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Review Article

Insight into the Pro-inflammatory and Profibrotic Role of Macrophage in Heart Failure With Preserved Ejection Fraction

Shen, Jin-lian MD; Xie, Xiao-jie MD, PhD

Author Information
Journal of Cardiovascular Pharmacology: September 2020 - Volume 76 - Issue 3 - p 276-285
doi: 10.1097/FJC.0000000000000858
  • Open

Abstract

INTRODUCTION

Prevalence of heart failure with preserved ejection fraction (HFpEF), a type of heart failure (HF) manifested by left ventricular ejection fraction (LVEF) ≥50%, is currently on the rise. In Asia, its prevalence significantly increased from 50.6% to 68.7%, according to 2 four-year-long cohort Japanese studies, CHART-1 and CHART-2.1,2 Although lots of guidelines have been provided for HF with reduced ejection fraction (HFrEF), including in the American Heart Association (AHA), European Society of Cardiology (ESC), and Japanese Circulation Society (JCS), similar evidence-based principles for HFpEF are nonexistent, owing to limited understanding of its pathophysiology.

A recent review by the ESC described the relationship between inflammation and HFpEF,3 in the context of measurements of the circulating inflammatory biomarkers, pathological examination of cardiac LV biopsy, and extra-cardiac evidence provided by indirect trials. Over the past decade, several studies have reported discovery of specific alterations in the myocardial tissue from patients with HFpEF. For instance, structural alterations, including cardiomyocyte hypertrophy and interstitial fibrosis, and functional changes, such as incomplete relaxation of myocardial strips and increased myocardial stiffness have been described.4 Such evidence indicates that inflammation and fibrosis may be playing important roles in the pathophysiology of HFpEF.

Macrophages are known to play an important role in innate and adaptive immunity. Currently, cardiac macrophage subsets can be defined based on expression profiles of MHC II and CCR2, a chemokine receptor that regulates migration and distinguishes peripheral monocyte influx from proliferating cardiac macrophages.5,6 In fact, 3 subsets, namely CCR2MHCIIlow, CCR2MHCIIhigh, and CCR2+MHCIIhigh can be differentiated. Recently, their contributions to cardiovascular diseases were elucidated. Particularly, their role in inflammation and repair after acute myocardial infarction (AMI), which is a leading cause of HFrEF, is now well understood. Conversely, little is known regarding HFpEF, although elevated macrophage infiltration in myocardium has been reported in animal models with diastolic dysfunction and HFpEF patients.7,8 This review outlines the current state of knowledge describing the pro-inflammatory and profibrotic roles of macrophages in HFpEF.

HFpEF COMORBIDITIES DRIVE SYSTEMIC MICROVASCULAR INFLAMMATION AND ENDOTHELIAL DYSFUNCTION

Unlike HFrEF, the etiology of HFpEF is not fully understood. Moreover, most HFpEF patients are aged, women,9,10 and exhibit comorbidities of coronary artery disease (CAD), obesity, systemic arterial hypertension (HTN), diabetes mellitus (DM), renal dysfunction, chronic obstructive pulmonary disease (COPD), iron deficiency, sleep disorders, and anemia. This is indicative of the potential role played by these comorbidities in the pathophysiology of HFpEF. In addition, whether HFpEF is merely a combination of comorbidities or a distinct disease remains unknown.

All these comorbidities can induce a systemic inflammatory condition. Studies exploring the role of inflammation in obesity-related cardiac diseases are burgeoning. For instance, macrophage infiltration in adipose tissue resulted in a systemic inflammation of visceral obesity.11 Generally, obesity is often accompanied by obstructive sleep apnea, although numerous studies found an independent association between obstructive sleep apnea and inflammation. In addition, Continuous Positive Airway Pressure therapy was reportedly effective in reversing this change.12–14 The interaction between inflammation and HTN has also been extensively explored. For example, an anti-immune therapy was reportedly effective in decreasing arterial pressure and immune-component cell levels in deoxycorticosterone acetate (DOCA)-salt hypertensive, Dahl salt-sensitive and genetically hypertensive rats that had exhibited an increase in inflammation.15 Numerous reviews have also summarized various evidence-linking systemic inflammation with type 2 DM.16 Regarding CAD, the current body of knowledge indicates that inflammation plays a key role in its pathophysiology. The role played by renal diseases in systemic microvascular inflammation in HFpEF can be attributed to a myriad of factors including vitamin D deficiency,17,18 microalbuminuria,19 accumulation of uremic toxins,20 advanced glycation end products (AGE),21 and fibroblast growth factor 23,22 as well as anemia.23 Accumulating evidence indicates that HF, renal impairment, anemia, and iron deficiency are comorbidities, whereas iron deficiency seems to be an independent predictor in HF prognosis, leading to a new concept termed the cardio-renal–iron deficiency syndrome or even cardio-renal–anemia–iron deficiency syndrome.24 Based on this, iron deficiency has been found to contribute to inflammation and oxidative stress beyond erythropoiesis.25 Chronic inflammation therefore occurs in COPD, based on the current understanding that it is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. On the other hand, endothelial dysfunction is affected by 2 main aspects: the state systemic inflammation and the oxidative stress independently induced by these comorbidities.13–15

