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Heart Inflammation

Immune Cell Roles and Roads to the Heart
Open ArchivePublished:May 17, 2019DOI:https://doi.org/10.1016/j.ajpath.2019.04.009
      Heart failure (HF) has been traditionally viewed as a disease of the cardiac muscle associated with systemic inflammation. Burgeoning evidence implicates immune effector mechanisms that include immune cell activation and trafficking to the heart. Immune cell infiltration in the myocardium can have adverse effects in the heart and contribute to the pathogenesis of HF. Both innate and adaptive immunity operate sequentially, and the specificity of these responses depends on the initial trigger sensed by the heart. Although the role of the immune system in the initial inflammatory response to infection and injury is well studied, what sets the trajectory to HF from different etiologies and the role of immunity once HF has been established is less understood. Herein, we review experimental and clinical knowledge of cardiac inflammation induced by different triggers that often result in HF from different etiologies. We focus on the mechanisms of immune cell activation systemically and on the pathways immune cells use to traffic to the heart.
      Heart failure (HF) is the clinical manifestation of numerous forms of cardiovascular disease that impact the ability of the heart to efficiently pump blood to organs and tissues. It is also the predominant cause of mortality in the United States, affecting 6.5 million of Americans. Prognosis after the first hospital admission is poor, with >50% mortality rate within 5 years.
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      For decades, research using experimental models of HF and data from clinical studies supported the concept that HF was a disease of the cardiac muscle, dominated mainly by aberrant activation of the neurohormonal and sympathetic systems. Early clinical observations that date back to the 1950s initially reported an association of C-reactive protein with different etiologies of HF that suggested an inflammatory component to be considered in the complexity of HF.
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      This review adds to the complexity of HF with a new view involving immune cells and pathways as orchestrators of local inflammation in the heart that may contribute to the initiation, maintenance, and progression of HF.
      Proinflammatory cytokines, bacterial endotoxins, and oxidized low-density lipoprotein, reported circulating in HF patients, induce the expression of vascular endothelial cell adhesion molecules and chemoattractants that contribute to leukocyte recruitment. Leukocytes roll on the activated endothelium by leukocyte selectin ligand–endothelial selectin and leukocyte α4β1 integrin-endothelial vascular cell adhesion molecule 1–mediated interactions. This step is followed by leukocyte integrin-endothelial intercellular adhesion molecule 1 (ICAM-1) adhesion and locomotion on the endothelial-cell vessel wall. These interactions precede leukocyte firm arrest near endothelial cell-cell junctions and transendothelial migration and extravasation into tissues,
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      a process in which ICAM-1 and several endothelial cell molecules participate.
      Different types of leukocytes, which include neutrophils, monocytes, and lymphocytes, have all been reported in the inflamed heart. Although special and temporal differences exist, depending on the initial stimuli triggering heart inflammation, neutrophils are generally the first ones being recruited. Monocytes, classified as proinflammatory or anti-inflammatory on the basis of Ly6C high or low expression, respectively, and T cells follow neutrophils.
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      T-cell progenitors arise from the bone marrow and populate the thymus, where self-reactive T cells are eliminated and non–self-reactive T cells mature and migrate to secondary lymphoid organs (spleen and lymph nodes) and respond to antigens presented by antigen-presenting cells (APCs) to mount an immune response. Effector CD8+ cytotoxic T cells and subsets of CD4+ T cells, which include T-helper (Th) cells and T-regulatory (Treg) cells, cooperate with innate cells during the immune response. Treg and Th cells are characterized by the expression of signature transcription factors, the production of different cytokines, and distinct effector functions. Th type 1 (Th1) cells produce interferon (IFN)-γ and activate macrophages and other cells, whereas Th type 17 (Th17) cells produce IL-17, IL-21, and IL-22 and promote neutrophil functions, and Th type 2 (Th2) cells produce IL-4, IL-5, and IL-13 and promote antibody production in B cells.
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      We are beginning to understand the specific mechanisms involved in the recruitment of different leukocytes to the heart and whether common or distinct pathways exist for specific leukocytes that contribute to the different etiologies of HF.
      Herein, we review the current knowledge from experimental models and humans with HF in the complexity of heart inflammation and the leukocyte recruitment mechanisms that may initiate, sustain, or perpetuate HF from different etiologies. We highlight similarities and differences in the activation of immune cells that participate in heart inflammation, which need to be taken into consideration for immunomodulation in HF.

