Inflammatory Dilated Cardiomyopathy Research Articles

Low-intensity pulsed ultrasound protects from inflammatory dilated cardiomyopathy through inciting extracellular vesicles.

CD4+ T cells are activated during inflammatory dilated cardiomyopathy (iDCM) development to induce immunogenic responses that damage the myocardium. Low-intensity pulsed ultrasound (LIPUS), a novel physiotherapy for cardiovascular diseases, has recently been shown to modulate inflammatory responses. However, its efficacy in iDCM remains unknown. Here, we investigated whether LIPUS could improve the severity of iDCM by orchestrating immune responses and explored its therapeutic mechanisms. In iDCM mice, LIPUS treatment reduced cardiac remodelling and dysfunction. Additionally, CD4+ T cell inflammatory responses were suppressed. LIPUS increased Treg cells while decreasing Th17 cells. LIPUS mechanically stimulates endothelial cells, resulting in increased secretion of extracellular vesicles (EVs), which are taken up by CD4+ T cells and alter their differentiation and metabolic patterns. Moreover, EVs selectively loaded with microRNA (miR)-99a are responsible for the therapeutic effects of LIPUS. The hnRNPA2B1 translocation from the nucleus to the cytoplasm and binding to caveolin-1 and miR-99a confirmed the upstream mechanism of miR-99a transport. This complex is loaded into EVs and taken up by CD4+ T cells, which further suppress mTOR and TRIB2 expression to modulate cellular differentiation. Our findings revealed that LIPUS uses an EV-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM.

The Role of Rituximab in the Management of Heart Failure

Rituximab is a chimeric monoclonal antibody mice/humans that bind the transmembrane antigen, CD20 specifically. The mechanism of heart failure is mediated by neurohormonal pathways: the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and the natriuretic peptide system, thereby triggering activation of the immune system. This literature review will discuss the role of B cell targeted therapy, in this case rituximab in the management of heart failure. Modulation of the immune response holds great promise in the 30% of cases of myocarditis where inflammation does not resolve and progression to chronic inflammatory dilated cardiomyopathy occurs. Pharmacologically, rituximab is a monoclonal immunoglobulin G1 antibody drug that is given intravenously. Rituximab targets the CD20 antigen expressed on the surface of mature B lymphocytes, including memory B cells but not on stem cells or plasma cells. In conclusion, rituximab causes a selective and temporary decrease in the CD20+ B cell subpopulation and represents a more specific and targeted approach to B cell-induced disorders including heart failure.

Genetic dilated cardiomyopathy with inflammation in an infant that responded to immunosuppressive therapy evaluated using cardiovascular magnetic resonance.

Cardiovascular magnetic resonance T1 and T2 mapping reflects inflammation, fibrosis, and myocardial oedema. However, its application in infants remains uncertain. Herein, we report a three-month-old boy with dilated cardiomyopathy successfully treated with steroids. Cardiovascular magnetic resonance was useful for diagnosis based on the elevated native T1, T2, and extracellular volume and evaluation of response to immunosuppressive therapy in infantile inflammatory dilated cardiomyopathy.

A clinical case of viral myocarditis associated with sars-cov-2 in a health worker

The study of various pathological conditions associated with COVID-19 remains an urgent task. In occupational medicine, COVID-19 is considered as a new biological factor that can occur not only in the environment, but also in production conditions. Medical workers are at an increased risk of infection with the SARS-CoV-2 virus when performing their professional duties, while a new coronavirus infection can be considered as an occupational disease. The presence of severe complications of a new coronavirus infection leading to disability gives relevance to the analysis of the features of occupational diseases of medical workers in order to improve their diagnosis, improve prevention, treatment and rehabilitation. The most important manifestation of a new coronavirus infection is a lesion of the cardiovascular system, one of the possible variants of which may be the development of myocarditis. In the Samara region in 2021–2022, 10 cases of chronic occupational diseases associated with a new coronavirus infection that caused permanent disability were identified to medical workers. Of these, viral myocarditis was diagnosed in four cases and inflammatory dilated cardiomyopathy in one case. The presented clinical case reflects one of the possible serious complications of coronavirus infection – myocarditis, which led to the development of cardiac arrhythmias. The article presents the principles and results of a medical examination conducted in order to establish a causal relationship of the disease with the professional activity of a medical worker. The need for a multidisciplinary approach to the diagnosis of manifestations, treatment of COVID-19 and its complications, with the mandatory participation of a cardiologist, improvement of the examination of the connection of COVID-19 with the profession and admission to work in conditions of high risk of infection with SARS-CoV-2 medical workers is emphasized.

