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Objective: To investigate plasma cytokines (interferon gamma, interleukin-4, and interleukin-17) in patients with viral myocarditis (VMC) and evaluate their predictive value in the progression from VMC to dilated cardiomyopathy (DCM)., Methods: A prospective, multicenter, observational study included 536 patients with newly diagnosed VMC admitted in cardiology departments of 24 tertiary super specialised university-affiliated hospitals in the China registry from January 2012 to June 2016. Demographics and clinical characteristics at baseline and after three months were collected, including laboratory blood tests, ECG, echocardiography, and drug treatment in each participating site. The plasma anti-viral antibodies (Abs), anti-heart autoimmune Abs, and cytokines were detected by ELISA., Results: Of the 536 patients, 534 were included for analysis after two patients died in less than a month. The plasma levels of IFN- γ , IL-4, and IL-17 were continually higher in patients with incident DCM than in those without incident DCM at baseline, from the 1st month and the 3rd month; all had a P value of <0.0001. There was a positive correlation between IL-4 and LVEDd ( r = 0.30, P < 0.0001) and between IL-17 and LVEDd ( r = 0.11, P = 0.02). When all these covariates have entered the model simultaneously, elevated IL-4 and IL-17 were still significantly associated with DCM incidence. The RR (95% CI) of DCM incidence were 1.04 (1.02-1.06) for IL-4 and 5.24 (2.81-9.79) for IL-17., Conclusion: The continued elevation of plasma IL-4 and IL-17 in VMC patients were associated with a high incidence of DCM at three months, and these two cytokines were independent predictors for the progression from VMC to DCM., Competing Interests: All authors declared that there is no conflict of interest., (Copyright © 2020 Z. H. Wang et al.)

Purpose: The aim of this study was to quantify the value of various clinical, laboratory, and instrumental signs in the diagnosis of myocarditis in comparison with morphological studies of the myocardium., Methods: In 100 patients (65 men, 44.7 ± 12.5 years old) with "idiopathic" arrhythmias (n = 20) and dilated cardiomyopathy (DCM; n = 80), we performed the following: 71 endomyocardial biopsies (EMB), 13 intraoperative biopsies, 5 studies of explanted hearts, and 11 autopsies with virus investigation (real-time PCR) of the blood and myocardium. Antiheart antibodies (AHA) were also measured as well as cardiac CT (n = 45), MRI (n = 25), and coronary angiography (n = 47). The comparison group included 50 patients (25 men, 53.7 ± 11.7 years old) with noninflammatory heart diseases who underwent open heart surgery., Results: Active/borderline myocarditis was diagnosed in 76.0% of the study group and in 21.6% of patients in the comparison group (p < 0.001). The myocardial viral genome was observed more frequently in patients in the comparison group than in the study group (65.0 and 40.2%; p < 0.01). We evaluated the diagnostic value of noninvasive markers of myocarditis. The panel of AHA had the greatest importance in the identification of myocarditis: sensitivity was 81.5%, and the positive and negative predictive values were 75.0 and 60.5%. This defined the diagnostic value of noninvasive markers of myocarditis and established a diagnostic algorithm providing an individual assessment of the likelihood of myocarditis development., Conclusion: AHA have the greatest significance in the diagnosis of latent myocarditis in patients with "idiopathic" arrhythmias and DCM. The use of a complex of noninvasive criteria allows the probability of myocarditis to be estimated and the indications for EMB to be determined., (© 2019 S. Karger AG, Basel.)

