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Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter–defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment. Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and impaired contractility without an underlying ischaemic origin. DCM has heterogeneous aetiologies (including gene mutations, infections and inflammation) and clinical presentations and can eventually result in heart failure.

Plasminogen activator inhibitor-1 (PAI-1) has a cardioprotective function in mice by repressing cardiac fibrosis through TGF-β and plasminogen-mediated pathways. In addition it is known to be involved in the recruitment and polarization of monocytes/macrophages towards a M2 phenotype in cancer. Here, we investigated the expression of PAI-1 in human dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi) and its effect on cardiac fibrosis and macrophage polarization. We retrospectively analyzed endomyocardial biopsies (EMBs) of patients with DCM or DCMi for PAI-1 expression by immunohistochemistry. Furthermore, EMBs were evaluated for the content of fibrotic tissue, number of activated myofibroblasts, TGF-β expression, as well as for M1 and M2 macrophages. Patients with high-grade DCMi (DCMi-high, CD3+ lymphocytes > 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 associated with a diminished degree of cardiac fibrosis, decreased levels of TGF-β and reduced number of myofibroblasts. In addition, DCMi-high patients revealed an increased proportion of non-classical M2 macrophages towards classical M1 macrophages, indicating M2 macrophage-favoring properties of PAI-1 in inflammatory cardiomyopathies. Our findings give evidence that elevated expression of cardiac PAI-1 in subjects with high-grade DCMi suppresses fibrosis by inhibiting TGF-β and myofibroblast activation. Moreover, our data indicate that PAI-1 is involved in the polarization of M2 macrophages in the heart. Thus, PAI-1 could serve as a potential prognostic biomarker and as a possible therapeutic target in inflammatory cardiomyopathies.

Erythroparvovirus (B19V) genomes have been detected in various organs of infected individuals including endothelial cells of the heart muscle. However, the role of B19V as a causative pathogen of myocardial damage is still unknown. The majority of reports focus on the presence of viral DNA ignoring proof of viral RNAs as important markers for viral activity. During this study, we established (RT-) qPCR to characterize expression of B19V RNAs (NS1 and VP1/2) in endomyocardial biopsies (EMBs) of 576 patients with unexplained heart failure. 403/576 (70%) EMBs were positive for B19V DNA. B19V mRNAs NS1 and/or VP1/2, indicating viral activity, could be detected in 38.5% of B19V DNA positive samples using the newly established B19V RT-PCRs. 22.1% of samples were characterized by only NS1 mRNA detection while 6.0% revealed only VP1/2 mRNA expression. Detection of both intermediates was successful in 10.4% of samples. Applying the molecular testing, our study revealed that a high proportion (38.5%) of B19V DNA positive EMBs was characterized by viral transcriptional activity. Further prospective studies will evaluate relevance of viral transcription intermediates as a diagnostic marker to differentiate between latent B19V infection and clinically relevant transcriptionally active B19V-infection of the heart muscle.

Aims Since December 2019, the novel coronavirus SARS‐CoV‐2 has spread rapidly throughout China and keeps the world in suspense. Cardiovascular complications with myocarditis and embolism due to COVID‐19 have been reported. SARS‐CoV‐2 genome detection in the heart muscle has not been demonstrated so far, and the underlying pathophysiological mechanisms remain to be investigated. Methods and results Endomyocardial biopsies (EMBs) of 104 patients (mean age: 57.90 ± 16.37 years; left ventricular ejection fraction: 33.7 ± 14.6%, sex: n = 79 male/25 female) with suspected myocarditis or unexplained heart failure were analysed. EMB analysis included histology, immunohistochemistry, and detection of SARS‐CoV‐2 genomes by real‐time reverse transcription polymerase chain reaction in the IKDT Berlin, Germany. Among 104 EMBs investigated, five were confirmed with SARS‐CoV‐2 infected by reverse real‐time transcriptase polymerase chain reaction. We describe patients of different history of symptoms and time duration. Additionally, we investigated histopathological changes in myocardial tissue showing that the inflammatory process in EMBs seemed to permeate vascular wall leading to small arterial obliteration and damage. Conclusions This is the first report that established the evidence of SARS‐CoV‐2 genomes detection in EMBs. In these patients, myocardial injury ischaemia may play a role, which could explain the ubiquitous troponin increases. EMB‐based identification of the cause of myocardial injury may contribute to explain the different evolution of complicated SARS‐CoV‐2‐infection and to design future specific and personalized treatment strategies.

