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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

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


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


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.

Summary cartoon. Bone marrow derived macrophages or CCR2+ macrophages infiltrate into endothelium, and initiate a series of inflammatory and fibrotic reactions in heart.
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).


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.

Targeted Animal Experiments in HFpEF

Human Studies


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.

Anti-cytokine Therapy in Human Studies


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


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.


1. Zakeri R, Chamberlain AM, Roger VL, et al. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Circulation. 2013;128:1085–1093.
2. Shiba N, Nochioka K, Miura M, et al. Trend of westernization of etiology and clinical characteristics of heart failure patients in Japan. Circ J. 2011;75:823–833.
3. Lam CSP, Voors AA, De Boer RA, et al. Heart failure with preserved ejection fraction: from mechanisms to therapies. Eur Heart J. 2018;39:2780–2792.
4. Mohammed SF, Hussain S, Mirzoyev SA, et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131:550–559.
5. Hulsmans M, Clauss S, Xiao L, et al. Macrophages facilitate electrical conduction in the heart. Cell. 2017;169:510–522.e520.
6. Epelman S, Lavine KJ, Beaudin AE, et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 2014;40:91–104.
7. Valero-Munoz M, Li S, Wilson RM, et al. Heart failure with preserved ejection fraction induces beiging in adipose tissue. Circ Heart Fail. 2016;9:e002724.
8. Hulsmans M, Sager HB, Roh JD, et al. Cardiac macrophages promote diastolic dysfunction. J Exp Med. 2018;215:423–440.
9. Redfield MM, Jacobsen SJ, Borlaug BA, et al. Age- and gender-related ventricular-vascular stiffening: a community-based study. Circulation. 2005;112:2254–2262.
10. Mohammed SF, Borlaug BA, Roger VL, et al. Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community-based study. Circ Heart Fail. 2012;5:710–719.
11. Glezeva N, Voon V, Watson C, et al. Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis. J Card Fail. 2015;21:167–177.
12. Mentz RJ, Kelly JP, Von Lueder TG, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64:2281–2293.
13. Jelic S, Padeletti M, Kawut SM, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation. 2008;117:2270–2278.
14. Araujo Lda S, Fernandes JF, Klein MR, et al. Obstructive sleep apnea is independently associated with inflammation and insulin resistance, but not with blood pressure, plasma catecholamines, and endothelial function in obese subjects. Nutrition. 2015;31:1351–1357.
15. Tian N, Moore RS, Braddy S, et al. Interactions between oxidative stress and inflammation in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol. 2007;293:H3388–H3395.
16. Lontchi-Yimagou E, Sobngwi E, Matsha TE, et al. Diabetes mellitus and inflammation. Curr Diab Rep. 2013;13:435–444.
17. Chitalia N, Recio-Mayoral A, Kaski JC, et al. Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients. Atherosclerosis. 2012;220:265–268.
18. Bucharles S, Barberato SH, Stinghen AE, et al. Hypovitaminosis D is associated with systemic inflammation and concentric myocardial geometric pattern in hemodialysis patients with low iPTH levels. Nephron Clin Pract. 2011;118:c384–c391.
19. Yilmaz MI, Sonmez A, Saglam M, et al. ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction. J Am Soc Nephrol. 2008;19:388–395.
20. Moradi H, Sica DA, Kalantar-Zadeh K. Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. Am J Nephrol. 2013;38:136–148.
21. Van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43–51.
22. Leifheit-Nestler M, Haffner D. Paracrine effects of FGF23 on the heart. Front Endocrinol (Lausanne). 2018;9:278.
23. Fraenkel PG. Understanding anemia of chronic disease. Hematol Am Soc Hematol Educ Program. 2015;2015:14–18.
24. Macdougall IC, Canaud B, De Francisco ALM, et al. Beyond the cardiorenal anaemia syndrome: recognizing the role of iron deficiency. Eur J Heart Fail. 2012;14:882–886.
25. Li Y, Hansen SL, Borst LB, et al. Dietary iron deficiency and oversupplementation increase intestinal permeability, ion transport, and inflammation in pigs. J Nutr. 2016;146:1499–1505.
26. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549–574.
