COVID-19 Can Unveil Brugada: A Rare Case.

Brugada syndrome (BRS) is a channelopathy with three characteristic electrocardiogram patterns and an increased risk of sudden cardiac death (SCD), in the absence of gross structural heart disease. Fever is shown to precipitate ventricular arrhythmias in patients with BRS. Here, we report a rare case of Brugada pattern in a patient with Coronavirus Disease 2019 (COVID-19) without fever. A baseline ECG should be considered for patients with COVID-19, even in the absence of fever. COVID-19 by itself may be a factor that can induce Brugada pattern ECGs.

Left Atrial Appendage Closure: What Do We Know?

Atrial fibrillation (AF) is the most common arrhythmia in the United States and the most common cause of embolic cerebrovascular events, with the majority of these thrombi originating in the left atrial appendage. The left atrial appendage (LAA) has separate developmental, ultrastructural, and physiological characteristics from the left atrium. Although LAA anatomy is highly variable, it can be categorized into 4 types: cactus, cauliflower, chicken wing, and windsock. The cauliflower type is associated with higher stroke risk in patients with nonvalvular AF. Although the cornerstone of therapy to prevent embolic strokes from AF has been anticoagulation with thrombin inhibitors, a large group of patients are unable to tolerate anticoagulation due to bleeding. This has led to the development and advancement of multiple surgical and percutaneous LAA closure devices to prevent embolic cerebrovascular accidents without the need for anticoagulation. In this article, we discuss the outcomes of major studies that utilized surgical LAA occlusion and its effectiveness. Furthermore, we summarize nonsurgical methods of LAA closure and future directions regarding LAA closure.

Systolic Anterior Motion of the Mitral Valve in the Presence of Annular Calcification.

BACKGROUND: Mitral annular calcification (MAC) has been reported as a possible cause of systolic anterior motion (SAM) of the mitral valve and dynamic left ventricular outflow tract (LVOT) obstruction. While morphologic features predisposing to SAM in other clinical settings have been described, patients with MAC+SAM have not been systematically investigated. We hypothesized that bulky calcium deposits in the mitral annulus could displace the valve toward the septum, thus promoting development of SAM. METHODS: We studied 30 patients with severe MAC who had SAM with septal contact. Three comparator groups (matched for age and sex) were developed: 30 controls without MAC or SAM, 30 with severe MAC but no SAM, and 30 with SAM but no MAC. RESULTS: Significant differences were found across groups for mitral valve coaptation point-septal distance (CSD), anterior mitral leaflet (AML) length, left ventricular diastolic dimension, and ejection fraction. Comparing all MAC subjects (n = 60) with controls, CSD was less (20.5 ± 4.1 vs 23.2 ± 3.7 mm, P = .003) and ejection fraction was higher (67.7% ± 7.8% vs 60.9% ± 6.4%, P < .0001) in MAC patients. Within MAC subjects AML was longer (21.9 ± 3.0 vs 17.4 ± 2.2 mm, P < .0001) and CSD was smaller (18.0 ± 2.7 vs 23.1 ± 3.6 mm, P < .0001) when SAM was present despite similar height of the calcium bar in the 2 MAC groups (12.4 ± 2.9 vs 11.1 ± 3.1 mm, P = .11). Regression analysis confirmed AML length and CSD as independent predictors of SAM. MAC+SAM patients also had more echocardiographic risk factors for SAM (acute aortomitral angle, small LVOT, long AML, small CSD, and presence of a septal bump) than MAC/no-SAM patients (3.4 ± 0.9 vs 1.8 ± 1.0, P < .0001). CONCLUSIONS: Bulky MAC appears to contribute to dynamic LVOT obstruction when it accumulates in such a way that the mitral valve is displaced anteriorly toward the septum. However, other features are also associated with SAM in these patients, particularly a long AML. A combination of morphologic features and favorable hemodynamics may be needed for SAM to develop in patients with severe MAC.

Incremental prognostic value of visually estimated coronary artery calcium in patients undergoing positron emission tomography imaging.

