ABSTRACT
Viral myocarditis is characterized by infiltration of mononuclear cells essential for virus elimination. GPR15 has been identified as a homing receptor for regulatory T cells in inflammatory intestine diseases, but its role in inflammatory heart diseases is still elusive. Here we show that GPR15 deficiency impairs coxsackievirus B3 elimination, leading to adverse cardiac remodeling and dysfunction. Delayed recruitment of regulatory T cells in GPR15-deficient mice was accompanied by prolonged persistence of cytotoxic and regulatory T cells. In addition, RNA sequencing revealed prolonged inflammatory response and altered chemotaxis in knockout mice. In line, we identified GPR15 and its ligand GPR15L as an important chemokine receptor-ligand pair for the recruitment of regulatory and cytotoxic T cells. In summary, the insufficient virus elimination might be caused by a delayed recruitment of T cells as well as delayed interferon-γ expression, resulting in a prolonged inflammatory response and an adverse outcome in GPR15-deficient mice.
Subject(s)
Coxsackievirus Infections , Disease Models, Animal , Enterovirus B, Human , Mice, Knockout , Myocarditis , Receptors, G-Protein-Coupled , Animals , Myocarditis/immunology , Myocarditis/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/immunology , Coxsackievirus Infections/immunology , Coxsackievirus Infections/genetics , Enterovirus B, Human/immunology , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/immunology , Acute Disease , Interferon-gamma/metabolism , Mice , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Male , Chemotaxis, Leukocyte/genetics , Chemotaxis, Leukocyte/immunology , Myocardium/metabolism , Myocardium/immunology , Myocardium/pathology , Signal TransductionABSTRACT
AIMS: Myocardial inflammation is increasingly detected non-invasively by tissue mapping with cardiovascular magnetic resonance (CMR). Intraindividual agreement with endomyocardial biopsy (EMB) or marker of myocardial injury, high-sensitive troponin (hs-cTnT) in patients with clinically suspected viral myocarditis not understood. METHODS AND RESULTS: Prospective multicentre study of consecutive patients with clinically suspected myocarditis who underwent blood testing for hs-cTnT, CMR and EMB as a part of diagnostic work-up. EMB was considered positive based on immunohistological criteria in line with the ESC definitions. CMR diagnoses employed tissue mapping using sequence-specific cut-off for native T1 and T2 mapping; active inflammation was defined as T1≥2SD and T2≥2SD above the mean of normal range. Hs-cTnT of greater than 13.9ng/1 was considered significant. A total of 114 patients (age (mean±SD) 54±16, 65% males) were included, of which 79(69%) had positive EMB-criteria, 64(56%) CMR criteria, and a total of 58 (51%) positive troponin. Agreement between EMB and CMR diagnostic criteria was poor (CMR vs. ESC: AUCs: 0.51 (0.39-0.62)). The agreement between the significant hs-cTnT rise and CMR-based diagnosis of myocarditis was good (AUC: 0.84 (0.68-0.92); p<0.001), but poor for EMB (0.50 (0.40-0.61). Hs-cTnT was significantly associated with native T1 and T2, hs-CRP and NT-pro BNP (r=0.37, r=0.35, r=0.30, r=0.25 p<0.001), but not immunohistochemical criteria or viral presence. CONCLUSIONS: In clinically suspected viral myocarditis, all diagnostic approaches reflect the pathophysiological elements of myocardial inflammation, however the differing underlying drivers only partially overlap. The EMB and CMR diagnostic algorithms are neither interchangeable in terms of interpretation of myocardial inflammation nor in their relationship with myocardial injury.
ABSTRACT
The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been associated with progressive hemodynamic deterioration. In this paper, we investigate the use of targeted next-generation sequencing (NGS) to detect EBV transcripts and their correlation with myocardial inflammation in EBV-positive patients with heart failure with reduced ejection fraction (HFrEF). Forty-four HFrEF patients with positive EBV DNA detection and varying degrees of myocardial inflammation were selected. EBV-specific transcripts from EMBs were enriched using a custom hybridization capture-based workflow and, subsequently, sequenced by NGS. The short-read sequencing revealed the presence of EBV-specific transcripts in 17 patients, of which 11 had only latent EBV genes and 6 presented with lytic transcription. The immunohistochemical staining for CD3+ T lymphocytes showed a significant increase in the degree of myocardial inflammation in the presence of EBV lytic transcripts, suggesting a possible influence on the clinical course. These results imply the important role of EBV lytic transcripts in the pathogenesis of inflammatory heart disease and emphasize the applicability of targeted NGS in EMB diagnostics as a basis for specific treatment.
