Active Myocarditis Research Articles

Continuous Electrical Monitoring in Patients with Arrhythmic Myocarditis: Insights from a Referral Center.

Background. The incidence and burden of arrhythmias in myocarditis are under-reported. Objective. We aimed to assess the diagnostic yield and clinical impact of continuous arrhythmia monitoring (CAM) in patients with arrhythmic myocarditis. Methods. We enrolled consecutive adult patients (n = 104; 71% males, age 47 ± 11 year, mean LVEF 50 ± 13%) with biopsy-proven active myocarditis and de novo ventricular arrhythmias (VAs). All patients underwent prospective monitoring by both sequential 24-h Holter ECGs and CAM, including either ICD (n = 62; 60%) or loop recorder (n = 42; 40%). Results. By 3.7 ± 1.6 year follow up, 45 patients (43%) had VT, 67 (64%) NSVT and 102 (98%) premature ventricular complexes (PVC). As compared to the Holter ECG (average 9.5 exams per patient), CAM identified more patients with VA (VT: 45 vs. 4; NSVT: 64 vs. 45; both p < 0.001), more VA episodes (VT: 100 vs. 4%; NSVT: 91 vs. 12%) and earlier NSVT timing (median 6 vs. 24 months, p < 0.001). The extensive ICD implantation strategy was proven beneficial in 80% of the population. Histological signs of chronically active myocarditis (n = 73, 70%) and anteroseptal late gadolinium enhancement (n = 26, 25%) were significantly associated with the occurrence of VTs during follow up, even in the primary prevention subgroup. Conclusion. In patients with arrhythmic myocarditis, CAM allowed accurate arrhythmia detection and showed a considerable clinical impact.

Features of the expression of fibroblast growth factor in patients with idiopathic atrial fibrillation and verified myocarditis

Abstract Introduction Myocarditis and inflammatory changes in the myocardium can be one of the causes of the development and progression of atrial fibrillation (AF). The biomarker FGFβ is involved in the processes of angiogenesis, repair of heart tissues and stimulates fibroblasts. Purpose To assess the dynamics and to identify the relationship of fibroblast growth factor (FGFβ) expression and myocardial inflammatory diseases revealed by the results of histological examination of endomyocardial biopsy in patients with various forms of idiopathic AF. Methods Subjects were 40 patients (41.0±9.2 y.o.) with idiopathic AF, the arrhythmic history constituted 4.9±3.9 years. The patients were divided into 3 groups: 1–with paroxysmal AF (n=15), 2–persistent (n=12), 3–long-term persistent (n=13) depending on the form of AF. All patients underwent radiofrequency ablation (RFA) of the pulmonary veins and endomyocardial byopsy with histologic and immunohistochemical studies. In 1st group active lymphocytic myocarditis (ALM) were found in 40% patients (n=6); in 2d and 3d groups – 66.7% (n=8 in each gr.). All other patients showed signs of lymphocytic infiltration (LI). The serum levels of FGFβ determined all patients in prior to intervention (T1) and in 6 months after RFA (T2). Results Comparative analysis showed, in patients with morphologically verified ALM, the FGFb levels in 6 months after RFA in 1st gr. was significantly higher than in 3d gr. (p=0.036). In patients gr.1 with ALM the levels of FGFb was higher (at stages T1 and T2) than in patients with LI (p=0.055 and p=0.06, respectively). In 1st gr., a positive association between the levels of FGFb (T1) and the degree of activity of inflammatory processes caused in 6 months after RFA (R=0.95 p=0.005) were identified. In 1st gr., the relationship between the degree of activity of inflammatory processes and fibrotic changes (R=−0.77 p=0.009) and an association of FGFb with the value of cardiac ejection fraction was obtained (R=0.90 p=0.037). In 2d gr., strong correlations of FGFb with the degree of activity of inflammatory processes (R=0.79 p=0.019) and ejection fraction (RT1=0.73 p=0.039, RT2=0.96 p=0.0002) were revealed. In 3d gr., the FGFb levels was significantly higher in patients with LI than with ALM (14.74 [13.28; 14.80] and 6.92 [5.65; 9.90] pg/ml, respectively; p=0.048). In 3d gr., the severity of fibrotic changes was associated with FGFb expression (RT1=−0.73 p=0.041, RT2=−0.85 p=0.008). Conclusion The relationships of FGFb with the degree of activity of inflammatory processes in groups with paroxysmal and persistent AF were revealed. In patients with active lymphocytic myocarditis, the FGFb level was significantly higher in paroxysmal AF than in long-term persistent AF. Our study showed, increased expression of FGFb is associated with inflammatory processes of active lymphocytic myocarditis, and may be due to intense proliferation and differentiation of fibroblasts in paroxysmal AF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Cardiology Research Institute, Tomsk NRMC

Longitudinal trajectory of cardiac magnetic resonance and cardiopulmonary exercise testing findings in moderate to severe COVID-19 and association with symptoms

