Association between Left Atrial Appendage Morphology and Clot Histology in Patients with Embolic Ischemic Stroke: An Exploratory Study.

BACKGROUND: Acute embolic ischemic stroke poses a significant healthcare challenge. Histological clot features' variability among patients with acute ischemic stroke treated by mechanical thrombectomy has potential implications for determining treatment and etiology. This study investigated the clot histological feature differences among patients who experienced cardioembolic stroke and embolic stroke of undetermined source with different left atrial appendage (LAA) morphologies. METHODS: We conducted a prospective observational study involving 79 patients with acute embolic ischemic stroke undergoing mechanical thrombectomy. Computed tomography angiography images were used to classify LAA morphologies. An artificial intelligence algorithm assessed the clot fibrin and red blood cell contents. RESULTS: Patients with chicken-wing LAA morphology exhibited lower mean clot fibrin proportions than did those with non-chicken-wing morphology (p < 0.001). Linear regression analysis showed that chicken-wing LAA was significantly associated with a lower clot fibrin proportion (estimate, -0.177; 95% CI [-0.259, -0.096]; p < 0.001). The successful recanalization rate and first-pass effect between the groups did not differ significantly. CONCLUSIONS: The chicken-wing LAA morphological type is associated with lower clot fibrin contents, suggesting potentially different embolism mechanisms or diverse embolic sources, compared with the non-chicken-wing LAA types. Further studies are required to investigate this association.

Rare c.302C>T TTR Variant Associated with Transthyretin Amyloidosis.

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by pathogenic variants in the transthyretin (TTR) gene. More than 140 different disease-causing variants in TTR have been reported. Only a few individuals with a rare TTR variant, c.302C>T, p.(Ala101Val) (historically known as p.(Ala81Val)), primarily associated with cardiac ATTRv, have been described. Therefore, our aim was to analyze the clinical characteristics of individuals with the identified c.302C>T TTR variant at our center. Materials and Methods: We analyzed data from individuals with ATTRv who were diagnosed and treated at Vilnius University Hospital Santaros Klinikos. ATTRv was confirmed by negative hematological analysis for monoclonal protein, positive tissue biopsy or bone scintigraphy and a pathogenic TTR variant. Results: During 2018-2021, the TTR NM_000371.3:c.302C>T, NP_000362.1:p.(Ala101Val) variant was found in one individual in a homozygous state and in three individuals in a heterozygous state. The age of onset of symptoms ranged from 44 to 74 years. The earliest onset of symptoms was in the individual with the homozygous variant. A history of carpal tunnel syndrome was identified in two individuals. On ECG, three individuals had low QRS voltage in limb leads. All individuals had elevated NT-proBNP and hsTroponine I levels on baseline laboratory tests and concentric left ventricular hypertrophy on transthoracic echocardiography. The individual with the homozygous c.302C>T TTR variant had the most pronounced polyneuropathy with tetraparesis. Other patients with the heterozygous variant had more significant amyloid cardiomyopathy. When screening family members, the c.302C>T TTR variant was identified in two phenotypically negative relatives at the ages of 33 and 47 years. Conclusions: c.302C>T is a rare TTR variant associated with ATTRv cardiomyopathy. The homozygous state of this variant was not reported before, and is associated with earlier disease onset and neurological involvement compared to the heterozygote state.

Giant intrapulmonary solitary fibrous tumor with signs of malignancy.

Solitary fibrous tumor (SFT) is an extremely rare mesenchymal neoplasm usually detected in the pleura, which generally follows a benign course. The localization inside lung parenchyma has more rarely been reported. We present a case of a 51-year-old male with a dry cough, dyspnea, chest pain, and increased perspiration. Radiological images revealed a giant circumscribed mass on the right side of the chest. A transbronchial cryobiopsy of the lung was performed and revealed an SFT. The right upper lobectomy through lateral thoracotomy was performed. The pathological examination confirmed an SFT with a central zone of necrosis that is a sign of malignancy. At a 2-year follow-up, the patient is free of symptoms and with no evidence of recurrence. Although the intrapulmonary localization of an SFT is a rare entity, we should be aware of it as a potential malignant pulmonary neoplasm.