Subject(s)
Epstein-Barr Virus Infections , Heart Failure , Herpesvirus 4, Human , Myocarditis , Humans , Herpesvirus 4, Human/genetics , Heart Failure/virology , Heart Failure/genetics , Heart Failure/pathology , Male , Female , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/pathology , Middle Aged , Myocarditis/virology , Myocarditis/pathology , Aged , High-Throughput Nucleotide Sequencing , Myocardium/pathology , Myocardium/metabolism , DNA, Viral/genetics , Adult , BiopsySubject(s)
Myocarditis , Humans , Myocarditis/diagnosis , Myocarditis/pathology , Heart , Myocardium/pathology , BiopsyABSTRACT
Lingering cardiac symptoms are increasingly recognised complications of severe acute respiratory syndrome coronavirus 2 infection, now referred to as post-acute cardiovascular sequelae of COVID-19 (PASC). In the acute phase, cardiac injury is driven by cytokine release and stems from ischaemic and thrombotic complications, resulting in myocardial necrosis. Patients with pre-existing cardiac conditions are particularly vulnerable. Myocarditis due to a direct viral infection is rare. Chronic symptoms relate to either worsening of pre-existing heart disease (PASC - cardiovascular disease) or delayed chronic inflammatory condition due to heterogenous immune dysregulation (PASC - cardiovascular syndrome), the latter affecting a broad segment of previously well people. Both PASC presentations are associated with increased cardiovascular risk, long-term disability and reduced quality of life. The recognition and management of PASC in clinical settings remains a considerable challenge. Sensitive diagnostic methods are needed to detect subtler inflammatory changes that underlie the persistent symptoms in PASC - cardiovascular syndrome, alongside considerable clinical experience in inflammatory cardiac conditions.
ABSTRACT
AIMS: 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). METHODS AND RESULTS: 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%. CONCLUSIONS: 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.
Subject(s)
Cardiomyopathy, Dilated , Heart Failure , MicroRNAs , Myocarditis , Virus Diseases , Humans , Myocarditis/diagnosis , Myocarditis/therapy , Inflammation , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/therapy , Biomarkers , Heart Failure/diagnosis , Heart Failure/therapyABSTRACT
The diagnosis and specific and causal treatment of myocarditis and inflammatory cardiomyopathy remain a major clinical challenge. Despite the rapid development of new imaging techniques, endomyocardial biopsies remain the gold standard for accurate diagnosis of inflammatory myocardial disease. With the introduction and continued development of immunohistochemical inflammation diagnostics in combination with viral nucleic acid testing, myocarditis diagnostics have improved significantly since their introduction. Together with new technologies such as miRNA and gene expression profiling, quantification of specific immune cell markers, and determination of viral activity, diagnostic accuracy and patient prognosis will continue to improve in the future. In this review, we summarize the current knowledge on the pathogenesis and diagnosis of myocarditis and inflammatory cardiomyopathies and highlight future perspectives for more in-depth and specialized biopsy diagnostics and precision, personalized medicine approaches.
ABSTRACT
BACKGROUND: The role of cardiac magnetic resonance imaging in the early management of chronic cardiac inflammatory conditions is growing. Our case enlightens the benefit of quantitative mapping in the monitoring and treatment guidance in systemic sarcoidosis. CASE PRESENTATION: We report about a 29-year-old man with an ongoing dyspnea and bihilar lymphadenopathy, suggesting sarcoidosis. Cardiac magnetic resonance showed high mapping values, but no scarring. In follow-ups, cardiac remodeling was noted; cardioprotective treatment normalized cardiac function and mapping markers. Definitive diagnosis was achieved in extracardiac lymphatic tissue during a relapse. CONCLUSION: This case shows the role that mapping markers can play in the detection and treatment at early stage of systemic sarcoidosis.
