29712858</pub-id></citation></ref>
<ref id="B109">
<label>109.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Candela</surname> <given-names>J</given-names></name> <name><surname>Wang</surname> <given-names>R</given-names></name> <name><surname>White</surname> <given-names>C</given-names></name></person-group>. <article-title>Microvascular endothelial dysfunction in obesity is driven by macrophage-dependent hydrogen sulfide depletion</article-title>. <source>Arterioscler Thromb Vasc Biol.</source> (<year>2017</year>) <volume>37</volume>:<fpage>889</fpage>. <pub-id pub-id-type="doi">10.1161/ATVBAHA.117.309138</pub-id><pub-id pub-id-type="pmid">28336559</pub-id></citation></ref>
<ref id="B110">
<label>110.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chan</surname> <given-names>CT</given-names></name> <name><surname>Moore</surname> <given-names>JP</given-names></name> <name><surname>Budzyn</surname> <given-names>K</given-names></name> <name><surname>Guida</surname> <given-names>E</given-names></name> <name><surname>Diep</surname> <given-names>H</given-names></name> <name><surname>Vinh</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice</article-title>. <source>Hypertension.</source> (<year>2012</year>) <volume>60</volume>:<fpage>1207</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1161/HYPERTENSIONAHA.112.201251</pub-id><pub-id pub-id-type="pmid">23033370</pub-id></citation></ref>
<ref id="B111">
<label>111.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gevaert</surname> <given-names>AB</given-names></name> <name><surname>Shakeri</surname> <given-names>H</given-names></name> <name><surname>Leloup</surname> <given-names>AJ</given-names></name> <name><surname>Van Hove</surname> <given-names>CE</given-names></name> <name><surname>De Meyer</surname> <given-names>GRY</given-names></name> <name><surname>Vrints</surname> <given-names>CJ</given-names></name> <etal/></person-group>. <article-title>Endothelial senescence contributes to heart failure with preserved ejection fraction in an aging mouse model</article-title>. <source>Circ Heart Fail.</source> (<year>2017</year>) <volume>10</volume>:<fpage>e003806</fpage>. <pub-id pub-id-type="doi">10.1161/CIRCHEARTFAILURE.116.003806</pub-id><pub-id pub-id-type="pmid">28611124</pub-id></citation></ref>
<ref id="B112">
<label>112.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Friebel</surname> <given-names>J</given-names></name> <name><surname>Weithauser</surname> <given-names>A</given-names></name> <name><surname>Witkowski</surname> <given-names>M</given-names></name> <name><surname>Rauch</surname> <given-names>BH</given-names></name> <name><surname>Savvatis</surname> <given-names>K</given-names></name> <name><surname>Dorner</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction</article-title>. <source>Eur Heart J.</source> (<year>2019</year>) <volume>40</volume>:<fpage>3318</fpage>&#x02013;<lpage>32</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehz117</pub-id><pub-id pub-id-type="pmid">31004144</pub-id></citation></ref>
<ref id="B113">
<label>113.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zeng</surname> <given-names>H</given-names></name> <name><surname>Chen</surname> <given-names>JX</given-names></name></person-group>. <article-title>Sirtuin 3, endothelial metabolic reprogramming, and heart failure with preserved ejection fraction</article-title>. <source>J Cardiovasc Pharmacol.</source> (<year>2019</year>) <volume>74</volume>:<fpage>315</fpage>&#x02013;<lpage>23</lpage>. <pub-id pub-id-type="doi">10.1097/FJC.0000000000000719</pub-id><pub-id pub-id-type="pmid">31425381</pub-id></citation></ref>
<ref id="B114">
<label>114.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kain</surname> <given-names>V</given-names></name> <name><surname>Ingle</surname> <given-names>KA</given-names></name> <name><surname>Colas</surname> <given-names>RA</given-names></name> <name><surname>Dalli</surname> <given-names>J</given-names></name> <name><surname>Prabhu</surname> <given-names>SD</given-names></name> <name><surname>Serhan</surname> <given-names>CN</given-names></name> <etal/></person-group>. <article-title>Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function</article-title>. <source>J Mol Cell Cardiol.</source> (<year>2015</year>) <volume>84</volume>:<fpage>24</fpage>&#x02013;<lpage>35</lpage>. <pub-id pub-id-type="doi">10.1016/j.yjmcc.2015.04.003</pub-id><pub-id pub-id-type="pmid">25870158</pub-id></citation></ref>