      Heart Inflammation in the Different Etiologies of HF

      The immune system is the main driver of the protective inflammatory response necessary for host defense from infections, wound healing and tissue repair, and maintaining immune tolerance to self-antigens, all functions indispensable for survival. However, continuous active immune responses typically result in chronic inflammation, characterized as inflammation extending over time, with tissue destruction and repair occurring simultaneously. In contrast to mucosal and connective tissues, such as the lung, the gastrointestinal tract, or the skin, which are in constant contact with the environment, the heart is not exposed to the outside world. The heart stromal cells also differ from those in other organs in their limited ability for self-renewal. Thus, a small degree of inflammation induced by sterile or infectious insults has fatal consequences in resident cells, which often lead to fatal arrythmias, sudden death, or HF.
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      Fortunately, there are mechanisms in place to protect the heart from this and sustain life. The current understanding of the complex immune response in the different etiologies of HF is reviewed in this section (Figure 1). Table 1 summarizes the immune cells that are recruited during heart inflammation and the main molecules involved in the process.
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      • Blanton R.M.
      • Alcaide P.
      Intercellular adhesion molecule 1 regulates left ventricular leukocyte infiltration, cardiac remodeling, and function in pressure overload-induced heart failure.
      • Meier L.A.
      • Binstadt B.A.
      The contribution of autoantibodies to inflammatory cardiovascular pathology.
      • Baldeviano G.C.
      • Barin J.G.
      • Talor M.V.
      • Srinivasan S.
      • Bedja D.
      • Zheng D.
      • Gabrielson K.
      • Iwakura Y.
      • Rose N.R.
      • Cihakova D.
      Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy.
      • Valaperti A.
      • Marty R.R.
      • Kania G.
      • Germano D.
      • Mauermann N.
      • Dirnhofer S.
      • Leimenstoll B.
      • Blyszczuk P.
      • Dong C.
      • Mueller C.
      • Hunziker L.
      • Eriksson U.
      CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmune myocarditis.
      • Tarrio M.L.
      • Grabie N.
      • Bu D.X.
      • Sharpe A.H.
      • Lichtman A.H.
      PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis.
      • Klee N.S.
      • McCarthy C.G.
      • Martinez-Quinones P.
      • Webb R.C.
      Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy.
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • Ravussin E.
      • Stephens J.M.
      • Dixit V.D.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      • Abdullah C.S.
      • Li Z.
      • Wang X.
      • Jin Z.Q.
      Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy.
      • Siegismund C.S.
      • Escher F.
      • Lassner D.
      • Kuhl U.
      • Gross U.
      • Fruhwald F.
      • Wenzel P.
      • Munzel T.
      • Frey N.
      • Linke R.P.
      • Schultheiss H.P.
      Intramyocardial inflammation predicts adverse outcome in patients with cardiac AL amyloidosis.
      • Smorodinova N.
      • Blaha M.
      • Melenovsky V.
      • Rozsivalova K.
      • Pridal J.
      • Durisova M.
      • Pirk J.
      • Kautzner J.
      • Kucera T.
      Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.
      • Chen M.C.
      • Chang J.P.
      • Liu W.H.
      • Yang C.H.
      • Chen Y.L.
      • Tsai T.H.
      • Wang Y.H.
      • Pan K.L.
      Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation.
      • Wu N.
      • Xu B.
      • Liu Y.
      • Chen X.
      • Tang H.
      • Wu L.
      • Xiang Y.
      • Zhang M.
      • Shu M.
      • Song Z.
      • Li Y.
      • Zhong L.
      Elevated plasma levels of Th17-related cytokines are associated with increased risk of atrial fibrillation.
      • Sulzgruber P.
      • Koller L.
      • Winter M.P.
      • Richter B.
      • Blum S.
      • Korpak M.
      • Hulsmann M.
      • Goliasch G.
      • Wojta J.
      • Niessner A.
      The impact of CD4(+)CD28(null) T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure.
      • Yamashita T.
      • Sekiguchi A.
      • Iwasaki Y.K.
      • Date T.
      • Sagara K.
      • Tanabe H.
      • Suma H.
      • Sawada H.
      • Aizawa T.
      Recruitment of immune cells across atrial endocardium in human atrial fibrillation.
      Figure thumbnail gr1
      Figure 1Immune cell development and trafficking to the heart. Lymphoid progenitors traffic to the thymus, where they undergo positive and negative selection on recognition of new antigens or self-antigens, respectively. Positively selected T-cell clones migrate to the secondary lymphoid organs [lymph nodes (LNs) and spleen] and wait for antigen presentation by dendritic cells (DCs) to induce specific T-cell responses and acquisition of migratory phenotypes that will guide them to the heart. Myeloid progenitors traffic to secondary lymphoid organs. Heart inflammation results in endothelial adhesion molecules in the intramyocardial vessels that mediate T-cell and myeloid extravasation. Data from ischemic (solid lines) and nonischemic (dotted lines) models of experimental heart failure (HF) suggest that neutrophils (1) and monocytes (2) will be recruited from the bone marrow and the spleen by the CCR2/chemokine (C-C motif) ligand (CCL) 2–CCL5 pathway and contribute to heart inflammation in response to ischemia and pressure overload T cell (3) traffic from lymph nodes and use CXC chemokine receptor 3 (CXCR3) and the lymphocyte function–associated antigen 1 (LFA-1)/intercellular adhesion molecule 1 (ICAM-1) to infiltrate the heart in nonischemic HF. T-cell expansion occurs in the spleen and LNs in response to ischemia, and LFA-1 and very late antigen 4 (VLA-4) mediate heart infiltration. CXCL, C-X-C motif ligand; IFN, interferon; MHC, major histocompatibility complex; PD-1, programmed cell death-1; PDL-1, PD-1 ligand; TCR, T-cell receptor; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1.
      Table 1Cell Recruitment during Heart Inflammation and the Main Molecules Involved in the Process
      EtiologyImmune cellsAdhesion moleculesCytokines/chemokinesChemokine receptorsReferences
      Infection
       Bacteria/LPSTh1 and Th17 cellsNAIFN-γ, IL-17A, CXCL10, and CCL5CXCR3 and CCR5
      • Sikder S.
      • Williams N.L.
      • Sorenson A.E.
      • Alim M.A.
      • Vidgen M.E.
      • Moreland N.J.
      • Rush C.M.
      • Simpson R.S.
      • Govan B.L.
      • Norton R.E.
      • Cunningham M.W.
      • McMillan D.J.
      • Sriprakash K.S.
      • Ketheesan N.
      • Group G.
      Streptococcus induces an autoimmune carditis mediated by interleukin 17A and interferon gamma in the Lewis rat model of rheumatic heart disease.
      ,
      • Wolf D.
      • Li J.
      • Ley K.
      HGF guides T cells into the heart.
       VirusLy6Chi monocytes, Treg cells, Th1 cells, and CD8+ T cellsVCAM-1 and ICAM-1/LFA-1CCL2, CCL7, CCL20, IFN-γ, TGF-β, and CXCL10CCR2
      • Shim S.H.
      • Kim D.S.
      • Cho W.
      • Nam J.H.
      Coxsackievirus B3 regulates T-cell infiltration into the heart by lymphocyte function-associated antigen-1 activation via the cAMP/Rap1 axis.
      ,
      • Leuschner F.
      • Courties G.
      • Dutta P.
      • Mortensen L.J.
      • Gorbatov R.
      • Sena B.
      • Novobrantseva T.I.
      • Borodovsky A.
      • Fitzgerald K.
      • Koteliansky V.
      • Iwamoto Y.
      • Bohlender M.
      • Meyer S.
      • Lasitschka F.
      • Meder B.
      • Katus H.A.
      • Lin C.
      • Libby P.
      • Swirski F.K.
      • Anderson D.G.
      • Weissleder R.
      • Nahrendorf M.
      Silencing of CCR2 in myocarditis.
      ,
      • Marchant D.J.
      • McManus B.M.
      Regulating viral myocarditis: allografted regulatory T cells decrease immune infiltration and viral load.
      ,
      • Shi Y.
      • Fukuoka M.
      • Li G.
      • Liu Y.
      • Chen M.
      • Konviser M.
      • Chen X.
      • Opavsky M.A.
      • Liu P.P.
      Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway.
       Protozoan (Chagas)Macrophages, Th1 cells, and CD8+ T cellsICAM-1/LFA-1, VCAM-1, and E-selectinCCL2, CXCL10, G-CSF, TNF-α, and IFN-γCCR5 and CXCR3
      • Talvani A.
      • Rocha M.O.
      • Barcelos L.S.
      • Gomes Y.M.
      • Ribeiro A.L.
      • Teixeira M.M.
      Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic cardiomyopathy.
      ,
      • Gomes J.A.
      • Bahia-Oliveira L.M.
      • Rocha M.O.
      • Martins-Filho O.A.
      • Gazzinelli G.
      • Correa-Oliveira R.
      Evidence that development of severe cardiomyopathy in human Chagas' disease is due to a Th1-specific immune response.
      ,
      • Silverio J.C.
      • Pereira I.R.
      • Cipitelli Mda C.
      • Vinagre N.F.
      • Rodrigues M.M.
      • Gazzinelli R.T.
      • Lannes-Vieira J.
      CD8+ T-cells expressing interferon gamma or perforin play antagonistic roles in heart injury in experimental Trypanosoma cruzi-elicited cardiomyopathy.
      ,
      • Alcaide P.
      • Fresno M.
      The Trypanosoma cruzi membrane mucin AgC10 inhibits T cell activation and IL-2 transcription through L-selectin.
      ,
      • Michailowsky V.
      • Celes M.R.
      • Marino A.P.
      • Silva A.A.
      • Vieira L.Q.
      • Rossi M.A.
      • Gazzinelli R.T.
      • Lannes-Vieira J.
      • Silva J.S.
      Intercellular adhesion molecule 1 deficiency leads to impaired recruitment of T lymphocytes and enhanced host susceptibility to infection with Trypanosoma cruzi.
      Myocardial infarction
       Inflammatory phaseNeutrophils and Ly6ChiCCR2hiCX3CR1lo monocytesVCAM-1CXCL1, CXCL2, CXCL8, IL-6, IL-18, CCL2, TNF-α, and TGF-βCCR2
      • King K.R.
      • Aguirre A.D.
      • Ye Y.X.
      • Sun Y.
      • Roh J.D.
      • Ng Jr., R.P.
      • Kohler R.H.
      • Arlauckas S.P.
      • Iwamoto Y.
      • Savol A.
      • Sadreyev R.I.
      • Kelly M.
      • Fitzgibbons T.P.
      • Fitzgerald K.A.
      • Mitchison T.
      • Libby P.
      • Nahrendorf M.
      • Weissleder R.
      IRF3 and type I interferons fuel a fatal response to myocardial infarction.
      ,
      • Cao D.J.
      • Schiattarella G.G.
      • Villalobos E.
      • Jiang N.
      • May H.I.
      • Li T.
      • Chen Z.J.
      • Gillette T.G.
      • Hill J.A.
      Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury.
      ,
      • Nahrendorf M.
      • Swirski F.K.
      • Aikawa E.
      • Stangenberg L.
      • Wurdinger T.
      • Figueiredo J.L.
      • Libby P.
      • Weissleder R.
      • Pittet M.J.
      The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
      ,
      • Majmudar M.D.
      • Keliher E.J.
      • Heidt T.
      • Leuschner F.
      • Truelove J.
      • Sena B.F.
      • Gorbatov R.
      • Iwamoto Y.
      • Dutta P.
      • Wojtkiewicz G.
      • Courties G.
      • Sebas M.
      • Borodovsky A.
      • Fitzgerald K.
      • Nolte M.W.
      • Dickneite G.
      • Chen J.W.
      • Anderson D.G.
      • Swirski F.K.
      • Weissleder R.
      • Nahrendorf M.
      Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice.
      ,
      • Kaikita K.
      • Hayasaki T.
      • Okuma T.
      • Kuziel W.A.
      • Ogawa H.
      • Takeya M.
      Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction.
       Resolution phase (wound healing)Ly6CloCX3CR1hi monocytes, Ly6Chi monocytes, DC CD4+ T cells, and Treg cellsNACXCL2, CXCL9, CXCL10, CCL5, and IL-1βCXCR3 and CCR5
      • Nahrendorf M.
      • Swirski F.K.
      • Aikawa E.
      • Stangenberg L.
      • Wurdinger T.
      • Figueiredo J.L.
      • Libby P.
      • Weissleder R.
      • Pittet M.J.
      The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
      ,
      • Hofmann U.
      • Beyersdorf N.
      • Weirather J.
      • Podolskaya A.
      • Bauersachs J.
      • Ertl G.
      • Kerkau T.
      • Frantz S.
      Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice.
      ,
      • Saxena A.
      • Bujak M.
      • Frunza O.
      • Dobaczewski M.
      • Gonzalez-Quesada C.
      • Lu B.
      • Gerard C.
      • Frangogiannis N.G.
      CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans.
      ,
      • Weirather J.
      • Hofmann U.D.
      • Beyersdorf N.
      • Ramos G.C.
      • Vogel B.
      • Frey A.
      • Ertl G.
      • Kerkau T.
      • Frantz S.
      Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.
      ,
      • Anzai A.
      • Anzai T.
      • Nagai S.
      • Maekawa Y.
      • Naito K.
      • Kaneko H.
      • Sugano Y.
      • Takahashi T.
      • Abe H.
      • Mochizuki S.
      • Sano M.
      • Yoshikawa T.
      • Okada Y.
      • Koyasu S.
      • Ogawa S.
      • Fukuda K.
      Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling.
      ,
      • Choo E.H.
      • Lee J.H.
      • Park E.H.
      • Park H.E.
      • Jung N.C.
      • Kim T.H.
      • Koh Y.S.
      • Kim E.
      • Seung K.B.
      • Park C.
      • Hong K.S.
      • Kang K.
      • Song J.Y.
      • Seo H.G.
      • Lim D.S.
      • Chang K.
      Infarcted myocardium-primed dendritic cells improve remodeling and cardiac function after myocardial infarction by modulating the regulatory T cell and macrophage polarization.
      ,
      • Van der Borght K.
      • Scott C.L.
      • Nindl V.
      • Bouche A.
      • Martens L.
      • Sichien D.
      • Van Moorleghem J.
      • Vanheerswynghels M.
      • De Prijck S.
      • Saeys Y.
      • Ludewig B.
      • Gillebert T.
      • Guilliams M.
      • Carmeliet P.
      • Lambrecht B.N.
      Myocardial infarction primes autoreactive T cells through activation of dendritic cells.
      ,
      • Dobaczewski M.
      • Xia Y.
      • Bujak M.
      • Gonzalez-Quesada C.
      • Frangogiannis N.G.
      CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells.
      ,
      • Bujak M.
      • Dobaczewski M.
      • Gonzalez-Quesada C.
      • Xia Y.
      • Leucker T.
      • Zymek P.
      • Veeranna V.
      • Tager A.M.
      • Luster A.D.
      • Frangogiannis N.G.
      Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.
      ,
      • Ridker P.M.
      • Everett B.M.
      • Thuren T.
      • MacFadyen J.G.
      • Chang W.H.
      • Ballantyne C.
      • Fonseca F.
      • Nicolau J.
      • Koenig W.
      • Anker S.D.
      • Kastelein J.J.P.
      • Cornel J.H.
      • Pais P.
      • Pella D.
      • Genest J.
      • Cifkova R.
      • Lorenzatti A.
      • Forster T.
      • Kobalava Z.
      • Vida-Simiti L.
      • Flather M.
      • Shimokawa H.
      • Ogawa H.
      • Dellborg M.
      • Rossi P.R.F.
      • Troquay R.P.T.
      • Libby P.
      • Glynn R.J.
      • Group C.T.
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
       Maturation phase and ischemic HFCD11b+ macrophages, Treg cells, and Th2 and Th17 cellsNAIFN-γ, IL-6, IL-4, IL-13, TGF-β, and CCL2
      • Ismahil M.A.
      • Hamid T.
      • Bansal S.S.
      • Patel B.
      • Kingery J.R.
      • Prabhu S.D.
      Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis.
      ,
      • Bansal S.S.
      • Ismahil M.A.
      • Goel M.
      • Patel B.
      • Hamid T.
      • Rokosh G.
      • Prabhu S.D.
      Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure.
      ,
      • Bansal S.S.
      • Ismahil M.A.
      • Goel M.
      • Zhou G.
      • Rokosh G.
      • Hamid T.
      • Prabhu S.D.
      Dysfunctional and proinflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy.
      Nonischemic HF
       HypertensionCCR2+ monocytes and CD4+ and CD8+ T cellsVCAM-1 and ICAM-1CCL2, CXCL1, IFN-γ, IL-17A, CCL2, TGF-β, and IL-6CXCR2 and CCR2
      • Coles B.
      • Fielding C.A.
      • Rose-John S.
      • Scheller J.
      • Jones S.A.
      • O'Donnell V.B.
      Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo.
      ,
      • Olsen F.
      Transfer of arterial hypertension by splenic cells from DOCA-salt hypertensive and renal hypertensive rats to normotensive recipients.
      ,
      • Guzik T.J.
      • Hoch N.E.
      • Brown K.A.
      • McCann L.A.
      • Rahman A.
      • Dikalov S.
      • Goronzy J.
      • Weyand C.
      • Harrison D.G.
      Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction.
      ,
      • Mian M.O.
      • Barhoumi T.
      • Briet M.
      • Paradis P.
      • Schiffrin E.L.
      Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses.
      ,
      • Nguyen H.
      • Chiasson V.L.
      • Chatterjee P.
      • Kopriva S.E.
      • Young K.J.
      • Mitchell B.M.
      Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension.
      ,
      • Haudek S.B.
      • Cheng J.
      • Du J.
      • Wang Y.
      • Hermosillo-Rodriguez J.
      • Trial J.
      • Taffet G.E.
      • Entman M.L.
      Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy.
      ,
      • Wang L.
      • Zhang Y.L.
      • Lin Q.Y.
      • Liu Y.
      • Guan X.M.
      • Ma X.L.
      • Cao H.J.
      • Liu Y.
      • Bai J.
      • Xia Y.L.
      • Du J.
      • Li H.H.
      CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.
      ,
      • Willeford A.
      • Suetomi T.
      • Nickle A.
      • Hoffman H.M.
      • Miyamoto S.
      • Heller Brown J.
      CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis.
      ,
      • Han Y.L.
      • Li Y.L.
      • Jia L.X.
      • Cheng J.Z.
      • Qi Y.F.
      • Zhang H.J.
      • Du J.
      Reciprocal interaction between macrophages and T cells stimulates IFN-gamma and MCP-1 production in Ang II-induced cardiac inflammation and fibrosis.
       Pressure overloadCCR2+ monocytes, Ly6Chi monocytes, Th1 cells, and DCsLFA-1 and ICAM-1CXCL9, CXCL10, IFN-γ, IL-10, TGF-β, and IL-6CXCR3 and CCR2
      • Zhao L.
      • Cheng G.
      • Jin R.
      • Afzal M.R.
      • Samanta A.
      • Xuan Y.T.
      • Girgis M.
      • Elias H.K.
      • Zhu Y.
      • Davani A.
      • Yang Y.
      • Chen X.
      • Ye S.
      • Wang O.L.
      • Chen L.
      • Hauptman J.
      • Vincent R.J.
      • Dawn B.
      Deletion of interleukin-6 attenuates pressure overload-induced left ventricular hypertrophy and dysfunction.
      ,
      • Suetomi T.
      • Willeford A.
      • Brand C.S.
      • Cho Y.
      • Ross R.S.
      • Miyamoto S.
      • Brown J.H.
      Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca(2+)/calmodulin-dependent protein kinase ii delta signaling in cardiomyocytes are essential for adverse cardiac remodeling.
      ,
      • Patel B.
      • Ismahil M.A.
      • Hamid T.
      • Bansal S.S.
      • Prabhu S.D.
      Mononuclear phagocytes are dispensable for cardiac remodeling in established pressure-overload heart failure.
      ,
      • Patel B.
      • Bansal S.S.
      • Ismahil M.A.
      • Hamid T.
      • Rokosh G.
      • Mack M.
      • Prabhu S.D.
      CCR2(+) monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload.
      ,
      • Laroumanie F.
      • Douin-Echinard V.
      • Pozzo J.
      • Lairez O.
      • Tortosa F.
      • Vinel C.
      • Delage C.
      • Calise D.
      • Dutaur M.
      • Parini A.
      • Pizzinat N.
      CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload.
      ,
      • Nevers T.
      • Salvador A.M.
      • Grodecki-Pena A.
      • Knapp A.
      • Velazquez F.
      • Aronovitz M.
      • Kapur N.K.
      • Karas R.H.
      • Blanton R.M.
      • Alcaide P.
      Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure.
      ,
      • Nevers T.
      • Salvador A.M.
      • Velazquez F.
      • Ngwenyama N.
      • Carrillo-Salinas F.J.
      • Aronovitz M.
      • Blanton R.M.
      • Alcaide P.
      Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure.
      ,
      • Wang H.
      • Kwak D.
      • Fassett J.
      • Liu X.
      • Yao W.
      • Weng X.
      • Xu X.
      • Xu Y.
      • Bache R.J.
      • Mueller D.L.
      • Chen Y.
      Role of bone marrow-derived CD11c(+) dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy.
      ,
      • Kallikourdis M.
      • Martini E.
      • Carullo P.
      • Sardi C.
      • Roselli G.
      • Greco C.M.
      • Vignali D.
      • Riva F.
      • Ormbostad Berre A.M.
      • Stolen T.O.
      • Fumero A.
      • Faggian G.
      • Di Pasquale E.
      • Elia L.
      • Rumio C.
      • Catalucci D.
      • Papait R.
      • Condorelli G.
      T cell costimulation blockade blunts pressure overload-induced heart failure.
      ,
      • Groschel C.
      • Sasse A.
      • Rohrborn C.
      • Monecke S.
      • Didie M.
      • Elsner L.
      • Kruse V.
      • Bunt G.
      • Lichtman A.H.
      • Toischer K.
      • Zimmermann W.H.
      • Hasenfuss G.
      • Dressel R.
      T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure.
      ,
      • Verma S.K.
      • Garikipati V.N.S.
      • Krishnamurthy P.
      • Schumacher S.M.
      • Grisanti L.A.
      • Cimini M.
      • Cheng Z.
      • Khan M.
      • Yue Y.
      • Benedict C.
      • Truongcao M.M.
      • Rabinowitz J.E.
      • Goukassian D.A.
      • Tilley D.
      • Koch W.J.
      • Kishore R.
      Interleukin-10 inhibits bone marrow fibroblast progenitor cell-mediated cardiac fibrosis in pressure-overloaded myocardium.
      ,
      • Altara R.
      • Manca M.
      • Hessel M.H.
      • Gu Y.
      • van Vark L.C.
      • Akkerhuis K.M.
      • Staessen J.A.
      • Struijker-Boudier H.A.
      • Booz G.W.
      • Blankesteijn W.M.
      CXCL10 is a circulating inflammatory marker in patients with advanced heart failure: a pilot study.
      ,
      • Ngwenyama N.
      • Salvador A.M.
      • Velazquez F.
      • Nevers T.
      • Levy A.
      • Aronovitz M.J.
      • Luster A.D.
      • Huggins G.S.
      • Alcaide P.
      CXCR3 regulates CD4+ T cell cardiotropism in pressure overload induced cardiac dysfunction.
      ,
      • Salvador A.M.
      • Nevers T.
      • Velazquez F.
      • Aronovitz M.
      • Wang B.
      • Abadia Molina A.
      • Jaffe I.Z.
      • Karas R.H.
      • Blanton R.M.
      • Alcaide P.
      Intercellular adhesion molecule 1 regulates left ventricular leukocyte infiltration, cardiac remodeling, and function in pressure overload-induced heart failure.
       AutoimmunityNeutrophils, CD11b+ macrophages, and Th1 and Th17 cellsNAIL-17A, IFN-γ, and CCL2CCR2
      • Leuschner F.
      • Courties G.
      • Dutta P.
      • Mortensen L.J.
      • Gorbatov R.
      • Sena B.
      • Novobrantseva T.I.
      • Borodovsky A.
      • Fitzgerald K.
      • Koteliansky V.
      • Iwamoto Y.
      • Bohlender M.
      • Meyer S.
      • Lasitschka F.
      • Meder B.
      • Katus H.A.
      • Lin C.
      • Libby P.
      • Swirski F.K.
      • Anderson D.G.
      • Weissleder R.
      • Nahrendorf M.
      Silencing of CCR2 in myocarditis.
      ,
      • Van der Borght K.
      • Scott C.L.
      • Nindl V.
      • Bouche A.
      • Martens L.
      • Sichien D.
      • Van Moorleghem J.
      • Vanheerswynghels M.
      • De Prijck S.
      • Saeys Y.
      • Ludewig B.
      • Gillebert T.
      • Guilliams M.
      • Carmeliet P.
      • Lambrecht B.N.
      Myocardial infarction primes autoreactive T cells through activation of dendritic cells.
      ,
      • Meier L.A.
      • Binstadt B.A.
      The contribution of autoantibodies to inflammatory cardiovascular pathology.
      ,
      • Baldeviano G.C.
      • Barin J.G.
      • Talor M.V.
      • Srinivasan S.
      • Bedja D.
      • Zheng D.
      • Gabrielson K.
      • Iwakura Y.
      • Rose N.R.
      • Cihakova D.
      Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy.
      ,
      • Valaperti A.
      • Marty R.R.
      • Kania G.
      • Germano D.
      • Mauermann N.
      • Dirnhofer S.
      • Leimenstoll B.
      • Blyszczuk P.
      • Dong C.
      • Mueller C.
      • Hunziker L.
      • Eriksson U.
      CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmune myocarditis.
      ,
      • Tarrio M.L.
      • Grabie N.
      • Bu D.X.
      • Sharpe A.H.
      • Lichtman A.H.
      PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis.
      Other etiologies
       Toxicity of chemotherapyT cellsNA
      • Klee N.S.
      • McCarthy C.G.
      • Martinez-Quinones P.
      • Webb R.C.
      Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy.
       Diabetic cardiomyopathyB cells and CD3+ T cellsNAIL-1β and TGF-β1
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • Ravussin E.
      • Stephens J.M.
      • Dixit V.D.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      ,
      • Abdullah C.S.
      • Li Z.
      • Wang X.
      • Jin Z.Q.
      Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy.
       Cardiac amyloid depositionCD3+ T cellsLFA-1
      • Siegismund C.S.
      • Escher F.
      • Lassner D.
      • Kuhl U.
      • Gross U.
      • Fruhwald F.
      • Wenzel P.
      • Munzel T.
      • Frey N.
      • Linke R.P.
      • Schultheiss H.P.
      Intramyocardial inflammation predicts adverse outcome in patients with cardiac AL amyloidosis.
       Atrial fibrillationCD4+ T cellsICAM-1 and VCAM-1IL-17A, IFN-γ, IL-6, and CCL2
      • Smorodinova N.
      • Blaha M.
      • Melenovsky V.
      • Rozsivalova K.
      • Pridal J.
      • Durisova M.
      • Pirk J.
      • Kautzner J.
      • Kucera T.
      Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.
      ,
      • Chen M.C.
      • Chang J.P.
      • Liu W.H.
      • Yang C.H.
      • Chen Y.L.
      • Tsai T.H.
      • Wang Y.H.
      • Pan K.L.
      Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation.
      ,
      • Wu N.
      • Xu B.
      • Liu Y.
      • Chen X.
      • Tang H.
      • Wu L.
      • Xiang Y.
      • Zhang M.
      • Shu M.
      • Song Z.
      • Li Y.
      • Zhong L.
      Elevated plasma levels of Th17-related cytokines are associated with increased risk of atrial fibrillation.
      ,
      • Sulzgruber P.
      • Koller L.
      • Winter M.P.
      • Richter B.
      • Blum S.
      • Korpak M.
      • Hulsmann M.
      • Goliasch G.
      • Wojta J.
      • Niessner A.
      The impact of CD4(+)CD28(null) T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure.
      ,
      • Yamashita T.
      • Sekiguchi A.
      • Iwasaki Y.K.
      • Date T.
      • Sagara K.
      • Tanabe H.
      • Suma H.
      • Sawada H.
      • Aizawa T.
      Recruitment of immune cells across atrial endocardium in human atrial fibrillation.
      CCL, chemokine (C-C motif) ligand; CXCR, CXC chemokine receptor; DC, dendritic cell; G-CSF, granulocyte colony-stimulating factor; HF, heart failure; ICAM-1, intercellular adhesion molecule 1; IFN-γ, interferon-γ; LFA, lymphocyte function-associated antigen; LPS, lipopolysaccharide; NA, not available; TGF-β, transforming growth factor-β; Th1, T-helper type 1; Th17, T-helper type 17; TNF-α, tumor necrosis factor-α; Treg, T regulatory; VCAM-1, vascular cell adhesion molecule 1.