Subject(s)
Cardiomyopathies , Sarcoidosis , Male , Humans , Adult , Cardiomyopathies/diagnosis , Myocardium/pathology , Magnetic Resonance Imaging , Heart , Sarcoidosis/therapyABSTRACT
OBJECTIVE: Inflammatory 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 inflammation.The effects of the gain of function FOXO3A single-nucleotide polymorphism (SNP) rs12212067 on inflammation and outcome were studied in a cohort of patients with inflammatory dilated cardiomyopathy (DCMi) in relation to cardiac viral presence. METHODS: Distribution of the SNP was determined in virus-positive and virus-negative DCMi patients and in control subjects without myocardial pathology. Baseline and outcome data were compared in 221 virus-negative patients with detection of cardiac inflammation and reduced LVEF according to their carrier status of the SNP. RESULTS: Distribution of SNP rs12212067 did not differ between virus-positive (n=22, 19.3%), virus-negative (n=45, 20.4 %) and control patients (n=18, 23.4 %), indicating the absence of susceptibility for viral infection or inflammation per se (p=0.199). Patients in the virus-negative DCMi group were characterised by reduced LVEF 35.5% (95% CI) 33.5 to 37.4) and increased LVEDD (LV end-diastolic diameter) 59.8 mm (95% CI 58.5 to 61.2). Within the group, SNP and non-SNP carriers had similarly impaired LVEF 39.2% (95% CI 34.3% to 44.0%) vs 34.5% (95% CI 32.4 to 36.5), p=0.083, and increased LVEDD 58.9 mm (95% CI 56.3 to 61.5) vs 60.1 mm (95% CI 58.6 to 61.6), p=0.702, respectively. The number of inflammatory infiltrates was not different in both SNP groups at baseline. Outcome after 6 months showed a significant improvement in LVEF and clinical symptoms in SNP rs12212067 carriers 50.9% (95% CI 45.4 to 56.3) versus non-SNP carriers 41.7% (95% CI 39.2 to 44.2), p≤0.01. The improvement in clinical symptoms and LVEF was associated with a significant reduction in cardiac inflammation (ΔCD45RO+ p≤0.05; ΔMac-1+ p≤0.05; ΔLFA-1+ p≤0.01; ΔCD54+ p≤0.01) in the SNP cohort versus non-SNP cohort, respectively. Subgroup analyses identified ΔMac-1+, ΔLFA-1+, ΔCD3+ and Δperforin+ as predictors for improvement in cardiac function in SNP-positive patients. CONCLUSION: FOXO3A might act as modulator of the cardiac immune response, diminishing cardiac inflammation and injury in pathogen-negative DCMi.
Subject(s)
Cardiomyopathy, Dilated , Myocarditis , Humans , Myocarditis/genetics , Ventricular Function, Left , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Inflammation , Stroke Volume , ImmunityABSTRACT
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.
Subject(s)
COVID-19 , Myocarditis , Biopsy , CD8-Positive T-Lymphocytes , COVID-19 Vaccines/adverse effects , Humans , Inflammation/etiology , Male , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination/adverse effectsABSTRACT
SCN5A was considered an exclusively cardiac expressed ion channel but discovered to also act as a novel innate immune sensor. We report on a young SCN5A variant carrier with recurrent ventricular fibrillation and massive myocardial inflammation whose peculiar clinical course is highly suggestive of such a dual role of SCN5A. (Level of Difficulty: Advanced.).
ABSTRACT
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-ß) 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.
Subject(s)
Cardiomyopathies/prevention & control , Endothelium, Vascular/drug effects , Interferon-beta/therapeutic use , Parvoviridae Infections/drug therapy , Parvovirus B19, Human/drug effects , Adult , Aged , Cardiomyopathies/virology , Endothelium, Vascular/pathology , Endothelium, Vascular/virology , Female , Humans , Interferon-beta/pharmacology , Male , Middle Aged , Parvoviridae Infections/complications , Prospective Studies , Retrospective Studies , Stroke Volume/drug effects , Ventricular Function, LeftABSTRACT
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.
Subject(s)
Hypertension , Animals , Carboxypeptidases , Cardiomegaly/genetics , Humans , Hypertrophy, Left Ventricular , Mice , Myocytes, Cardiac , RatsABSTRACT
AIMS: Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. METHODS AND RESULTS: In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset 'Heart Cell Atlas' and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value <0.05 (e.g. up: IFI44L, IFT3, TRIM25; down: NPPB, MB, MYPN). The upregulated DEGs were linked to interferon pathways and originate predominantly from endothelial cells. In contrast, the downregulated DEGs originate predominately from cardiomyocytes. Immunofluorescent staining showed viral protein in cells positive for the endothelial marker ICAM1 but rarely in cardiomyocytes. The Gene Ontology (GO) term analysis revealed that downregulated GO terms were linked to cardiomyocyte structure, whereas upregulated GO terms were linked to anti-virus immune response. CONCLUSION: This study reveals that cardiac infection induced transcriptomic alterations mainly linked to immune response and destruction of cardiomyocytes. While endothelial cells are primarily targeted by the virus, we suggest cardiomyocyte destruction by paracrine effects. Increased pro-inflammatory gene expression was detected in SARS-CoV-2-infected cardiac tissue but no increased SARS-CoV-2 associated immune cell infiltration was observed.