Abstract Background Cardiac magnetic resonance (CMR) and cardiopulmonary exercise testing (CPET) have provided important insights into the prevalence of early cardiopulmonary abnormalities in COVID-19 patients. It is currently unknown whether such abnormalities persist over time and relate to ongoing symptoms. Purpose To describe the longitudinal trajectory of cardiopulmonary abnormalities on CMR and CPET in moderate to severe COVID-19 patients and assess their relationship with ongoing symptoms. Methods Fifty-eight previously hospitalised COVID-19 patients and 30 age, sex, body mass index, comorbidity-matched controls underwent CMR, CPET and a symptom-based questionnaire at 2–3 months (2–3m). Repeat assessments (including gas transfer) were performed in 46 patients at 6 months (6m). Results During admission, 1/3rd of patients needed ventilation or intensive care (Table 1) and three (5%) had a raised troponin. On CMR, patients had preserved left (LV) and right ventricular (RV) volumes and function at 2–3m from infection. By 6m, LV function did not change but RV end diastolic volume decreased (mean difference −4.3 mls/m2, p=0.005) and RV function increased (mean difference +3.2%, p&amp;lt;0.001, Fig. 1A). Patients had higher native T1 (a marker of fibroinflammation) at 2–3m compared to controls (Table 1, Fig. 1B), which normalised by 6m. Extracellular volume was normal and improved by 6m. Native T2, a marker of myocardial oedema, did not differ between patients and controls on serial CMR. At 2–3m, late gadolinium enhancement (LGE) was higher in patients (p=0.023) but became comparable to controls by 6m (p=0.62). Six (12%) patients had LGE in a myocarditis pattern and one (2%) had myocardial infarction. None had active myocarditis using the Modified Lake Louise Criteria. Lung imaging (T2-weighted) revealed parenchymal abnormalities in 2/3rds of patients at 2–3 and 6 months. The extent of abnormalities improved on serial imaging (Table 1). Gas transfer (DLco) was worse in those with lung abnormalities (77% vs 91% of predicted, p=0.009). CPET revealed reduced peak oxygen consumption (pVO2) in patients at 2–3m, which normalised by 6m (80.5% to 93.3% of predicted, p=0.001) (Table 1, Fig. 1C). At 2–3m, 49% of patients had submaximal tests (respiratory exchange ratio &amp;lt;1.1), reducing to 25% by 6m (p=0.057). VE/VCO2 slope, a marker of lung efficiency, was abnormal in patients but improved on serial CPET (Table 1, Fig. 1D). Cardiac symptoms (chest pain, dyspnoea, palpitations, dizziness or syncope) were present in 83% of patients at 2–3m, reducing to 52% by 6m (p&amp;lt;0.001). There was no significant association between CMR or CPET parameters and persistent cardiac symptoms at 6m (Fig. 1E). Conclusions Cardiopulmonary parameters (on CMR and CPET) improved in moderate-severe COVID-19 patients from 2–3 to 6 months post infection. Despite this, patients continued to experience cardiac symptoms which had no relationship with measured parameters. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): 1. NIHR Oxford and Oxford Health Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust2. Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107 Table 1Figure 1

Post-COVID morphologically proved endocarditis: infective and nonbacterial forms

PurposeTo study clinical features of endocarditis and its possible mechanisms (infective and nonbacterial) in the long-term period after acute COVID-19.MethodsThree patients (two male and one female, age 64, 39 and 46 years) diagnosed with postcovid endocarditis were included in the study. One patient had severe bilateral coronavirus pneumonia; the other two had only fever and weakness. The diagnosis of COVID-19 was confirmed by seroconversion. The time of admission after COVID-19 was from 4 to 7 months. All patients had study for anti-heart antibodies (AHA), EchoCG, Holter ECG, and endomyocardial biopsy (EMB) with PCR for SARS-Cov2 and cardiotropic viruses. The indication for EMB was suspected myocarditis. Blood cultures and procalcitonin levels were tested in one patient due to a prolonged febrile fever.ResultsTwo variants of postcovid endocarditis have been diagnosed. The first variant was detected in two patients by EMB only. This patients had severe lymphocytic and giant cell myocarditis. In addition, EMB showed signs of lymphocytic endocarditis with infiltrates, marked thickening and fibrosis of the endocardium (Fig. 1). Some biopsy specimen were represented by fresh thrombotic masses, infiltrated with neutrophilic leukocytes. No intraventricular thrombus was detected on EchoCG and MRI. The second variant of postcovid endocarditis developed in a patient with bicuspid aortic valve and met the criteria of infectious endocarditis 2015: mobile vegetations on the valve with aortic regurgitation II, splenomegaly, irregular fever up to 39°C for six months, marked increase of CRP, procalcitonin and ferritin, hypochromic anemia, LV EF 25%. Blood culture was negative. After intravenous therapy with antibiotics and immunoglobulin, EMB confirmed the active lymphocytic myocarditis and only slight fibrosis of right ventricular endocardium. The bacteriological study of endocardium was negative. SARS-Cov-2 RNA was detected by PCR in myocardial biopsy specimens of two patients; the biopsy of one patient is in the study now. All patients had significantly elevated antibody titers to various cardiac antigens, but the level of antibodies to endothelial antigens remained completely normal. It is possible to suggest an active deposition of immune complexes in the endothelium. Two surviving patients receive steroid therapy (in case of IE with antibiotics).ConclusionsSARS-Cov-2 infection induces the prolonged non-bacterial thromboendocarditis or infective endocarditis. In both cases, autoimmune mechanisms play a significant role, as evidenced by the simultaneous lymphocytic/giant cell myocarditis and high titers of AHA. Long-term persistence of coronavirus in the myocardium can also be considered as an etiological factor of endocarditis. In favor of this hypothesis is the parietal thrombosis in the absence of bacterial infection. Corticosteroids and anticoagulants should be considered for the treatment of postcovid endocarditis.Funding AcknowledgementType of funding sources: None. Figure 1. The EMB in in postcovid endocarditis