       Infection-Triggered Heart Inflammation

      Several pathogens infect a variety of cardiac cells and induce the acute immune response and inflammation necessary for pathogen killing. Infection often resolves but with off-target/damaging effects on surrounding cardiac cells. A delicate balance is required to control infection while avoiding irreparable cardiac damage.

       Bacterial Myocarditis

      In recent years, bacteria have been proposed as a cause of myocarditis, which was previously thought to be dominated by viral and parasitic infections. Autopsies and myocardial biopsies of patients treated with immunosuppressive drugs, patients who underwent cardiac open surgeries, and patients with AIDS have shown an increased incidence of bacterial myocarditis.
      • Blauwet L.A.
      • Cooper L.T.
      Myocarditis.
      • Wada H.
      • Ogita M.
      • Miyauchi K.
      • Suwa S.
      • Yamano M.
      • Daida H.
      Case report: fulminant myocarditis associated with overwhelming pneumococcal infection.
      A handful of studies using experimental animal models of streptococcal infection have demonstrated that IL-17A and IFN-γ are enhanced in the heart.
      • Sikder S.
      • Williams N.L.
      • Sorenson A.E.
      • Alim M.A.
      • Vidgen M.E.
      • Moreland N.J.
      • Rush C.M.
      • Simpson R.S.
      • Govan B.L.
      • Norton R.E.
      • Cunningham M.W.
      • McMillan D.J.
      • Sriprakash K.S.
      • Ketheesan N.
      • Group G.
      Streptococcus induces an autoimmune carditis mediated by interleukin 17A and interferon gamma in the Lewis rat model of rheumatic heart disease.
      Lipopolysaccharide, the main component of Gram-negative bacteria, was recently used in mice to identify a novel mechanism of T-cell cardiotropism, which involves cardiac release of hepatocyte growth factor, triggering T-cell recruitment to the heart through CXCL10 and chemokine (C-C motif) ligand (CCL) 5 signals.
      • Wolf D.
      • Li J.
      • Ley K.
      HGF guides T cells into the heart.
      Thus, bacteria-induced myocarditis is a combination of decreased cell viability by infection itself and by potent antibacterial Th17 and Th1 responses. How this acute response contributes to HF is not clear, but it is likely that early cytokine release and cell death lead to adverse cardiac remodeling and HF.