Inflammatory dilated cardiomyopathy associated with psoriasis: a case report

BackgroundPsoriasis is a chronic inflammatory skin disease with a genetic basis. Psoriasis is accepted as a systemic, immune-mediated disease. Hypertension, obesity, metabolic disorders including diabetes mellitus and hyperlipidemia, and psychiatric disorders are more prevalent among children with psoriasis compared to children without psoriasis. In this study, we report a case of dramatic response of inflammatory cardiomyopathy to anti-inflammatory treatment of psoriasis; which might reveal similar pathogenesis basis of these two diseases.Case presentationA 9-year-old Caucasian boy presenting with signs and symptoms of heart failure refractory to conventional therapies was admitted to our pediatric cardiology service. As the patient also had psoriasis, and considering the fact that there might be an association between the two conditions, immunosuppressive drugs were administered, which led to a dramatic improvement in heart function.ConclusionsThe results of this study add to evidence linking psoriasis with inflammatory dilated cardiomyopathy. Clinicians, particularly cardiologists, must pay special attention to the cardiac complications of systemic diseases.

Does aetiology of dilated cardiomyopathy impact the outcome in Eastern Europe?

Abstract Introduction There are regional variations (West vs. East vs. North vs. South) in aetiology and outcomes in patients with cardiomyopathies according to EORP Registry. However, those preliminary observations have not been systematically verified. Here we report on the large cohort of dilated cardiomyopathy (DCM) patients managed in a tertiary centre in Eastern Europe. Purpose Analysis of all-cause mortality in DCM patients with different aetiology. Methods 500 DCM patients (aged 53.1±13.6 years, 81% male, LVEF 26.6±10.4%, LVEDd 65.9±10.3mm, symptoms duration 38.6±61.2 months) from 2010-2021 with complete baseline and follow-up data were included retrospectively. DCM aetiology was diagnosed according to medical documentation as: idiopathic, inflammatory, toxic: alcohol-induced or other (including chemotherapy and drug-induced), arrhythmic and familial or genetic (ref genetic). After mean follow-up (FU) of 45.6±31.0 months, the all-cause mortality and composite endpoint (all-cause mortality, heart transplant – HTX, left ventricle assist device implantation - LVAD) were assessed. Results Out of 500 DCM patients no clear aetiology was found in 41% of patients (idiopathic DCM). The most common was inflammatory DCM, followed by alcohol-induced, arrhythmic, and genetic DCM (Figure 1-A). The least common was toxic DCM (18 - after chemotherapy, 2 – drug-induced). During FU there were 97 (19%) patients with the following events: 88 (18%) patients died, 7 (1%) had LVAD and 15 (3%) had HTX (Figure 1-B). Statistically, all groups did not differ in terms of events (all p>0.05), however on the Kaplan-Meier plot patients with toxic DCM (chemotherapy or drug-induced) had the worst outcome while patients with inflammatory DCM had the best outcome during 6-years FU (Figure 1-C, 1-D). Conclusion More than one-third of DCM patients were diagnosed with idiopathic DCM. Toxic DCM was the second most prevalent aetiology and was diagnosed in nearly a quarter of patients. Alcohol-induced DCM was present in every fifth of patients. Although statistically no difference in outcome was found, according to Kaplan-Meier curves, patients with inflammatory DCM have the best prognosis and those with chemotherapy- or drug-induced – the worst.Figure 1.

Interleukin-17 and interferon-gamma in patients with different forms of non-ischemic cardiomyopathies