Clinical impact of continuous electrical monitoring in patients with arrhythmic myocarditis: a prospective cohort study

Abstract Background Although potentially life-threatening, arrhythmias in myocarditis are under-reported. Purpose To assess diagnostic yield and clinical impact of continuous arrhythmia monitoring (CAM) in patients with arrhythmic myocarditis. Methods We enrolled consecutive adult patients (n=104; 71% males, age 47±11y, mean LVEF 50±13%) with biopsy-proven active myocarditis and de novo ventricular arrhythmias (VA). All patients underwent prospective monitoring by both sequential 24-hour Holter ECGs (4/y in the first year; 2/y in years 2–5; 1/y later) and CAM, including either ICD (n=62; 60%) or loop recorder (n=42; 40%). Results By 3.7±1.6 y follow-up, 45 patients (43%) had VT, 67 (64%) NSVT, and 102 (98%) premature ventricular complexes (PVC). As compared to Holter ECG (average 9.5 exams per patient), CAM identified more patients with VA (VT: 45 vs. 4; NSVT: 64 vs. 45; both p&amp;lt;0.001), more VA episodes (VT: 100 vs. 4%; NSVT: 91 vs. 12%), and earlier NSVT timing (median 6 vs. 24 months, p&amp;lt;0.001). Conversely, Holter ECG allowed VA morphology characterization and daily PVC quantification. The time to first treatment modification was 12±9 months by CAM vs. 33±16 months by Holter ECG (p&amp;lt;0.001), and drug withdrawal was always CAM-dependent. Guided by CAM findings, 8 patients (8%) started anticoagulants for newly-diagnosed atrial arrhythmias. Differently from ICDs, loop recorders did not interfere with the interpretation of cardiac magnetic resonance. Conclusion In patients with arrhythmic myocarditis, CAM allowed accurate arrhythmia detection and showed a considerable clinical impact. As a complementary exam, VA characterization and PVC burden were better assed by repeated Holter ECGs. Funding Acknowledgement Type of funding sources: None.

Cardiomyopathy and multiple arterial thrombosis in a patient with severe tachyform atrial fibrillation after COVID-19

We present a case of cardiomyopathy with a reduced left ventricular ejection fraction of up to 18%, multivessel arterial thrombosis in a patient who had undergone severe COVID-19 3.5 months earlier. The cardiopathy was initially considered as an outcome of SARSCoV2-induced myocarditis, but MRI with delayed gadolinium contrast revealed no fibrosis or evidence of active myocarditis. A detailed collection of the medical history showed that the duration of tachyform atrial fibrillation exceeded the 4 months indicated in the medical records. Oligosymptomatic manifestation of arrhythmia occurred 8 months earlier, the patient did not consult a physician due to epidemic conditions. Coronary angiography revealed subtotal stenosis of the anterior descending artery. Most probably, the cardiopathy was arrhythmogenic and ischemic. After achieving normosystole and coronary stenting, the left ventricular ejection fraction was 25-27%. At the first hospitalization 4 months ago, left atrial auricular thrombus was detected. After COVID-19 the patient received inadequately low dose of apixaban 5 mg per day. Three weeks after COVID-19, the patient was diagnosed with infarction of the right kidney, wall thrombosis in the abdominal aorta, thrombosis of the superficial femoral, deep femoral, popliteal, anterior tibial arteries on the left, right popliteal artery; thrombotic complications could have developed both in situ and as a result of cardioembolism. Administration of dabigatran 300 mg per day and aspirin helped to dissolve the thrombus in the left atrial auricle, improve the course of intermittent claudication, and avoid recurrent thrombotic complications. COVID-19 could contribute to the progression of atherosclerosis, more malignant course of atrial fibrillation, development of thrombosis, but coronavirus infection is not the only cause of severe disease in a patient. СOVID-19 can not only be the cause of direct lesions of the heart and vessels, but also have an indirect negative effect - to delay the detection of cardiac pathology and be the cause of its hypodiagnosis under the mask of “postcovid”.

The Role of Cardiac Magnetic Resonance in Evaluation of Idiopathic Ventricular Arrhythmia in Children.

