56 results found
Sattler S, 2023, Is ischaemic heart failure an autoimmune disease?, ESC Heart Failure, ISSN: 2055-5822
Racine JJ, Misherghi A, Dwyer JR, et al., 2023, HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice., J Immunol
In an effort to improve HLA-"humanized" mouse models for type 1 diabetes (T1D) therapy development, we previously generated directly in the NOD strain CRISPR/Cas9-mediated deletions of various combinations of murine MHC genes. These new models improved upon previously available platforms by retaining β2-microglobulin functionality in FcRn and nonclassical MHC class I formation. As proof of concept, we generated H2-Db/H2-Kd double knockout NOD mice expressing human HLA-A*0201 or HLA-B*3906 class I variants that both supported autoreactive diabetogenic CD8+ T cell responses. In this follow-up work, we now describe the creation of 10 new NOD-based mouse models expressing various combinations of HLA genes with and without chimeric transgenic human TCRs reactive to proinsulin/insulin. The new TCR-transgenic models develop differing levels of insulitis mediated by HLA-DQ8-restricted insulin-reactive T cells. Additionally, these transgenic T cells can transfer insulitis to newly developed NSG mice lacking classical murine MHC molecules, but expressing HLA-DQ8. These new models can be used to test potential therapeutics for a possible capacity to reduce islet infiltration or change the phenotype of T cells expressing type 1 diabetes patient-derived β cell autoantigen-specific TCRs.
Patel H, Sintou A, Chowdhury RA, et al., 2023, Evaluation of autoantibody binding to cardiac tissue in multisystem inflammatory syndrome in children and COVID-19 vaccination-induced myocarditis., JAMA Network Open, Vol: 6, Pages: 1-11, ISSN: 2574-3805
IMPORTANCE: Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children. OBJECTIVE: To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate-conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023. MAIN OUTCOMES AND MEASURES: IgG, IgM and IgA antibody binding to cardiac tissue. RESULTS: By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditi
Kuppe C, Flores ROR, Li Z, et al., 2022, Spatial multi-omic map of human myocardial infarction, NATURE, Vol: 608, Pages: 766-+, ISSN: 0028-0836
Chimenti I, Sattler S, del Monte-Nieto G, et al., 2022, Editorial: Fibrosis and inflammation in tissue pathophysiology, Frontiers in Physiology, Vol: 12, ISSN: 1664-042X
Kouame E, Noel JC, Wane M, et al., 2021, Black in Immuno Week: Who We Are, What We Did, and Why It Matters, JOURNAL OF IMMUNOLOGY, Vol: 207, Pages: 1941-1947, ISSN: 0022-1767
Sattler S, 2021, Single-cell immunology in cardiovascular medicine: do we know yet what we do not know?, Circulation, Vol: 144, Pages: 843-844, ISSN: 0009-7322
Forte E, Sattler S, 2021, Response by Forte and Sattler to Letter Regarding Article, "Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart", CIRCULATION, Vol: 144, Pages: E94-E95, ISSN: 0009-7322
Sintou A, Rodriguez T, Sattler S, 2021, B cell activation and auto-antibodies in mitochondria- mediated cardiomyopathy and post-MI heart failure, Publisher: WILEY, Pages: 165-165, ISSN: 0014-2980
Jenkins C, Ng FS, Sattler S, 2021, Establishment of a mouse model of systemic autoimmunity to study the role of autoimmunity in post-myocardial infarction cardiac electrophysiological remodelling, Publisher: WILEY, Pages: 316-316, ISSN: 0014-2980
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, Vol: 25, Pages: 229-243, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Forte E, Perkins B, Sintou A, et al., 2020, Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart, Circulation, Vol: 143, Pages: 821-836, ISSN: 0009-7322
Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helperand CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross priming DC in post-MI myocardial impairment through presentation of self-antigen fromnecrotic cardiomyocytes to cytotoxic CD8+ T cells.Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function.Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely dueto dampened activation of cytotoxic CD8+ T cells.Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.