Abstract Introduction Dilated cardiomyopathy (DCM) characterized by left ventricular dilation and impaired left ventricular function represents a common and severe cause of heart failure (HF). Predominantly affecting younger patients, it is considered a leading cause for sudden cardiac death and heart transplantation. Several studies identified myocarditis as a substantive precursor and potential cause of DCM. Inflammatory cardiomyopathy (DCMi) can lead to cardiomyocytal damage and exposure of cardiac myosin and other heart proteins. This cascade can in susceptible individuals trigger an altered immune response consecutively leading to autoimmunity and chronic inflammation. A variety of inflammatory and immunologic agents are discussed to be involved in the pathophysiology of myocardial inflammation. Several studies suggested a role of Interleukin -17 (IL-17) and Interferon-γ (IFN-γ) in chronic HF, myocardial infarction and other cardiovascular diseases. Underlying pathomechanisms, however, are poorly understood. Methods In this study we measured IL-17 and IFN-γ levels in serum by ELISA in patients in which an endomyocardial biopsy (EMB) was performed due to chronic unexplained heart failure symptoms after exclusion of ischemic or valvular heart disease at our center. All patients underwent transthoracic echocardiography prior to EMB sampling. Patients were classified according to the histological presence of inflammation into DCMi, DCM and patients with preserved left ventricular ejection fraction (LVEF) without inflammation. EMB specimens were analyzed including histology, immunohistochemistry and molecular virology. Results A total of 289 patients were included into the final analysis. Mean age was 47 years and 71% were male. Mean LVEF was 50% and mean left ventricular end-diastolic diameter (LVEDD) was 57 mm. Based on EMB results, 71 (25%) samples were categorized as DCMi and 113 (39%) as DCM. 105 (36%) samples were assigned to the group without myocardial inflammation and normal LVEF. The groups differed significantly in their inflammatory profiles. Levels of IL-17 (p < 0.001) and IFN-γ (p < 0.01) were significantly higher in patients with DCMi compared to the DCM as well as the normal LVEF group (Figure 1, Figure 2). Therefore, this effect is not specific for heart failure, but seems to be an important mediator in inflammatory cardiomyopathy. Conclusion Our data showed a significant elevation of IL-17 and IFN-γ in patients with inflammatory dilated cardiomyopathy. These findings suggest that these agents play an important role in the disease entity development and progression that remains poorly understood. So far treatment strategies in DCMi are unspecific. Therefore, blocking IL-17 expression could be an interesting potential therapeutic target in future (personalized) treatment for a wide group of patients with heart failure generated by inflammatory causes.Serum IL-17 levels.t-SNE analysis of the different groups.

COVID-19‑associated myocarditis: clinical picture, diagnosis, and assessment of the causal relationship between the disease and occupation in a healthcare worker (clinical case)

One of the most serious complications of the novel coronavirus infection is damage to the cardiovascular system, the main variants of which are acute and chronic myocarditis, as well as decompensation of existing cardiovascular diseases. Clinical manifestations of myocardial damage can be non-specific and blurred, with unknown long-term consequences for the patient. Therapy carried out in COVID-19 patients presents a potential threat to the myocardium. In the Samara Region in 2021–2022, medical workers were diagnosed with 10 cases of chronic occupational diseases associated with the novel coronavirus infection, which caused permanent disability. Of these, four patients were diagnosed with viral myocarditis, and one case was inflammatory dilated cardiomyopathy. The article presents a clinical case of the development of myocarditis associated with the novel coronavirus infection in a healthcare worker, with the establishment of its causal relationship with professional activities. The need for a multidisciplinary approach to the diagnosis and treatment of COVID-19, with the mandatory par ticipation of a cardiologist, is emphasized.

MicroRNAs as novel biomarkers and potential therapeutic options for inflammatory cardiomyopathy.

Inflammation of the heart is a complex biological and pathophysiological response of the immune system to a variety of injuries leading to tissue damage and heart failure. MicroRNAs (miRNAs) emerge as pivotal players in the development of numerous diseases, suggesting their potential utility as biomarkers for inflammation and as viable candidates for therapeutic interventions. The primary aim of this investigation was to pinpoint and assess particular miRNAs in individuals afflicted by virus-negative inflammatory dilated cardiomyopathy (DCMi). The study involved the analysis of 152 serum samples sourced from patients diagnosed with unexplained heart failure through endomyocardial biopsy. Among these samples, 38 belonged to DCMi patients, 24 to DCM patients, 44 to patients displaying inflammation alongside diverse viral infections, and 46 to patients solely affected by viral infections without concurrent inflammation. Additionally, serum samples from 10 healthy donors were included. The expression levels of 754 distinct miRNAs were evaluated using TaqMan OpenArray. MiR-1, miR-23, miR-142-5p, miR-155, miR-193, and miR-195 exhibited exclusive down-regulation solely in DCMi patients (P<0.005). These miRNAs enabled effective differentiation between individuals with inflammation unlinked to viruses (DCMi) and all other participant groups (P<0.005), boasting a specificity surpassing 86%. The identification of specific miRNAs offers a novel diagnostic perspective for recognizing intramyocardial inflammation within virus-negative DCMi patients. Furthermore, these miRNAs hold promise as potential candidates for tailored therapeutic strategies in the context of virus-negative DCMi.