       Viral Infections

      Viral infection of the heart involves viral particle processing by innate immune cells that function as APCs to induce an antiviral cytotoxic CD8+ T-cell response, helped by CD4+ T cells. Several viruses infect cardiac cells, but Coxsackie virus of group B (CVB), an enterovirus with high tropism for cardiomyocytes, endothelial cells, and leukocytes in humans and mice, may be the best studied.
      • Cheung P.K.
      • Yuan J.
      • Zhang H.M.
      • Chau D.
      • Yanagawa B.
      • Suarez A.
      • McManus B.
      • Yang D.
      Specific interactions of mouse organ proteins with the 5′untranslated region of coxsackievirus B3: potential determinants of viral tissue tropism.
      Macrophage and T-cell immune responses typically clear CVB in 2 weeks, but this strong immune response results in myocarditis.
      • Fung G.
      • Luo H.
      • Qiu Y.
      • Yang D.
      • McManus B.
      Myocarditis.
      CVB infection induces the expression of heart endothelial cell ICAM-1 that the virus uses as a cellular entry point to propagate the infection. Integrin lymphocyte function–associated antigen 1 (LFA-1), the ligand of ICAM-1, is also induced in leukocytes by CVB, thus further promoting leukocyte extravasation and inflammation.
      • Shim S.H.
      • Kim D.S.
      • Cho W.
      • Nam J.H.
      Coxsackievirus B3 regulates T-cell infiltration into the heart by lymphocyte function-associated antigen-1 activation via the cAMP/Rap1 axis.
      Bone marrow–derived proinflammatory Ly6Chi macrophages expressing the chemokine receptor CCR2 respond to cardiac release of chemokines CCL2 and CCL7 and infiltrate the heart.
      • Leuschner F.
      • Courties G.
      • Dutta P.
      • Mortensen L.J.
      • Gorbatov R.
      • Sena B.
      • Novobrantseva T.I.
      • Borodovsky A.
      • Fitzgerald K.
      • Koteliansky V.
      • Iwamoto Y.
      • Bohlender M.
      • Meyer S.
      • Lasitschka F.
      • Meder B.
      • Katus H.A.
      • Lin C.
      • Libby P.
      • Swirski F.K.
      • Anderson D.G.
      • Weissleder R.
      • Nahrendorf M.
      Silencing of CCR2 in myocarditis.
      CVB induces IFN-γ– and Th1-mediated proinflammatory responses that can lead to cardiac damage, although IFN-γ was also reported to inhibit CVB replication and protect from myocarditis through CXCL10 release by cardiac myocytes.
      • Yuan J.
      • Liu Z.
      • Lim T.
      • Zhang H.
      • He J.
      • Walker E.
      • Shier C.
      • Wang Y.
      • Su Y.
      • Sall A.
      • McManus B.
      • Yang D.
      CXCL10 inhibits viral replication through recruitment of natural killer cells in coxsackievirus B3-induced myocarditis.
      In contrast, Treg cells were shown to exert protective effects through transforming growth factor-β and IL-10 release.
      • Marchant D.J.
      • McManus B.M.
      Regulating viral myocarditis: allografted regulatory T cells decrease immune infiltration and viral load.
      • Shi Y.
      • Fukuoka M.
      • Li G.
      • Liu Y.
      • Chen M.
      • Konviser M.
      • Chen X.
      • Opavsky M.A.
      • Liu P.P.
      Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway.
      Thus, the so far unmet goal for immunomodulation in viral myocarditis is to prevent proinflammatory macrophage or T-cell recruitment by decreasing endothelial cell activation and adhesion molecule expression, while maintaining proper antiviral responses. Dampening acute myocarditis is expected to limit adverse cardiac remodeling and the progression to HF, although less is known about this transition.

       Chagas Disease

      Trypanosoma cruzi, the protozoan parasite responsible for Chagas disease, infects several cell types of immune and nonimmune nature, including endothelial cells, fibroblasts, and cardiomyocytes, and is another variant for the infectious myocarditis etiology.
      • Marin-Neto J.A.
      • Cunha-Neto E.
      • Maciel B.C.
      • Simoes M.V.
      Pathogenesis of chronic Chagas heart disease.
      Chagas patients also have high systemic levels of TNF-α, CCL2, ICAM-1, vascular cell adhesion molecule 1, and E-selectin, which correlate with a worse cardiac output.
      • Talvani A.
      • Rocha M.O.
      • Barcelos L.S.
      • Gomes Y.M.
      • Ribeiro A.L.
      • Teixeira M.M.
      Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic cardiomyopathy.
      Mechanistic studies in mice demonstrate that the acute phase of T. cruzi infection is characterized by CD4+ and CD8+ T-cell activation and release of TNF-α and IFN-γ, to control T. cruzi replication.
      • Gomes J.A.
      • Bahia-Oliveira L.M.
      • Rocha M.O.
      • Martins-Filho O.A.
      • Gazzinelli G.
      • Correa-Oliveira R.
      Evidence that development of severe cardiomyopathy in human Chagas' disease is due to a Th1-specific immune response.
      • Silverio J.C.
      • Pereira I.R.
      • Cipitelli Mda C.
      • Vinagre N.F.
      • Rodrigues M.M.
      • Gazzinelli R.T.
      • Lannes-Vieira J.
      CD8+ T-cells expressing interferon gamma or perforin play antagonistic roles in heart injury in experimental Trypanosoma cruzi-elicited cardiomyopathy.
      As a well-evolved protozoan parasite, T. cruzi expresses surface proteins that suppress T-cell activation and allow parasite evasion of the immune system and survival in the infected host
      • Alcaide P.
      • Fresno M.
      The Trypanosoma cruzi membrane mucin AgC10 inhibits T cell activation and IL-2 transcription through L-selectin.
      for a period of time that can take months (in mice) and years (in patients) to develop cardiomyopathy. Interestingly, T. cruzi is rarely found in the heart once cardiomyopathy has evolved, despite a strong ICAM-1–dependent recruitment of macrophages and CD8+ T cells to the heart.
      • Michailowsky V.
      • Celes M.R.
      • Marino A.P.
      • Silva A.A.
      • Vieira L.Q.
      • Rossi M.A.
      • Gazzinelli R.T.
      • Lannes-Vieira J.
      • Silva J.S.
      Intercellular adhesion molecule 1 deficiency leads to impaired recruitment of T lymphocytes and enhanced host susceptibility to infection with Trypanosoma cruzi.
      These data suggest that intramyocardial CD8+ T cells contribute not only to parasite killing, but also to cardiomyopathy and HF.
      Taken together, the mechanistic contribution of heart-infiltrated leukocytes has been best characterized in experimental models of CVB and Chagas disease. CD8+ T cells and Th17 cells dominate the acute response required for pathogen killing, as well as the pathology associated with HF. We know less about HF resulting from bacterial infections, but what seems to be common is that a balance between host defense and off-target effects resulting from a strong immune response contributes to the degree of tissue remodeling leading to cardiac dysfunction. Immunomodulation in infection-induced HF is a major challenge to allow pathogen killing with optimal resolution that prevents cardiac damage that may lead to HF.

       Heart Inflammation in Ischemic Heart Disease

      Thrombotic occlusion of a coronary vessel as a result of atherogenesis causes immune cell recruitment to the vessel wall and myocardial infarction (MI).
      • Abdolmaleki F.
      • Gheibi Hayat S.M.
      • Bianconi V.
      • Johnston T.P.
      • Sahebkar A.
      Atherosclerosis and immunity: a perspective.
      Plaque rupture in the vicinity of the heart can result in ischemic death of cardiomyocytes, which lack the capacity to regenerate and are replaced by scar tissue. Intense sterile inflammation and immune cell infiltration in response to cardiomyocyte necrotic death are critical for cardiac repair after MI. This proinflammatory phase is aimed to clear damaged cells, takes 3 to 4 days in mice, and is followed by a reparative phase in which a different set of immune cells promote wound healing in the heart. The payback is excessive fibrosis in the maturation phase, leading to ischemic HF. An inflammatory phase that is insufficiently suppressed in the reparative phase results in sustained tissue damage, improper healing, and worse outcomes of HF.
      • Prabhu S.D.
      • Frangogiannis N.G.
      The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis.
      In clinical practice, timely coronary reperfusion limits the infarction extent; however, reperfusion itself also induces robust tissue inflammation and, thus, therapeutic manipulation is challenging.
      • Abdolmaleki F.
      • Gheibi Hayat S.M.
      • Bianconi V.
      • Johnston T.P.
      • Sahebkar A.
      Atherosclerosis and immunity: a perspective.
      This section reviews the type or immune response taking place during myocardial ischemia, repair, and ischemic HF.

       Inflammatory Phase after MI

      The mechanisms involved have been mainly characterized in mice undergoing myocardial ischemia or myocardial ischemia and reperfusion that mimic how patients are treated after MI. As myocardial cells undergo necrosis, damage-associated molecular patterns, such as high-mobility group box 1 and ATP,
      • Borg N.
      • Alter C.
      • Gorldt N.
      • Jacoby C.
      • Ding Z.
      • Steckel B.
      • Quast C.
      • Bonner F.
      • Friebe D.
      • Temme S.
      • Flogel U.
      • Schrader J.
      CD73 on T cells orchestrates cardiac wound healing after myocardial infarction by purinergic metabolic reprogramming.
      are released. These induce the release of chemokines and cytokines, such as TNF-α, IL-1β, and IL-18, by cardiac resident cells, which, in turn, activate endothelial cells. Recent studies demonstrate that heart macrophage uptake of cell debris induces a type I IFN response that initiates inflammation after MI.
      • King K.R.
      • Aguirre A.D.
      • Ye Y.X.
      • Sun Y.
      • Roh J.D.
      • Ng Jr., R.P.
      • Kohler R.H.
      • Arlauckas S.P.
      • Iwamoto Y.
      • Savol A.
      • Sadreyev R.I.
      • Kelly M.
      • Fitzgibbons T.P.
      • Fitzgerald K.A.
      • Mitchison T.
      • Libby P.
      • Nahrendorf M.
      • Weissleder R.
      IRF3 and type I interferons fuel a fatal response to myocardial infarction.
      • Cao D.J.
      • Schiattarella G.G.
      • Villalobos E.
      • Jiang N.
      • May H.I.
      • Li T.
      • Chen Z.J.
      • Gillette T.G.
      • Hill J.A.
      Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury.
      Neutrophils are the first wave of inflammatory cell recruited after ischemia (within 12 to 24 hours after MI) via the chemoattractants CXCL1, CXCL2, and CXCL8. They release matrix metalloproteases to break down the extracellular membrane and dead cells within the infarct, and they also produce IL-6, which activates endothelial cells and induces CCL2 and vascular cell adhesion molecule 1 for subsequent monocyte recruitment.
      • Prabhu S.D.
      • Frangogiannis N.G.
      The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis.
      Splenic Ly6ChiCCR2hiCX3CR1loCD62L+ monocytes, which are recruited via CCL2-CCR2 chemoattraction, scavenge debris and release inflammatory cytokines and matrix metalloproteases at the infarct site.
      • Nahrendorf M.
      • Swirski F.K.
      • Aikawa E.
      • Stangenberg L.
      • Wurdinger T.
      • Figueiredo J.L.
      • Libby P.
      • Weissleder R.
      • Pittet M.J.
      The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
      Inhibition of the CCL2-CCR2 pathways has been efficient in preventing monocyte recruitment, improving infarct healing, and attenuating left ventricular (LV) remodeling after MI.
      • Majmudar M.D.
      • Keliher E.J.
      • Heidt T.
      • Leuschner F.
      • Truelove J.
      • Sena B.F.
      • Gorbatov R.
      • Iwamoto Y.
      • Dutta P.
      • Wojtkiewicz G.
      • Courties G.
      • Sebas M.
      • Borodovsky A.
      • Fitzgerald K.
      • Nolte M.W.
      • Dickneite G.
      • Chen J.W.
      • Anderson D.G.
      • Swirski F.K.
      • Weissleder R.
      • Nahrendorf M.
      Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice.
      • Kaikita K.
      • Hayasaki T.
      • Okuma T.
      • Kuziel W.A.
      • Ogawa H.
      • Takeya M.
      Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction.