Electrocardiographic Markers of Adverse Left Ventricular Remodeling and Myocardial Fibrosis in Severe Aortic Stenosis.

The optimal timing for aortic valve replacement (AVR) in aortic stenosis (AS) is still controversial and may be guided by markers of adverse left ventricular (LV) remodeling. We aim to assess electrocardiographic (ECG) strain in relation to LV remodeling and myocardial fibrosis. 83 severe AS patients underwent surgical AVR, with preoperative 12-lead ECG, cardiovascular magnetic resonance with T1 mapping and echocardiography with global longitudinal strain analysis. Collagen volume fraction (CVF) was measured in myocardial biopsies sampled during AVR. Patients with ECG strain had more severe AS, more advanced LV remodeling and evidence of heart failure. Patients with ECG strain had more diffuse fibrosis, as evident by higher mean native T1 values (974.8 ± 34 ms vs. 946.5 ± 28 ms, p < 0.001). ECG strain was the only predictor of increased LV mass index on multivariate regression analysis (OR = 7.10, 95% CI 1.46-34.48, p = 0.02). Patients with persistent ECG strain at 1 year following AVR had more advanced LV remodeling and more histological fibrosis (CVF 12.5% vs. 7.3%, p = 0.009) at baseline assessment. Therefore, ECG strain is a marker of adverse LV remodeling and interstitial myocardial fibrosis. Lack of improvement in ECG strain following AVR indicates more advanced baseline LV injury and higher levels of myocardial fibrosis.

Lymphocyte Subsets and Pulmonary Nodules to Predict the Progression of Sarcoidosis.

The search for biological markers, which allow a relatively accurate assessment of the individual course of pulmonary sarcoidosis at the time of diagnosis, remains one of the research priorities in this field of pulmonary medicine. The aim of our study was to investigate possible prognostic factors for pulmonary sarcoidosis with a special focus on cellular immune inflammation markers. A 2-year follow-up of the study population after the initial prospective and simultaneous analysis of lymphocyte activation markers expression in the blood, as well as bronchoalveolar lavage fluid (BALF) and lung biopsy tissue of patients with newly diagnosed pulmonary sarcoidosis, was performed. We found that some blood and BAL fluid immunological markers and lung computed tomography (CT) patterns have been associated with a different course of sarcoidosis. We revealed five markers that had a significant negative association with the course of sarcoidosis (worsening pulmonary function tests and/or the chest CT changes)-blood CD4+CD31+ and CD4+CD44+ T lymphocytes, BALF CD8+CD31+ and CD8+CD103+ T lymphocytes and a number of lung nodules on chest CT at the time of the diagnosis. Cut-off values, sensitivity, specificity and odds ratio for predictors of sarcoidosis progression were calculated. These markers may be reasonable predictors of sarcoidosis progression.

Wide-field Stokes polarimetric microscopy for second harmonic generation imaging.

We employ wide-field second harmonic generation (SHG) microscopy together with nonlinear Stokes polarimetry for quick ultrastructural investigation of large sample areas (700 µm × 700 µm) in thin histology sections. The Stokes vector components for SHG are obtained from the polarimetric measurements with incident and outgoing linear and circular polarization states. The Stokes components are used to construct the images of polarimetric parameters and deduce the maps of ultrastructural parameters of achiral and chiral nonlinear susceptibility tensor components ratios and cylindrical axis orientation in fibrillar materials. The large area imaging was employed for lung tumor margin investigations. The imaging shows reduced SHG intensity, increased achiral susceptibility ratio values, and preferential orientation of collagen strands along the boarder of tumor margin. The wide-field Stokes polarimetric SHG microscopy opens a possibility of quick large area imaging of ultrastructural parameters of tissue collagen, which can be used for nonlinear histopathology investigations.

Unsupervised determination of lung tumor margin with widefield polarimetric second-harmonic generation microscopy.