MACROPHAGES CONTRIBUTE TO INFLAMMATION AND FIBROSIS IN HFpEF IN 3 PHASES

Although the pathophysiological mechanisms of fibrosis in HF vary across patients with different etiologies, the effector and molecular transduction of fibrotic remodeling remain the same.26 In addition, processes that follow classical AMI in HFrEF occur in 3 phases, namely inflammation, repair, and resolution. In summary, the inflammation phase entails obstructive occlusion of the coronary artery which directly causes cardiomyocyte damage, to release myocardial damage associated molecular patterns. Both are involved in induction of CCR2+ macrophage recruitment from the bone marrow to the myocardium and initiate apoptosis or necrosis. This is followed by the repair phase, in which fibroblasts are activated to produce collagen fiber, following the clearing of dead cells and debris by neutrophil granulocytes and polarized macrophages. The final phase, resolution, involves local restoration of a new balance. Therefore, we hypothesize that macrophages contribute to inflammation and fibrosis in a similar fashion to these 3 phases. A detailed description of these processes is provided in the subsequent sections (Figure 1.) In addition, inflammatory biomarkers involved in the processes are further summarized in Table 1.

FIGURE 1.
FIGURE 1.:
Summary cartoon. Bone marrow derived macrophages or CCR2+ macrophages infiltrate into endothelium, and initiate a series of inflammatory and fibrotic reactions in heart.
TABLE 1.
TABLE 1.:
Inflammatory Biomarkers in HFpEF

Inflammation Phase

Endothelial inflammation is associated with coronary microvasculature rarefaction, which causes reduction in capillary density that may impair the coronary flow reserve.4,27 The resultant reduction in coronary microvascular density may also impair, or lead to stressful oxygen delivery which in turn causes local cell damage.28 Besides, endothelial inflammation has also been associated with production of reactive oxygen species (ROS), vascular cell adhesion molecule (VCAM),29 intercellular cell adhesion molecule (ICAM),30–32 selectins,31 and integrins.33,34 ROS produces peroxynitrite (ONOO–) and reduces nitric oxide (NO) bioavailability, both of which disrupt the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway.31 Specifically, they reduce soluble guanylyl cyclase (sGC) activation, decrease cGMP content, and lower PKG activity. ONOO– can also inhibit cellular respiration,35 promote local cell damage and activate specific apoptotic pathways.36–38 Resident CCR2 macrophages are replaced by newly recruited CCR2+ monocyte-derived ones.11 In fact, the latter macrophages are mainly attracted by local cytokines, including chemokine C-C motif ligand 2 (CCL2), also referred to as monocyte chemoattractant protein 1 (MCP1)39 and small inducible cytokine A2, granulocyte macrophage colony-stimulating factor (GM-CSF)40 released by local CCR2+ macrophages and cardiac fibroblasts.

Macrophage recruitment is also aided by other chemokines, such as expression of VCAM and ICAM on endothelial cells and circulating monocytes (selectins, integrins), a manifestation of coronary endothelial microvascular inflammation. Generally, this recruitment is always accompanied by subsequent infiltration into the heart. Specifically, tissue injury induces release of damage-associated molecular patterns outside the cell,41 which in turn initiate inflammatory signal transduction pathways in monocyte-derived macrophages. These pathways are activated via specialized innate immune receptors, such as toll-like receptors (TLRs)42 and a nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome complex,43 CCR2+ macrophages that secret cytokines such as interleukin-1β (IL-1β, the dominant circulating form of IL-1), tumor necrosis factor-alpha (TNF-α),3 interleukin 6 (IL-6),11,44 interleukin 16 (IL-16),45 and interleukin 18 (IL-18). Expression of NLRP3 is reportedly regulated by the cytokine macrophage migration inhibitory factor (MIF), and forms an essential step for activation of the NLRP3 inflammasome, thus indirectly arming monocyte and macrophage functions.46,47