J C, Najer A, Blakney A, et al., 2020, Neutrophils enable local and non-invasive liposome delivery to inflamed skeletal muscle and ischemic heart, Advanced Materials, Vol: 32, Pages: 1-10, ISSN: 0935-9648
Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease, and cancer. Improving localized delivery of immunosuppressive drugs to inflamed tissue in a non‐invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Here, a neutrophil‐mediated delivery system able to transport drug‐loaded nanocarriers to inflamed tissue by exploiting the inherent ability of neutrophils to migrate to inflammatory tissue is reported. This hybrid system (neutrophils loaded with liposomes ex vivo) efficiently migrates in vitro following an inflammatory chemokine gradient. Furthermore, the triggered release of loaded liposomes and reuptake by target macrophages is studied. The migratory behavior of liposome‐loaded neutrophils is confirmed in vivo by demonstrating the delivery of drug‐loaded liposomes to an inflamed skeletal muscle in mice. A single low‐dose injection of the hybrid system locally reduces inflammatory cytokine levels. Biodistribution of liposome‐loaded neutrophils in a human‐disease‐relevant myocardial ischemia reperfusion injury mouse model after i.v. injection confirms the ability of injected neutrophils to carry loaded liposomes to inflammation sites. This strategy shows the potential of nanocarrier‐loaded neutrophils as a universal platform to deliver anti‐inflammatory drugs to promote tissue regeneration in inflammatory diseases.
Patel K, Jones T, Sattler S, et al., 2020, Pro-arrhythmic electrophysiological and structural remodelling in rheumatoid arthritis, American Journal of Physiology: Heart and Circulatory Physiology, Vol: 319, Pages: H1008-H1020, ISSN: 0363-6135
Chronic inflammatory disorders, including rheumatoid arthritis (RA), are associated with a two-fold increase in the incidence of sudden cardiac death (SCD) compared to the healthy population. Although this is partly explained by an increased prevalence of coronary artery disease, growing evidence suggests that ischaemia alone cannot completely account for the increased risk. The present review explores the mechanisms of cardiac electrophysiological remodelling in response to chronic inflammation in RA. In particular, it focuses on the roles of non-ischaemic structural remodelling, altered cardiac ionic currents and autonomic nervous system dysfunction in ventricular arrhythmogenesis and SCD. It also explores whether common genetic elements predispose to both RA and SCD. Finally, it evaluates the potential dual effects of disease-modifying therapy in both diminishing and promoting the risk of ventricular arrhythmias and SCD.
Forte E, Alsubaie M, Perkins B, et al., 2020, Post-MI dendritic cells trigger an adaptive immune reaction, and cytotoxic T cells persist during heart failure., Publisher: WILEY, Pages: 265-265, ISSN: 1388-9842
Sintou A, Mansfield C, Iacob A-O, et al., 2020, Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X
Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.
Rifai SE, Sintou A, Mansfield C, et al., 2020, Humoral factors in serum of rats with chronic heart failure induce cardiomyocyte hypertrophy and reduce viability., Clinical medicine (London, England), Vol: 20, Pages: s107-s107, ISSN: 1470-2118
<jats:title>Abstract</jats:title><jats:p>Heart failure is the common final pathway of a range of conditions resulting in myocardial damage and a major cause of morbidity and mortality worldwide. Strategies to improve tissue repair and prevent heart failure thus remain an urgent clinical need. Recent studies have documented activation of the adaptive immune system in response to myocardial damage and have implicated anti-heart autoimmunity in the development of heart failure. In an attempt to target anti-heart autoimmune responses as new therapeutic avenue, the number of experimental studies using <jats:italic>in vivo</jats:italic> models of myocardial damage to study the ensuing immune response has surged.</jats:p><jats:p>The beta-adrenergic agonist isoproterenol-hydrochloride has been used for its cardiac effects in a variety of different dosing and administration regimes. Most prominently, low doses (<10mg/kg sc) over an extended time period induce cardiac hypertrophy and fibrosis. In addition, single injections of high doses (>100mg/kg) induce cardiomyocyte necrosis and have been used to mimic acute myocardial necrotic lesions as seen in myocardial infarction (MI). However, despite significant resource and animal welfare advantages, concerns about off-target effects and clinical relevance have so far limited uptake in the cardiovascular research community.</jats:p><jats:p>To assess suitability of the isoproterenol model for the analysis of chronic post-MI immunological readouts, we treated C57BL/6J mice with a single intra-peritoneal bolus injection of 160mg/kg isoproterenol. Our results confirm the presence of necrotic lesions in the myocardium with significant resemblance of the histopathology of Type 2 MI. Kidneys develop mild fibrosis secondary to early cardiac damage, while other organs remain unaffected. Most importantly, we showed that isoproterenol treatment causes myocardial inflammation
Bjornmalm A, Wong LM, Wojciechowski J, et al., 2019, In vivo biocompatibility and immunogenicity of metal-phenolic gelation, Chemical Science, Vol: 10, Pages: 10179-10194, ISSN: 2041-6520
