Electro-anatomically-guided endomyocardial biopsy in a patient with focal myocardial infiltration and chronic lymphocytic leukemia.

A 53-year-old female was admitted to the cardiology department on account of signs and symptoms of congestive heart failure (HF) with severe peripheral edema and dyspnea on exertion (New York Heart Association class III) for the past 3 months.

Expression of Tissue Inhibitors of Metalloproteinases (TIMP-1, TIMP-2, TIMP-3, TIMP-4) in Blood Serum of Patients with Keratoconus.

BACKGROUND: The etiology of keratoconus is unclear. Current evidence suggests that inflammatory and systemic mechanisms might play a role in its pathophysiology. The proper interaction of proteolytic enzymes-matrix metalloproteinases-and their specific tissue inhibitors (TIMPs) within the cornea is essential in maintaining its structure, transparency and healing processes. The aim of the study was to determine the concentration of the TIMPs TIMP-1, TIMP-2, TIMP-3, and TIMP-4 in the blood serum samples of patients with keratoconus compared to the control group. METHODS: The study encompassed 132 patients, of which 83 people constituted the study group and 49 the control group. The concentration of selected TIMPs was determined using the Human Magnetic Luminex® Performance Assay method. RESULTS: In the study group, the concentrations of TIMP-1 and TIMP-3 were statistically significantly reduced, and TIMP-2 and TIMP-4 increased compared to the control group. The analysis of individual TIMPs in terms of their usefulness as potential predictors of keratoconus showed high results of diagnostic sensitivity and specificity for all TIMPs, in particular for TIMP-1 and TIMP-2. CONCLUSION: The above results may indicate systemic disturbances in the TIMPs regulation among keratoconus patients. High diagnostic sensitivity and specificity of all TIMPs, in particular TIMP-1 and TIMP-2, may confirm their participation in the etiopathogenesis of this disease.

Myocarditis: Etiology, Pathogenesis, and Their Implications in Clinical Practice.

Myocarditis is an inflammatory disease of the myocardium caused by infectious or non-infectious agents. It can lead to serious short-term and long-term sequalae, such as sudden cardiac death or dilated cardiomyopathy. Due to its heterogenous clinical presentation and disease course, challenging diagnosis and limited evidence for prognostic stratification, myocarditis poses a great challenge to clinicians. As it stands, the pathogenesis and etiology of myocarditis is only partially understood. Moreover, the impact of certain clinical features on risk assessment, patient outcomes and treatment options is not entirely clear. Such data, however, are essential in order to personalize patient care and implement novel therapeutic strategies. In this review, we discuss the possible etiologies of myocarditis, outline the key processes governing its pathogenesis and summarize best available evidence regarding patient outcomes and state-of-the-art therapeutic approaches.

Switch them off or not: selective rRNA gene repression in grasses.

Nucleolar dominance (ND) is selective epigenetic silencing of 35-48S rDNA loci. In allopolyploids, it is frequently manifested at the cytogenetic level by the inactivation of nucleolar organiser region(s) (NORs) inherited from one or several evolutionary ancestors. Grasses are ecologically and economically one of the most important land plant groups, which have frequently evolved through hybridisation and polyploidisation events. Here we review common and unique features of ND phenomena in this monocot family from cytogenetic, molecular, and genomic perspectives. We highlight recent advances achieved by using an allotetraploid model grass, Brachypodium hybridum, where ND commonly occurs at a population level, and we cover modern genomic approaches that decipher structural features of core arrays of NORs.

A Systematic Review of miRNA and cfDNA as Potential Biomarkers for Liquid Biopsy in Myocarditis and Inflammatory Dilated Cardiomyopathy.

Myocarditis and inflammatory dilated cardiomyopathy are cardiac diseases leading to heart failure. Liquid biopsy is a concept of replacing traditional biopsy with specialized blood tests. The study aim was to summarize and assess the usefulness of microRNAs and circulating free DNA as biomarkers of myocardial inflammation. For this systematic review, we searched Scopus, Embase, Web of Science, and PubMed. All studies measuring microRNAs in serum/plasma/cardiac tissue or circulating free DNA during myocarditis and non-ischemic dilated cardiomyopathy in humans in which healthy subjects or another cardiac disease served as a comparator were included. Data were extracted and miRNAs were screened and assessed using a scale created in-house. Then, highly graded miRNAs were assessed for usability as liquid biopsy biomarkers. Of 1185 records identified, 56 were eligible and 187 miRNAs were found. We did not identify any studies measuring circulating free DNA. In total, 24 of the screened miRNAs were included in the final assessment, 3 of which were selected as the best and 3 as potential candidates. We were not able to assess the risk of bias and the final inclusion decision was made by consensus. Serum levels of three miRNAs-miR-Chr8:96, miR-155, and miR-206-are the best candidates for myocardial inflammation liquid biopsy panel. Further studies are necessary to prove their role, specificity, and sensitivity.