Aim: To determine the diagnostic value of different clinical, laboratory, and instrumental signs in the diagnosis of myocarditis in patients with the picture of idiopathic arrhythmias, dilated cardiomyopathy (DCM) and in a comparison group when comparing with myocardial morphological examination., Subjects and Methods: A study group included 100 patients (35 women; mean age, 44.7±12.5 years) with idiopathic arrhythmias (n=20) and DCM as a syndrome (n=100). All underwent myocardial morphological examination: endomyocardial biopsy (EMB) (n=71), intraoperative biopsy (n=13), study of the explanted heart (n=6), and autopsy (n=11). A comparison group consisted of 50 patients (25 women; mean age, 53.7±11.7 years) with non-inflammatory diseases of the heart (left ventricular end-diastolic dimension <6.0 cm, ejection fraction >50%) who underwent open-heart surgery (n=47), EMB (n=2), or autopsy (n=1). The investigators also performed polymerase chain reaction for cardiotropic viral DNA in the blood and myocardium, anticardiac antibody (ACA) identification, myocardial scintigraphy (n=26), coronary angiography (n=47), magnetic resonance imaging (MRI) (n=25), and multislice computed tomography of the heart (n=45). The diagnostic value of the extended spectrum of clinical, laboratory, and instrumental markers for myocarditis was estimated., Results: Active/borderline myocarditis was diagnosed in 76% of the patients in the study group (75.5% in the arrhythmia subgroup and 76.3% in the DCM one) and in 24.3% of those in the comparison group (p<0.001). A viral genome in the myocardium was detected statistically significantly less frequently in the study group than that in the comparison one (40.2 and 65%, respectively; p<0.01): in 46.6% in the DCM subgroup and 15.8% in the arrhythmia one. An ACA set (sensitivity, specificity, and predictive value of positive and negative test results (45.7, 80, 80.4, and 45%, respectively)) was of the greatest diagnostic importance in identifying myocarditis; antibodies to cardiomyocyte nuclei in a titer of 1:160-1:320 had the highest specificity (93.3%). A specificity above 70% was seen for a full medical history triad (acute onset, an association between onset and infection, a symptom duration of less than one year), systemic immune manifestations, anginas in the history and elevated anti-O-streptolysin levels, systemic blood changes, Q waves/QS complexes on ECGs, local hypokinesias, pericardial effusion, atriomegalia (in arrhythmias), angina/ischemia with intact coronary arteries, and focal perfusion defects during myocardial scintigraphy. A sensitivity higher than 50% was observed for age over 40 years (differential diagnosis with genetic forms), acute onset, a correlation with infection, and delayed contrast agent accumulation, as evidenced by MSCT/MRI., Conclusion: When the incidence of myocarditis is similar in the arrhythmia and DCM subgroups, the viral genome detection rate is statistically significantly higher in DCM. Among the non-invasive markers, an ACA set (high sensitivity and specificity) is of the greatest diagnostic value in the diagnosis of myocarditis. The diagnostic rule based on counting the number of scores has been developed, which makes it possible to individually establish the risk of myocarditis in patients with idiopathic arrhythmias and DCM for both the determination of indications for biopsy and the lack of the possibility of its performance. The risk of myocarditis is high if there are 5-7 scores; that is close to 100% if there are 8 scores or more.

Myocarditis, i.e. inflammation of the myocardium, is one of the leading causes of sudden cardiac death (SCD) and dilated cardiomyopathy (DCM) in young adults, and is an important cause of symptoms such as chest pain, dyspnea and palpitations. The pathophysiological process of disease progression leading to DCM involves an ongoing inflammation as a result of a viral-induced auto-immune response or a persisting viral infection. It is therefore crucial to detect the disease early in its course and prevent persisting inflammation that may lead to DCM and end-stage heart failure. Because of the highly variable clinical presentation, ranging from mild symptoms to severe heart failure, and the limited available diagnostic tools, the evaluation of patients with suspected myocarditis represents an important clinical dilemma in cardiology. New approaches for the diagnosis of myocarditis are needed in order to improve recognition, to help unravel its pathophysiology, and to develop new therapeutic strategies to treat the disease. In this review, we give a comprehensive overview of the current diagnostic strategies for patients with suspected myocarditis, and demonstrate several new techniques that may help to improve the diagnostic work-up., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Procollagen type III amino-terminal propeptide is a collagen III cleavage product released in blood. The serum levels of this propeptide in adults with dilated cardiomyopathy are associated with cardiac remodelling and prognosis. The utility of procollagen type III amino-terminal propeptide as a biomarker in paediatric dilated cardiomyopathy is unknown., Methods: This was a prospective, longitudinal study of children with dilated cardiomyopathy and changes in procollagen type III amino-terminal propeptide. The serum level of propeptide was measured serially, compared with paediatric normal values, and correlated with clinical status and left ventricular size and function on echocardiograms and cardiac magnetic resonance imaging., Results: Procollagen type III amino-terminal propeptide was measured serially in 149 samples from 39 patients, age 9.0±6.4 years, followed up for 16.8±16.3 months. Procollagen type III amino-terminal propeptide in dilated cardiomyopathy was higher than in normal children. On multivariate analyses, procollagen type III amino-terminal propeptide had a positive correlation with left ventricular dilation, left ventricular end-diastolic diameter index (p<0.0001), and left ventricular end-diastolic diameter Z-score (p=0.0003), and a negative correlation with shortening fraction changes over time (p=0.001). Patients with myocarditis (n=12) had higher procollagen type III amino-terminal propeptide values than those with idiopathic dilated cardiomyopathy (n=20)., Conclusions: Procollagen type III amino-terminal propeptide increases with left ventricular dilation and decreases with improvement in systolic function in paediatric dilated cardiomyopathy, indicating a role as a biomarker of cardiac remodelling in children. The diagnostic utility of procollagen type III amino-terminal propeptide to differentiate myocarditis from idiopathic dilated cardiomyopathy warrants further investigation.