Sex and age differences in AMPK phosphorylation, mitochondrial homeostasis, and inflammation in hearts from inflammatory cardiomyopathy patients.

Linked to exacerbated inflammation, myocarditis is a cardiovascular disease, which may lead to dilated cardiomyopathy. Although sex and age differences in the development of chronic myocarditis have been postulated, underlying cellular mechanisms remain poorly understood. In the current study, we aimed to investigate sex and age differences in mitochondrial homeostasis, inflammation, and cellular senescence. Cardiac tissue samples from younger and older patients with inflammatory dilated cardiomyopathy (DCMI) were used. The expression of Sirt1, phosphorylated AMPK, PGC-1α, Sirt3, acetylated SOD2, catalase, and several mitochondrial genes was analyzed to assess mitochondrial homeostasis. The expression of NF-κB, TLR4, and interleukins was used to examine the inflammatory state in the heart. Finally, several senescence markers and telomere length were investigated. Cardiac AMPK expression and phosphorylation were significantly elevated in male DCMI patients, whereas Sirt1 expression remained unchanged in all groups investigated. AMPK upregulation was accompanied by a preserved expression of all mitochondrial proteins/genes investigated in older male DCMI patients, whereas the expression of TOM40, TIM23, and the mitochondrial oxidative phosphorylation genes was significantly reduced in older female patients. Mitochondrial homeostasis in older male patients was further supported by the reduced acetylation of mitochondrial proteins as indicated by acetylated SOD2. The inflammatory markers NF-κB and TLR4 were downregulated in older male DCMI patients, whereas the expression of IL-18 was increased in older female patients. This was accompanied by progressed senescence in older DCMI hearts. In conclusion, older women experience more dramatic immunometabolic disorders on the cellular level than older men.

Immunopathogenesis and immunomodulatory therapy for myocarditis.

Myocarditis is an inflammatory cardiac disease characterized by the destruction of myocardial cells, infiltration of interstitial inflammatory cells, and fibrosis, and is becoming a major public health concern. The aetiology of myocarditis continues to broaden as new pathogens and drugs emerge. The relationship between immune checkpoint inhibitors, severe acute respiratory syndrome coronavirus 2, vaccines against coronavirus disease-2019, and myocarditis has attracted increased attention. Immunopathological processes play an important role in the different phases of myocarditis, affecting disease occurrence, development, and prognosis. Excessive immune activation can induce severe myocardial injury and lead to fulminant myocarditis, whereas chronic inflammation can lead to cardiac remodelling and inflammatory dilated cardiomyopathy. The use of immunosuppressive treatments, particularly cytotoxic agents, for myocarditis, remains controversial. While reasonable and effective immunomodulatory therapy is the general trend. This review focuses on the current understanding of the aetiology and immunopathogenesis of myocarditis and offers new perspectives on immunomodulatory therapies.

FOXO3A acts as immune response modulator in human virus-negative inflammatory cardiomyopathy

ObjectiveInflammatory cardiomyopathy is characterised by inflammatory infiltrates leading to cardiac injury, left ventricular (LV) dilatation and reduced LV ejection fraction (LVEF). Several viral pathogens and autoimmune phenomena may cause cardiac...