The aim of the study was to assess the role of cardiovascular magnetic resonance (CMR) in the diagnosis of idiopathic VA in children. This retrospective single-centre study included a total of 80 patients with idiopathic ventricular arrhythmia that underwent routine CMR imaging between 2016 and 2020 at our institution. All patients underwent a 3.0 T scan involving balanced steady-state free precession cine images as well as dark-blood T2W images and assessment of late gadolinium enhancement (LGE). In 26% of patients (n = 21) CMR revealed cardiac abnormalities, in 20% (n = 16) not suspected on prior echocardiography. The main findings included: non-ischemic ventricular scars (n = 8), arrhythmogenic right ventricular cardiomyopathy (n = 6), left ventricular clefts (n = 4) and active myocarditis (n = 3). LGE was present in 57% of patients with abnormal findings. Univariate predictors of abnormal CMR result included abnormalities in echocardiography and severe VA (combination of >10% of 24 h VA burden and/or presence of ventricular tachycardia and/or polymorphic VA). CMR provides valuable clinical information in many cases of idiopathic ventricular arrhythmia in children, mainly due to its advanced tissue characterization capabilities and potential to assess the right ventricle.

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

BackgroundTroponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.Methods and resultsOne hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).ConclusionsDuring convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

Neutrophil Infiltration Induces Myocardial Injury in COVID-19 Post-Mortem Cases

Background: The pathological features of severe cardiac injury induced by COVID-19 and relevant clinical features is unknown.Methods: This autopsy cohort study, including hearts from 26 deceased patients hospitalized in intensive care unit due to COVID-19, was conducted at four sites in Wuhan, China. Cases were divided into neutrophil-infiltration group and no-neutrophil group according to histopathological identification of neutrophilic infiltrates or not.Findings: Among 26 cases, four cases had active myocarditis with histopathological examination. All cases with myocarditis accompanied with extensive neutrophil infiltration, while cases without myocarditis did not. Detection rates of interleukin-6 (100% vs 4.6%) and tumor necrosis factor-α (100% vs 31.8%) in neutrophil-infiltration group were significantly higher compared to no-neutrophil group (pInterpretation: In hearts from deceased patients with severe COVID-19 , active myocarditis was commonly infiltrated with neutrophils. Cases with neutrophil-infiltrated myocarditis had a series of severe abnormal laboratory tests at admission, and a high maximum of CK-MB during hospitalization. Role of neutrophil on severe heart injury and even systemic condition in COVID-19 should be emphasized.Funding Information: : Emergency Key Program of Guangzhou Laboratory, Grant No. EKPG21-32. Declaration of Interests: None exist.Ethics Approval Statement: Full autopsy was performed after patient death with the approval of the ethics committees and written consent of patient relatives in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration.

Histopathological changes in the right atrial appendages triggering atrial fibrillation: A tertiary care center study.

Atrial fibrillation(AF) is as an abnormal irregular rhythm with chaotic generation of electrical signals in the atria of the heart. Various studies in the West have proved that atrial substrates, like isolated atrial amyloidosis can trigger the development of atrial fibrillation. In India, these structural changes have been analyzed on autopsied hearts. To determine the role of Atrial Amyloid as a substrate for Atrial fibrillation in ante mortem hearts. Atrial appendages were obtained from seventy five patients undergoing open heart surgery at a tertiary care hospital in south India. They were stained with Hematoxylin &Eosin, Masson's Trichrome and Congo red stains and were examined for myocarditis, fibrosis and amyloidosis, respectively. 30 (40%) patients were in AF. Amyloid deposits were seen in 3 cases. All the three were in AF and had undergone mitral valve replacement (MVR) (P<0.05). 2 out of the 3 amyloid-positive cases showed active myocarditis and severe scarring but there was no statistically significant correlation between these factors. Amyloid and myocarditis, independently act as an arrythmogenic substrates in the development of atrial fibrillation and are also increasingly associated with female gender and MVR. We hypothesize that the amyloid deposits are due to isolated atrial amyloidosis as they were seen only in young individuals. Some patients in sinus rhythm (SR) had large left atria and myocarditis and probably are at a higher risk for developing AF. Hence, follow-up of these patients is required for prevention of severe organ damage and timely therapeutic intervention.

Predictors of left ventricular remodelling in patients after active myocarditis

Abstract Background Myocarditis may be a challenging diagnosis because of diversity of clinical presentations. Thus, the clinical course and ventricular remodelling in this disease seems to be unpredictable. Aims To assess predictors of left ventricular remodelling in patients after active myocarditis. Methods Database from a high-volume, tertiary cardiology center was analysed to identify patients with active myocarditis, based on clinical presentation and ≥1 diagnostic criteria from different categories (including electrocardiography/ holter, elevated troponin T/I levels, functional or structural abnormalities on cardiac imaging or tissue characterization by cardiac magnetic resonance) between 2016 and 2019. Left ventricle global longitudinal strain (GLS), mechanical dispersion (standard deviation of time to peak longitudinal strain derived from all left ventricle segments in 3 apical views) were calculated. Response (left ventricular positive remodeling measured by transthoracic echocardiography) was defined as end-systolic volume (ESV) reduction ≥15% from a baseline value or end-diastolic volume (EDV) reduction ≥15%. Results 61 consecutive patients were enrolled. The median follow-up was 1.4 years (range: 0.3–4.0). During entire follow-up period mortality rate in patients was 1.6%. Multivariate Cox regression model including significant baseline differences as covariates reported that QRS durations (HR 1.31, 95% CI 1.17–1.57, P=0.049) and mechanical dispersion (HR 1.03, 95% CI 1.01–1.07, P=0.036) were independently associated with left ventricular positive remodelling with ESV reduction. Mechanical dispersion (HR 1.04, 95% CI 1.02–1.06, P=0.040) was independently associated with left ventricular positive remodelling with EDV reduction. Conclusions Mechanical dispersion and QRS duration are independent predictors of left ventricular remodelling in patients after active myocarditis. Funding Acknowledgement Type of funding source: None