27. Goligorsky MS. Microvascular rarefaction. Organogenesis. 2010;6:1–10.
28. Hoenig MR, Bianchi C, Rosenzweig A, et al. The cardiac microvasculature in hypertension, cardiac hypertrophy and diastolic heart failure. Curr Vasc Pharmacol. 2008;6:292–300.
29. Wilson RM, De Silva DS, Sato K, et al. Effects of fixed-dose isosorbide dinitrate/hydralazine on diastolic function and exercise capacity in hypertension-induced diastolic heart failure. Hypertension. 2009;54:583–590.
30. Salvador AM, Nevers T, Velazquez F, et al. Intercellular adhesion molecule 1 regulates left ventricular leukocyte infiltration, cardiac remodeling, and function in pressure overload-induced heart failure. J Am Heart Assoc. 2016;5:e003126.
31. Franssen C, Chen S, Unger A, et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail. 2016;4:312–324.
32. Kuwahara F, Kai H, Tokuda K, et al. Roles of intercellular adhesion molecule-1 in hypertensive cardiac remodeling. Hypertension. 2003;41:819–823.
33. Shimojo N, Hashizume R, Kanayama K, et al. Tenascin-c may accelerate cardiac fibrosis by activating macrophages via the integrin αvβ3/nuclear factor-κb/interleukin-6 axis. Hypertension. 2015;66:757–766.
34. Meagher P, Adam M, Civitarese R, et al. Heart failure with preserved ejection fraction in diabetes: mechanisms and management. Can J Cardiol. 2018;34:632–643.
35. Xie Y-W, Wolin Michael S. Role of nitric oxide and its interaction with superoxide in the suppression of cardiac muscle mitochondrial respiration. Circulation. 1996;94:2580–2586.
36. Ishida H, Ichimori K, Hirota Y, et al. Peroxynitrite-induced cardiac myocyte injury. Free Radic Biol Med. 1996;20:343–350.
37. Elahi MM, Naseem KM, Matata BM. Nitric oxide in blood. The nitrosative-oxidative disequilibrium hypothesis on the pathogenesis of cardiovascular disease. FEBS J. 2007;274:906–923.
38. Briasoulis A, Androulakis E, Christophides T, et al. The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure. Heart Fail Rev. 2016;21:169–176.
39. Matsuda S, Umemoto S, Yoshimura K, et al. Angiotensin activates MCP-1 and induces cardiac hypertrophy and dysfunction via toll-like receptor 4. J Atheroscler Thromb. 2015;22:833–844.
40. Vistnes M, Waehre A, Nygård S, et al. Circulating cytokine levels in mice with heart failure are etiology dependent. J Appl Physiol (1985). 2010;108:1357–1364.
41. Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 2007;28:429–436.
42. Dhondup Y, Sjaastad I, Scott H, et al. Sustained Toll-like receptor 9 activation promotes systemic and cardiac inflammation, and aggravates diastolic heart failure in SERCA2a ko mice. PLoS One. 2015;10:e0139715.
43. Suetomi T, Miyamoto S, Brown JH. Inflammation in nonischemic heart disease: initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling. Am J Physiol Heart Circ Physiol. 2019;317:H877–H890.
44. Melendez GC, Mclarty JL, Levick SP, et al. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 2010;56:225–231.
45. Tamaki S, Mano T, Sakata Y, et al. Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction. PLoS One. 2013;8:e68893.
46. Yu XY, Chen HM, Liang JL, et al. Hyperglycemic myocardial damage is mediated by proinflammatory cytokine: macrophage migration inhibitory factor. PLoS One. 2011;6:e16239.
47. Lang T, Lee JPW, Elgass K, et al. Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation. Nat Commun. 2018;9:2223.
48. Larson DF, Ingham R, Alwardt CM, et al. TGF-beta1 overexpression: a mechanism of diastolic filling dysfunction in the aged population. J Extra Corpor Technol. 2004;36:69–74.
49. Jung M, Ma Y, Iyer RP, et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112:33.
50. Krishnamurthy P, Rajasingh J, Lambers E, et al. IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of stat3 and suppression of hur. Circ Res. 2009;104:e9–18.
51. Gonzalez GE, Rhaleb NE, D'ambrosio MA, et al. Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol. 2016;311:H1287–H1296.
52. Zile MR, Jhund PS, Baicu CF, et al. Plasma biomarkers reflecting profibrotic processes in heart failure with a preserved ejection fraction: data from the prospective comparison of ARNI with ARB on management of heart failure with preserved ejection fraction study. Circ Heart Fail. 2016;9:e002551
53. Talior-Volodarsky I, Connelly KA, Arora PD, et al. α11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy. Cardiovasc Res. 2012;96:265–275.
54. Ren J, Avery J, Zhao H, et al. Beta3 integrin deficiency promotes cardiac hypertrophy and inflammation. J Mol Cell Cardiol. 2007;42:367–377.