DILATED CARDIOMYOPATHY WITH CARDIOGENIC SHOCK SECONDARY TO COVID-19 INFECTION

DILATED CARDIOMYOPATHY WITH CARDIOGENIC SHOCK SECONDARY TO COVID-19 INFECTION

Cardiac MRI in nonischemic cardiomyopathies

HintergrundDie in Deutschland angewandte Einteilung der Kardiomyopathien geht auf die Klassifikation der Europäischen Gesellschaft für Kardiologie (ESC) von 2008 zurück. Dort werden sie nach ihrem Phänotyp unterteilt, so dass die Magnetresonanztomographie (MRT) in der Lage ist, die unterschiedlichen Kardiomyopathien zu differenzieren.Bildgebung und DifferenzialdiagnostikDie Stärke der MRT ist es, anhand der Möglichkeiten der Gewebsdifferenzierung nichtischämische Kardiomyopathien von anderen Erkrankungen mit ähnlichen morphofunktionellen Aspekten zu differenzieren. So gelingt im Fall der dilatativen Kardiomyopathie (DCM) eine Differenzierung zur inflammatorischen DCM. Im Fall der hypertrophen Kardiomyopathie (HCM) kann analog zur Echographie eine obstruktive und nichtobstruktive Form differenziert werden, aber auch die Detektion einer Amyloidose oder eines Morbus Fabry ist möglich. Die Evaluation der rechtsventrikulären Funktion gelingt im Rahmen einer arrhythmogenen rechtsventrikulären Kardiomyopathie (ARVC) zuverlässig. Außerdem ist die MRT in der Lage, die charakteristische fettige Ersatzfibrose direkt nachzuweisen. Bei den seltenen restriktiven Kardiomyopathien kann sie die Restriktion nachvollziehen und z. B. mittels T1-, T2- und T2*-Mapping die Sphingolipid-Akkumulation im Myokard bei einem Morbus Fabry oder eine Eisenüberladung bei Hämochromatose nachvollziehen.InnovationenDie quantitativen Verfahren des parametrischen Mappings bieten die Möglichkeit eines Therapiemonitorings; die klinische Relevanz dieses Monitorings ist aber noch Gegenstand aktueller Forschung. Die unklassifizierten Kardiomyopathien können sich klinisch mit ähnlicher Symptomatik wie ischämische oder inflammatorische Erkrankungen präsentieren, so dass im Fall eines Myokardinfarkts ohne verschlossene Koronararterien („myocardial infarction without obstructive coronary arteries“, MINOCA) in der Herzkatheteruntersuchung die MRT ein entscheidendes diagnostisches Instrument ist, um die tatsächlich zugrundeliegende Erkrankung festzustellen. Gleichermaßen kann sie bei neuen Kardiomyopathien wie der Non-compaction-Kardiomyopathie der Wegbereiter für eine morphologische Krankheitsdefinition sein.

Implication of inflammation on Coxsackie virus and Adenovirus receptor expression on cardiomyocytes and the role of platelets in patients with dilated cardiomyopathy

BackgroundCoxsackie Virus and Adenovirus Receptor (CXADR or CAR) is involved in the pathogenesis of inflammatory dilated cardiomyopathy (DCM). We aimed to examine the relationship of CAR expression on platelets and cardiomyocytes with virus persistence, local and systemic inflammation and platelet activity in patients with DCM. MethodsEndomyocardial biopsy (EMB) samples of 38 patients (mean age 39.5±11.3 years, 20 male) with DCM were analyzed for CAR expression, local inflammation grade by immunohistochemistry and virus persistence by real-time PCR. Platelet morphology was analyzed in all patients and 30 healthy subjects (HS) using scanning electron microscopy, platelet activity by light transmission aggregation, and CAR persistence by immunofluorescence. Platelets of 20 patients were analyzed for cytomegalovirus and herpes simplex virus 1-2 by immunofluorescence. Serum levels of tumor necrosis factor alpha (TNF α) and Interleukin-6 were assessed using ELISA in all studied subjects. ResultsCAR expression in EMB samples was related to the heart failure functional class and the level of IL-6. Platelets from DCM patients showed enhanced spontaneous and ADP induced aggregation. Platelets’ CAR expression was >4 fold higher in DCM than HS and was observed predominantly at sites of intercellular communications in microaggregates and leukocyte-platelet aggregates. CAR-positive patients showed significantly higher TNF-α and IL-6 serum levels in CAR-negative patients. Platelets of 6 (30%) DCM patients revealed the mature cytomegalovirus and herpes simplex viruses particles. ConclusionTight junction protein CAR may serve as a docking pin creating a new type of contact structure that could be responsible for signaling between neighboring cells in pathological conditions.

Prevalence and prognostic relevance of myocardial inflammation and cardiotropic viruses in non-ischemic dilated cardiomyopathy.