The value of regional myocardial function assessment in patients with acute myocarditis at baseline and mid term follow-up

Abstract Background The clinical course and ventricular remodeling in inflammatory myocardial disease could be unpredictable. No single functional parameter has been confirmed as a powerful predictor of clinical course and functional recovery assessment in patients with acute inflammatory myocardial disease. Purpose The aim of the study was to assess the mechanical properties of the myocardium in patients with active myocarditis at baseline and follow-up. Methods Database from a high volume, tertiary cardiology center was analysed to identify patients with active myocarditis, based on clinical presentation and ≥1 diagnostic criteria from different categories (including electrocardiography/holter, elevated troponin T/I levels, functional or structural abnormalities on cardiac imaging or tissue characterization by cardiac magnetic resonance) between 2016 and 2019. Conventional and speckle tracking echocardiography including global longitudinal strain (GLS) mechanical dispersion (MD) was completed at baseline and at 17±13 months follow-up. MD was calculated as a standard deviation of time to peak longitudinal strain derived from all left ventricle segments in 3 apical views. Results 61 consecutive patients [50 M, 11F, end-diastolic volume 212±84 ml, end-systolic volume 130±90ml, ejection fraction (EF) 42±16%] were enrolled. During the entire follow-up 1 patient died at early observation. Implantable cardioverter-defibrillator was implanted in 5 patients (primary prevention 4, secondary 1), cardiac resynchronization therapy pacemaker in 1 patient. Despite of significant global improvement (EF 42±16% vs 52±10%, p&amp;lt;0.001) the limited regional improvement was noticed (GLS 14±6% vs 15±4%, p = NS; MD 47±18 ms vs 45±20 ms, p=NS) in all patients at 17±13 months follow-up. There was a strong negative association between GLS and MD at baseline (Figure 1), and slightly weaker at follow-up (R=0.47, Pearson's correlation). Moreover, the GLS correlated well the change of MD in each individual patient. Conclusions Mechanical dispersion and global longitudinal strain may serve as an additional markers of myocardial damage and potential predictive markers in non ischemic cardiomyopathy patients with proven inflammatory origin. Funding Acknowledgement Type of funding source: None

Lymphocytic myocarditis: a genetically predisposed disease?

Abstract Background Clinical presentation of myocarditis is extremely heterogeneous from asymptomatic to overt severe heart failure (HF). A complex interaction between pre-existing genetic background and inflammation might be responsible for this heterogeneity. Purpose The aim of the present study was to investigate whether positive genetic background for pathogenic cardiomyopathy-related variants might underlie a higher susceptibility to left ventricular dysfunction in patients with active lymphocytic myocarditis. Methods We prospectively performed genetic tests in 36 patients (46±15 years; 61% males; no relatives included) with biopsy-proven active lymphocytic myocarditis according to Dallas criteria and immunohistochemistry. Only pathogenic (P) or likely pathogenic (LP) variants were considered. Results After genetic test, 31% of patients (n=11) were carriers of P/LP truncating variants in structural Cardiomyopathy related genes: Titin (TTN, n=8, 73%), Desmoplakin (DSP, n=1), Filamin C (FLNC, n=1) and RNA binding protein 20 (RBM20, n=1). Among the 27 patients presenting with HF and LV dysfunction, the positive genetic yield was similar to the total cohort (n=9, 34%; 90% with TTN). Two out of six arrhythmic patients (30%) were carriers in arrhythmogenic genes (i.e. DSP and FLNC), whereas no patients with infarct-like presentation were carriers. During follow-up, 44% of patients (n=16) presented normal Left Ventricular Ejection Fraction (LVEF). Carriers had a lower rate of LVEF normalization compared to non-carriers (18% vs 56%, respectively; p=0.035). Conclusion Positive genetic testing for cardiomyopathy-related-genes might be found in a non-negligible percentage of patients with biopsy-proven myocarditis, especially if presenting with heart failure and LV dysfunction. Compared to non-carriers, carriers of P/LP variants show lower likelihood of LVEF normalization during follow-up. Funding Acknowledgement Type of funding source: None

Association of actin-myosin interaction biomarkers and fibrosis with myocardial inflammatory changes in patients with idiopathic atrial fibrillation