Repair Phase

This phase follows inflammation, and is mainly characterized by activation of fibroblasts and deposition of collagen. Particularly, macrophages first engulf and clear apoptotic cardiomyocytes, which is followed by secretion of pro-inflammatory and tissue reparative cytokines, such as transforming growth factor-β (TGF-β, a prototype of multifunctional cytokine) from CCR2+ macrophages.48 The secretion induces synthesis of extracellular matrix (ECM) by fibroblasts and remodels the tissue. Conversely, CCR2 macrophages play opposite roles to the traditional type during AMI period, where they secret anti-inflammatory cytokine-like interleukin-10 (IL-10) to preserve neighboring tissues and cardiac function.49,50 Hulsmans et al8 reported that tissue-resident macrophage secretion, IL-10 (the dominant source), is a profibrotic cytokine that indirectly activates cardiac fibroblasts and promotes collagen deposition and myocardial stiffness in diastolic dysfunction. Furthermore, Osteopontin (OPN), a matricellular protein and multifunctional cytokine is also produced by macrophages and acts as a paracrine fibroblast activator.8 Apart from these, cardiac macrophages also secrete galectin-3 (gal-3), a member of the β-galactoside lectin family, which promotes myocardial fibrosis by activating myofibroblasts.51,52

Resolution Phase

During the resolution phase, homeostasis is restored, a balance between cardiomyocyte apoptosis and myofibroblast repair is attained, and myocardial fibrosis is eventually attained. In conclusion, inflammatory HFpEF biomarkers can be summarized by 3 clusters, according to the pathophysiological processes as follows; recruitment or transformation-associated, pro-inflammation and profibrotic inflammatory mediators (Table 1).

SIGNAL TRANSDUCTION PATHWAY-TARGETED THERAPIES

Animal Experiments

Previous studies have used basic experiments to confirm the relationship between inflammation, especially macrophages and HFpEF. In this section, we discuss a number of approaches that have been used to investigate chemokine antagonism or inhibition in HFpEF.

Recruitments or Transformation-Associated Inflammatory Mediators

Kuwahara et al32 used anti–ICAM-1 monoclonal neutralizing antibody (Nab), an established and effective tool for blocking ICAM-1 function, to successfully attenuate macrophage accumulation, reduce TGF-β induction as well as fibroblast proliferation, and prevent myocardial fibrosis in pressure-overloaded rat hearts. On the other hand, Talior–Volodarsky et al53 found that deletion of all integrins in streptozotocin-treated animals attenuated the change in cardiac fibrosis, whereas Ren et al54 reported that β3 integrin deficiency promoted cardiac hypertrophy and inflammation in pressure-overload mice. These findings indicate that different integrin subunits work differentially. Regarding MCP1, Kuwahara et al55 demonstrated that a monoclonal MCP1 antibody ameliorates diastolic dysfunction with no effect on blood pressure or systolic function using a rat cardiac hypertrophy model. Little is known regarding GM-CSF, with a handful of existing studies indicate that GM-CSF ameliorates diastolic dysfunction, which conflicts with its role in pro-inflammation area.56,57 This may be attributed to its ability to mobilize stem cells from the bone marrow and trans-differentiate into cardiomyocytes or endothelial cells when brought into contact with injured regions of the myocardium.58

Pro-inflammation Inflammatory Mediators

Dhondup and his colleagues reported that sustained TLR9 activation promoted cardiac and systemic inflammation,42 whereas its depletion reduced59 the survival rate of sacro/endoplasmic reticulum Ca2+ ATPase (SERCA)2a KO mice (a diastolic HF60). This finding indicates the vital role played by TLR9 in some subsets of diastolic HF. Initial studies exploring the effect of inhibiting the NLRP3 inflammasome in cardiac dysfunction included the use of Chinese herbal medicines for treating fibrosis. For example, triptolide61 and pirfenidone62 successfully downregulated IL-1β and IL-18, leading to decreased macrophage infiltration and fibrosis, and improved cardiac diastolic and systolic function in a pressure-overload mice model. Recently, MCC950, a more selective NLRP3 inhibitor, was found to significantly attenuate adverse remodeling in the same mouse model.63,64 Besides, Carbone et al65 found that compound 16673-34-0, an orally active NLRP3 inhibitor, prevented cardiac systolic and diastolic dysfunction in mice with western diet-induced cardiac dysfunction. Generally, administration of IL-1 has been shown to impair cardiac diastolic function, although effect of its blockade in diastolic function remains unclear.