The extracellular matrix (ECM) is amongst many tissue components affected by cancer, however, morphological changes of the ECM are not well-understood and thus, often omitted from diagnostic considerations. Polarimetric second-harmonic generation (P-SHG) microscopy allows for visualization and characterization of collagen ultrastructure in the ECM, aiding in better understanding of the changes induced by cancer throughout the tissue. In this paper, a large region of hematoxylin and eosin (H&E) stained human lung section, encompassing a tumor margin, connecting a significant tumor portion to normal tissue was imaged with P-SHG microscopy. The resulting polarimetric parameters were utilized in principal components analysis and unsupervised K-Means clustering to separate normal- and tumor-like tissue. Consequently, a pseudo-color map of the clustered tissue regions is generated to highlight the irregularity of the ECM collagen structure throughout the region of interest and to identify the tumor margin, in the absence of morphological characteristics of the cells.

Machine learning-enabled cancer diagnostics with widefield polarimetric second-harmonic generation microscopy.

The extracellular matrix (ECM) collagen undergoes major remodeling during tumorigenesis. However, alterations to the ECM are not widely considered in cancer diagnostics, due to mostly uniform appearance of collagen fibers in white light images of hematoxylin and eosin-stained (H&E) tissue sections. Polarimetric second-harmonic generation (P-SHG) microscopy enables label-free visualization and ultrastructural investigation of non-centrosymmetric molecules, which, when combined with texture analysis, provides multiparameter characterization of tissue collagen. This paper demonstrates whole slide imaging of breast tissue microarrays using high-throughput widefield P-SHG microscopy. The resulting P-SHG parameters are used in classification to differentiate tumor from normal tissue, resulting in 94.2% for both accuracy and F1-score, and 6.3% false discovery rate. Subsequently, the trained classifier is employed to predict tumor tissue with 91.3% accuracy, 90.7% F1-score, and 13.8% false omission rate. As such, we show that widefield P-SHG microscopy reveals collagen ultrastructure over large tissue regions and can be utilized as a sensitive biomarker for cancer diagnostics and prognostics studies.

Exploring myocardial fibrosis in severe aortic stenosis: echo, CMR and histology data from FIB-AS study.

Myocardial fibrosis in aortic stenosis is associated with worse survival following aortic valve replacement. We assessed myocardial fibrosis in severe AS patients, integrating echocardiographic, cardiovascular magnetic resonance (CMR) and histological data. A total of 83 severe AS patients (age 66.4 ± 8.3, 42% male) who were scheduled for surgical AVR underwent CMR with late gadolinium enhancement and T1 mapping and global longitudinal strain analysis. Collagen volume fraction was measured in myocardial biopsies (71) that were sampled at the time of AVR. Results. CVF correlated with imaging and serum biomarkers of LV systolic dysfunction and left side chamber enlargement and was higher in the sub-endocardium compared with midmyocardium (p<0.001). CVF median values were higher in LGE-positive versus LGE-negative patients [28.7% (19-33) vs 20.7% (15-30), respectively, p=0.040]. GLS was associated with invasively (CVF; r=-0.303, p=0.013) and non-invasively (native T1; r=-0.321, p<0.05) measured myocardial fibrosis. GLS and native T1 correlated with parameters of adverse LV remodelling, systolic and diastolic dysfunction and serum biomarkers of heart failure and myocardial injury. Conclusion. Our data highlight the role of myocardial fibrosis in adverse cardiac remodelling in AS. GLS has potential as a surrogate marker of myocardial fibrosis, and high native T1 and low GLS values differentiated patients with more advanced cardiac remodelling.

Molecular Mechanisms behind Persistent Presence of Parvovirus B19 in Human Dilated Myocardium.

The role of parvovirus B19 (PVB19) in the pathogenesis of idiopathic dilated cardiomyopathy (DCM) remains poorly understood. Therefore, we have measured the levels of inflammation, fibrosis, apoptosis, and necrosis in endomyocardial biopsies (EMBs) and sera of nonischemic PVB19-positive (n = 14) and PVB19-negative (n = 18) DCM patients. Chronic persistence of PVB19 in myocardium did not induce significant infiltration of T cells (CD3 and CD45Ro) and macrophages (CD68), and did not secrete TNFα, IL-6, and CRB. The fibrosis in PVB19-positive EMBs was also lower compared to the virus-negative ones, while ECM degrading matrix metalloproteinase MMP1 and gelatinase MMP2 were significantly (by twofold) upregulated. In addition, there was no activation of neither apoptotic nor necrotic pathways. However, levels of antiapoptotic mitochondrial Bcl-2 and heat shock protein 60 (Hsp60) in PVB19-positive biopsies were almost threefold lower than in PVB19-negative ones revealing impairment of mitochondria. Altogether, data indicate that persistence of PVB19 in myocardiums of nonischemic DCM patients can cause myocardial ECM remodeling through the MMPs, such as MMP1 and MMP2, and mitochondrial impairment. The correlative analysis of measured biomarkers suggested likely further activation of apoptotic cell death pathways rather than fibrosis. Data also suggest that antiviral therapy could be beneficial for PVB19-positive DCM patients by managing further pathological myocardial remodeling.