Abstract Introduction Myocarditis and inflammatory changes in the myocardium are causes of the development and progression of atrial fibrillation (AF). Inflammatory processes may also lead to the development of fibrosis, electrical and structural myocardial remodeling, adversely affecting the effectiveness of interventional treatment. Purpose To assess the dynamics and to identify relationships between serum levels of tropomyosin I, myosin light chain kinase (MLCK), myosin heavy (MYH7) and light chains (CMLC), transforming growth factor (TGF-β1) and myocardial inflammatory changes in patients with idiopathic AF. Methods Subjects were 40 patients (41.0±9.2 y.o.) with idiopathic AF (arrhythmic history constituted 4.9±3.9 years). Paroxysmal AF (ParAF) was detected in 37% (n=15), persistent AF (PerAF)–30% (n=12), and long-standing persistent (LPerAF)–33% (n=13). All patients underwent radiofrequency ablation (RFA) of the pulmonary veins and endomyocardial byopsy with histologic and immunohistochemical studies. Depending on the results of histological study, the patients were divided into 2 groups: 1–with active lymphocytic myocarditis (ALM) (n=22); 2–with lymphocytic infiltration (IL) (n=18). Blood for biomarkers evaluation was collected prior to RFA and in 6 months after RFA. Results In patients with ALM levels of biomarkers significant differed depending on the form of AF. In patients with PerAF, the levels of MYH7, MLCK and tropomyosin I were significantly lower than in patients with ParAF (p&amp;lt;0.005). In 6 months the levels of MLCK, tropomyosin I, and CMLC significantly differed in patients with ALM depending on the form of AF (p&amp;lt;0.05). In patients with PerAF in the group 1, the concentrations of MYH7, CMLC, and tropomyosin I were lower, than the group 2 (p&amp;lt;0.05). In 6 months in patients with PerAF, the TGF-β1 levels also differed between groups 1 and 2 (Me: 24.09 and 40.34 ng/ml, p&amp;lt;0.05). The content of TGF-β1 before the RFA and in 6 months in patients with PerAF was associated with the development of infiltration in 6 months after RFA (R=0.696, p=0.025). In LPerAF patients we showed correlation between the content of TGF-β1 and the severity of fibrosis in 6 months after RFA (R=0.607, p=0.047). At LPerAF TGF-β1 content correlated with degree of fibrosis in 6 months after RFA (R=0.607, p=0.047). The relationship between the form of AF and the inflammatory changes were identified (r=0.32, p=0.049). Thus, in patients with LPerAF and PerAF, ALM was diagnosed in 69% and 50% of cases, while in patients with ParAF the frequency of ALM detection constituted 33%. Conclusion Our study showed that ALM was detected in 55% of patients, and IL–in 45% of cases. Significant differences in the levels of MYH7, MLCK, CLCK, tropomyosin I in patients with PerAF and various forms of inflammatory myocardial changes were revealed. The content of the TGF-β1 is reduced in ALM in patients with PerAFP. The incidence of ALM was higher in patients with long-term persistent AF. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Cardiology Research Institute, Tomsk NRMC

Clinical effectiveness of catheter treatment for atrial fibrillation depending on the dynamics of histological changes in the myocardium