Other studies have also reported on TNF. For example, selective p38 mitogen-activated protein kinase (MAPK) inhibitors were found to successfully block secretion of TNF-α and improve systolic function in a mouse DM model.66 However, no change in cardiac fibrosis and diastolic dysfunction was observed. IL-6 production was reported to increase, and either its genetic deletion or neutralization found to attenuate LV hypertrophy, thereby preserving both systolic and diastolic function in pressure-overload mice.67,68 Studies targeting VCAM, selectins, IL-16 are too limited to provide compelling evidence. MIF, a pro-inflammatory cytokine, has shown a cardio-protective effect by promoting cardiac stem cell proliferation and endothelial differentiation.69 Besides, MIF may also help preserve cardiac function by activating autophagy.70,71 Despite these findings, further studies are needed to elucidate the role of MIF in HFpEF.

Profibrotic Inflammatory Mediators

Previous studies have also described TGF-β-targeted therapy. For instance, Kuwahara et al72 reported that anti–TGF-β neutralizing antibody, could inhibit fibroblast activation, induce collagen mRNA and myocardial fibrosis, and preserve diastolic function in pressure overload rats. Other studies have demonstrated that indirect downregulation of TGF-β prevented pathological remodeling of the heart in AngII-induced hypertensive mice and high-fat diet-induced obesity rat model.73–75 In addition, IL-10 has been implicated in inhibition of inflammation and attenuation of the LV remodeling in AMI. A similar conclusion could be drawn in HFpEF, as evidenced by the findings of Verma et al76. Moreover, IRF1-mutant, which downregulates IL-18 and OPN expression, was found to reduce cardiac fibrotic development, and increase left ventricular function compared to wild type in pressure-overload mice.77 Furthermore, Calvier et al (2013) discovered that aldosterone (Aldo) could increase aortic gal-3 expression, and cause fibrotic changes in wild-type mice, whereas no changes were observed in gal-3 knock-out mice, suggesting that Aldo antagonists could play important roles in HFpEF patients with high levels of galectin-3.78 In addition, both Aldo treatment and genetic or pharmacological inhibition of galectin-3 attenuated cardiac fibrosis, LV dysfunction, and subsequent HF development.79–81

NO-cGMP-PKG Transduction Pathway

Therapies targeting the NO-sGC-cGMP-PKG pathway have also achieved notable progress. For instance, sGC stimulator was found to enhance NO signaling by directly binding sGC, thereby regulating the NO-sGC-cGMP pathway. Wilck et al82 reported that NO-independent stimulator BAY 41-8543, drastically improved survival rates of treated double-transgenic rat (dTGR) HFpEF models. In addition, the stimulator also reduced cardiac fibrosis, macrophage infiltration, and gap junction remodeling. In another study, Tobin and his colleagues found that IW-1973, a novel clinical stage sGC stimulator currently being used in clinical research to treat HFpEF and diabetic nephropathy, exhibited reno-protective, anti-inflammation, and antifibrotic effects in nonclinical models.83 Two other ways of accumulating cGMP, including downregulation of specific phosphodiesterases (PDEs) and inhibition of the enzyme dipeptidyl-peptidase 4 (DPP-4), have been described. According to Nagiub et al84, long-acting PDE5 inhibitor tadalafil (Tada) was limited in preserving cardiac function against doxorubicin (Dox) cardiotoxicity in juvenile mice. Another study, comparing effect of saxagliptin and Tada in altering cGMP signaling and left ventricular function in aortic-banded mini-swine, found that both inhibitors mediated a decrease in LV collagen deposition. However, saxagliptin appears superior for treating HFpEF based on its effects on integrated LV systolic and diastolic function.85 Recently, Gao et al86 explored sacubitril/valsartan, LCZ696, a complex of RAS blocker and endogenous vasoactive peptide system augment, on HFpEF using abdominal aortic constriction in adult male New Zealand rabbits. Their results indicated significant improvement in cardiac function, echocardiographic results, including interventricular septal thickness at diastole (IVSd), mitral valve's early diastolic flow velocity(E)/late mitral diastolic maximum flow rate (A), as well as lower serum NT-proBNP, AngII and soluble suppression of tumorigenesis-2 (sST2) levels. A summary of studies on these animal experiments is provided in Table 2.