Prevalence and prognostic relevance of myocardial inflammation and cardiotropic viruses in non-ischemic dilated cardiomyopathy.

BACKGROUND: Non-ischemic dilated cardiomyopathy (DCM) is a heterogeneous disease with a spectrum of etiological factors. However, subsets of the disease are not well-characterized with respect to these factors. The aim of this study was to evaluate the prevalence of myocardial inflammation and cardiotropic viruses in DCM patients and their impact on clinical outcome. METHODS: Fifty-seven patients with DCM underwent endomyocardial biopsy between 2010 and 2013. Biopsies were analyzed by polymerase chain reaction (PCR) for the presence of cardiotropic viruses, and inflammatory cell infiltration was assessed by immunohistochemistry. During a 5-year follow-up, 27 (47%) patients reached the composite outcome measure: heart transplantation, left ventricle assist device implantation or cardiovascular-related death. RESULTS: Thirty-one (54%) patients had myocardial inflammation and cardiotropic viruses were detected in 29 (52%). The most frequent viruses were parvovirus B19 and human herpesvirus type-6. Four specific sub-groups were distinguished by PCR and immunohistochemistry: virus-positive (chronic) myocarditis, autoreactive inflammatory DCM, viral DCM, non-inflammatory DCM. The presence of a viral genome in myocardium or diagnosis of inflammatory DCM did not predict the outcome of composite outcome measures (p > 0.05). However, univariate Cox regression and survival function estimation revealed an association between inflammation by a high number of T-cells and poor prognosis. CONCLUSIONS: This study has shown that two markers - cardiotropic viruses and myocardial inflammation - are prevalent among DCM patients. They are also helpful in identifying sub-groups of DCM. An increased number of T-lymphocytes in the myocardium is a predictor of poor mid-term and long-term prognosis.

Inflammation-Related Biomarkers Are Associated with Heart Failure Severity and Poor Clinical Outcomes in Patients with Non-Ischemic Dilated Cardiomyopathy.

Inflammation-related biomarkers are associated with clinical outcomes in mixed-etiology chronic heart failure populations. Inflammation-related markers tend to be higher in ischemic than in non-ischemic dilated cardiomyopathy (NI-DCM) patients, which might impact their prognostic performance in NI-DCM patients. Therefore, we aimed to assess the association of inflammation-related biomarkers with heart failure severity parameters and adverse cardiac events in a pure NI-DCM patient cohort. Fifty-seven patients with NI-DCM underwent endomyocardial biopsy. Biopsies were evaluated by immunohistochemistry for CD3+, CD45ro+, CD68+, CD4+, CD54+, and HLA-DR+ cells. Blood samples were tested for high-sensitivity C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor-α (TNF-α), soluble urokinase-type plasminogen activator receptor and adiponectin. During a five-year follow-up, twenty-seven patients experienced at least one composite adverse cardiac event: left ventricle assist device implantation, heart transplantation or death. Interleukin-6, TNF-α and adiponectin correlated with heart failure severity parameters. Patients with higher levels of interleukin-6, TNF-α, adiponectin or hs-CRP, or a higher number of CD3+ or CD45ro+ cells, had lower survival rates. Interleukin-6, adiponectin, and CD45ro+ cells were independently associated with poor clinical outcomes. All patients who had interleukin-6, TNF-α and adiponectin concentrations above the threshold experienced an adverse cardiac event. Therefore, a combination of these cytokines can identify high-risk NI-DCM patients.

CD31+, CD38+, CD44+, and CD103+ lymphocytes in peripheral blood, bronchoalveolar lavage fluid and lung biopsy tissue in sarcoid patients and controls.