BackgroundNon-ischemic dilated cardiomyopathy (DCM) is a heterogeneous disease with a spectrum of etiological factors. However, subsets of the disease are not well-characterized with respect to these factors. The aim of this study was to evaluate the prevalence of myocardial inflammation and cardiotropic viruses in DCM patients and their impact on clinical outcome.MethodsFifty-seven patients with DCM underwent endomyocardial biopsy between 2010 and 2013. Biopsies were analyzed by polymerase chain reaction (PCR) for the presence of cardiotropic viruses, and inflammatory cell infiltration was assessed by immunohistochemistry. During a 5-year follow-up, 27 (47%) patients reached the composite outcome measure: heart transplantation, left ventricle assist device implantation or cardiovascular-related death.ResultsThirty-one (54%) patients had myocardial inflammation and cardiotropic viruses were detected in 29 (52%). The most frequent viruses were parvovirus B19 and human herpesvirus type-6. Four specific sub-groups were distinguished by PCR and immunohistochemistry: virus-positive (chronic) myocarditis, autoreactive inflammatory DCM, viral DCM, non-inflammatory DCM. The presence of a viral genome in myocardium or diagnosis of inflammatory DCM did not predict the outcome of composite outcome measures (p > 0.05). However, univariate Cox regression and survival function estimation revealed an association between inflammation by a high number of T-cells and poor prognosis.ConclusionsThis study has shown that two markers — cardiotropic viruses and myocardial inflammation — are prevalent among DCM patients. They are also helpful in identifying sub-groups of DCM. An increased number of T-lymphocytes in the myocardium is a predictor of poor mid-term and long-term prognosis.

Matrix Metalloproteinase 2 and 9 Enzymatic Activities are Selectively Increased in the Myocardium of Chronic Chagas Disease Cardiomyopathy Patients: Role of TIMPs.

Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients.

Abstract 11929: PAI-1 is Cardioprotective in Human Inflammatory Cardiomyopathy

Introduction: Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing fibrosis through TGF-β and plasminogen mediated pathways. Moreover, PAI-1 is suggested to be involved in the recruitment and polarization of M2 macrophages. Hypothesis: Elevated myocardial PAI-1 expression protects from fibrosis and acute inflammatory response. Methods: Endomyocardial biopsies (EMBs) of patients with dilated cardiomyopathy (DCM, n=27) and inflammatory dilated cardiomyopathy (DCMi, n=149) were retrospectively analyzed for PAI-1 expression, markers of fibrosis and M1/M2 macrophage polarization. Results: Patients with high-grade myocardial inflammation (DCMi-high, CD3 + lymphocytes &gt; 30 cells/mm 2 ) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3 + lymphocytes = 14 - 30 cells/mm 2 ) (15.5 ± 0.4 % vs. 1.0 ± 0.1 % and 4.0 ± 0.1 %, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of tissue fibrosis, accompanied by decreased levels of TGF-β and a reduced number of cardiac myofibroblasts. In addition, elevation of PAI-1 led to a shift from M1 to M2 macrophages. Conclusions: Our findings give evidence that increased expression of PAI-1 in DCMi patients suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies.

Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients.

Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients’ myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.

Plasminogen activator inhibitor-1 (PAI-1) is anti-fibrogenic in human inflammatory cardiomyopathy

Abstract Background/Introduction Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing cardiac fibrosis through TGF-β and plasminogen mediated pathways. In addition it is linked to the recruitment and polarization of non-classical M2 macrophages in cancer. Purpose The role of cardiac PAI-1 in fibrogenesis and macrophage polarization is investigated in patients with dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Methods We retrospectively analyzed endomyocardial biopsies (EMBs) of patients with DCM (n=27) and DCMi (n=149) for PAI-1 expression, number of activated myofibroblasts and M1/M2 macrophage polarization. Results Patients with high-grade DCMi (DCMi-high, CD3+ lymphocytes &amp;gt;30 cells/mm2) had significantly increased PAI-1 levels compared to DCM and low grade DCMi patients (DCMi-low, CD3+ lymphocytes = 14 - 30 cells/mm2) (15.5±0.4% vs. 1.0±0.1% and 4.0±0.1%, p≤0.001). Elevated PAI-1 expression in DCMi-high subjects was accompanied by a reduced number of alpha smooth muscle actin (α-SMA) positive myofibroblasts and an increased number of CD16+ CD68+ M2 macrophages, indicating anti-fibrogenic and M2 macrophage-favoring properties of PAI-1 in DCMi. Conclusion Our findings give evidence that elevated expression of PAI-1 suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERA-Net on Cardiovascular Diseases (ERA-CVD) of the German Research Foundation (DFG)Transregional Collaborative Research Center “Inflammatory Cardiomyopathy-Molecular Pathogenesis and Therapy”