Children with myocarditis and dilated cardiomyopathy may recover clinically and echocardiographically. Plasma levels of the N-terminal segment of B-type natriuretic peptide prohormone (NT-proBNP), a sensitive marker for cardiac dysfunction, may reflect residual cardiac damage in these patients. The purpose of this study was to evaluate NT-proBNP status in pediatric patients with a history of myocarditis and dilated cardiomyopathy. Cardiac evaluation was performed and the levels of NT-proBNP were measured in 23 children who had a history of myocarditis or dilated cardiomyopathy. NT-proBNP levels were also measured in 56 age-matched control children. Nine of the 23 patients had evidence of left ventricular dysfunction (DCM group), whereas 14 had none (recovery). NT-proBNP levels were higher in the DCM group (3154 +/- 2858 pg/ml) than in the recovery group (122 +/- 75 pg/ml, p < 0.001) and the control group (113 +/- 96 pg/ml, p < 0.001). There was no difference between the recovery and the control groups (p = 0.45), and none of the recovered patients had a NT-proBNP level higher than the upper limit of normal. The area under the receiver operating characteristics curve for the diagnosis of persistent left ventricular dysfunction was 0.984. NT-proBNP levels correlated with echocardiographically derived shortening fraction and with clinical score. NT-proBNP is a good marker for persistent left ventricular dysfunction in children who have had myocarditis or cardiomyopathy. In this group of patients, NT-proBNP levels are normal in children who recover echocardiographically, suggesting no residual hemodynamic abnormalities.

This study was conducted to assess the use of the serum cardiac troponin T (cTnT) level as a noninvasive indicator to differentiate acute myocarditis and chronic dilated cardiomyopathy in pediatric patients. Myocarditis and dilated cardiomyopathy are clinically difficult to differentiate. Endomyocardial biopsy proved to be quite useful. However, the nature of the procedure--invasiveness, time-consuming, and limited sensitivity--caused some concerns, especially in pediatric patients. Hence, we attempted to find an alternative method that could give a prompt diagnosis of acute myocarditis. Twenty cases with clinically suspected myocarditis or dilated cardiomyopathy and a control group of 21 cases with moderate left-to-right shunt and congestive heart failure were recruited. History, physical examination, electrocardiogram, chest roentgenogram, echocardiogram, cTnT, creatine kinase MB isoenzyme (CK-MB mass), and/or endomyocardial biopsy were compared. The gold standard used to diagnose myocarditis is endomyocardial biopsy (Dallas criteria) and/or recovery from cardiovascular problems within 6 months of follow-up. Ten patients were diagnosed as having myocarditis (group 1) and 10 with chronic dilated cardiomyopathy (group 2). The control group of 21 cases was designated as group 3. The median serum cTnT levels were 0.088 (0.04-3.11), 0.010 (0.010-0.990), and 0.010 (0.010-0.550) ng/ml in groups 1, 2, and 3, respectively. The mean CK-MB mass level for groups, 1, 2, and 3 were 18.35 (7.14-70.00), 4.80 (0.54-108.00), and 2.26 (0.95-7.06) ng/ml. The study showed that both the cTnT and CK-MB mass levels were significantly higher in group 1 than either group 2 or group 3. Histopathology was studied in 9 cases. In 2 of 5 cases and in all 4 cases in group 1 and group 2 histopathology was pathologically proved. Levels of cTnT and CK-MB were significantly higher for myocarditis than for dilated cardiomyopathy and left-to-right shunt with CHF. Further study is needed to assess the optimum cTnT level for differentiating both conditions.