BACKGROUND: The mechanisms driving the transition from inflammation to fibrosis in sarcoidosis patients are poorly understood; prognostic features are lacking. Immune cell profiling may provide insights into pathogenesis and prognostic factors of the disease. This study aimed to establish associations in simultaneous of lymphocyte subset profiles in the blood, bronchoalveolar lavage fluid (BALF), and lung biopsy tissue in the patients with newly diagnosed sarcoidosis. METHODS: A total of 71 sarcoid patients (SPs) and 20 healthy controls (HCs) were enrolled into the study. CD31, CD38, CD44, CD103 positive T lymphocytes in blood and BALF were analysed. Additionally, the densities of CD4, CD8, CD38, CD44, CD103 positive cells in lung tissue biopsies were estimated by digital image analysis. RESULTS: Main findings: (I) increase of percentage of CD3+CD4+CD38+ in BALF and blood, and increase of percentage of CD3+CD4+CD44+ in BALF in Löfgren syndrome patients comparing with patients without Löfgren syndrome, (II) increase of percentage of CD3+CD4+103+ in BALF and in blood in patients without Löfgren syndrome (comparing with Löfgren syndrome patients) and increase of percentage of CD3+CD4+103+ in BALF and in blood in more advanced sarcoidosis stage. (III) Increasing percentage of BALF CD3+CD4+CD31+ in sarcoidosis patients when comparing with controls independently of presence of Löfgren syndrome, smoking status or stage of sarcoidosis. Several significant correlations were found. CONCLUSIONS: Lymphocyte subpopulations in blood, BALF, and lung tissue were substantially different in SPs at the time of diagnosis compared to HCs. CD3+CD4+CD31+ in BALF might be a potential supporting marker for the diagnosis of sarcoidosis. CD3+CD4+CD38+ in BALF and blood and CD3+CD4+CD44+ in BALF may be markers of the acute immune response in sarcoidosis patients. CD4+CD103+ T-cells in BALF and in blood are markers of the persistent immune response in sarcoidosis patients and are potential prognostic features of the chronic course of this disease.

Case of Severe Treatment-Resistant Cryptogenic Organizing Pneumonia.

Cryptogenic organizing pneumonia is a rare interstitial lung disease with different onset of symptoms, which responds rapidly to glucocorticoid treatment. We present a case of cryptogenic organizing pneumonia which manifested as a progressive 3-year dyspnea that ultimately has led to acute respiratory failure. Moreover, treatment with prednisone for this patient exhibited slow onset of the effect.

Prognostic value of myocardial fibrosis in severe aortic stenosis: study protocol for a prospective observational multi-center study (FIB-AS).

BACKGROUND: Adverse cardiac remodeling with a myocardial fibrosis as a key pathophysiologic component may be associated to worse survival in aortic stenosis (AS) patients. Therefore, with the application of advanced cardiac imaging we aim to investigate left ventricular myocardial fibrosis in severe AS patients undergoing aortic valve replacement (AVR) and determine its impact with post-intervention clinical outcomes. METHODS: In a prospective, observational, cohort study patients with severe AS scheduled either for surgical or transcatheter AVR will be recruited from two tertiary heart centers in Denmark and Lithuania. All patients will receive standard of care in accordance with the current guidelines and will undergo additional imaging testing before and after AVR: echocardiography with deformation analysis and cardiovascular magnetic resonance (CMR) with T1 parametric mapping. Those undergoing surgical AVR will also have a myocardial biopsy sampled at the time of a surgery for histological validation. Patients will be recruited over a 2-year period and followed up to 2 years to ascertain clinical outcomes. Follow-up CMR will be performed 12 months following AVR, and echocardiography with deformation analysis will be performed 3, 12, and 24 months following AVR. The study primary outcome is a composite of all-cause mortality and major adverse cardiovascular events. DISCUSSION: Despite continuous effort of research community there is still a lack of early predictors of left ventricular decompensation in AS, which could improve patient risk stratification and guide the optimal timing for aortic valve intervention, before irreversible left ventricular damage occurs. Advanced cardiac imaging and CMR derived markers of diffuse myocardial fibrosis could be utilized for this purpose. FIB-AS study is intended to invasively and non-invasively assess diffuse myocardial fibrosis in AS patients and investigate its prognostic significance in post-interventional outcomes. The results of the study will expand the current knowledge of cardiac remodeling in AS and will bring additional data on myocardial fibrosis and its clinical implications following AVR. ETHICS/DISSEMINATION: The study has full ethical approval and is actively recruiting patients. The results will be disseminated through scientific journals and conference presentations. TRIAL REGISTRATION: ClinicalTrials.govNCT03585933. Registered on 02 July 2018.