       Resolution Phase

      The process of scar formation in areas of cardiomyocyte loss is critical for maintaining the heart beating function. In mice, it starts 5 days after MI and continues to 14 days, when the scar is considered to be mature. Activated cardiac fibroblasts are essential to secrete the extracellular membrane components that offer structural support in areas of cardiomyocyte loss to prevent cardiac rupture. Ly6CloCX3CR1hi monocytes accumulate in the myocardium and end up outnumbering Ly6Chi and suppressing the initial inflammatory phase.
      • Nahrendorf M.
      • Swirski F.K.
      • Aikawa E.
      • Stangenberg L.
      • Wurdinger T.
      • Figueiredo J.L.
      • Libby P.
      • Weissleder R.
      • Pittet M.J.
      The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
      Studies using CD4+ T-cell deficient mice demonstrate that CD4+ T cells are necessary to promote wound healing.
      • Hofmann U.
      • Beyersdorf N.
      • Weirather J.
      • Podolskaya A.
      • Bauersachs J.
      • Ertl G.
      • Kerkau T.
      • Frantz S.
      Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice.
      Treg cells, specifically, were shown to modulate cardiac fibroblast phenotype and function and promote healing and tissue repair.
      • Saxena A.
      • Bujak M.
      • Frunza O.
      • Dobaczewski M.
      • Gonzalez-Quesada C.
      • Lu B.
      • Gerard C.
      • Frangogiannis N.G.
      CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans.
      • Weirather J.
      • Hofmann U.D.
      • Beyersdorf N.
      • Ramos G.C.
      • Vogel B.
      • Frey A.
      • Ertl G.
      • Kerkau T.
      • Frantz S.
      Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.
      Dendritic cells (DCs), the main APC-inducing T-cell activation, also participate in healing, potentially through T-cell–dependent mechanisms.
      • Anzai A.
      • Anzai T.
      • Nagai S.
      • Maekawa Y.
      • Naito K.
      • Kaneko H.
      • Sugano Y.
      • Takahashi T.
      • Abe H.
      • Mochizuki S.
      • Sano M.
      • Yoshikawa T.
      • Okada Y.
      • Koyasu S.
      • Ogawa S.
      • Fukuda K.
      Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling.
      • Choo E.H.
      • Lee J.H.
      • Park E.H.
      • Park H.E.
      • Jung N.C.
      • Kim T.H.
      • Koh Y.S.
      • Kim E.
      • Seung K.B.
      • Park C.
      • Hong K.S.
      • Kang K.
      • Song J.Y.
      • Seo H.G.
      • Lim D.S.
      • Chang K.
      Infarcted myocardium-primed dendritic cells improve remodeling and cardiac function after myocardial infarction by modulating the regulatory T cell and macrophage polarization.
      • Van der Borght K.
      • Scott C.L.
      • Nindl V.
      • Bouche A.
      • Martens L.
      • Sichien D.
      • Van Moorleghem J.
      • Vanheerswynghels M.
      • De Prijck S.
      • Saeys Y.
      • Ludewig B.
      • Gillebert T.
      • Guilliams M.
      • Carmeliet P.
      • Lambrecht B.N.
      Myocardial infarction primes autoreactive T cells through activation of dendritic cells.
      Several chemokines participate in leukocyte recruitment to the heart during the resolution phase after MI. Genetic deletion of CCR5, the receptor of CCL5, caused enhanced inflammation and exacerbated dilative remodeling, which was associated with decreased infiltration of Treg cells. These data support that the recruitment of anti-inflammatory lymphocyte subsets is protective in the infarcted myocardium and prevents from dilation associated with ischemic HF.
      • Dobaczewski M.
      • Xia Y.
      • Bujak M.
      • Gonzalez-Quesada C.
      • Frangogiannis N.G.
      CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells.
      Other chemokines, such as CXCL9 and CXCL10, the ligands of CXC chemokine receptor 3 (CXCR3), mainly expressed in Th1 cells, were also found up-regulated in the heart after ischemia. CXCL10 was reported to inhibit growth factor–induced fibroblast migration as a mechanism to protect from excessive fibrotic remodeling.
      • Bujak M.
      • Dobaczewski M.
      • Gonzalez-Quesada C.
      • Xia Y.
      • Leucker T.
      • Zymek P.
      • Veeranna V.
      • Tager A.M.
      • Luster A.D.
      • Frangogiannis N.G.
      Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.
      Interestingly, the antifibrotic role of CXCL10 in the infarcted heart was independent of CXCR3, supporting the complexity of the inflammatory signals converging in several reparative processes after MI.
      • Saxena A.
      • Bujak M.
      • Frunza O.
      • Dobaczewski M.
      • Gonzalez-Quesada C.
      • Lu B.
      • Gerard C.
      • Frangogiannis N.G.
      CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans.
      Human data support these mechanistic studies, including the presence of intramyocardial T cells,
      • Abbate A.
      • Bonanno E.
      • Mauriello A.
      • Bussani R.
      • Biondi-Zoccai G.G.
      • Liuzzo G.
      • Leone A.M.
      • Silvestri F.
      • Dobrina A.
      • Baldi F.
      • Pandolfi F.
      • Biasucci L.M.
      • Baldi A.
      • Spagnoli L.G.
      • Crea F.
      Widespread myocardial inflammation and infarct-related artery patency.
      and the correlation between decreased myocardial DCs with impaired fibrosis and increased cardiac rupture in MI patients.
      • Nagai T.
      • Honda S.
      • Sugano Y.
      • Matsuyama T.A.
      • Ohta-Ogo K.
      • Asaumi Y.
      • Ikeda Y.
      • Kusano K.
      • Ishihara M.
      • Yasuda S.
      • Ogawa H.
      • Ishibashi-Ueda H.
      • Anzai T.
      Decreased myocardial dendritic cells is associated with impaired reparative fibrosis and development of cardiac rupture after myocardial infarction in humans.

       Maturation Phase and Ischemic HF

      We are only beginning to understand the specific immune response taking place during the maturation phase in ischemic HF (8 weeks after MI in the mice). Initial work in this direction demonstrated a robust expansion of monocytes, macrophages, and DCs in the spleen. Splenectomy experiments in mice with MI revealed that the spleen functions as a reservoir of myeloid cells that migrate to the heart to induce tissue injury
      • Ismahil M.A.
      • Hamid T.
      • Bansal S.S.
      • Patel B.
      • Kingery J.R.
      • Prabhu S.D.
      Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis.
      (Figure 1). Follow-up studies demonstrated a spatiotemporal divergence in Th subsets during the development of ischemic HF. T-cell expansion included all CD4+ Th cell subsets and CD8+ T cells and occurred predominantly in the spleen in chronic ischemic HF. Th2 and Th17, as well as dysfunctional Treg cells that lack immunomodulatory capabilities, but not Th1 cells are present in the failing heart. Elegant adoptive transfer studies further evidenced that systemic CD4+ T cells primed with cardiac antigens, and dysfunctional Treg cells, are indispensable for the progression to HF, through mechanisms that involve profibrotic and antiangiogenic functions of Th17, Th2, and dysfunctional Treg cells.
      • Bansal S.S.
      • Ismahil M.A.
      • Goel M.
      • Patel B.
      • Hamid T.
      • Rokosh G.
      • Prabhu S.D.
      Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure.
      • Bansal S.S.
      • Ismahil M.A.
      • Goel M.
      • Zhou G.
      • Rokosh G.
      • Hamid T.
      • Prabhu S.D.
      Dysfunctional and proinflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy.
      Taken together, the extent of cardiac injury after ischemia defines the repertoire of leukocytes in the heart. Leukocyte cross talk with myocardial cells contributes to cardiac dysfunction observed in ischemic HF.

       Heart Inflammation in Nonischemic HF

      Excluding MI, hypertension is the most common risk factor for HF, accounting for approximately 25% of HF cases.
      • Benjamin E.J.
      • Virani S.S.
      • Callaway C.W.
      • Chamberlain A.M.
      • Chang A.R.
      • Cheng S.
      • et al.
      American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics-2018 update: a report from the American Heart Association.
      Hypertensive heart disease is associated with cardiac hypertrophy and cardiac fibrosis and manifests clinically as systolic or diastolic HF.
      • Drazner M.H.
      The progression of hypertensive heart disease.
      The contribution of inflammation to hypertension is well established, with several immune cell types accumulating in the vasculature and impairing vessel function. However, mechanistic insight into the role of the immune system in the heart in response to chronic hypertension is not so extensively studied. Most of our knowledge in nonischemic and noninfectious HF comes from experimental animal models of hypertension induced by angiotensin II (Ang-II) infusion that increases blood pressure and from experimental animal models of transverse-aortic constriction (TAC) that produces an abrupt pressure overload in the LV that mimics LV pressure in patients with HF (>140 mmHg). Common features of these models include the pathogenic role of IL-6, which, when inhibited pharmacologically or genetically depleted, improves adverse cardiac remodeling,
      • Coles B.
      • Fielding C.A.
      • Rose-John S.
      • Scheller J.
      • Jones S.A.
      • O'Donnell V.B.
      Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo.
      • Zhao L.
      • Cheng G.
      • Jin R.
      • Afzal M.R.
      • Samanta A.
      • Xuan Y.T.
      • Girgis M.
      • Elias H.K.
      • Zhu Y.
      • Davani A.
      • Yang Y.
      • Chen X.
      • Ye S.
      • Wang O.L.
      • Chen L.
      • Hauptman J.
      • Vincent R.J.
      • Dawn B.
      Deletion of interleukin-6 attenuates pressure overload-induced left ventricular hypertrophy and dysfunction.
      and the activation of certain immune pathways.