<ref id="B115">
<label>115.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rettl</surname> <given-names>R</given-names></name> <name><surname>Dachs</surname> <given-names>T-M</given-names></name> <name><surname>Duca</surname> <given-names>F</given-names></name> <name><surname>Binder</surname> <given-names>C</given-names></name> <name><surname>Dusik</surname> <given-names>F</given-names></name> <name><surname>Seirer</surname> <given-names>B</given-names></name> <etal/></person-group>. <article-title>What type of patients did paragon-hf select? insights from a real-world prospective cohort of patients with heart failure and preserved ejection fraction</article-title>. <source>J Clin Med.</source> (<year>2020</year>) <volume>9</volume>:<fpage>3669</fpage>. <pub-id pub-id-type="doi">10.3390/jcm9113669</pub-id><pub-id pub-id-type="pmid">33203151</pub-id></citation></ref>
<ref id="B116">
<label>116.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zindel</surname> <given-names>J</given-names></name> <name><surname>Kubes</surname> <given-names>P</given-names></name></person-group>. <article-title>DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation</article-title>. <source>Annu Rev Pathol.</source> (<year>2019</year>) <volume>15</volume>:<fpage>493</fpage>&#x02013;<lpage>518</lpage>. <pub-id pub-id-type="doi">10.1146/annurev-pathmechdis-012419-032847</pub-id><pub-id pub-id-type="pmid">31675482</pub-id></citation></ref>
<ref id="B117">
<label>117.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>McAlpine</surname> <given-names>CS</given-names></name> <name><surname>Kiss</surname> <given-names>MG</given-names></name> <name><surname>Rattik</surname> <given-names>S</given-names></name> <name><surname>He</surname> <given-names>S</given-names></name> <name><surname>Vassalli</surname> <given-names>A</given-names></name> <name><surname>Valet</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Sleep modulates haematopoiesis and protects against atherosclerosis</article-title>. <source>Nature.</source> (<year>2019</year>) <volume>566</volume>:<fpage>383</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1038/s41586-019-0948-2</pub-id><pub-id pub-id-type="pmid">30760925</pub-id></citation></ref>
<ref id="B118">
<label>118.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Frodermann</surname> <given-names>V</given-names></name> <name><surname>Rohde</surname> <given-names>D</given-names></name> <name><surname>Courties</surname> <given-names>G</given-names></name> <name><surname>Severe</surname> <given-names>N</given-names></name> <name><surname>Schloss</surname> <given-names>MJ</given-names></name> <name><surname>Amatullah</surname> <given-names>H</given-names></name> <etal/></person-group>. <article-title>Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells</article-title>. <source>Nat Med.</source> (<year>2019</year>) <volume>25</volume>:<fpage>1761</fpage>&#x02013;<lpage>71</lpage>. <pub-id pub-id-type="doi">10.1038/s41591-019-0633-x</pub-id><pub-id pub-id-type="pmid">31700184</pub-id></citation></ref>
<ref id="B119">
<label>119.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Halade</surname> <given-names>GV</given-names></name> <name><surname>Kain</surname> <given-names>V</given-names></name></person-group>. <article-title>Obesity and cardiometabolic defects in heart failure pathology</article-title>. <source>Compr Physiol.</source> (<year>2017</year>) <volume>7</volume>:<fpage>1463</fpage>&#x02013;<lpage>77</lpage>. <pub-id pub-id-type="doi">10.1002/cphy.c170011</pub-id><pub-id pub-id-type="pmid">28915332</pub-id></citation></ref>
<ref id="B120">
<label>120.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Alvarez-Curto</surname> <given-names>E</given-names></name> <name><surname>Milligan</surname> <given-names>G</given-names></name></person-group>. <article-title>Metabolism meets immunity: the role of free fatty acid receptors in the immune system</article-title>. <source>Biochem Pharmacol.</source> (<year>2016</year>) <volume>114</volume>:<fpage>3</fpage>&#x02013;<lpage>13</lpage>. <pub-id pub-id-type="doi">10.1016/j.bcp.2016.03.017</pub-id><pub-id pub-id-type="pmid">27002183</pub-id></citation></ref>
</ref-list>
<fn-group>
<fn fn-type="financial-disclosure"><p><bold>Funding.</bold> The authors acknowledge the support from the National Institutes of Health (NIH)&#x02014;National Heart, Lung, and Blood Institute (NHLBI) HL144788 and HL132989.</p>
</fn>
</fn-group>
</back>
</article>