Chest Pain of Atypical Cause in a Young Man.

Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis that classically affects the upper respiratory tract, lungs, and kidneys. The involvement of other organs occurs but is less frequent. Clinically overt cardiac involvement is rare. We present a rare case of thoracic pain caused by cardiac involvement in GPA, without any other symptoms. The diagnosis was made using an integral approach, with several complementary imaging modalities, including cardiac histology.

Systemic Brucellosis with Arrhythmogenic Cardiac Inflammatory Pseudotumor.

BACKGROUND Cardiac inflammatory pseudotumors are rarely observed. Their etiology might include immunologic abnormalities, fibrogenetic disorders, specific reactions to infections or abnormalities related to trauma, necrosis, or neoplasm. Life-threatening ventricular tachycardia and cases of sudden death related to cardiac tumors have been reported. The present report describes and discusses diagnostic and therapeutic solutions for the treatment of nonsarcoid multiorgan pseudotumors with cardiac involvement. CASE REPORT A 38-year-old woman presented to the clinic with symptomatic ventricular tachycardia. As coronary artery disease, cardiomyopathy, and channelopathy were ruled out, and electrocardiograms were not typical of idiopathic arrhythmia, the patient underwent detailed diagnostics which included targeted endomyocardial biopsy, which revealed a cardiac inflammatory pseudotumor. Laborious testing (and eventually, antibiotic therapy) led to ex juvantibus diagnosis of multiorgan disseminated brucellosis with cardiac involvement. Treatment with ceftriaxone, doxycycline, and rifampicin resulted in a complete resolution of all lesions after 3 months, and sustained recovery was observed during a 5-year follow-up. As the risk of ventricular tachycardia could not be reliably predicted, the patient had a subcutaneous implantable cardioverter-defibrillator implanted. CONCLUSIONS A vast diagnostic armamentarium of modern medicine allowed us to diagnose an unsuspected and rare cardiac inflammatory pseudotumor. In the case of travelers, the possibility of regionally specific illnesses, especially infections, must be taken into consideration as possible causes of arrhythmias. Cardiac magnetic resonance imaging may be useful in patients with 'idiopathic ventricular tachycardias' to detect non-apparent myocardial lesions which may result from the underlying cause of the arrhythmia.

The presence of E-selectin in the myocardium indicates a sustained inflammatory reaction in patients with dilated cardiomyopathy.

BACKGROUND: It is still uncertain whether de-novo expression of E-selectin in endothelial cells may be considered an additional marker of chronic inflammation in heart failure (HF). METHODS: We studied 393 consecutive patients (313 M, 80 F) with HF secondary to dilated cardiomyopathy in whom the right ventricular endomyocardial biopsy was performed. For immunohistochemistry, HLA class I and II, E-selectin (ELAM-1), CD3 + lymphocytes and CD68 + macrophages were studied. Patients were divided into two groups: Group A, with ELAM-1 (+), and Group B with ELAM-1 (-) in the biopsy sections. RESULTS: Of all patients, 140 (35.6%) subjects were presented with ELAM-1 expression in endomyocardial biopsies. Patients in the Group A had a significantly lower LV ejection fraction compared to those from the Group B (31.3 ± 12.9 vs. 34.2 ± 12.7; 95% CI, 0.3-5.6, P = 0.029) and they showed a higher mean number of CD3 (+) lymphocytes in the biopsy sections, P = 0.006. In addition, ELAM-1 reasonably correlated with CD3 lymphocytes (r = 0.3, P < 0.001). CONCLUSIONS: Our findings suggest that de-novo ELAM-1 expression in endothelial cells may be a useful marker of chronic inflammation in the biopsies of patients with HF secondary to dilated cardiomyopathy.

The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients.

Accumulated evidence suggest that the adverse outcome of severe coronavirus disease 2019 (COVID-19) is closely related to prothrombotic microvascular pathology with a high risk of venous thromboembolism. Furthermore, the first observational studies indicated that adjunct therapy with low-molecular weight heparin (LMWH) was associated with lower mortality in this cohort of patients. However, the timing of starting LMWH and the dose remain controversial in COVID-19 patients. Considering the above, the aim of this study was to reveal the rationale for using LMWH in the therapy of symptomatic COVID-19 patients based on experimental and clinical studies on LMWH in inflammatory settings with special consideration given to randomized trials.

Impact of cellular myocardial infiltration on clinical outcome in non-ischaemic heart failure.