55. Kuwahara F, Kai H, Tokuda K, et al. Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation? Hypertension. 2004;43:739–745.
56. Shin JH, Lim YH, Song YS, et al. Granulocyte-colony stimulating factor reduces cardiomyocyte apoptosis and ameliorates diastolic dysfunction in Otsuka Long-Evans Tokushima fatty rats. Cardiovasc Drugs Ther. 2014;28:211–220.
57. Lim YH, Joe JH, Jang KS, et al. Effects of granulocyte-colony stimulating factor (G-CSF) on diabetic cardiomyopathy in Otsuka Tokushima fatty rats. Cardiovasc Diabetol. 2011;10:92.
58. Kim J, Kim NK, Park SR, et al. GM-CSF enhances mobilization of bone marrow mesenchymal stem cells via a CXCR4-medicated mechanism. Tissue Eng Regen Med. 2018;16:59–68.
59. Dhondup Y, Sjaastad I, Sandanger O, et al. Toll-like receptor 9 promotes survival in SERCA2a ko heart failure mice. Mediators Inflamm. 2017;2017:9450439.
60. Combes A, Frye CS, Lemster BH, et al. Chronic exposure to interleukin 1beta induces a delayed and reversible alteration in excitation-contraction coupling of cultured cardiomyocytes. Pflugers Arch. 2002;445:246–256.
61. Li R, Lu K, Wang Y, et al. Triptolide attenuates pressure overload-induced myocardial remodeling in mice via the inhibition of NLRP3 inflammasome expression. Biochem Biophys Res Commun. 2017;485:69–75.
62. Wang Y, Wu Y, Chen J, et al. Pirfenidone attenuates cardiac fibrosis in a mouse model of TAC-induced left ventricular remodeling by suppressing NLRP3 inflammasome formation. Cardiology. 2013;126:1–11.
63. Sano S, Oshima K, Wang Y, et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J Am Coll Cardiol. 2018;71:875–886.
64. Suetomi T, Willeford A, Brand Cameron S, et al. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase II δ signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation. 2018;138:2530–2544.
65. Carbone S, Mauro AG, Prestamburgo A, et al. An orally available NLRP3 inflammasome inhibitor prevents western diet-induced cardiac dysfunction in mice. J Cardiovasc Pharmacol. 2018;72:303–307.
66. Westermann D, Rutschow S, Van Linthout S, et al. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia. 2006;49:2507–2513.
67. Zhao L, Cheng G, Jin R, et al. Deletion of interleukin-6 attenuates pressure overload-induced left ventricular hypertrophy and dysfunction. Circ Res. 2016;118:1918–1929.
68. Kumar S, Wang G, Zheng N, et al. HIMF (hypoxia-induced mitogenic factor)-IL (interleukin)-6 signaling mediates cardiomyocyte-fibroblast crosstalk to promote cardiac hypertrophy and fibrosis. Hypertension. 2019;73:1058–1070.
69. Cui J, Zhang F, Wang Y, et al. Macrophage migration inhibitory factor promotes cardiac stem cell proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK pathways. Int J Mol Med. 2016;37:1299–1309.
70. Xu X, Bucala R, Ren J. Macrophage migration inhibitory factor deficiency augments doxorubicin-induced cardiomyopathy. J Am Heart Assoc. 2013;2:e000439.
71. Xu X, Hua Y, Nair S, et al. Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through mitigating autophagy. Hypertension. 2014;63:490–499.
72. Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation. 2002;106:130–135.
73. Jia N, Dong P, Ye Y, et al. Allopurinol attenuates oxidative stress and cardiac fibrosis in angiotensin II-induced cardiac diastolic dysfunction. Cardiovasc Ther. 2012;30:117–123.
74. Zhang CL, Zhao Q, Liang H, et al. Cartilage intermediate layer protein-1 alleviates pressure overload-induced cardiac fibrosis via interfering TGF-beta1 signaling. J Mol Cell Cardiol. 2018;116:135–144.
75. Hong SK, Choo EH, Ihm SH, et al. Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-betal and Smad2/3 pathways in high-fat diet-induced obesity rat model. Metabolism. 2017;76:42–55.
76. Verma SK, Krishnamurthy P, Barefield D, et al. Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB. Circulation. 2012;126:418–429.
77. Yu Q, Vazquez R, Khojeini EV, et al. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am J Physiol Heart Circ Physiol. 2009;297:H76–H85.
78. Calvier L, Miana M, Reboul P, et al. Galectin-3 mediates aldosterone-induced vascular fibrosis. Arterioscler Thromb Vasc Biol. 2013;33:67–75.
79. Yu L, Ruifrok WP, Meissner M, et al. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis. Circ Heart Fail. 2013;6:107–117.
80. Martinez-Martinez E, Calvier L, Fernandez-Celis A, et al. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension. Hypertension. 2015;66:767–775.
81. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013;9:459–469.
82. Wilck N, Marko L, Balogh A, et al. Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction. JCI Insight. 2018;3:e96006
83. Tobin JV, Zimmer DP, Shea C, et al. Pharmacological characterization of IW-1973, a novel soluble guanylate cyclase stimulator with extensive tissue distribution, antihypertensive, anti-Inflammatory, and antifibrotic effects in preclinical models of disease. J Pharmacol Exp Ther. 2018;365:664–675.
84. Nagiub M, Filippone S, Durrant D, et al. Long-acting PDE5 inhibitor tadalafil prevents early doxorubicin-induced left ventricle diastolic dysfunction in juvenile mice: potential role of cytoskeletal proteins. Can J Physiol Pharmacol. 2017;95:295–304.
85. Hiemstra JA, Lee DI, Chakir K, et al. Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine. J Am Heart Assoc. 2016;5:e003277.
86. Gao SY, Yao DH, Li JF, et al. Effect of sacubitril/valsartan on cardiac function in heart failure rabbits with preserved ejection fraction [in Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi. 2019;47:887–893.
87. Van Tassell BW, Arena R, Biondi-Zoccai G, et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am J Cardiol. 2014;113:321–327.
88. Van Tassell BW, Trankle CR, Canada JM, et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2018;11:e005036.
89. Van Tassell BW, Buckley LF, Carbone S, et al. Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the diastolic heart failure anakinra response trial 2 (D-HART2). Clin Cardiol. 2017;40:626–632.
90. Trankle CR, Canada JM, Cei L, et al. Usefulness of canakinumab to improve exercise capacity in patients with long-term systolic heart failure and elevated C-reactive protein. Am J Cardiol. 2018;122:1366–1370.
91. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation. 2003;107:3133–3140.
92. Coletta AP, Clark AL, Banarjee P, et al. Clinical trials update: renewal (renaissance and recover) and attach. Eur J Heart Fail. 2002;4:559–561.
93. Kotyla PJ, Owczarek A, Rakoczy J, et al. Infliximab treatment increases left ventricular ejection fraction in patients with rheumatoid arthritis: assessment of heart function by echocardiography, endothelin 1, interleukin 6, and NT-pro brain natriuretic peptide. J Rheumatol. 2012;39:701–706.
94. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med. 2015;373:2314–2324.
95. Pieske B, Maggioni AP, Lam CSP, et al. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the soluble guanylate cyclase stimulator in heart failure patients with preserved ef (socrates-preserved) study. Eur Heart J. 2017;38:1119–1127.
96. Solomon SD, Mcmurray JJV, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609–1620.
97. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268–1277.
98. Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164–174.
99. Hoendermis ES, Liu LC, Hummel YM, et al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J. 2015;36:2565–2573.
100. Liu LC, Hummel YM, Van Der Meer P, et al. Effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing and health-related quality of life measures in heart failure patients with preserved ejection fraction and pulmonary hypertension. Eur J Heart Fail. 2017;19:116–125.
101. Hage C, Michaëlsson E, Linde C, et al. Inflammatory biomarkers predict heart failure severity and prognosis in patients with heart failure with preserved ejection fraction. Circ Cardiovasc Genet. 2017;10:e001633.
102. Krüger M, Kötter S, Grützner A, et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2009;104:87–94.
103. Lim SL, Lam CSP, Segers VFM, et al. Cardiac endothelium–myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J. 2015;36:2050–2060.
104. Shah SJ, Katz DH, Deo RC. Phenotypic spectrum of heart failure with preserved ejection fraction. Heart Fail Clin. 2014;10:407–418.
105. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131:269–279.
106. Shah SJ, Borlaug BA, Kitzman DW, et al. Research priorities for heart failure with preserved ejection fraction: national heart, lung, and blood institute working group summary. Circulation. 2020;141:1001–1026.
107. Dubrock HM, Abouezzeddine OF, Redfield MM. High-sensitivity C-reactive protein in heart failure with preserved ejection fraction. PLoS One. 2018;13:e0201836.
108. Van Linthout S, Tschöpe C. Inflammation-cause or consequence of heart failure or both?. Curr Heart Fail Rep. 2017;14:251–265.

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

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