       Hypertensive Heart Disease

      The contribution of the immune system to hypertension was recognized in earlier studies demonstrating that transfer of splenocytes from deoxycorticosterone acetate salt hypertensive rats to normal recipient rats was sufficient to trigger hypertensive responses.
      • Olsen F.
      Transfer of arterial hypertension by splenic cells from DOCA-salt hypertensive and renal hypertensive rats to normotensive recipients.
      Decades later, studies in recombination-activating gene 1 (Rag1)–deficient mice, which lack T cells and B cells, demonstrated a pathologic function for T cells in vascular inflammation associated with Ang-II–induced hypertension.
      • Guzik T.J.
      • Hoch N.E.
      • Brown K.A.
      • McCann L.A.
      • Rahman A.
      • Dikalov S.
      • Goronzy J.
      • Weyand C.
      • Harrison D.G.
      Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction.
      Treg cell deficiency exaggerated Ang-II–induced microvascular injury by enhancing proinflammatory immune responses.
      • Mian M.O.
      • Barhoumi T.
      • Briet M.
      • Paradis P.
      • Schiffrin E.L.
      Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses.
      A glance at the mechanisms of vascular inflammation in hypertension identifies IFN-γ and IL-17A as dominant cytokines that alter the synthesis and degradation of vasodilators and vasoconstrictors, and the expression of Ang-II itself, thereby promoting hypertension.
      • Nguyen H.
      • Chiasson V.L.
      • Chatterjee P.
      • Kopriva S.E.
      • Young K.J.
      • Mitchell B.M.
      Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension.
      The presence of T cells and DCs in the vessel wall suggests that antigen presentation must be occurring during hypertension. γ-Ketoaldehydes have been reported as endogenous antigens inducing T-cell–dependent vascular inflammation.
      • Kirabo A.
      • Fontana V.
      • de Faria A.P.
      • Loperena R.
      • Galindo C.L.
      • Wu J.
      • Bikineyeva A.T.
      • Dikalov S.
      • Xiao L.
      • Chen W.
      • Saleh M.A.
      • Trott D.W.
      • Itani H.A.
      • Vinh A.
      • Amarnath V.
      • Amarnath K.
      • Guzik T.J.
      • Bernstein K.E.
      • Shen X.Z.
      • Shyr Y.
      • Chen S.C.
      • Mernaugh R.L.
      • Laffer C.L.
      • Elijovich F.
      • Davies S.S.
      • Moreno H.
      • Madhur M.S.
      • Roberts 2nd, J.
      • Harrison D.G.
      DC isoketal-modified proteins activate T cells and promote hypertension.
      Whether these early changes in the vasculature eventually lead to adverse cardiac remodeling was not evaluated in the studies listed above. Recent studies demonstrated that Ang-II infusion results in increased numbers of infiltrating CCR2+ and of resident proliferating cardiac macrophages.
      • Epelman S.
      • Lavine K.J.
      • Beaudin A.E.
      • Sojka D.K.
      • Carrero J.A.
      • Calderon B.
      • Brija T.
      • Gautier E.L.
      • Ivanov S.
      • Satpathy A.T.
      • Schilling J.D.
      • Schwendener R.
      • Sergin I.
      • Razani B.
      • Forsberg E.C.
      • Yokoyama W.M.
      • Unanue E.R.
      • Colonna M.
      • Randolph G.J.
      • Mann D.L.
      Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.
      • Falkenham A.
      • de Antueno R.
      • Rosin N.
      • Betsch D.
      • Lee T.D.
      • Duncan R.
      • Legare J.F.
      Nonclassical resident macrophages are important determinants in the development of myocardial fibrosis.
      CCR2+ macrophages are profibrotic in response to Ang-II infusion because Ccl2−/− mice show decreased macrophages in the heart and decreased cardiac fibrosis.
      • Haudek S.B.
      • Cheng J.
      • Du J.
      • Wang Y.
      • Hermosillo-Rodriguez J.
      • Trial J.
      • Taffet G.E.
      • Entman M.L.
      Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy.
      The CXCL1/CXCR2 chemokine pathway has also been recently shown to regulate monocyte recruitment to the heart.
      • Wang L.
      • Zhang Y.L.
      • Lin Q.Y.
      • Liu Y.
      • Guan X.M.
      • Ma X.L.
      • Cao H.J.
      • Liu Y.
      • Bai J.
      • Xia Y.L.
      • Du J.
      • Li H.H.
      CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.
      Recent studies using cardiomyocyte-specific calmodulin kinase II–deficient mice demonstrate that cardiac myocytes are initial sensors of Ang-II. This initial sensing induces early macrophage infiltration in the heart and cardiac fibrosis in hypertensive heart disease.
      • Willeford A.
      • Suetomi T.
      • Nickle A.
      • Hoffman H.M.
      • Miyamoto S.
      • Heller Brown J.
      CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis.
      The Ang-II pathway is currently being successfully targeted in the clinic, and some potential benefit may be attributed to its actions in several arms of the immune response. Targeting calmodulin kinase II delta in myocytes may be an additional therapeutic approach.

       Pressure Overload–Induced HF

      Mechanical stress induced by cardiac pressure overload in response to TAC is a well-established model of nonischemic HF
      • Suetomi T.
      • Willeford A.
      • Brand C.S.
      • Cho Y.
      • Ross R.S.
      • Miyamoto S.
      • Brown J.H.
      Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca(2+)/calmodulin-dependent protein kinase ii delta signaling in cardiomyocytes are essential for adverse cardiac remodeling.
      that induces low-grade cardiac inflammation, adverse cardiac remodeling, and progressive cardiac dysfunction.
      • Rockman H.A.
      • Ross R.S.
      • Harris A.N.
      • Knowlton K.U.
      • Steinhelper M.E.
      • Field L.J.
      • Ross Jr., J.
      • Chien K.R.
      Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy.
      Cardiomyocyte calmodulin kinase II delta has also been shown to contribute to inflammation as early as 3 days after TAC. Cardiomyocyte-specific calmodulin kinase II–deficient mice had decreased activation of the nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome in response to TAC.
      • Suetomi T.
      • Willeford A.
      • Brand C.S.
      • Cho Y.
      • Ross R.S.
      • Miyamoto S.
      • Brown J.H.
      Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca(2+)/calmodulin-dependent protein kinase ii delta signaling in cardiomyocytes are essential for adverse cardiac remodeling.
      These data are in agreement with IL-1β being increased early after TAC as a possible inducer of early induction of ICAM-1, and they support that the cardiac myocyte is an initiator of inflammation in response to cardiac pressure overload. T-cell expansion occurs in response to TAC specifically in the mediastinal lymph nodes that drain the heart (Figure 1). CCR2+ macrophage recruitment to the heart precedes systolic dysfunction and the recruitment of CD4+ T cells.
      • Patel B.
      • Ismahil M.A.
      • Hamid T.
      • Bansal S.S.
      • Prabhu S.D.
      Mononuclear phagocytes are dispensable for cardiac remodeling in established pressure-overload heart failure.
      • Patel B.
      • Bansal S.S.
      • Ismahil M.A.
      • Hamid T.
      • Rokosh G.
      • Mack M.
      • Prabhu S.D.
      CCR2(+) monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload.
      In vivo studies in mice demonstrate that pharmacologic blockade of CCR2 attenuates adverse ventricular remodeling and dysfunction, as well as the T-cell responses associated with adverse cardiac remodeling in response to TAC.
      • Suetomi T.
      • Willeford A.
      • Brand C.S.
      • Cho Y.
      • Ross R.S.
      • Miyamoto S.
      • Brown J.H.
      Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca(2+)/calmodulin-dependent protein kinase ii delta signaling in cardiomyocytes are essential for adverse cardiac remodeling.
      • Patel B.
      • Bansal S.S.
      • Ismahil M.A.
      • Hamid T.
      • Rokosh G.
      • Mack M.
      • Prabhu S.D.
      CCR2(+) monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload.
      Interestingly, in contrast with ischemic HF, spleen remodeling does not occur in nonischemic HF. Several studies support that CD4+ T cells dominate the pathologic immune response to cardiac pressure overload induced by TAC. These include findings demonstrating lack of cardiac fibrosis and preserved cardiac function in Rag1−/− mice (lacking T cells and B cells), in Mhc-II−/− mice (lacking CD4+ T cells),
      • Laroumanie F.
      • Douin-Echinard V.
      • Pozzo J.
      • Lairez O.
      • Tortosa F.
      • Vinel C.
      • Delage C.
      • Calise D.
      • Dutaur M.
      • Parini A.
      • Pizzinat N.
      CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload.
      and in T-cell receptor α knockout (Tcra−/−) mice (lacking CD4+ and CD8+ T cells) and by pharmacologically depleting T cells with an anti-CD3 antibody.
      • Nevers T.
      • Salvador A.M.
      • Grodecki-Pena A.
      • Knapp A.
      • Velazquez F.
      • Aronovitz M.
      • Kapur N.K.
      • Karas R.H.
      • Blanton R.M.
      • Alcaide P.
      Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure.
      CD8+-deficient mice, in contrast, are not protected from TAC-induced HF.
      • Laroumanie F.
      • Douin-Echinard V.
      • Pozzo J.
      • Lairez O.
      • Tortosa F.
      • Vinel C.
      • Delage C.
      • Calise D.
      • Dutaur M.
      • Parini A.
      • Pizzinat N.
      CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload.
      Adoptive transfer of Th1 cells into Tcra−/− mice partially reconstitutes cardiac fibrosis and cardiac dysfunction, supporting a profibrotic role for Th1 cells.
      • Nevers T.
      • Salvador A.M.
      • Velazquez F.
      • Ngwenyama N.
      • Carrillo-Salinas F.J.
      • Aronovitz M.
      • Blanton R.M.
      • Alcaide P.
      Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure.
      Moreover, blockade of T-cell costimulatory molecules on APCs and depletion of bone marrow–derived CD11c+ DCs significantly attenuate cardiac fibrosis and hypertrophy, further supporting that T-cell activation depends on antigen presentation.
      • Wang H.
      • Kwak D.
      • Fassett J.
      • Liu X.
      • Yao W.
      • Weng X.
      • Xu X.
      • Xu Y.
      • Bache R.J.
      • Mueller D.L.
      • Chen Y.
      Role of bone marrow-derived CD11c(+) dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy.
      • Kallikourdis M.
      • Martini E.
      • Carullo P.
      • Sardi C.
      • Roselli G.
      • Greco C.M.
      • Vignali D.
      • Riva F.
      • Ormbostad Berre A.M.
      • Stolen T.O.
      • Fumero A.
      • Faggian G.
      • Di Pasquale E.
      • Elia L.
      • Rumio C.
      • Catalucci D.
      • Papait R.
      • Condorelli G.
      T cell costimulation blockade blunts pressure overload-induced heart failure.
      In this line, OTII mice that express a transgenic CD4+ T-cell receptor specific for exogenous ovalbumin peptide are protected from adverse cardiac remodeling in response to TAC.
      • Laroumanie F.
      • Douin-Echinard V.
      • Pozzo J.
      • Lairez O.
      • Tortosa F.
      • Vinel C.
      • Delage C.
      • Calise D.
      • Dutaur M.
      • Parini A.
      • Pizzinat N.
      CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload.
      When ovalbumin peptide is exclusively expressed on cardiomyocytes, cardiac inflammation is partially restored, suggesting that T-cell activation with ovalbumin peptide can mediate some pathology, but other signals are required to progress to HF.
      • Groschel C.
      • Sasse A.
      • Rohrborn C.
      • Monecke S.
      • Didie M.
      • Elsner L.
      • Kruse V.
      • Bunt G.
      • Lichtman A.H.
      • Toischer K.
      • Zimmermann W.H.
      • Hasenfuss G.
      • Dressel R.
      T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure.
      Although IFN-γ is profibrotic, IL-10 is antifibrotic, in TAC.
      • Nevers T.
      • Salvador A.M.
      • Velazquez F.
      • Ngwenyama N.
      • Carrillo-Salinas F.J.
      • Aronovitz M.
      • Blanton R.M.
      • Alcaide P.
      Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure.
      • Verma S.K.
      • Garikipati V.N.S.
      • Krishnamurthy P.
      • Schumacher S.M.
      • Grisanti L.A.
      • Cimini M.
      • Cheng Z.
      • Khan M.
      • Yue Y.
      • Benedict C.
      • Truongcao M.M.
      • Rabinowitz J.E.
      • Goukassian D.A.
      • Tilley D.
      • Koch W.J.
      • Kishore R.
      Interleukin-10 inhibits bone marrow fibroblast progenitor cell-mediated cardiac fibrosis in pressure-overloaded myocardium.
      The mechanisms of immune cell trafficking to the heart in response to cardiac pressure overload are starting to be unveiled. The levels of circulating CXCL9 and CXCL10 positively correlated with Th1 cytokines in the circulation of patients with symptomatic HF.
      • Altara R.
      • Manca M.
      • Hessel M.H.
      • Gu Y.
      • van Vark L.C.
      • Akkerhuis K.M.
      • Staessen J.A.
      • Struijker-Boudier H.A.
      • Booz G.W.
      • Blankesteijn W.M.
      CXCL10 is a circulating inflammatory marker in patients with advanced heart failure: a pilot study.
      We recently demonstrated the presence of CXCR3+ T cells in the human hearts of patients with nonischemic end-stage HF.
      • Ngwenyama N.
      • Salvador A.M.
      • Velazquez F.
      • Nevers T.
      • Levy A.
      • Aronovitz M.J.
      • Luster A.D.
      • Huggins G.S.
      • Alcaide P.
      CXCR3 regulates CD4+ T cell cardiotropism in pressure overload induced cardiac dysfunction.
      CXCR3 is predominantly expressed in Th1 cells, and most CXCR3+ cells colocalized with T-cell markers. However, some non–T-cell CXCR3+ cells were also found in the failing human heart. Interestingly, Cxcr3−/− mice are protected from TAC-induced cardiac fibrosis and dysfunction. CD4+ T cells did not infiltrate the Cxcr3−/− TAC hearts, but the numbers of CCR2+ myeloid cells were comparable between wild-type and Cxcr3−/− TAC hearts. These data support that both CCR2+ macrophages and CXCR3+ T cells infiltrate the heart. Although blocking CCR2 prevents T-cell heart infiltration,
      • Patel B.
      • Bansal S.S.
      • Ismahil M.A.
      • Hamid T.
      • Rokosh G.
      • Mack M.
      • Prabhu S.D.
      CCR2(+) monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload.
      deficiency of CXCR3 specifically prevents CD4+ T-cell recruitment in response to TAC.
      • Ngwenyama N.
      • Salvador A.M.
      • Velazquez F.
      • Nevers T.
      • Levy A.
      • Aronovitz M.J.
      • Luster A.D.
      • Huggins G.S.
      • Alcaide P.
      CXCR3 regulates CD4+ T cell cardiotropism in pressure overload induced cardiac dysfunction.
      Both CCR2+ monocytes and Th1 cells express LFA-1, the ligand of endothelial ICAM-1. The fact that Icam-1−/− shows decreased CD4+ T cells and Ly6Chi cells in the LV in response to TAC and does not develop maladaptive cardiac remodeling, or dysfunction,
      • Salvador A.M.
      • Nevers T.
      • Velazquez F.
      • Aronovitz M.
      • Wang B.
      • Abadia Molina A.
      • Jaffe I.Z.
      • Karas R.H.
      • Blanton R.M.
      • Alcaide P.
      Intercellular adhesion molecule 1 regulates left ventricular leukocyte infiltration, cardiac remodeling, and function in pressure overload-induced heart failure.
      supports the relevance of leukocyte LFA-1–endothelial ICAM-1 interactions for monocyte and T-cell recruitment to the heart in this model.
      Taken together, inflammation in nonischemic HF, induced by hypertension or by cardiac pressure overload, is dominated by CD4+ T cells and IFN-γ signatures. CCR2+ monocytes precede CD4+ T-cell infiltration in the heart, and the antigens inducing this response remain elusive. Coexistence of these mechanisms is critical in cardiac inflammation by a nonischemic insult and differs from the immune response triggered by myocardial ischemia at the site of immune cell activation (mediastinal lymph nodes versus spleen) (Figure 1) and in the T-cell subsets involved (Th1 versus Th2 and Th17) (Figure 2). More studies need to be performed to understand the antigens responsible for T-cell activation.
      Figure thumbnail gr2
      Figure 2Distinct triggers of cardiac inflammation and progression of adverse cardiac remodeling and chronic inflammation in heart failure (HF) from different etiologies. A: Viral, bacterial, or parasite infection of the myocardium/endocardium leads to cell death and triggers a highly proinflammatory response to induce pathogen killing. Many monocytes/macrophages, neutrophils, and T cells infiltrate the heart during the acute phase of infection through different adhesion molecules. The payback of pathogen killing is off-target effects of inflammation in the myocardium and tissue fibrosis, which develop into chronic inflammation and cardiac hypertrophy. Pathogen titers are low inexistent in the chronic inflammatory phase dominated by heart-infiltrated macrophages and T cells, which contribute to cardiac fibrosis and remodeling. B: Myocardial ischemia induces cardiomyocyte death and recruitment of many neutrophils (first) and sequential waves of monocytes (second) and T cells (third) to promote healing and scar formation by inducing fibrosis in the infarct zone (acute inflammation). Acute strong inflammation and scar formation lead to more fibrosis to maintain the tissue integrity filling in areas of cardiomyocyte death, and expanded fibrosis [by transforming growth factor-β (TGF-β) production], cardiac hypertrophy, but lower numbers of immune cells that include T-helper type 2 and T-helper type 17 (Th17) cells are found in the heart in chronic inflammation after ischemia. C: Hypertension and pressure overload, unlike infection or ischemia, are not characterized by extensive inflammation in the acute phase. Monocytes and T-helper type 1 (Th1) cells progressively infiltrate the heart in low numbers as cardiac fibrosis and cardiac hypertrophy develop, initially in response to cardiac pressure overload, and later resulting in dilated cardiomyopathy, cardiac dysfunction, and HF. D: Several other factors, which include diabetes, chemotherapy, and genetic mutations, can induce adverse cardiac remodeling and progress into HF, but the role of inflammation is largely unexplored. CaMKIIδ, calmodulin kinase II delta; CCL, chemokine (C-C motif) ligand; CCR, C-C motif receptor; CXCL, C-X-C motif ligand; CXCR, C-X-C motif receptor; DAMP, damage-associated molecular pattern; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; LFA-1, lymphocyte function-associated antigen 1; LPS, lipopolysaccharide; LV, left ventricular; MMP, matrix metalloprotease; T. cruzi, Trypanosoma cruzi; TNF-α, tumor necrosis factor-α; Treg, T regulatory; VCAM-1, vascular cell adhesion molecule 1.