Enteroviruses, the most common cause of acute myocarditis, are also supposed aetiological agents of dilated cardiomyopathy. Autoantibodies (anti-M7; Klein & Berg, Clin Exp Immunol 1990; 58:283-92) directed against flavoproteins with covalently bound flavin (alphaFp-Ab; Otto et al., Clin Exp Immunol 1998; 111:541-2) are detected in up to 30% of sera of patients with myocarditis and idiopathic dilated cardiomyopathy (IDCM). Mice inoculated with a myocarditic variant of coxsackievirus B3 (CVB3) were employed to study the occurrence of serum alphaFp-Ab following viral infection. The presence of alphaFp-Ab was analysed by Western blotting with the flavoprotein antigens 6-hydroxy-D-nicotine oxidase (6HDNO) and sarcosine oxidase (SaO). Of 10 sera from CVB3-infected mice, five showed a strong reaction with both antigens. The sera were reactive also to the mitochondrial covalently flavinylated proteins dimethylglycine dehydrogenase and sarcosine dehydrogenase. Sera of non-infected mice did not react with these antigens. A 6HDNO mutant protein with non-covalently bound FAD no longer reacted on Western blots with sera of CVB3-infected mice. Preincubation with FAD abolished or reduced the reaction of the sera with the 6HDNO antigen. At 2 weeks p.i. the alphaFp-Ab were of the IgM and IgG isotypes, at 7 and 9 weeks p.i. of the IgG isotype. The sera of CVB3-infected mice reproduced closely the antigenic specificity of the anti-M7 sera of patients, lending further support to the role of coxsackieviruses in the pathogenesis of IDCM.

In a preceding communication (Wallukat et al., 1992, Z Kardiol 81 [Suppl. 4]: 79-83), it was reported that synthetic peptides, corresponding in amino acid sequence to either the first or the second extracellular loop of the human beta 1-adrenoceptor, selectively suppressed the metoprolol- and bisoprolol-sensitive positive chronotropic action exerted in cultures of beating neonatal rat cardiomyocytes by the serum immunoglobulin fraction of patients with myocarditis and idiopathic dilated cardiomyopathy (DCM) and by affinity-purified autoantibodies from that fraction. These observations added to existing evidence that these antibodies were directed against the beta 1-adrenoceptor and might thus contribute to the harmful chronic cardiac adrenergic drive to which patients with DCM are believed to be exposed. Specifically, they pointed to the putative first and second extracellular loops of this receptor (these loops are each identical in man and the rat) as the sites of epitopes recognized by the chronotropically active, beta 1-agonistic autoantibodies. Now we report on the mapping of these epitopes with the help of two series of short synthetic overlap peptides, one series forming part of the first and the other of the second extracellular loop of the beta 1-adrenoceptor. Inhibition of the positive chronotropic response of cultured rat cardiomyocytes to the anti-beta 1-receptor autoantibodies (EC50 = 0.14 +/- 0.01 nM) from the serum immunoglobulin fraction of patients with DCM was taken as reflecting the neutralization of these antibodies by a particular overlap peptide. In this way the sequences S-F-F-C-E-L (residues 129-134) and A-R-R-C-Y-N-D (residues 206-212) emerged as the dominant epitopes in the first and second extracellular loops, respectively, followed with respect to neutralizing ability by the first loop sequence E-Y-G-S-F-F (residues 126-131) and the second loop sequences H-W-W-R-A-E (residues 197-202) and P-K-C-C-D-F (residues 213-218). Synthetic peptides corresponding to the sequences of the third extracellular loop of the beta 1-receptor (residues 346-356) and of the second extracellular loop of the human beta 2-receptor (residues 172-197) failed to neutralize the beta 1-agonistic autoantibodies. Using dithiothreitol as a reducing agent a disulfide bridge between cysteine 132 in the first and cysteine 209 in the second extracellular loop was considered to be essential for the chronotropic action of these autoantibodies.(ABSTRACT TRUNCATED AT 400 WORDS)