AIMS: So far, little has been known on whether myocardial inflammatory infiltration influences heart failure (HF) progression. Thus, the aim of this study was to test the impact of intramyocardial infiltration on clinical outcomes. METHODS: Biopsy samples from 358 patients with stable HF secondary to dilated cardiomyopathy were studied. Immunohistochemistry for lymphocyte (CD3) and macrophage (CD68) markers was performed and counted. After a 1-year follow-up, patients were classified as improved based on the predefined definition of improvement. The clinical data were collected from 324 patients (90.5%). RESULTS: According to the predefined definition of improvement, 133 patients improved (41.0%) but 191 remained unchanged or deteriorated (58.9%). After a 12-month follow-up, the OR with 95% CI of counts of myocardial inflammatory CD68-positive ≥4 cell/high power field (HPF) compared with CD68-positive <4 cell/HPF for lack of improvement was 1.91 (1.65-2.54). However, the number of CD3 positive cell infiltration had no impact on clinical outcome after a 1-year follow-up. In the baseline study, a reasonably negative correlation was found between the number of CD68 positive cells and troponin T (r=-0.39; p<0.001 by Spearman's r). This was corroborated with a low negative correlation between these cells and myocardial form of creatine kinase (CK-MB) fraction (r=-0.27; p=0.006). There was no correlation between CD3 and CD68 positive cells (Spearman's r; r=-0.17, p=0.16). CONCLUSIONS: The current results provide evidence that high macrophage counts may be a predisposing factor for HF progression.

New insights into the pathogenesis of cardiac papillary fibroelastomas.

INTRODUCTION: Cardiac papillary fibroelastomas (CPFs) are rare benign cardiac tumors typically found on the heart valves. The previously published data on the CPF focused on its clinical presentation, optimal management, and prognosis. However, histogenesis of these lesions remains controversial. Accordingly, the aim of this study was to establish the role of endocardial endothelium (EE) in CPF formation. MATERIALS AND METHODS: Four CPF tumors removed from the right atrioventricular valves were analyzed using hematoxylin & eosin, orcein, and Masson trichrome staining together with immunochemistry for CD-34, CD-68, vimentin, vWF and a-SMA. Moreover, conventional transmission electron microscopy was used for morphological analysis and a-SMA presence confirmation. RESULTS: Ultrastructural morphology, immunohisto- and immunocytochemical analyses indicated that cells covering collagenous core have an endothelial origin. Some endocardial endothelium cells have the potential to undergo a transition to mesenchymal cells. Moreover, the abundant presence of extracellular vesicles may indicate an active intercellular communication. Within the intermediate translucent zone, amorphous substances with monocytes/macrophage-like cells and fibroblastic cells were found. Finally, within collagenous core activated (myo)fibroblasts were observed. CONCLUSIONS: Our study demonstrated that the endocardial endothelium of the CPF was "double-sided", i.e., it presented both endothelial and mesenchymal cell characteristics. Another finding was the presence of monocytes, and macrophages which were integrated into CPF core and displayed features of a fibroblast that have been shown to contribute to extracellular matrix production. This could be interpreted as being attributed to the CPF histogenesis.

Decreased immunoreactivity of von Willebrand factor may reflect persistent nature of the endothelial dysfunction in non-ischemic heart failure.

INTRODUCTION: Endothelial dysfunction is a critical part of heart failure (HF) pathophysiology. It is not clear, however, whether it is present at the similar level in the early and late HF stages. MATERIAL AND METHODS: von Willebrand factor (vWF) and its mRNA levels in biopsies of non-ischemic patients with HF secondary to dilated cardiomyopathy were studied. Consecutive patients with HF were divided into two groups: group A with disease duration ≤ 12 months (n = 59) and group B with disease duration > 12 months (n = 68). The immunoreactivity of the vWF was compared with autopsy sections of 19 control cases. Tissue vWF gene expression was analyzed at the mRNA level by RT-PCR. RESULTS: In the group A, there was lower vWF immunoreactivity in the coronary microvessels compared to the group B [1.5 (1.0-2.0) vs. 2.0 (1.5-2.4), P = 0.001]. In the control group, only weak vWF expression was observed. Protein expression was not accompanied by vWF mRNA whose levels were significantly higher in the Group A as compared to the Group B [14671 (4932-51561) vs. 3643 (185.3-9030.8), P = 0.005]. Protein vWF expression was inversely associated with its mRNA levels (r = -0.34, P = 0.04). CONCLUSIONS: High myocardial protein expression of vWF in patients with long-lasting HF symptoms may highlight the persistent nature of endothelial dysfunction in such a cohort of patients.

The vaping product use associated lung injury: is this a new pulmonary disease entity?