OBJECTIVE: Visually estimated coronary artery calcium (VECAC) from chest CT or attenuation correction (AC)/CT obtained during positron emission tomography (PET)-myocardial perfusion imaging (MPI) is feasible. Our aim was to determine the prognostic value of VECAC beyond conventional risk factors and PET imaging parameters, including coronary flow reserve (CFR). METHODS: We analysed 608 patients without known coronary artery disease who underwent PET-MPI between 2012 and 2016 and had AC/CT and/or chest CT images. We used Cox regression to estimate the association of VECAC categories (≤10, 11-400, >400 Agatston units (AU)) with the primary outcome of all-cause death, acute coronary syndrome or stroke (mean follow-up 4.3±1.8 years). C-statistics assessed the relationship between PET parameters and VECAC with the primary outcome. RESULTS: Mean age was 58±11 years, 65% were women and 67% were black. VECAC ≤10, 11-400 and >400 AU was observed in 68%, 12% and 20% of subjects, respectively. Compared with VECAC ≤10, VECAC categories 11-400 (HR 2.25, 95% CI 1.24 to 4.08) and >400 AU (HR 3.05, 95% CI 1.87 to 4.98) were associated with the primary outcome after adjusting for traditional risk factors, MPI findings and CFR. Adding VECAC to a model that included PET-MPI, CFR and clinical risk factors improved the prognostic value for the primary outcomes (c-statistic 0.71 to 0.75 with VECAC, p=0.01). CONCLUSIONS: VECAC is a potent predictor of events beyond traditional risk factors and PET imaging markers, including CFR. These data further support the importance for routine VECAC implementation.

Energy loss associated with in-vitro modeling of mitral annular calcification.

INTRODUCTION: Study aims were to compare hemodynamics and viscous energy dissipation (VED) in 3D printed mitral valves-one replicating a normal valve and the other a valve with severe mitral annular calcification (MAC). Patients with severe MAC develop transmitral gradients, without the commissural fusion typifying rheumatic mitral stenosis (MS), and may have symptoms similar to classical MS. A proposed mechanism relates to VED due to disturbed blood flow through the diseased valve into the ventricle. METHODS: A silicone model of a normal mitral valve (MV) was created using a transesophageal echocardiography dataset. 3D printed calcium phantoms were incorporated into a second valve model to replicate severe MAC. The synthetic MVs were tested in a left heart duplicator under rest and exercise conditions. Fine particles were suspended in a water/glycerol blood analogue for particle image velocimetry calculation of VED. RESULTS: Catheter mean transmitral gradients were slightly higher in the MAC valve compared to the normal MV, both at rest (3.2 vs. 1.3 mm Hg) and with exercise (5.9 vs. 5.0 mm Hg); Doppler gradients were 2.7 vs. 2.1 mm Hg at rest and 9.9 vs 8.2 mm Hg with exercise. VED was similar between the two valves at rest. During exercise, VED increased to a greater extent for the MAC valve (240%) versus the normal valve (127%). CONCLUSION: MAC MS is associated with slightly increased transmitral gradients but markedly increased VED during exercise. These energy losses may contribute to the exercise intolerance and exertional dyspnea present in MAC patients.

Atrioventricular and Sinus Node Dysfunction in Stable COVID-19 Patients.

There are now well-documented cardiac complications of COVID-19 infection which include myocarditis, heart failure, and acute coronary syndrome resulting from coronary artery thrombosis or SARS-CoV-2-related plaque ruptures. There is growing evidence showing that arrhythmias are also one of the major complications. We report two patients with no known history of cardiac conduction disease who presented with COVID-19 symptoms, positive SARS-CoV-2 infection, and developed cardiac conduction abnormalities. Cardiac conduction system disease involving the sino-atrial (SA) node and atrioventricular (AV) node could be a manifestation of SARS-CoV-2 infection.

Polymorphic Ventricular Tachycardia with a Normal QTc Interval in a Patient with COVID-19 and Fever: Case Report.

Arrhythmias or conduction system disease are not the most common manifestation of COVID-19 infection in patients requiring hospital admission. Torsade de pointes typically occurs in bursts of self-limiting episodes with symptoms of dizziness and syncope. However, it may occasionally progress to ventricular fibrillation and sudden death. In this article, we report a case of COVID-19 patient who developed polymorphic ventricular tachycardia with torsade de pointes morphology with normal QTc interval in the setting of fever. An 81-year-old woman was admitted with symptoms of COVID-19. She was treated with hydroxychloroquine, azithromycin, and doxycycline at an outside facility and finished the treatment 5 days prior to admission to our facility. Her course was complicated by atrial fibrillation with rapid ventricular response requiring cardioversion. Later, she developed two episodes of polymorphic ventricular tachycardia with TdP morphology with normal QTc. There was a correlation with fever triggering the ventricular tachycardia. We advocated aggressive fever control given the QTc was normal and stable. Following fever control, the patient remained stable and had no abnormal rhythm. COVID-19 patients are prone to different arrhythmias including life-threatening ventricular arrhythmias with normal left ventricular systolic function and normal QTc, and they should be monitored for fever and electrolyte abnormality during their hospital stay.