Objectives: To elucidate the potential role of cytokines in the pathogenesis of cardiomyopathy and myocarditis., Background: Experimental studies show that certain cytokines depress myocardial contractility and that tumour necrosis factor-alpha plays an important part in the pathogenesis of myocardial injury in animal models of viral and autoimmune myocarditis., Methods: Plasma interleukin 1-alpha, interleukin 1-beta, interleukin-2, interleukin-6, tumour necrosis factor-alpha, tumour necrosis factor-beta, granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor, interferon-alpha and interferon-gamma were measured in 13 patients with acute myocarditis, 23 patients with dilated cardiomyopathy, 51 patients with hypertrophic cardiomyopathy, nine patients with acute myocardial infarction, 18 patients with angina pectoris, 12 patients with essential hypertension and 17 healthy controls., Results: Increased concentrations of cytokines were not detected in the controls. In patients with acute myocarditis, interleukin 1-alpha was detected in 23% (mean (SD) 25 (11) pg/ml), tumour necrosis factor-alpha in 46% (61 (31) pg/ml), and macrophage colony stimulating factor was 2.5 (1.8) ng/ml (normal 1.9 (0.4)). In patients with dilated cardiomyopathy, tumour necrosis factor-alpha was detected in 35% (402 (555) pg/ml). In patients with hypertrophic cardiomyopathy, interleukin-2 was detectable in 14% (2318 (4738) pg/ml) and tumour necrosis factor-alpha ws detected in 20% (992 (1517) pg/ml). The concentration of macrophage colony stimulating factor was raised in patients with acute myocardial infarction. Granulocyte colony stimulating factor was often increased in myocarditis, cardiomyopathies, acute myocardial infarction, and angina pectoris--suggesting activation of macrophages and/or endothelial cells--but this increase was not specific to these diseases. Increased concentrations of cytokines were not found in patients with essential hypertension., Conclusion: These results suggest that cytokines may play a part in the pathogenesis of myocardial injury in myocarditis and cardiomyopathies and that further studies to explore the potential pathogenetic role of cytokines in myocardial diseases may be warranted.

41 patients with dilated cardiomyopathy (DCMP), 62 patients with infectious allergic myocarditis (IAMC) and 36 patients with myocarditis cardiosclerosis (MCCS) were examined cytochemically. This involved assessment of the activity of alpha-glycerophosphate- and glucose 6-phosphate dehydrogenases, nicotinamide adenine dinucleotide- and nicotinamide adenine dinucleotide phosphate diaphorases, NBT test parameters, measurements of endogenic cytochrome C and cation protein, activity of acid and alkaline phosphatase, lymphocyte peroxidase and that in peripheral blood polymorphonuclear leukocytes. The findings of the study confirmed a close functional and metabolic relation of the above cytochemical indices. This allows their introduction as additional laboratory criteria in differential diagnosis of inflammatory and idiopathic myocardial affections.

The diagnosis of acute infectious myocarditis can be made on clinical grounds with reasonable certainty. Dynamically evolving electrocardiographic, echocardiographic, and serum cardiac enzyme level changes in a patient with symptoms of both an infection and a heart disease are the basis for the diagnosis. In contrast, the diagnosis of lymphocytic or giant cell myocarditis can be made only on the basis of an endomyocardial biopsy finding. The diagnosis and differential diagnosis of dilated cardiomyopathy are discussed in brief.

The paper presents the information on the involvement of the cardiovascular system in the patients with Lyme's disease as well as the results of serological investigation in patients with myocarditis and dilatation cardiomyopathy for the presence of antibodies to the causative agent of Lyme's disease with the aid of enzyme immunoassay. Out of 71 sera 3 specimens had the values of optical density higher than the upper normal limits. Based on the investigation conducted and the analysis of the clinical picture, the authors suspected a Borrelia origin of these cardiac involvements. However, to verify the diagnosis morphological examination of endomyocardiac biopsy specimens was found to be mandatory.

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum neopterin was measured over time (from 3 to 24 months) by RIA in 15 patients with dilated cardiomyopathy. Comparison with the clinical data revealed that the initially normal concentration of neopterin (less than 9 nM/l) was associated with a stable disease course on a long-term observation (group I). The second group with an initially high neopterin concentration showed an objective improvement of the health status together with normalization of the neopterin level. The third group of patients were characterized by an increase of the neopterin level measured over time, coupled with a disease progress. It should be noted that 5 out of 8 patients died. In addition to neopterin measurements, the patients with dilated cardiomyopathy were examined for serum beta-2-microglobulin (beta-2M). Analysis of the data obtained has demonstrated a similar relationship between the level of neopterin and beta-2M and the clinical course of dilated cardiomyopathy. Still, neopterin is a more sensitive marker. Therefore, the data obtained attest to a possibility of the use of serum neopterin as a prognostic marker in patients suffering from dilated cardiomyopathy.

The authors presented some data on the investigation of the interferon system in patients with dilatation cardiomyopathy (DCM) and viral myocarditis (VM). Diagnosis was verified according to the WHO criteria. Altogether 10 DCM patients and 24 VM patients with a grave course were investigated. Antibodies to Coxsackie B virus and influenza were detected in the VM patients. A decrease in the alpha- and gamma-interferon activity was shown in all DCM patients. The VM patients with a grave course also demonstrated a decrease in the alpha- and especially gamma-interferon (immune) activity. Methods of immune correction in such patients were discussed.