Myopathic Cardiac Genotypes Increase Risk for Myocarditis.
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ABSTRACT:
SUBMITTER: Kontorovich AR
PROVIDER: S-EPMC8326270 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than in women, but the reasons for the sex difference remain unclear. The aim of this study was to assess whether gene changes in the heart during coxsackievirus B3 (CVB3) myocarditis in male and female BALB/c mice predicted worse DCM in males. Although myocarditis (P = 4.2 × 10(-5)) and cardiac dilation (P = 0.008) were worse in males, there was no difference in viral replication in the heart. Fibrotic remodeling genes, such as tissue inhibitor of metalloproteinase (TIMP)-1 and serpin A 3n, were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement, we showed that testosterone increased cardiac TIMP-1 (P = 0.04), serpin A 3n (P = 0.007), and matrix metalloproteinase (MMP)-8 (P = 0.04) during myocarditis. Testosterone increased IL-1? levels in the heart (P = 0.02), a cytokine known to regulate cardiovascular remodeling, and IL-1? in turn increased cardiac serpin A 3n mRNA (P = 0.005). We found that 39 of 118 (33%) genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including serpin A 3n (3.3-fold change, P = 0.0001). Recombinant serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (P = 0.0008) while decreasing MMP-3 (P = 0.04) and MMP-9 (P = 0.03) levels in the heart. Thus, serpin A 3n was identified as a gene associated with fibrotic cardiac remodeling and progression to DCM in male myocarditis patients and mice.
| S-EPMC3330806 | biostudies-literature
Project description:BackgroundMyocarditis is a known cause of sudden cardiac death of the athlete. The impact of direct chest trauma in at-risk sports or activities in patients with a history of myocarditis has never been demonstrated or studied. We report herein two cases of life-threatening ventricular arrhythmia secondary to non-penetrating blunt chest trauma while playing contact sports.Case summaryThe first patient, a 26-year-old man described a brief loss of consciousness after having received blunt impact to the chest (typical intensity) while playing a rugby match. The loss of consciousness was total and proceeded by rapid and regular palpitations. He had a history of viral myocarditis 10 years prior with a fibrotic sequalae in the inferolateral wall on cardiac magnetic resonance imaging (left ventricular ejection fraction 71%). Right apical ventricular pacing induced a sustained monomorphic ventricular tachycardia reproducing the patient's symptoms. A subcutaneous implantable cardioverter-defibrillator was implanted. The second patient is a 22-year-old professional rugby player with no known notable history. During a match, a direct blow to the chest wall was followed by a cardiac arrest. A ventricular fibrillation was cardioverted to pulseless electrical activity. Patient died despite cardiopulmonary resuscitation. An autopsy identified a myocardial sequela of fibrosis with no acute inflammatory remodelling compatible with a previous myocarditis.DiscussionMyocarditis may increase the risk of life-threatening ventricular arrhythmias caused by blunt impact to the chest, particularly in contact sports. Screening and prevention measures should be considered to reduce this risk.
| S-EPMC8185879 | biostudies-literature
Project description:We aimed to evaluate the outcomes of patients with fulminant myocarditis and investigate the factors associated with mortality. This is a retrospective single-center cohort study that included adult and pediatric patients with fulminant myocarditis treated at Samsung Medical Center between September 2004 and December 2019. The primary outcome was in-hospital mortality. Among 100 patients, 71 underwent veno-arterial extracorporeal membrane oxygenation (ECMO) (ECMO group). Comorbidities were not significantly different between the ECMO and non-ECMO groups. Cardiac enzymes, creatinine, and median sequential organ failure assessment (SOFA) score at intensive care unit admission were significantly different between the groups. Twenty patients (28.7%) in the ECMO group and two (6.9%) in the non-ECMO group died in-hospital (p = 0.02). The significant risk factors of in-hospital mortality were creatine kinase MB fraction (CK-MB) and SOFA score (p = 0.009 and p = 0.001, respectively) in the ECMO group. In the receiver-operating characteristic curve analysis, the cutoffs of SOFA score and CK-MB were 12 and 94.74 ng/mL, respectively. The patients with both variables above the cutoffs showed significantly worse outcomes (p < 0.001). ECMO can be an effective treatment option for fulminant myocarditis. SOFA score and CK-MB are significant risk factors for in-hospital mortality.