In vivo forming hydrogels are of interest for diverse biomedical applications due totheir ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled usingmetal–phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. TiIVor ZrIV) provide a versatile and robust platform for engineering such materials. However, the in situformation and in vivoresponse tothis new class of materials has not yet been reported. Here, we demonstrate that metal–phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. TheTiIV–tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivogelation), TiIV–tannic acid materials show a substantially improved in vitrodrug release profile for the corticosteroid dexamethasone (from <1 dayto >10 days). These results provide essential in vivo characterization for this new class of metal–phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug deliveryand regenerative medicine
Sattler S, Baxan N, Chowdhury R, et al., 2019, Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multi-parametric quantitative cardiac MRI, Disease Models & Mechanisms, Vol: 12, Pages: 1-10, ISSN: 1754-8403
Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the TLR-7 agonist Resiquimod induces auto-antibodies and systemic tissue damage including in the heart, and is used as an inducible mouse model of Systemic Lupus Erythematosus (SLE).Here, we show that over-activation of the TLR-7 pathway of viral recognition by Resiquimod-treatment of CFN mice induces severe thrombocytopenia and internal bleeding which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results to ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed a detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes.In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis will improve interpretation of disease mechanisms and diagnostic sensitivity.
Björnmalm M, Wong LM, Wojciechowski J, et al., 2019, In vivo biocompatibility and immunogenicity of metal-phenolic gelation, Publisher: ChemRxiv
In vivo forming hydrogels are of interest for diverse biomedical applications due to their ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled using metal–phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. Ti<sup>IV </sup>or Zr<sup>IV</sup>) provide a versatile and robust platform for engineering such materials. However, the in situ formation and in vivo response to this new class of materials has not yet been reported. Here, we demonstrate that metal–phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. The Ti<sup>IV</sup>–tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivo gelation), Ti<sup>IV</sup>–tannic acid materials show substantially improved in vitro drug loading and release profile for the corticosteroid dexamethasone (from <1 day to >10 days). These results provide essential in vivo characterization for this new class of metal–phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug delivery and regenerative medicine.<br>
Björnmalm M, Wong LM, Wojciechowski J, et al., 2019, In Vivo Biocompatibility and Immunogenicity of Metal-Phenolic Gelation, Publisher: Royal Society of Chemistry
<jats:p>In vivo forming hydrogels are of interest for diverse biomedical applications due to their ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled using metal–phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. Ti<sup>IV </sup>or Zr<sup>IV</sup>) provide a versatile and robust platform for engineering such materials. However, the in situ formation and in vivo response to this new class of materials has not yet been reported. Here, we demonstrate that metal–phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. The Ti<sup>IV</sup>–tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivo gelation), Ti<sup>IV</sup>–tannic acid materials show substantially improved in vitro drug loading and release profile for the corticosteroid dexamethasone (from <1 day to >10 days). These results provide essential in vivo characterization for this new class of metal–phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug delivery and regenerative medicine.<br></jats:p>
Ferrini A, Stevens MM, Sattler S, et al., 2019, Toward regeneration of the heart: Bioengineering strategies for immunomodulation, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X
Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF development. Two newly emerging fields of biomedical research, immunomodulatory therapies and cardiac bioengineering, provide potential options to target the causative mechanisms underlying HF development. Combining these two fields to develop biomaterials for delivery of immunomodulatory bioactive molecules holds great promise for HF therapy. Specifically, minimally invasive delivery of injectable hydrogels, loaded with bioactive factors with angiogenic, proliferative, anti-apoptotic and immunomodulatory functions, is a promising route for influencing the cascade of immune events post-MI, preventing adverse left ventricular remodeling, and offering protection from early inflammation to fibrosis. Here we provide an updated overview on the main injectable hydrogel systems and bioactive factors that have been tested in animal models with promising results and discuss the challenges to be addressed for accelerating the development of these novel therapeutic strategies.