Color Doppler Splay: A Clue to the Presence of Significant Mitral Regurgitation.

BACKGROUND: The authors describe a previously unreported Doppler signal associated with mitral regurgitation (MR) as imaged using transthoracic echocardiography. Horizontal "splay" of the color Doppler signal along the atrial surface of the valve may indicate significant regurgitation when the MR jet otherwise appears benign. METHODS: Splay was defined as a nonphysiologic arc of color centered at the point at which the MR jet emerges into the left atrium. The authors present a series of 10 cases of clinically significant MR (moderately severe or severe as defined by transesophageal echocardiography) that were misclassified on transthoracic echocardiography as less than moderate. The splay signal was present on at least one standard transthoracic view in each case. To better characterize the splay signal, two groups were created from existing clinically driven transthoracic echocardiograms: 100 consecutive patients with severe MR and 100 with mild MR. RESULTS: Splay was present in the majority of severe MR cases (81%) regardless of vendor machine, ejection fraction, or MR etiology. Splay was particularly prevalent among patients with wall-hugging jets (28 of 30 [93%]). In patients with mild MR, splay was present less often (16%), on fewer frames per clip, and had smaller dimensions compared with severe MR. Color scale did not differ between subjects with and those without splay, but color gain was higher when splay was present (P = .04). Machine settings were further explored in a single subject with prominent splay: increasing transducer frequency reduced splay, while increasing color gain increased it. CONCLUSIONS: The authors describe a new transthoracic echocardiographic sign of MR. Horizontal splay may be a clue to the presence of severe MR when the main body of the jet is out of the imaging plane. Splay is likely generated as a side-lobe artifact due to a high-flux regurgitant jet.

Percutaneous Vertebroplasty: A History of Procedure, Technology, Culture, Specialty, and Economics.

Percutaneous vertebroplasty (VP) progressed from a virtually unknown procedure to one performed on hundreds of thousands of patients annually. The development of VP provides a historically exciting case study into a rapidly adopted procedure. VP was the synthesis of information gained from spinal biopsy developments, the inception of biomaterials used in medicine, and the unique health care climate in France during the 1980s. It was designed as a revolutionary technique to treat vertebral body fractures with minimal side effects and was rapidly adopted and marketed in the United States. The impact of percutaneous vertebroplasty on spine surgery was profound.

Monocyte-derived cells of the brain and malignant gliomas: the double face of Janus.

OBJECTIVE: Monocyte-derived cells of the brain (MDCB) are a diverse group of functional immune cells that are also highly abundant in gliomas. There is growing evidence that MDCB play essential roles in the pathogenesis of gliomas. The aim of this review was to collate and systematize contemporary knowledge about these cells as they relate to glioma progression and antiglioblastoma therapeutic modalities with a view toward improved effectiveness of therapy. METHODS: We reviewed relevant studies to construct a summary of different MDCB subpopulations in steady state and in malignant gliomas and discuss their role in the development of malignant gliomas and potential future therapies. RESULTS: Current studies suggest that MDCB subsets display different phenotypes and differentiation potentials depending on their milieu in the brain and exposure to tumoral influences. MDCB possess specific and unique functions, including those that are protumoral and those that are antitumoral. CONCLUSIONS: Elucidating the role of mononuclear-derived cells associated with gliomas is crucial in designing novel immunotherapy strategies. Much progress is needed to characterize markers to identify cell subsets and their specific regulatory roles. Investigation of MDCB can be clinically relevant. Specific MDCB populations potentially can be used for glioma therapy as a target or as cell vehicles that might deliver cytotoxic substances or processes to the glioma microenvironment.

Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part 1: stimulatory effects on blood monocytes and monocyte-derived cells of the brain.