Myocarditis and inflammatory cardiomyopathy are inflammatory diseases of the heart muscle that can have both infectious and non-infectious causes. They can be caused by an unresolved viral infection or other infection, or they can be autoimmune, toxic, or allergic in nature. The specific identification of the pathogen and/or confirmation of inflammation can only be achieved through direct tissue analysis using endomyocardial biopsy (EMB), as neither detection of the virus nor assessment of the quality and intensity of the inflammation is possible using non-invasive methods. Accordingly, the removal and analysis of an EMB is considered the diagnostic gold standard in international guidelines and statements. The sudden onset of atypical angina pectoris and initially exertion-dependent dyspnea, as well as arrhythmias, pericardial effusion, and progressive symptoms of heart failure, indicate an acute inflammatory process of the myocardium. In addition, nonspecific symptoms such as fatigue and reduced physical performance may also occur. Diagnostic evaluation includes an electrocardiogram (ECG), cardiac imaging, and laboratory tests. The analysis of the EMB is crucial for a definitive diagnosis and thus for the initiation of an etiology-based, specific and personalized therapy. This includes histological and immunohistochemical inflammation diagnostics as well as molecular virological diagnostics. These enable both the detection of viruses and the assessment of transcriptional virus activity. New analyses using metagenomic next generation sequencing (NGS) techniques provide insights of enormous diagnostic and therapeutic relevance. This applies both to the spectrum of detectable pathogens and to the possibility of confirming transcriptional viral activity. In addition, gene expression profiling enables the differentiation of specific forms of myocardial inflammation (e.g., giant cell myocarditis, cardiac sarcoidosis, and eosinophilic myocarditis) and reduces the influence of “sampling errors” in focal inflammatory processes. The treatment of heart failure or ventricular arrhythmias is always symptomatic according to general evidence-based guidelines. In severe cases, mechanical circulatory support or even a heart transplant may be necessary. Patients with histologically confirmed myocardial inflammation or intramyocardial viral infection can be offered specific, causal, and personalized therapy. These patients can be successfully treated with immunosuppressive or antiviral therapy, which significantly improves the prognosis of the disease.

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14–39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty® (Pfizer-BioNTech) (n = 11), Vaxzevria® (AstraZenica) (n = 2) and Janssen® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4+ and CD8+ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4+ lymphocytic infiltrates indicate an autoimmunological response to the vaccination.

Treatment of hypertension-mediated cardiac damage with left ventricular (LV) hypertrophy (LVH) and heart failure remains challenging. To identify novel targets, we performed comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP). Here, we identified carboxypeptidase X 2 (Cpxm2) as a genetic locus affecting LV mass. Analysis of isolated rat cardiomyocytes and cardiofibroblasts indicated Cpxm2 expression and intrinsic upregulation in genetic hypertension. Immunostaining indicated that CPXM2 associates with the t-tubule network of cardiomyocytes. The functional role of Cpxm2 was further investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA). WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage, including increases in LV masses and diameters, impairment of LV systolic and diastolic function and reduced ejection fraction. These changes were significantly ameliorated or even normalized (i.e., ejection fraction) in KO-DOCA animals. LV transcriptome analysis showed a molecular cardiac hypertrophy/remodeling signature in WT but not KO mice with significant upregulation of 1234 transcripts, including Cpxm2, in response to DOCA. Analysis of endomyocardial biopsies from patients with cardiac hypertrophy indicated significant upregulation of CPXM2 expression. These data support further translational investigation of CPXM2.