In the summer of 2019, an epidemic of e-cigarette or vaping product use associated lung injury (EVALI) broke out in the United States of America. EVALI is a lung disease that can be severe and life-threatening. It should be emphasized that EVALI is not a clinical diagnosis, but surveillance case definition. Due to the profile of users of such devices, the pathology mainly affects young adults, although cases of EVALI have been reported in almost all age groups, from teenage children to seniors. The worst prognosis is in patients over 35 years of age, with accompanying diseases. A significant number of patients declared the use of products containing tetrahydrocannabinol (THC). The most likely factor responsible for the occurrence of EVALI is vitamin E acetate, which is sometimes added to liquids necessary for the use of electronic cigarette type devices, especially those liquids that contain THC. Nevertheless, it is possible that other substances used in liquids may also be a causative factor. Typical for EVALI are respiratory, gastrointestinal and systemic symptoms, while in imaging tests, a characteristic feature of EVALI is the presence of opacities on the chest radiogram and ground-glass clouds on computed tomography scans. In the course of this disease, respiratory failure often occurs (58%). In the vast majority of cases oxygen substitution is necessary. Currently, the best treatment of EVALI is considered to be the administration of systemic glucocorticosteroids. Over 90% of patients with EVALI required hospitalization, while the mortality rate was about 2.42%. Median age of the fatalities was 51 years. The aim of this review is to summarise the available information on EVALI and to consider possible causative factors and pathomechanism.

The concentration of interleukin-33 in heart failure with reduced ejection fraction.

OBJECTIVE: Despite several improvements in the management of heart failure (HF), it is still an incurable and a progressive disease. Several trials demonstrated that the process of inflammation may be responsible for initiation and progression of HF. The aim of the present study was to investigate the role of interleukin-33 (IL-33) in the pathogenesis of HF and to assess whether disease etiology and course of the disease affect the expression of cytokines. METHODS: The study included 155 (106 male and 49 female) patients with systolic HF with a mean left ventricle ejection fraction of 32.13+-12.8% and 60 (36 male and 24 female) healthy individuals. IL-33 concentrations were evaluated using enzyme-linked immunosorbent assay. RESULTS: The concentration of IL-33 was statistically significantly lower in patients with HF than in healthy subjects, 16.91 (0-81.00) pg/mL and 92.51 (33.61-439.61) pg/mL, respectively. Patients with HF with ischemic etiology had lower concentration of IL-33 (10.75 pg/mL) than subjects with HF with non-ischemic etiology (21.05 pg/mL). Patients with stable HF (10.46 pg/mL) had lower IL-33 levels than those with unstable HF (19.02 pg/mL). CONCLUSION: The concentrations of IL-33 were lower in patients with HF than in healthy controls, which may play an important role of above cytokine in HF development and progression. In addition, interleukin concentrations varied depending on the etiology and severity of the course of the disease.

Kidney Function, Nutritional Status, and the Left Ventricle Dysfunction Are Associated with Serum Uric Acid Levels in Patients with Heart Failure with Reduced Ejection Fraction.

OBJECTIVE: The aim of this study was to assess the role of potential factors explaining variability of serum uric acid (SUA) levels in patients with chronic heart failure with reduced ejection fraction (HFrEF) not receiving xanthine oxidase inhibitors and acetylsalicylic acid, with multivariate adaptive regression splines and fuzzy c-regression models. MATERIAL AND METHODS: Between 1998 and 2010, we prospectively enrolled 294 patients (44 females, 250 males; mean age 43.1±11.6 years) not receiving allopurinol or febuxostat, who underwent right ventricular endomyocardial biopsy due to unexplained HFrEF (duration of symptoms ≥6 months) with New York Heart Association functional class II and III and decreased left ventricular ejection fraction <40% in radionuclide study. The following factors were analyzed: left ventricular ejection fraction, concentrations of serum creatinine, high-sensitivity C-reactive protein, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), SUA, glucose, total cholesterol, HDL and LDL fractions of cholesterol, triglycerides, fibrate, D-dimers, and medication. Multivariate Adaptive Regression Splines, local polynomial smoothing with Epanechnikov kernel function as well as the Time Domain Constrained Fuzzy c-Regression Models were used. RESULTS: SUA concentration variability was explained by BMI, eGFR values, serum NT-pro BNP levels and the use of thiazide diuretics. The SUA declined with eGFR and increased with BMI values, serum NT-proBNP levels and the use of thiazide diuretics. A weak negative correlation between log10(SUA) levels and the LVEF was found (r=-0.130; p<0.05). CONCLUSIONS: Kidney function, nutritional status, the use of thiazide diuretics and the severity of left ventricle dysfunction reflected by serum NT-proBNP levels explain the serum uric acid levels variability in patients with HFrEF.