| S-EPMC8038703 | biostudies-literature
Project description:The aim of this study was to describe the method used to perform electrogram-guided EMB and correlate electrogram characteristics with pathological and clinical outcomes.Endomyocardial biopsy (EMB) is valuable in determining the underlying etiology of a cardiomyopathy. The sensitivity, however, for focal disorders, such as lymphocytic myocarditis and cardiac sarcoidosis (CS), is low. The sensitivity of routine fluoroscopically guided EMB is low. Abnormal intracardiac electrograms are seen at sites of myocardial disease. However, the exact value of electrogram-guided EMB is unknown.We report 11 patients who underwent electrogram-guided EMB for evaluation of myocarditis and CS.Of 40 total biopsy specimens taken from 11 patients, 19 had electrogram voltage <5 mV, all of which resulted in histopathologic abnormality (100% specificity and positive predictive value). A voltage amplitude cutoff value of 5 mV had substantially higher sensitivity (70% vs. 26%) and negative predictive value (62%) than 1.5 mV. Abnormal electrogram appearance at biopsy site had good sensitivity (67%) and specificity (92%) in predicting abnormal myocardium. Normal signals with voltage >5 mV signified normal myocardium with no significant diagnostic yield. Biopsy results guided therapy in all patients, including 5 with active myocarditis or CS, all of whom subsequently received immunosuppressive therapy. There were no procedural complications.In patients with suspected myocarditis or CS, electrogram-guided EMB targeting sites with abnormal or low-amplitude electrograms may increase the diagnostic yield for detecting abnormal pathological findings.
| S-EPMC4459501 | biostudies-literature
Project description:BackgroundAlthough congenital heart defects (CHDs) are a common and serious group of birth defects, relatively little is known about the causes of these conditions, and there are no established prevention strategies. There is, however, evidence suggesting that the risk of CHDs in general, and conotruncal and related defects (CTRDs) in particular, may be associated with maternal folate status and genetic variants of folate-related genes. Although several folate-related genes have been studied as they relate to CHDs and CTRDs (e.g., MTHFR), others have not been adequately assessed.MethodsCase-parent triads were examined using log-linear analyses to assess the associations between CTRDs and both the genotype inherited by the case and the maternal genotype for the following variants: NAT1 1095C>A, NOS3 894G>T, and TYMS 1494del6. Subgroup analyses were also conducted among cases with classic conotruncal defects and cases with normally related great arteries.ResultsThe results provided little evidence that CTRD risk was associated with the genotype inherited by the case for any of the analyzed variants. However, our results suggest that CTRD risk may be associated with the maternal genotype for NOS3 894G>T (p = 0.024 in the subgroup with normally related great arteries) and TYMS 1494del6 (p = 0.048 in the subgroup with classic conotruncal defects). However, these results were not significant after correcting for multiple comparisons.ConclusionThis study provides further evidence that CTRD risk may be related to variation within folate-pathway genes and suggests that these associations are, at least in part, mediated through the maternal genotype.
| S-EPMC4404296 | biostudies-literature
Project description:Infectious myocarditis is the result of an immune response to a microbial infection of the heart. The blood vessels of the heart, both the intramyocardial microvasculature and the large epicardial coronary arteries, play an important role in the pathogenesis of infectious myocarditis. First of all, in addition to cardiomyocytes, endothelial cells of the cardiac (micro)vasculature are direct targets for infection. Moreover, through the expression of adhesion molecules and antigen presenting Major Histocompatibility Complex molecules, the blood vessels assist in shaping the cellular immune response in infectious myocarditis. In addition, damage and dysfunction of the cardiac (micro)vasculature are associated with thrombus formation as well as aberrant regulation of vascular tone including coronary vasospasm. These in turn can cause cardiac perfusion abnormalities and even myocardial infarction. In this review, we will discuss the role of the cardiac (micro)vasculature in the pathogenesis of infectious myocarditis.
| S-EPMC6010496 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) are improving cancer treatments strikingly. The raising use leads to the augmented occurrence of immune related events. Myocarditis is a rare, but severe form of these adverse events. Nine patients with proven ICI induced myocarditis were subjected to myocardial biopsy. The tissue was used for RNA-seq analyses.
2020-11-01 | E-MTAB-8867 | biostudies-arrayexpress
Project description:Differentiating between sarcoidosis and giant cell myocarditis (GCM) based on clinical presentation is difficult. We present the case of a 57-year-old woman who was initially diagnosed with GCM based on endomyocardial biopsy. The patient was refractory to standard management for GCM and went on to develop bidirectional ventricular tachycardia, a finding suggestive of sarcoidosis. Unfortunately, the patient eventually needed cardiac transplantation. The explanted heart demonstrated cardiac sarcoidosis. Bidirectional ventricular tachycardia has not been demonstrated in GCM, and its presence may help in distinguishing between GCM and cardiac sarcoidosis.
| S-EPMC8712583 | biostudies-literature
Project description:Giant cell myocarditis, but not cardiac sarcoidosis, is known to cause fulminant myocarditis resulting in severe heart failure. However, giant cell myocarditis and cardiac sarcoidosis are pathologically similar, and attempts at pathological differentiation between the two remain difficult. We are presenting a case of fulminant myocarditis that has pathological features suggestive of cardiac sarcoidosis, but clinically mimicking giant cell myocarditis. This patient was treated with cyclosporine and prednisone and recovered well. This case we believe challenges our current understanding of these intertwined conditions. By obtaining a sense of severity of cardiac involvement via delayed hyperenhancement of cardiac magnetic resonance imaging, we were more inclined to treat this patient as giant cell myocarditis with cyclosporine. This resulted in excellent improvement of patient's cardiac function as shown by delayed hyperenhancement images, early perfusion images, and SSFP videos.
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Project description:In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF-secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17-producing T cells and IL-17-promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option.
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