TABLE 2.
TABLE 2.:
Targeted Animal Experiments in HFpEF

Human Studies

IL-1

Currently, L-1 inhibition has been suggested as the most successful and promising anti-inflammation intervention therapy for human HFpEF. IL-1β is a powerful inducer of innate immunity, whereas Anakinra has been tested using 2 trials. The pilot feasibility study, which had a randomized, crossover assignment, quadruple blinded design, with 12 participants, announced its results in 2013. Particularly, subjects treated for 14 days using daily doses of 100 mg of anakinra, administered subcutaneously, exhibited increased peak oxygen consumption (peak VO2) which correlated with a reduction in C reactive protein (CRP).87 On the other hand, diastolic HF–anakinra response trial 2 (D-HART2) study involved a randomized, parallel assignment, quadruple blinded trial, which enrolled 31 participants later in 2018. Results showed no significant differences in peak VO2 or in ventilatory efficiency (the minute ventilation/carbon dioxide production, VE/VCO2) slope at 12 weeks, although good downtrends in high-sensitivity CRP and NT-proBNP were still observed.88,89 A small prespecified secondary analysis of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) has shown that specifically targeting IL-1β can significantly improve peak oxygen consumption, confirming that IL-1 is a potential therapeutic target for HF treatment.90 However, positive results on canakinumab remains restricted to HFrEF, with no such study showing its efficacy in HFpEF.

TNF and Others

Studies on anti-TNF therapy in HF have not yielded positive results and data on HFpEF are relatively limited. Results from an anti-TNF therapy against congestive HF (ATTACH) trial, performed in 2003 on 150 HFrEF subjects, showed that this therapy could not improve the clinical conditions of the patients. On the other hand, Coletta et al terminated the randomized etanercept worldwide evaluation (RENEWAL) trial because of poor clinical outcomes.91 The trial, which had been conducted for 5.7 months, was a combination of the randomized etanercept North American strategy to study antagonism of cytokines (RENAISSANCE) and research into etanercept cytokine antagonism in ventricular dysfunction trial (RECOVER) studies, and involved a large randomized, phase 2/3 placebo-controlled, double-blind trials of etanercept in patients with NYHA III-IV HF. In contrast, Kotyla et al (2012) trialed infliximab, an anti-TNF-α antagonist, in 23 female patients with rheumatoid arthritis (RA) resistant to treatment with disease-modifying anti-rheumatic drugs.92 The study revealed a significant increase, from 58.5% to 63%, in LVEF.93 However, the effect of IL-10 administration in HF patients, especially for HFrEF is not fully understood. Researches on anti-MCP1, anti-GM-CSF, and anti-TGF-β also come to similar results.

NO-cGMP-PKG Transduction Pathway

Despite the limited success reported from studies targeting the sGC-cGMP-PKG pathway, such as IL-1, multiple clinical trials on the pathway are still underway. For example, the nitrate's effect on activity tolerance in HF with preserved ejection fraction (NEAT-HFpEF) trial, a randomized, crossover assignment, triple blinded study, which enrolled 110 participants has been reported. Particularly, results indicate that the interventional group, isosorbide mononitrate crossover to placebo, exhibited dramatically fewer arbitrary accelerometry units, and shorter 6-minute walk distance.94 On the other hand, vericiguat, a new oral sGC stimulator, in the sGC stimulator in HFpEF (SOCRATES-PRESERVED) trial resulted in potential improvements to health status of the patients, although NT-proBNP was not decreased at 12 weeks, necessitating further investigations to explore the mechanism.95 Other strategies for enhancing cGMP in HFpEF, such as sacubitril/valsartan96 or sildenafil (PDE-5 inhibition),97–100 have also produced suboptimal results. For example, results from prospective comparison of ARNI with ARB global outcomes in HF with preserved ejection fraction (PARAGON-HF) trial, presented on ESC Congress (2019),96 indicated that the use of sacubitril/valsartan in HFpEF could not significantly lower the rate of total hospitalizations for HF and cardiovascular-related deaths compared with valsartan alone. However, a subgroup of patients with HFpEF may benefit from the use of sacubitril/valsartan, although further investigations are needed to clarify the efficacy of this therapy. These clinical trials are summarized in Table 3.