Background. Atrial fibrillation (AF) is combined with an inflammatory process that occurs in the myocardium. Diagnosis of histological changes, including inflammatory changes, in the myocardium is a complex task in the field of modern medicine. The only reliable way of determining the inflammatory changes in the myocardium is endomyocardial biopsy (EMB). As per our literature review, there are no data on the effect of histological changes in the myocardium on the efficacy of interventional treatment for AF. Moreover, assessing the dynamics of EMB results allows us to approach the treatment of patients in greater detail, thereby lowering the risk of the development and progression of serious cardiac pathologies, particularly AF.Aim. To study the effectiveness of catheter treatment for ‘idiopathic’ AF, depending on the dynamics of histological changes in the myocardium.Methods. We enrolled 48 patients with an ‘idiopathic’ form of AF; the median patient age was 39.0 y (33.5–48.0 y). Of these, 42 (87.5 %) were men and 6 (12.5 %) were women. The median duration of arrhythmic history was 4.0 y (2.0–7.0 y). All the patients underwent radiofrequency isolation of the pulmonary veins (Rcil) and EMB from the right ventricle. Histological tests, using the criteria of Cristina Basso, and immunohistochemical (IHC) tests were performed to determine the antigens of the following viruses: herpes simplex virus (HSV) types 1, 2 and 6, enterovirus (EV), Epstein-Barr, adenovirus and parvovirus (PV). After 6 mon, EMB, histological and IHC studies were repeated. Depending on the clinical form of AF, the patients are divided into the following three groups: group 1—paroxysmal form [21 (43.7 %) patients], group 2—persistent [13 (27.1 %) patients], group 3—long-term persistent [14 (29.2 %) patients]. Based on the results of the observation and evaluation of effectiveness, all the groups were divided into the following three subgroups: a—absence of AF during 12 mon of observation, b—early arrhythmia recurrences were registered during the first 3 mon of observation, c—presence of late arrhythmia recurrence after 3 mon of observation.Results. According to the histological criteria for active lymphocytic myocarditis identified in the subgroups, there were 5 patients (35.7 %) in 1a, 2 (50 %) in 1b, 6 (75 %) in 2a, 2 (66,7 %) in 2b, 7 (70 %) in 3a, 2 (66.7 %) in 3b, and 1 (100 %) in 3c. The rest of the patients showed signs of lymphocytic infiltration. After 6 mon, only in group 2a, there was a significant reduction in the number of patients with active lymphocytic myocarditis (p &lt; 0.05). All the patients showed fibrotic changes and expression of HSV 6 and EV antigens of varying severity; this persisted till after 6 mon. The overall effectiveness of the surgical treatment was 66.7 % for paroxysmal, 61.5 % for persistent and 71.4 % for long-term persistent forms of AF during 12 mon of follow-up.Conclusion. Patients with ‘idiopathic’ AF show inflammatory changes in the myocardium, and 48.7 % met the criteria for myocarditis. All the patients showed the expression of viral antigens and the development of fibrosis that met the criteria for post-inflammatory changes. A repeat study that was conducted after 6 mon showed no significant dynamics of inflammatory and fibrotic changes. Despite the presence of inflammatory changes in the myocardium, the effectiveness of catheter treatment was 66.7 % for paroxysmal, 61.5 % for persistent and 71.4 % for long-term persistent forms of AF. Received 29 April 2020. Revised 1 June 2020. Accepted 3 June 2020. Funding: The study did not have sponsorship. Conflict of interest: Authors declare no conflict of interest. Author contributionsConception and design: A.E. Shelemekhov, R.E. BatalovData collection and analysis: A.E. Shelemekhov, Yu.V. Rogovskaya, S.Yu. Usenkov, E.A. Archakov, M.S. Rebenkova Drafting the article: A.E. ShelemekhovStatistical analysis: A.E. Shelemekhov, A.M. GusakovaCritical revision of the article: R.E. Batalov, Yu.V. Rogovskaya, A.M. GusakovaFinal approval of the version to be published: A.E. Shelemehov, R.E. Batalov, Yu.V. Rogovskaya, S.Yu. Usenkov, E.A. Archakov, A.M. Gusakova, M.S. Rebenkova

Inflammation as a Predictor of Recurrent Ventricular Tachycardia After Ablation in Patients With Myocarditis

BackgroundLittle is known about the risk stratification of patients with myocarditis undergoing ventricular tachycardia (VT) ablation. ObjectivesThis study sought to describe VT ablation results and identify factors associated with arrhythmia recurrences in a cohort of patients with myocarditis. MethodsThe authors enrolled 125 consecutive patients with myocarditis, undergoing VT ablation. Before ablation, disease stage was evaluated, to identify active (AM) versus previous myocarditis (PM). The primary study endpoint was assessment of VT recurrences by 12-month follow-up. Predictors of VT recurrences were retrospectively identified. ResultsAll patients (age 51 ± 14 years, 91% men, left ventricular ejection fraction 52% ± 9%) had history of myocarditis diagnosed by endomyocardial biopsy (59%) and/or cardiac magnetic resonance (90%). Furthermore, all had multiple episodes of drug-refractory VTs. Multimodal pre-procedural staging identified 47 patients with AM (38%) and 78 patients with PM (62%). All patients showed low-voltage areas (LVA) at electroanatomical map (97% epicardial or endoepicardial); of them, 25 (20%) had wide borderzone (WBZ, constituting >50% of the whole LVA). VT recurrences were documented in 25 patients (20%) by 12 months, and in 43 (34%) by last follow-up (median 63 months; interquartile range: 39 to 87). At multivariable analysis, AM stage was the only predictor of VT recurrences by 12 months (hazard ratio: 9.5; 95% confidence interval: 2.6 to 35.3; p < 0.001), whereas both AM stage and WBZ were associated with arrhythmia recurrences anytime during follow-up. No VT episodes were found after redo ablation was performed in 23 patients during PM stage. ConclusionOur findings suggest that VT ablation should be avoided during AM, but is often of benefit for recurrent VT after the acute phase of myocarditis.

Study on existence of inflammation in the myocardium in unequivocal acute traumatic deaths

BackgroundOver-diagnosis of myocarditis is possible, where presence of scant/negligible inflammatory foci are interpreted as active myocarditis in autopsy cases. A Prospective descriptive study on 100 young healthy individuals who died of known sudden traumatic causes was performed to study the existence, frequency and severity of inflammatory foci in myocardium of a normal population who died suddenly of acute trauma, in order to develop an autopsy diagnostic criteria. ResultsOut of 100 hearts, 48 had scant inflammatory foci. Thirteen had mild inflammation and three with moderate inflammation. Presence of scant inflammation was significantly associated with the age of the individual (P = 0.0182). However, the presence or severity of inflammation did not show any significant association with the clinical symptoms (P = 0.4924), gross pathology (P = 0.3954) or weight of the heart (P = 0.3109). ConclusionsPresence of scant inflammation in the myocardium is a common occurrence and it may be an age related change, which cannot account for the cause of death. Much severe forms of myocarditis with no clinically apparent picture could exist among young individuals. Thus, in the absence of other causes of death, conclusion of myocarditis as a cause of death in these cases needs a careful evaluation of other positive signs.