OBJECTIVES: Immunotherapy with immunostimulants is an attractive therapy against gliomas. C-type lectin receptors specific for galactose/N-acetylgalactosamine (GCLR) regulate cellular differentiation, recognition, and trafficking of monocyte-derived cells. A peptide mimetic of GCLR ligands (GCLRP) was used to activate blood monocytes and populations of myeloid-derived cells against a murine glioblastoma. METHODS: The ability of GCLRP to stimulate phagocytosis by human microglia and monocyte-derived cells of the brain (MDCB) isolated from a human glioblastoma was initially assessed in vitro. Induction of activation markers on blood monocytes was assayed by flow cytometry after administration of GCLRP to naive mice. C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells and were randomized for tumor size by magnetic resonance imaging, which was also used to assess increase in tumor size. Brain tumor tissues were analyzed using flow cytometry, histology, and enzyme-linked immunosorbent assay with respect to tumor, peritumoral area, and contralateral hemisphere regions. RESULTS: GCLRP exhibited strong stimulatory effect on MDCBs and blood monocytes in vitro and in vivo. GCLRP was associated with an increased percentage of precursors of dendritic cells in the blood (P = 0.003), which differentiated into patrolling macrophages in tumoral (P = 0.001) and peritumoral areas (P = 0.04), rather than into dendritic cells, as in control animals. Treatment with GCLRP did not result in a significant change in survival of mice bearing a tumor. CONCLUSIONS: In vitro and in vivo activation of monocytes was achieved by administration of GCLR to mice. GCLRP-activated blood monocytes were recruited to the brain and exhibited specific phenotypes corresponding with tumor region (glioma, peritumoral zone, and contralateral glioma-free hemisphere). GCLRP treatment alone was associated with increased glioma mass as the result of the infiltration of phagocytic cells. Regional specificity for MDCB may have significant tumor treatment implications.

Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part II: combination with external radiation improves survival.

BACKGROUND: A peptide mimetic of a ligand for the galactose/N-acetylgalactosamine-specific C-type lectin receptors (GCLR) exhibited monocyte-stimulating activity, but did not extend survival when applied alone against a syngeneic murine malignant glioma. In this study, the combined effect of GCLRP with radiation was investigated. METHODS: C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells. Animals were grouped based on randomized tumor size by magnetic resonance imaging on day seven. One group that received cranial radiation (4 Gy on days seven and nine) only were compared with animals treated with radiation and GCLRP (4 Gy on days seven and nine combined with subcutaneous injection of 1 nmol/g on alternative days beginning on day seven). Magnetic resonance imaging was used to assess tumor growth and correlated with survival rate. Blood and brain tissues were analyzed with regard to tumor and contralateral hemisphere using fluorescence-activated cell sorting analysis, histology, and enzyme-linked immunosorbent assay. RESULTS: GCLRP activated peripheral monocytes and was associated with increased blood precursors of dendritic cells. Mean survival increased (P < 0.001) and tumor size was smaller (P < 0.02) in the GCLRP + radiation group compared to the radiation-only group. Accumulation of dendritic cells in both the tumoral hemisphere (P < 0.005) and contralateral tumor-free hemisphere (P < 0.01) was associated with treatment. CONCLUSION: Specific populations of monocyte-derived brain cells develop critical relationships with malignant gliomas. The biological effect of GCLRP in combination with radiation may be more successful because of the damage incurred by tumor cells by radiation and the enhanced or preserved presentation of tumor cell antigens by GCLRP-activated immune cells. Monocyte-derived brain cells may be important targets for creating effective immunological modalities such as employing the receptor system described in this study.

The discovery of the pyramidal neurons: Vladimir Betz and a new era of neuroscience.

As a consequence of nascent technology, the 19th century witnessed a profound change in orientation to the nervous system. For example, improved microscopy in the first half of the 19th century allowed high magnification without blurring. The subsequent observation of nucleated cells led to the identification of individual brain cells. Philosophical changes in approach to the natural sciences took their lead from those applied to physical observations. The Ukrainian anatomist and histologist, Vladimir Alekseyevich Betz (1834-94) played a pivotal role in reshaping scientific and philosophical approaches to the brain, connecting cerebral localization, function and brain microstructure. Betz revolutionized methods of cell fixation and staining. Sometimes his efforts yielded enormously complicated technological improvements. Betz's greatest contribution, however, was connecting his discovery of the function of giant pyramidal neurons of the primary motor cortex ('cells of Betz') with the cortical organization. Considering cortical cytoarchitectonics in relation with physiological function, Betz recognized this organization in two areas: motor and sensory. He defined a functional area on histological grounds and thereby opened the way to study precise cortical areas. Betz participated in the scientific transformation of cytoarchitectonics based on macro- and microscopic studies of the cortical surface, enabling him to view the paths of nerve cells in the brain. Betz's influence allowed systemization of scattered scientific findings. The discovery of pyramidal cells was a turning point in the prevailing philosophical and scientific approach to the brain, linking cytoarchitecture, neurophysiology and cerebral localization.