TABLE 3.
TABLE 3.:
Anti-cytokine Therapy in Human Studies

DISCUSSION

Systemic inflammation is central to comorbidities associated with HFpEF. In fact, clinical studies have indicated that elevated inflammatory biomarkers are associated with poor clinical outcomes.101 Systemic microvascular inflammation causes ROS production, with both systemic inflammation and ROS separately implicated in local cell damage via ONOO–35,36 and reduction of coronary microvascular density.4,27,28 In addition, macrophages are important immune modulators that participate in the inflammation phases in the heart following cardiac injury. Besides, inflammation also impairs the NO-cGMP-PKG signal transduction pathway, which plays a key role in myocardial stiffness.102 Based on the aforementioned evidence, systemic inflammation and macrophages involved in inflammatory events on the coronary microvasculature and myocardium have been recognized as primary contributors to pathogenesis of HFpEF, hence a potential target for intervention.103 Consequently, experimental studies using animal models have been conducted, contributing to important discoveries and breakthroughs for understanding the underlying mechanism of HFpEF. However, their predictive value remains low, leading to translational failure, owing to the fact that no single animal study has fully executed all steps.

Given the complexity of HFpEF diagnosis, etiology, and pathophysiology, a reasonably conservative approach to analyzing results is needed. In animal experiments, the biggest barrier is that all existing models do not recapitulate the full HFpEF spectrum in patients. Considering the heterogeneity of HFpEF in clinical trials in patients using human subjects, current studies have focused on phenotype-based classification, with a variety of clinical phenotypes proposed. These include “garden variety” HFpEF, CAD-associated HFpEF, AF-predominate HFpEF, pulmonary HTN-HFpEF, hypertrophic cardiomyopathy-like HFpEF, multivalvular HFpEF, and restrictive cardiomyopathies.104 Because different clinical phenotypes show different prognosis,105 no consensus has recently been reached regarding classification of phenotypes. Additional translation barriers include, lack of certain HFpEF diagnoses and detailed sub-phenotyping, one-size fits all approach to all patients without multi-disciplinary care, or adequate prevention measures, and lack of innovative clinical trial designs.106 These barriers, and corresponding initial optimal solutions have been discussed by Shah et al.106 Nevertheless, further studies are required to guide development of novel approaches for effective treatments.

Apart from the aforementioned translational barriers, other aspects need our attention. First, comorbidities may contribute to the disease in a stage-dependent manner. For example, the phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic HF (RELAX) trial, in which sildenafil showed neither improvement in exercise nor clinical status in HFpEF patients, revealed that only about 57% patients exhibited elevated CRP levels. Among these subjects, high CRP levels were associated with increased comorbidity and higher degrees of disease severity. The potential causal relationship between inflammation and HFpEF has been previously reviewed by Van Linthout et al (2017) in detail.107 Therefore, better approaches for detecting HFpEF patients with a high risk of inflammation may enhance the chances of identifying a subgroup of HFpEF patients who would benefit from the therapy.

Second, it is not known whether inflammation directly causes HFpEF. Despite studies reporting increased levels of circulating inflammatory markers and human biopsies, and improved outcomes in inflammation-targeted animal experiments, clinical trials have revealed poor efficacy. It is, therefore, possible that this could be a chicken-and-egg problem, in which either inflammation causes HFpEF or vice versa. However, this is outside the scope of this paper, as detailed descriptions have been provided in other reviews.108

CONCLUSIONS

The number of experimental studies explicating the relationship between inflammation and HFpEF pathogenesis has rapidly grown in the last 20 years. However, whether inflammatory modulators can effectively inhibit cardiac fibrosis in HFpEF patients remain elusive. Based on the current body of knowledge, it is evident that numerous barriers need to be circumvented before developing successful pharmacological therapy. Currently, HFpEF patients with high inflammation levels may benefit from immunoregulator treatments. However, further studies are needed to elucidate the exact mechanisms of HFpEF and immune-pathogenesis of cardiac fibrosis.

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Keywords:

heart failure; preserved ejection fraction; inflammation; fibrosis; macrophage; treatment

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.