       Autoimmunity and Heart Inflammation

      Autoimmunity, the immune response to self-antigens, can induce cardiac inflammation that evolves to HF. The heart is normally protected from autoimmune responses through mechanisms that involve immune tolerance. These include the presence of tolerogenic DCs and Treg cells in the heart, as well as the expression of inhibitory molecules, such as programmed cell death-1 (PD-1) in T cells and its ligand in heart cells. The nature of the antigens triggering cardiac autoimmunity is not fully understood, but pathogen-induced host molecular mimicry may result in immune tolerance breaching.
      • Fung G.
      • Luo H.
      • Qiu Y.
      • Yang D.
      • McManus B.
      Myocarditis.
      In addition, T-cell clones that escape these filters may be responsible for autoimmunity. For instance, cardiac antigens from necrotic cardiomyocytes have been reported in mice after MI, are presented by DCs to autoreactive CD4+ T cells, and induce their transformation to Th1/Th17 effector cells.
      • Van der Borght K.
      • Scott C.L.
      • Nindl V.
      • Bouche A.
      • Martens L.
      • Sichien D.
      • Van Moorleghem J.
      • Vanheerswynghels M.
      • De Prijck S.
      • Saeys Y.
      • Ludewig B.
      • Gillebert T.
      • Guilliams M.
      • Carmeliet P.
      • Lambrecht B.N.
      Myocardial infarction primes autoreactive T cells through activation of dendritic cells.
      The presence of autoantibodies to troponin and cardiac myosin in humans after MI and postinfection with T. cruzi and with Coxsackievirus
      • Meier L.A.
      • Binstadt B.A.
      The contribution of autoantibodies to inflammatory cardiovascular pathology.
      support that infectious or sterile injury induces breaching of immune tolerance that can lead to myocarditis and HF.
      The experimental mouse model of myocarditis, induced by immunization with cardiac myosin, has been broadly used to study the mechanisms regulating autoimmunity and its progression to dilated cardiomyopathy and HF. Neutrophils are recruited to the heart in experimental autoimmune myocarditis (EAM) and are thought to help recruit Th17 cells. I117−/− mice are not protected from acute myocarditis but show delayed transition to dilated cardiomyopathy in EAM.
      • Baldeviano G.C.
      • Barin J.G.
      • Talor M.V.
      • Srinivasan S.
      • Bedja D.
      • Zheng D.
      • Gabrielson K.
      • Iwakura Y.
      • Rose N.R.
      • Cihakova D.
      Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy.
      CCR2 blockade with siRNA resulted in decreased monocyte recruitment and reduced Th17 cell-mediated pathology.
      • Leuschner F.
      • Courties G.
      • Dutta P.
      • Mortensen L.J.
      • Gorbatov R.
      • Sena B.
      • Novobrantseva T.I.
      • Borodovsky A.
      • Fitzgerald K.
      • Koteliansky V.
      • Iwamoto Y.
      • Bohlender M.
      • Meyer S.
      • Lasitschka F.
      • Meder B.
      • Katus H.A.
      • Lin C.
      • Libby P.
      • Swirski F.K.
      • Anderson D.G.
      • Weissleder R.
      • Nahrendorf M.
      Silencing of CCR2 in myocarditis.
      • Valaperti A.
      • Marty R.R.
      • Kania G.
      • Germano D.
      • Mauermann N.
      • Dirnhofer S.
      • Leimenstoll B.
      • Blyszczuk P.
      • Dong C.
      • Mueller C.
      • Hunziker L.
      • Eriksson U.
      CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmune myocarditis.
      Thus, neutrophils and monocytes dominate acute myocarditis, whereas Th17 cells do so in chronic autoimmune myocarditis.
      Direct evidence that self-tolerance mechanisms are in place to protect the heart comes from studies in which disruption of inhibitory molecules, such as PD-1, expressed on T cells, and its ligand, broadly expressed on APCs, led to lethal myocarditis in studies using Pd1−/− mice.
      • Tarrio M.L.
      • Grabie N.
      • Bu D.X.
      • Sharpe A.H.
      • Lichtman A.H.
      PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis.
      PD-1/PD-1 ligand pathway inhibitors are frequently given to cancer patients to achieve T-cell activation with antitumor activity, and recently, cases of lethal myocarditis with robust T-cell infiltration were reported in patients treated with the anti–PD-1 drug prembrolizumab.
      • Johnson D.B.
      • Balko J.M.
      • Compton M.L.
      • Chalkias S.
      • Gorham J.
      • Xu Y.
      • Hicks M.
      • Puzanov I.
      • Alexander M.R.
      • Bloomer T.L.
      • Becker J.R.
      • Slosky D.A.
      • Phillips E.J.
      • Pilkinton M.A.
      • Craig-Owens L.
      • Kola N.
      • Plautz G.
      • Reshef D.S.
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      • Diaz Jr., L.A.
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      • Moslehi J.J.
      Fulminant myocarditis with combination immune checkpoint blockade.
      These results support that maintenance of immune tolerance is critical to prevent heart autoimmunity, and they highlight that the heart should closely be monitored in patients treated with immune checkpoint inhibitors. Patients with autoimmune diseases that include systemic lupus erythematosus and rheumatoid arthritis are also at higher risk of developing cardiovascular disease and HF, but the genetic predisposition, the nature of the antigens, and whether primed immune cells in these conditions result in heart inflammation remain unknown.
      • Binstadt B.A.
      • Hebert J.L.
      • Ortiz-Lopez A.
      • Bronson R.
      • Benoist C.
      • Mathis D.
      The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms.
      Because of the nonregenerative nature of the heart, any autoimmune reaction that induces irreversible damage can progress into HF. Understanding the specific mechanisms leading to cardiac autoimmunity is necessary to develop optimal therapeutics in HF.

       How Much More We Need to Learn about Inflammation in Other Etiologies of HF

      Several additional risk factors for HF potentially involve cardiac inflammation and negatively impact cardiac health. Diabetic cardiomyopathy resulting in HF is strongly associated with the activation of the immune system and chronic inflammation. In contrast, it is not clear whether inflammation plays a role in HF induced by cardiotoxicity of chemotherapy, cardiac amyloidosis, or inherited cardiomyopathies. In this section, we also review recent findings that position heart-infiltrating immune cells as regulators of electrical conduction and, thus, participate in atrial fibrillation (AF).

       Toxicity of Cancer Chemotherapy and HF

      Several studies demonstrate that children exposed to chemotherapy, and generally lacking cardiovascular risk factors, exhibit greater chances of cardiovascular diseases later in life, suggesting that chemotherapy is one of the factors leading to increased incidence of cardiac complication.
      • Mulrooney D.A.
      • Armstrong G.T.
      • Huang S.
      • Ness K.K.
      • Ehrhardt M.J.
      • Joshi V.M.
      • Plana J.C.
      • Soliman E.Z.
      • Green D.M.
      • Srivastava D.
      • Santucci A.
      • Krasin M.J.
      • Robison L.L.
      • Hudson M.M.
      Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study.
      Doxorubicin may be the most known cardiotoxic chemotherapeutic agent. It induces cell death and subsequent damage-associated molecular pattern release that may be responsible for the systemic inflammation observed in doxorubicin-treated cancer patients.
      • Klee N.S.
      • McCarthy C.G.
      • Martinez-Quinones P.
      • Webb R.C.
      Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy.
      We know little about the role of inflammation in cardiac complications developed in response to chemotherapy, but it is likely that damage-associated molecular patterns induce immune cell–mediated cardiac inflammation. Cardiac function and systemic inflammation must be carefully monitored in cancer patients to prevent HF.