Transthyretin cardiac amyloidosis in aortic stenosis: Prevalence, diagnostic challenges, and clinical implications.

Transthyretin cardiac amyloidosis (ATTR-CA) is a challenging and underdiagnosed cause of heart failure. Advances in cardiac imaging have enabled noninvasive diagnosis of ATTR-CA, causing the recent upsurge in disease awareness and detection. ATTR-CA has been increasingly recognized in patients with degenerative aortic stenosis (AS). With the growing number of elderly patients undergoing aortic valve intervention, the identification of ATTR-CA in this group of patients is of high clinical importance. Timely and correct diagnosis is essential for amyloid-directed therapies, as well as deciding on the AS treatment strategy. This review provides a comprehensive overview of the recent studies investigating coexistence of these two entities. We present the data on the prevalence of ATTR-CA in AS and their prognostic associations. As the diagnosis of ATTR-CA may be challenging, special attention is paid to the diagnostic utility of different imaging modalities, namely, echocardiography, cardiovascular magnetic resonance, nuclear imaging, and distinctive imaging features, in patients with dual pathology. We also present a flowchart summarizing integrated imaging in patients with suspected ATTR-CA.

Polar organization of collagen in human cardiac tissue revealed with polarimetric second-harmonic generation microscopy.

Polarimetric second-harmonic generation (P-SHG) microscopy is used to characterize the composition and polarity of collagen fibers in various regions of human cardiac tissue. The boundary between the cardiac conduction system and myocardium is shown to possess a distinct composition of collagen compared to other regions in the heart. Moreover, collagen fibers in this region are macroscopically organized in a unipolar arrangement, which may consequently aid in effective propagation of the electrical signal through the cardiac conduction system.

Prostate cancer solitary metastasis to anal canal: case report and review of literature.

BACKGROUND: Here we present the first cases of prostate cancer solitary metastasis to anal canal. CASE PRESENTATION: A 67-year-old male patient underwent radical prostatectomy with ilio-obturator lymphonodectomy in 2016 due to poorly differentiated ductal adenocarcinoma (Gleason 4 + 5(40%) = 9) pT3bN0. Two months later increasing PSA rate was noted and the patient started adjuvant intermittent androgen deprivation therapy combined with radiotherapy. Year after patient was admitted to the hospital complaining of dyschezia, pain in anal canal, and bloody stool. Digital rectal examination revealed an anal fissure with ulceration. A biopsy from ulcerated area showed poorly differentiated ductal adenocarcinoma of the prostate. Because there was no evidence of distant metastases on abdominal computed tomography (CT) scan and pelvic magnetic nuclear resonance imaging (MRI) and the only metastasis was in anal canal patient underwent laparoscopic abdominoperineal resection (APR). Postoperative course was uneventful and patient was discharged at postoperative day 7. CONCLUSIONS: Our presented case is the first to describe prostate cancer solitary metastasis to anal canal and we always have to be aware of possible rare disease while assessing the patient with rectal bleeding. Biopsy most of the time is the only and the most reliable test to differentiate between the diseases.

Enterogenous cyst of the small bowel mesentery: a case report and review of the literature.

INTRODUCTION: Enterogenous cysts are a very rare congenital abnormality that can be found anywhere within the gastrointestinal tract, most commonly in the small intestine. The incidence is approximately one in 4500-10,000 live births. Diagnosis can be suggested by ultrasound (US), computed tomography (CT) scans or magnetic resonance imaging (MRI) findings, although histological examination confirms the definitive diagnosis. PATIENTS: We present a case of enterogenous cyst in an adult female who underwent a resection of the tumour. RESULTS: After two years of observation, there is no evidence of tumour recurrence.