Subject(s)
COVID-19/complications , Heart/virology , SARS-CoV-2/isolation & purification , Transcriptome , Aged , Aged, 80 and over , Autopsy , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Female , Humans , Inflammation/complications , Male , Myocardium/metabolism , Myocardium/pathology , SARS-CoV-2/physiology , Virus ReplicationABSTRACT
Parvovirus B19 (B19V) is the predominant cardiotropic virus currently found in endomyocardial biopsies (EMBs). However, direct evidence showing a causal relationship between B19V and progression of inflammatory cardiomyopathy are still missing. The aim of this study was to analyze the impact of transcriptionally active cardiotropic B19V infection determined by viral RNA expression upon long-term outcomes in a large cohort of adult patients with non-ischemic cardiomyopathy in a retrospective analysis from a prospective observational cohort. In total, the analyzed study group comprised 871 consecutive B19V-positive patients (mean age 50.0 ± 15.0 years) with non-ischemic cardiomyopathy who underwent EMB. B19V-positivity was ascertained by routine diagnosis of viral genomes in EMBs. Molecular analysis of EMB revealed positive B19V transcriptional activity in n = 165 patients (18.9%). Primary endpoint was all-cause mortality in the overall cohort. The patients were followed up to 60 months. On the Cox regression analysis, B19V transcriptional activity was predictive of a worse prognosis compared to those without actively replicating B19V (p = 0.01). Moreover, multivariable analysis revealed transcriptional active B19V combined with inflammation [hazard ratio 4.013, 95% confidence interval 1.515-10.629 (p = 0.005)] as the strongest predictor of impaired survival even after adjustment for age and baseline LVEF (p = 0.005) and independently of viral load. The study demonstrates for the first time the pathogenic clinical importance of B19V with transcriptional activity in a large cohort of patients. Transcriptionally active B19V infection is an unfavourable prognostic trigger of adverse outcome. Our findings are of high clinical relevance, indicating that advanced diagnostic differentiation of B19V positive patients is of high prognostic importance.
ABSTRACT
The diagnosis of acute and chronic myocarditis remains a challenge for clinicians. Characterization of this disease has been hampered by its diverse etiologies and heterogeneous clinical presentations. Most cases of myocarditis are caused by infectious agents. Despite successful research in the last few years, the pathophysiology of viral myocarditis and its sequelae leading to severe heart failure with a poor prognosis is not fully understood and represents a significant public health issue globally. Most likely, at a certain point, besides viral persistence, several etiological types merge into a common pathogenic autoimmune process leading to chronic inflammation and tissue remodeling, ultimately resulting in the clinical phenotype of dilated cardiomyopathy. Understanding the underlying molecular mechanisms is necessary to assess the prognosis of patients and is fundamental to appropriate specific and personalized therapeutic strategies. To reach this clinical prerequisite, there is the need for advanced diagnostic tools, including an endomyocardial biopsy and guidelines to optimize the management of this disease. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has currently led to the worst pandemic in a century and has awakened a special sensitivity throughout the world to viral infections. This work aims to summarize the pathophysiology of viral myocarditis, advanced diagnostic methods and the current state of treatment options.
ABSTRACT
Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.