Assessment of MR-ProADM and N-Terminal B-Type Natriuretic Peptide of Serum Levels in Patients with Heart Failure.

Background: Heart failure timely and effective diagnosis and treatment directly affects the prognosis of patients, so early diagnosis of heart failure treatment is very important. The current diagnosis of heart failure has yet to be further improved. To investigate the relationship between plasma levels of MR-ProADM and NT-proBNP in cardiac structure and function in patients with heart failure (HF) and the early detection of failure. Methods: Patients were recruited from the coronary care unit (CCU) of Al-Yarmouk Teaching Hospital and were admitted and verified as cases of HF by specialist cardiologists. Between the 1st of November 2017 and the 1st of April 2018; 48 patients (29 males and 19 females), were diagnosed to have HF and were included in the study. The total number of HF patients admitted to the CCU of the hospital during the study period was 100 patients but 52 patients were ruled out according to the exclusion criteria of the study such as Acute Myocardial Infarction, active myocarditis, Drug abuse or an alcohol drinker, renal failure .Apparently healthy subjects were recruited from the staff of Al-Mustanseryeah Medicine College. They comprised (40) subjects (30 males and 10 females). Each subject who was recruited in the control group has underwent a full history and physical examination with a recording of : age, gender, smoking, chronic diseases and medications. Any subject in control group in this study must be fasting for 8-14 hours at the time of drawing of blood specimen. Consent was taken from all subjects in the control group after being told about the aim of the study. The plasma MR-ProADM and NT-proBNP levels were compared between the two groups to observe the value of plasma MR-ProADM combined with NT-proBNP in the diagnosis of heart failure. Results: the levels of plasma MR-ProADM and NT-proBNP were significantly higher in patients with heart failure Compared with the healthy control group. The levels of plasma MR-ProADM and NT-proBNP increased significantly (P &lt; 0.01). The area under the ROC curve for the combined detection of plasma MR-ProADM and NT-proBNP was greater than the area under the three alone tests. Conclusion: The combined detection of MR-ProADM and NT-proBNP has high sensitivity and specificity in the diagnosis of heart failure and can be used as a new detection mode.

Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation

BackgroundVentricular arrhythmias (VAs) have never been systematically investigated in patients with myocarditis at different stages. ObjectivesThe purpose of this study was to compare baseline and follow-up characteristics of VAs in patients with active myocarditis (AM) versus previous myocarditis (PM). MethodsA total of 185 consecutive patients (69% males, age 44 ± 15 years, left ventricular ejection fraction 49 ± 14%) with myocarditis and VA at index hospitalization, including ventricular fibrillation, ventricular tachycardia (VT), nonsustained ventricular tachycardia (NSVT), and Lown’s grade ≥2 premature ventricular complexes, were enrolled. AM and PM groups were defined based on endomyocardial biopsy and cardiac magnetic resonance findings. A subset of patients (n = 46, 25%) also underwent electroanatomic mapping and VA transcatheter ablation. ResultsAt presentation, AM patients (n = 123, 66%) more commonly had ventricular fibrillation (8 cases vs. 0 cases; p = 0.053), and both irregular (61% vs. 11%; p < 0.001) and polymorphic VA (NSVT and VT: 19% vs. 2%; p = 0.002; premature ventricular complexes: 63% vs. 16%; p < 0.001). Only in PM patients with NSVT or VT, the dominant morphology (right-bundle branch block with superior axis) was 100% predictive of abnormal LV inferoposterior substrate at both cardiac magnetic resonance and electroanatomic mapping. At 27 ± 7 months prospective follow-up, 55 patients (30%) experienced malignant VA (AM vs. PM, p = 0.385). Although a prevalence of polymorphic and irregular VA was confirmed in AM patients with persistent inflammation in follow-up (58%), a predominance of monomorphic and regular VA was found in AM patients after myocarditis healing (42%), as well as in PM patients (all p < 0.001). ConclusionsIn myocarditis patients, polymorphic and irregular VA are more common during the active inflammatory phase, whereas monomorphic and regular VA are associated with healed myocarditis.

Diagnostic and therapeutic approach to myocarditis patients presenting with arrhythmias

Myocarditis is a complex inflammatory disease of the myocardium, occurring secondary to viral infections or autoimmune mechanisms in most cases. Among its multiple clinical manifestations, arrhythmias are often underdiagnosed, in spite of their important prognostic value. In particular, ventricular arrhythmias complicating either active or previous myocarditis, are a significant cause of sudden cardiac death, especially in young people. Because of the absence of clinical trials specifically addressing this topic, nowadays updated international guidelines report extremely generic recommendations about optimal clinical management of patients with arrhythmic myocarditis. This review aims at both (i) showing the state of the art about patients with myocarditis and arrhythmias (ventricular arrhythmias in particular); and (ii) suggesting optimal diagnostic and therapeutic strategies for these patients, based on the experience of a high-volume referral center for arrhythmic myocarditis and ventricular arrhythmia management.