Sintou A, Rifai SE, Mansfield C, et al., 2019, Persistent anti-heart autoimmunity causes cardiomyocyte damage in chronic heart failure, Publisher: bioRxiv
Although clinicians and researchers have long appreciated the detrimental effects of excessive acute inflammation after myocardial infarction (MI), less is known about the role of the adaptive immune system in MI complications including heart failure. Yet, abundant cardiac self-antigens released from necrotic cardiomyocytes in a highly inflammatory environment are likely to overwhelm peripheral mechanisms of immunological self-tolerance and adaptive auto-reactivity against the heart may cause ongoing tissue destruction and exacerbate progression to chronic heart failure (CHF). Here, we confirm that the adaptive immune system is indeed persistently active in CHF due to ischemic heart disease triggered by MI in rats. Heart draining mediastinal lymph nodes contain active secondary follicles with mature class-switched IgG2a positive cells, and mature anti-heart auto-antibodies binding to cardiac epitopes are still present in serum as late as 16 weeks after MI. When applied to healthy cardiomyocytes in vitro, humoral factors present in CHF serum promoted apoptosis, cytotoxicity and signs of hypertrophy. These findings directly implicate post-MI autoimmunity as an integral feature of CHF progression, constituting a roadblock to effective regeneration and a promising target for therapeutic intervention.
Sanghera C, Wong LM, Panahi M, et al., 2019, Cardiac phenotype in mouse models of systemic autoimmunity, Disease Models & Mechanisms, Vol: 12, ISSN: 1754-8403
Patients suffering from systemic autoimmune diseases are at significant risk of cardiovascular complications. This can be due to systemically increased levels of inflammation leading to accelerated atherosclerosis, or due to direct damage to the tissues and cells of the heart. Cardiac complications include an increased risk of myocardial infarction, myocarditis and dilated cardiomyopathy, valve disease, endothelial dysfunction, excessive fibrosis, and bona fide autoimmune-mediated tissue damage by autoantibodies or auto-reactive cells. There is, however, still a considerable need to better understand how to diagnose and treat cardiac complications in autoimmune patients. A range of inducible and spontaneous mouse models of systemic autoimmune diseases is available for mechanistic and therapeutic studies. For this Review, we systematically collated information on the cardiac phenotype in the most common inducible, spontaneous and engineered mouse models of systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis. We also highlight selected lesser-known models of interest to provide researchers with a decision framework to choose the most suitable model for their study of heart involvement in systemic autoimmunity.
Sattler S, Couch LS, Harding SE, 2018, Takotsubo Syndrome: Latest addition to the expanding family of immune-mediated diseases?, JACC: Basic to Translational Science, Vol: 3, Pages: 779-781, ISSN: 2452-302X
Sattler S, Ng FS, Panahi M, 2018, Immunopharmacology of post-myocardial infarction and heart failure medications, Journal of Clinical Medicine, Vol: 7, ISSN: 2077-0383
The immune system responds to acute tissue damage after myocardial infarction (MI) and orchestrates healing and recovery of the heart. However, excessive inflammation may lead to additional tissue damage and fibrosis and exacerbate subsequent functional impairment, leading to heart failure. The appreciation of the immune system as a crucial factor after MI has led to a surge of clinical trials investigating the potential benefits of immunomodulatory agents previously used in hyper-inflammatory conditions, such as autoimmune disease. While the major goal of routine post-MI pharmacotherapy is to support heart function by ensuring appropriate blood pressure and cardiac output to meet the demands of the body, several drug classes also affect a range of immunological pathways and modulate the post-MI immune response, which is crucial to take into account when designing future immunomodulatory trials. This review outlines how routine post-MI pharmacotherapy affects the immune response and may thus influence post-MI outcomes and development towards heart failure. Current key drug classes are discussed, including platelet inhibitors, statins, β-blockers, and renin–angiotensin–aldosterone inhibitors.
Panahi M, Papanikolaou A, Torabi A, et al., 2018, Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition, Cardiovascular Research, Vol: 114, Pages: 1445-1461, ISSN: 1755-3245
Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies.
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