Human parvovirus B19 (B19V) is the predominant virus currently detected in endomyocardial biopsies (EMBs). Recent findings indicate that, specifically, transcriptionally active B19V with detectable viral RNA is of prognostic relevance in inflammatory viral cardiomyopathy. We aimed to evaluate B19V replicative status (viral RNA) and beneficial effects in a sub-collective of the prospective randomized placebo-controlled phase II multi-center BICC-Trial (Betaferon In Chronic Viral Cardiomyopathy) after interferon beta-1b (IFN-β) treatment. EMBs of n = 64 patients with B19V mono-infected tissue were retrospectively analyzed. Viral RNA could be detected in n = 18/64 (28.1%) of B19V DNA positive samples (mean age 51.7 years, 12 male), of whom n = 13 had been treated with IFN-ß. Five patients had received placebo. PCR analysis confirmed in follow-up that EMBs significantly reduced viral RNA loads in n = 11/13 (84.6%) of IFN-ß treated patients (p = 0.001), independently from the IFN-ß dose, in contrast to the placebo group, where viral RNA load was not affected or even increased. Consequently, a significant improvement of left ventricular ejection fraction (LVEF) after treatment with IFN-ß was observed (LVEF mean baseline 51.6 ± 14.1% vs. follow-up 61.0 ± 17.5%, p = 0.03). In contrast, in the placebo group, worsening of LVEF was evaluated in n = 4/5 (80.0%) of patients. We could show for the first-time the beneficial effects from treatment with IFN-ß, suppressing B19V viral RNA and improving the hemodynamic course. Our results need further verification in a larger prospective randomized controlled trial.

Background Enteroviral cardiomyopathy is a life-threatening disease, and detection of enterovirus (EV) RNA in the initial endomyocardial biopsy is associated with adverse prognosis and increased mortality. Some patients with EV infection may spontaneously eliminate the virus and recover, whereas those with virus persistence deteriorate and progress to heart failure. Interferon-beta (IFN-β) therapy eliminates the virus, resulting in increased survival of treated patients. CCR5 is expressed on antigen-presenting cells (both macrophages and dendritic cells) and immune effector cells (T-lymphocytes with memory/effector phenotype and natural killer cells). Its 32-bp deletion (CCR5del32) is the most frequent human coding sequence mutation. This study addresses the correlation of CCR5 polymorphism to the clinical course of EV infection and the necessity for IFN-β treatment. Methods We examined 97 consecutive patients with chronic/inflammatory cardiomyopathy and biopsy-proven EV infection and reliable information on clinical outcomes by CCr5 genotyping. These data were evaluated in relation to virus persistence in follow-up biopsies and survival rates over a 15-year period. Results Genotyping revealed a strong correlation between the CCR5del32 genotype and spontaneous virus clearance with improved outcomes. All patients with CCR5del32 eliminated EV spontaneously and none of them died within the observed period. In the group of untreated CCR5 wildtype patients, 33% died (Kaplan–Meier log-rank p = 0.010). However, CCR5 wildtype individuals treated with IFN-β are more likely to survive than without therapy (Kaplan–Meier log-rank p = 0.004) in identical proportions to individuals with the CCR5del32 genotype. Conclusions These data suggest that CCR5 genotyping is a novel predictive genetic marker for the clinical course of human EV cardiomyopathies. Hereby clinicians can identify those EV positive individuals who will eliminate the virus spontaneously based on CCR5 phenotype and those patients with CCR5 wildtype genotype who would be eligible for immediate antiviral IFN-β treatment to minimize irreversible cardiac damage.

Aims MicroRNAs (miRNAs) might be used as prospective biomarkers for the identification of unexplained heart failure caused by a viral and/or inflammatory process. The aim of this study was to identify and to evaluate prognostic miRNAs in serum of patients with inflammatory heart diseases diagnosed by endomyocardial biopsies. Methods and results After TaqMan® OpenArray® screening of 754 unique circulating miRNAs in serum of biopsy‐proven patients [184 patients with inflammatory and/or virally induced myocardial diseases (DCMi), 25 patients with dilated cardiomyopathy (DCM), and 25 healthy donors], we identified seven miRNAs of interest (P < 0.05). These data have been verified by single qRT–PCR assays in other biopsy‐proven patients (159 patients with viral and/or inflammatory myocardial diseases, 46 patients with DCM, and 60 healthy donors). The expression of let‐7f, miR‐197, miR‐223, miR‐93, and miR‐379 allowed us to differentiate between patients with a virus and/or inflammation and healthy donors (P < 0.05) with the specificity over 93%. Based on the expression of miR‐21 and miR‐30a‐5p, we could sort out patients with DCM from all other study groups (P < 0.05) with the specificity over 95%. Conclusions This miRNA profile provides for the first time a new non‐invasive diagnostic perspective to identify patients with intramyocardial inflammation and/or viral persistence only from single serum sample, independently of prescribed therapy and time of symptoms onset. It allows the early finding of those patients relevant for myocardial biopsy for exact diagnosis and further proscription of causal aetiology‐driven specific treatment.