       Diabetic Cardiomyopathy and HF

      Many diabetic patients present to the hospital with LV dysfunction. Experimental studies support a role for cardiac macrophage infiltration in the development of insulin resistance.
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • Ravussin E.
      • Stephens J.M.
      • Dixit V.D.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      Cardiac inflammation in this setting seems to be mediated in part through IL-1β–dependent signals, although studies using Rag1−/− mice and streptozotocin to induce hyperglycemia demonstrate protection, supporting a role for B and T lymphocytes in diabetic cardiomyopathy as well.
      • Abdullah C.S.
      • Li Z.
      • Wang X.
      • Jin Z.Q.
      Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy.
      Although it is well established that both macrophages and T cells infiltrate the heart in diabetic cardiomyopathy, the mechanisms of recruitment remain unknown.

       Inherited Cardiomyopathies and HF

      There are >900 genetic mutations identified as either critical initiating factors of cardiac disease or altering the response to an insult that leads to HF.
      • Xu Q.
      • Dewey S.
      • Nguyen S.
      • Gomes A.V.
      Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes.
      Unfortunately, studies in mice overexpressing human mutations have not explored the role of inflammation, representing a major gap in the field. Because many of these mutations lead to highly fibrotic hearts and several immune cells regulate cardiac fibrosis, one could speculate that immune cell activation either drives or contributes to the progression of HF resulting from structural abnormalities of the heart.
      • Smorodinova N.
      • Blaha M.
      • Melenovsky V.
      • Rozsivalova K.
      • Pridal J.
      • Durisova M.
      • Pirk J.
      • Kautzner J.
      • Kucera T.
      Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.

       Cardiac Amyloid Deposition and HF

      Deposition of amyloid proteins cleaved from breakdown of normal or abnormal proteins in the heart is known as cardiac amyloidosis, which can lead to cardiac dysfunction. A recent study observed cardiac amyloidosis patients from the first diagnostic biopsy for as long as 36 months and found that intramyocardial inflammation, characterized by the presence of CD3+LFA-1+ cells in the heart, directly correlated with increased mortality. In contrast, CD45R0 memory T cells and macrophages were not found to be predictive of mortality.
      • Siegismund C.S.
      • Escher F.
      • Lassner D.
      • Kuhl U.
      • Gross U.
      • Fruhwald F.
      • Wenzel P.
      • Munzel T.
      • Frey N.
      • Linke R.P.
      • Schultheiss H.P.
      Intramyocardial inflammation predicts adverse outcome in patients with cardiac AL amyloidosis.
      Transgenic mice overexpressing soluble preamyloid oligomers show cardiomyocyte death and HF.
      • Pattison J.S.
      • Sanbe A.
      • Maloyan A.
      • Osinska H.
      • Klevitsky R.
      • Robbins J.
      Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure.
      Coffilin-2, an actin-depolymerizing protein known to participate in neurodegenerative disease, was also found to promote cardiac amyloid deposition and to impair contractility when overexpressed in mice.
      • Subramanian K.
      • Gianni D.
      • Balla C.
      • Assenza G.E.
      • Joshi M.
      • Semigran M.J.
      • Macgillivray T.E.
      • Van Eyk J.E.
      • Agnetti G.
      • Paolocci N.
      • Bamburg J.R.
      • Agrawal P.B.
      • Del Monte F.
      Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy.
      These mouse models could be used to mechanistically understand whether cardiac inflammation contributes to HF resulting from cardiac amyloidosis.

       AF and HF

      AF is the most common form of heart rhythm disorder. Abnormal atrial depolarization leads to poor atrial contraction and poor ventricle function in HF. There is evidence of increased heart T-cell infiltration in AF patients.
      • Chen M.C.
      • Chang J.P.
      • Liu W.H.
      • Yang C.H.
      • Chen Y.L.
      • Tsai T.H.
      • Wang Y.H.
      • Pan K.L.
      Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation.
      IL-17A, IFN-γ, and IL-6 were independently associated with AF risk
      • Wu N.
      • Xu B.
      • Liu Y.
      • Chen X.
      • Tang H.
      • Wu L.
      • Xiang Y.
      • Zhang M.
      • Shu M.
      • Song Z.
      • Li Y.
      • Zhong L.
      Elevated plasma levels of Th17-related cytokines are associated with increased risk of atrial fibrillation.
      and with CD4+ T cells in patients.
      • Smorodinova N.
      • Blaha M.
      • Melenovsky V.
      • Rozsivalova K.
      • Pridal J.
      • Durisova M.
      • Pirk J.
      • Kautzner J.
      • Kucera T.
      Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.
      • Sulzgruber P.
      • Koller L.
      • Winter M.P.
      • Richter B.
      • Blum S.
      • Korpak M.
      • Hulsmann M.
      • Goliasch G.
      • Wojta J.
      • Niessner A.
      The impact of CD4(+)CD28(null) T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure.
      CCL2 was also associated with the presence of macrophages in the atrial endocardium of AF patients, who also expressed ICAM-1 and vascular cell adhesion molecule 1.
      • Smorodinova N.
      • Blaha M.
      • Melenovsky V.
      • Rozsivalova K.
      • Pridal J.
      • Durisova M.
      • Pirk J.
      • Kautzner J.
      • Kucera T.
      Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.
      • Yamashita T.
      • Sekiguchi A.
      • Iwasaki Y.K.
      • Date T.
      • Sagara K.
      • Tanabe H.
      • Suma H.
      • Sawada H.
      • Aizawa T.
      Recruitment of immune cells across atrial endocardium in human atrial fibrillation.
      However, whether the presence of immune cells and cytokines mechanistically influences electrical conduction has only recently become evident in elegant studies in mice. Myeloperoxidase, abundantly expressed in neutrophils, was deemed a critical prerequisite for increased vulnerability to AF in studies using Mpo−/− mice, which were protected from AF induced by electrophysiological stimulation.
      • Rudolph V.
      • Andrie R.P.
      • Rudolph T.K.
      • Friedrichs K.
      • Klinke A.
      • Hirsch-Hoffmann B.
      • Schwoerer A.P.
      • Lau D.
      • Fu X.
      • Klingel K.
      • Sydow K.
      • Didie M.
      • Seniuk A.
      • von Leitner E.C.
      • Szoecs K.
      • Schrickel J.W.
      • Treede H.
      • Wenzel U.
      • Lewalter T.
      • Nickenig G.
      • Zimmermann W.H.
      • Meinertz T.
      • Boger R.H.
      • Reichenspurner H.
      • Freeman B.A.
      • Eschenhagen T.
      • Ehmke H.
      • Hazen S.L.
      • Willems S.
      • Baldus S.
      Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation.
      IL-1β was also found to induce cardiac arrythmias in diabetic mice.
      • Monnerat G.
      • Alarcon M.L.
      • Vasconcellos L.R.
      • Hochman-Mendez C.
      • Brasil G.
      • Bassani R.A.
      • Casis O.
      • Malan D.
      • Travassos L.H.
      • Sepulveda M.
      • Burgos J.I.
      • Vila-Petroff M.
      • Dutra F.F.
      • Bozza M.T.
      • Paiva C.N.
      • Carvalho A.B.
      • Bonomo A.
      • Fleischmann B.K.
      • de Carvalho A.C.
      • Medei E.
      Macrophage-dependent IL-1beta production induces cardiac arrhythmias in diabetic mice.
      And recently, direct leukocyte participation in aberrant electrical conduction has been demonstrated: Macrophages express ion channels and communicate with conducting cells through gap junctions, which, in turn, induce action potential in cardiac myocytes. Interestingly, resident cardiac macrophages are necessary to stabilize electrical conduction at steady state. In response to MI, cell death impairs these connections and bone marrow–derived monocytes infiltrate the heart and further impair electrical conduction.
      • Hulsmans M.
      • Clauss S.
      • Xiao L.
      • Aguirre A.D.
      • King K.R.
      • Hanley A.
      • Hucker W.J.
      • Wulfers E.M.
      • Seemann G.
      • Courties G.
      • Iwamoto Y.
      • Sun Y.
      • Savol A.J.
      • Sager H.B.
      • Lavine K.J.
      • Fishbein G.A.
      • Capen D.E.
      • Da Silva N.
      • Miquerol L.
      • Wakimoto H.
      • Seidman C.E.
      • Seidman J.G.
      • Sadreyev R.I.
      • Naxerova K.
      • Mitchell R.N.
      • Brown D.
      • Libby P.
      • Weissleder R.
      • Swirski F.K.
      • Kohl P.
      • Vinegoni C.
      • Milan D.J.
      • Ellinor P.T.
      • Nahrendorf M.
      Macrophages facilitate electrical conduction in the heart.
      It is, thus, likely that in HF, similar mechanisms contribute to deadly arrythmias. However, further mechanistic studies are needed to support this conclusion.

      Is Modulating Immune Responses and Leukocyte Trafficking to the Heart a Science Fiction or Reality?

      The immune response to different insults to the heart is complex. To achieve successful immunomodulation, in-depth understanding of the type and the timing of immune cell response is critical. Moreover, understanding how and when different immune cells traffic to the heart and their interactions with cardiac stromal cells is needed. These also need to be considered in the different etiologies of HF for successful immunomodulation. For instance, on the basis of solid data from experimental models in mice, inhibiting IFN-γ and Th1 responses may be detrimental in myocarditis,
      • Fairweather D.
      • Frisancho-Kiss S.
      • Yusung S.A.
      • Barrett M.A.
      • Davis S.E.
      • Gatewood S.J.
      • Njoku D.B.
      • Rose N.R.
      Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart.
      beneficial in hypertension and pressure overload–induced stress,
      • Nevers T.
      • Salvador A.M.
      • Velazquez F.
      • Ngwenyama N.
      • Carrillo-Salinas F.J.
      • Aronovitz M.
      • Blanton R.M.
      • Alcaide P.
      Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure.
      and inefficient after MI,
      • Bansal S.S.
      • Ismahil M.A.
      • Goel M.
      • Patel B.
      • Hamid T.
      • Rokosh G.
      • Prabhu S.D.
      Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure.
      given the distinct roles played in the different etiologies by the same cytokine. A significant limitation to achieve immunomodulation is our lack of knowledge of the timing of activation and trafficking to the heart in human patients with symptoms of HF from different etiologies. Recent results from the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, inhibiting IL-1β, showed benefit in preventing the recurrence of secondary ischemic events after MI. Although promising, these results are still far from providing information for HF.
      • Ridker P.M.
      • Everett B.M.
      • Thuren T.
      • MacFadyen J.G.
      • Chang W.H.
      • Ballantyne C.
      • Fonseca F.
      • Nicolau J.
      • Koenig W.
      • Anker S.D.
      • Kastelein J.J.P.
      • Cornel J.H.
      • Pais P.
      • Pella D.
      • Genest J.
      • Cifkova R.
      • Lorenzatti A.
      • Forster T.
      • Kobalava Z.
      • Vida-Simiti L.
      • Flather M.
      • Shimokawa H.
      • Ogawa H.
      • Dellborg M.
      • Rossi P.R.F.
      • Troquay R.P.T.
      • Libby P.
      • Glynn R.J.
      • Group C.T.
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      With the next-generation single-cell sequencing technology, more information will arise about the cellular composition of the failing heart, which eventually could lead to potential new avenues for therapy.

      Conclusions

      When intramyocardial inflammation occurs, the limited replicative ability of the heart results in irreparable damage that often leads to HF. This may be why the heart has mechanisms in place that limit inflammation. We keep learning about immune mechanisms that are critical in cardiac inflammation in response to different infectious or sterile insults. We are beginning to understand how the initial inflammatory response modulates the progression to the different etiologies of HF. Thus, we are moving from considering HF merely associated with systemic inflammation to consider it more as an inflammatory chronic disease with specific sites for immunity. We now know that immune cell trafficking to the heart and their cross talk with heart cells are major determinants of cardiac dysfunction. Yet, we are still far from identifying new pathways that can translate to human disease, given the complexity of HF and the difficulty of testing in humans what we can extrapolate from experimental animal work. Despite considerable progress in our understanding of immunity in cardiac inflammation and HF, limiting human disease remains a major goal of future research.

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