Subject(s)
COVID-19/virology , Cardiomyopathy, Dilated/virology , Myocarditis/virology , Parvoviridae Infections/virology , Parvovirus B19, Human/pathogenicity , SARS-CoV-2/pathogenicity , Animals , Antiviral Agents/therapeutic use , COVID-19/diagnosis , COVID-19/immunology , COVID-19/therapy , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/immunology , Cardiomyopathy, Dilated/therapy , Genetic Therapy , Host-Pathogen Interactions , Humans , Myocarditis/diagnosis , Myocarditis/immunology , Myocarditis/therapy , Parvoviridae Infections/diagnosis , Parvoviridae Infections/immunology , Parvoviridae Infections/therapy , Parvovirus B19, Human/immunology , SARS-CoV-2/immunology , COVID-19 Drug TreatmentABSTRACT
AIMS: Acute cellular rejection (ACR) following heart transplantation (HTX) is associated with long-term graft loss and increased mortality. Disturbed mitochondrial bioenergetics have been identified as pathophysiological drivers in heart failure, but their role in ACR remains unclear. We aimed to prove functional disturbances of myocardial bioenergetics in human heart transplant recipients with mild ACR by assessing myocardial mitochondrial respiration using high-resolution respirometry, digital image analysis of myocardial inflammatory cell infiltration, and clinical assessment of HTX patients. We hypothesized that (i) mild ACR is associated with impaired myocardial mitochondrial respiration and (ii) myocardial inflammation, systemic oxidative stress, and myocardial oedema relate to impaired mitochondrial respiration and myocardial dysfunction. METHODS AND RESULTS: We classified 35 HTX recipients undergoing endomyocardial biopsy according International Society for Heart and Lung Transplantation criteria to have no (0R) or mild (1R) ACR. Additionally, we quantified immune cell infiltration by immunohistochemistry and digital image analysis. We analysed mitochondrial substrate utilization in myocardial fibres by high-resolution respirometry and performed cardiovascular magnetic resonance (CMR). ACR (1R) was diagnosed in 12 patients (34%), while the remaining 23 patients revealed no signs of ACR (0R). Underlying cardiomyopathies (dilated cardiomyopathy 50% vs. 65%; P = 0.77), comorbidities (type 2 diabetes mellitus: 50% vs. 35%, P = 0.57; chronic kidney disease stage 5: 8% vs. 9%, P > 0.99; arterial hypertension: 59% vs. 30%, P = 0.35), medications (tacrolimus: 100% vs. 91%, P = 0.54; mycophenolate mofetil: 92% vs. 91%, P > 0.99; prednisolone: 92% vs. 96%, P > 0.99) and time post-transplantation (21.5 ± 26.0 months vs. 29.4 ± 26.4 months, P = 0.40) were similar between groups. Mitochondrial respiration was reduced by 40% in ACR (1R) compared with ACR (0R) (77.8 ± 23.0 vs. 128.0 ± 33.0; P < 0.0001). Quantitative assessment of myocardial CD3+ -lymphocyte infiltration identified ACR (1R) with a cut-off of >14 CD3+ -lymphocytes/mm2 (100% sensitivity, 82% specificity; P < 0.0001). Myocardial CD3+ infiltration (r = -0.41, P < 0.05), systemic oxidative stress (thiobarbituric acid reactive substances; r = -0.42, P < 0.01) and myocardial oedema depicted by global CMR derived T2 time (r = -0.62, P < 0.01) correlated with lower oxidative capacity and overt cardiac dysfunction (global longitudinal strain; r = -0.63, P < 0.01). CONCLUSIONS: Mild ACR with inflammatory cell infiltration associates with impaired mitochondrial bioenergetics in cardiomyocytes. Our findings may help to identify novel checkpoints in cardiac immune metabolism as potential therapeutic targets in post-transplant care.
Subject(s)
Diabetes Mellitus, Type 2 , Heart Diseases , Heart Transplantation , Heart Transplantation/adverse effects , Humans , Mitochondria, Heart , Oxidative StressABSTRACT
Human parvovirus B19 (B19V) is the predominant cardiotropic virus associated with dilated inflammatory cardiomyopathy (DCMi). Transcriptionally active cardiotropic B19V infection is clinically relevant and triggers adverse long-term mortality. During the study; we evaluated whether antiviral treatment with the nucleoside analogue telbivudine (LTD) is effective in suppressing transcriptional active B19V in endomyocardial biopsies (EMBs) of B19V positive patients and improving clinical outcomes. Seventeen B19V-positive patients (13 male; mean age 45.7 ± 13.9 years; mean left ventricular ejection fraction (LVEF) 37.7 ± 13.5%) with positive B19V DNA and transcriptional activity (B19V mRNA) in EMBs were treated with 600 mg/d LTD over a period of six months. Patients underwent EMBs before and after termination of the LTD treatment. B19V RNA copy numbers remained unchanged in 3/17 patients (non-responder) and declined or disappeared completely in the remaining 14/17 patients (responder) (p ≤ 0.0001). Notably; LVEF improvement was more significant in patients who reduced or lost B19V RNA (responder; p = 0.02) in contrast to non-responders (p = 0.7). In parallel; responder patients displayed statistically significant improvement in quality of life (QoL) questionnaires (p = 0.03) and dyspnea on exertion (p = 0.0006), reflecting an improvement in New York Heart Association (NYHA) Classification (p = 0.001). Our findings demonstrated for the first time that suppression of B19V transcriptional activity by LTD treatment improved hemodynamic and clinical outcome significantly. Thus; the present study substantiates the clinical relevance of detecting B19V transcriptional activity of the myocardium.