Maleszewski, Joseph J.

Background Description of cerebral and retinal infarction in patients with bicuspid aortic valve (BAV) is limited to case reports. We aimed to characterize cerebral and retinal infarction and examine outcomes in patients with BAV. Methods and Results Consecutive patients from 1975 to 2015 with BAV (n=5401) were retrospectively identified from the institutional database; those with confirmed cerebral or retinal infarction were analyzed. Infarction occurring after aortic valve replacement was not included. Patients were grouped according to infarction pathogenesis: embolism from a degenerative calcific BAV (BAVi); non‐BAV, large artery atherosclerotic or lacunar infarction (LAi); and non‐BAV, non‐large artery embolic infarction (nLAi). There were 83/5401 (1.5%) patients, mean age 54±12 years and 28% female, with confirmed cerebral or retinal infarction (LAi 23/83 [28%]; nLAi 30/83 [36%]; BAVi 26/83 [31%]; other 4/83 [5%]). Infarction was embolic in 72/83 (87%), and 35/72 (49%) were cardioembolic. CHA 2 DS 2 ‐VASc score was 1.4±1.2 in BAVi ( P =0.188 versus nLAi) and 2.3±1.2 in LAi ( P =0.005). Recurrent infarction occurred in 41% overall (50% BAVi, P =0.164 and 0.803 versus LAi and nLAi). BAVi was more commonly retinal (39% BAVi versus 13% LAi, P =0.044 versus 0% nLAi, P =0.002). Patients with BAVi and LAi were more likely to have moderate‐to‐severe aortic stenosis and undergo aortic valve replacement compared with patients with nLAi. Conclusions Cardioembolism, often from degenerative calcification of the aortic valve, is a predominant cause of cerebral and retinal infarction in patients with BAV and is frequently recurrent. Cerebral and retinal infarction should be regarded as a complication of BAV.

Abstract Hands‐on dissections using cadaveric tissues for neuroanatomical education are not easily available in many educational institutions due to financial, safety, and ethical factors. Supplementary pedagogical tools, for instance, 3D models of anatomical specimens acquired with photogrammetry are an efficient alternative to democratize the 3D anatomical data. The aim of this study was to describe a technical guideline for acquiring realistic 3D anatomic models with photogrammetry and to improve the teaching and learning process in neuroanatomy. Seven specimens with different sizes, cadaveric tissues, and textures were used to demonstrate the step‐by‐step instructions for specimen preparation, photogrammetry setup, post‐processing, and display of the 3D model. The photogrammetry scanning consists of three cameras arranged vertically facing the specimen to be scanned. In order to optimize the scanning process and the acquisition of optimal images, high‐quality 3D models require complex and challenging adjustments in the positioning of the specimens within the scanner, as well as adjustments of the turntable, custom specimen holders, cameras, lighting, computer hardware, and its software. MeshLab® software was used for editing the 3D model before exporting it to MedReality® (Thyng, Chicago, IL) and SketchFab® (Epic, Cary, NC) platforms. Both allow manipulation of the models using various angles and magnifications and are easily accessed using mobile, immersive, and personal computer devices free of charge for viewers. Photogrammetry scans offer a 360° view of the 3D models ubiquitously accessible on any device independent of operating system and should be considered as a tool to optimize and democratize the teaching of neuroanatomy.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy. Currently, hypertrophy pathways responsible for HCM have not been fully elucidated. Their identification could serve as a nidus for the generation of novel therapeutics aimed at halting disease development or progression. Herein, we performed a comprehensive multi-omic characterization of hypertrophy pathways in HCM. Methods: Flash-frozen cardiac tissues were collected from genotyped HCM patients (n=97) undergoing surgical myectomy and tissue from 23 controls. RNA sequencing and mass spectrometry–enabled deep proteome and phosphoproteomic assessment were performed. Rigorous differential expression, gene set enrichment, and pathway analyses were performed to characterize HCM-mediated alterations with emphasis on hypertrophy pathways. Results: We identified transcriptional dysregulation with 1246 (8%) differentially expressed genes and elucidated downregulation of 10 hypertrophy pathways. Deep proteomic analysis identified 411 proteins (9%) that differed between HCM and controls with strong dysregulation of metabolic pathways. Seven hypertrophy pathways were upregulated with antagonistic upregulation of 5 of 10 hypertrophy pathways shown to be downregulated in the transcriptome. Most upregulated hypertrophy pathways encompassed the rat sarcoma-mitogen-activated protein kinase signaling cascade. Phosphoproteomic analysis demonstrated hyperphosphorylation of the rat sarcoma-mitogen-activated protein kinase system suggesting activation of this signaling cascade. There was a common transcriptomic and proteomic profile regardless of genotype. Conclusions: At time of surgical myectomy, the ventricular proteome, independent of genotype, reveals widespread upregulation and activation of hypertrophy pathways, mainly involving the rat sarcoma-mitogen-activated protein kinase signaling cascade. In addition, there is a counterregulatory transcriptional downregulation of the same pathways. Rat sarcoma-mitogen-activated protein kinase activation may serve a crucial role in hypertrophy observed in HCM.

Context.— Progressive independence in medicine is critical to building confidence and decisiveness in trainees. However, this can be difficult to accomplish in the strict regulatory environment of pathology. Objective.— To pilot and adopt a process whereby surgical pathology fellows independently manage a subset of cases and release preliminary reports. Design.— Upon program approval, board-certified surgical pathology fellows were eligible for preliminary report sign-out at their discretion. Eligible cases were sent from outside institutions for confirmatory review. Preliminary reports were viewable in the electronic medical record. Safety measures were used to ensure timely release of final reports by attending pathologists. Results.— Fellows participating in the pilot (n = 4) released 59 preliminary reports out of 101 cases reviewed (58%), with 1 potentially significant discrepancy between preliminary and final report. Turnaround time was not affected. The process was endorsed by all participants and adopted as standard practice. During the first year, eligible fellows (n = 8) released 123 preliminary reports out of 1260 cases reviewed (9.8%). There were no major diagnostic discrepancies and no effects on turnaround time. The number of preliminary reports released by each fellow was variable (range, 2–48; median, 8), likely a reflection of both external factors (number of trainees on service, volume) and trainee-specific factors (confidence, efficiency). Conclusions.— Fellows showed good judgment when independently managing cases, with just 1 potentially significant discrepancy out of 182 cases (<1%). No patients were adversely impacted. Use of this process varied widely among fellows and may require closer monitoring and encouragement for fellows who are tentative about releasing preliminary reports.

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficient levels and/or activity of glycosaminoglycan (GAG)-degradative enzymes. MPS are characterized by accumulation of the mucopolysaccharides heparan sulfate, dermatan sulfate, keratan sulfate, or chondroitin sulfate in tissues. We report the case of a 38-year-old woman with a history of joint restriction and retinitis pigmentosa who developed bivalvular heart failure requiring surgery. It was not until pathological examination of surgically excised valvular tissue that a diagnosis of MPS I was made. Her musculoskeletal and ophthalmologic symptoms, when placed in the context of MPS I, painted the diagnostic picture of a genetic syndrome that was overlooked until a diagnosis was made in late middle age.

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood–derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases characterized by asymmetric left ventricular hypertrophy (LVH) and vast clinical and genetic heterogeneity. Several transcriptional studies in HCM heart tissues have shown severe alterations in gene expression. However, these earlier studies relied on microarray technology or were limited by small sample size or lack of genotype-specific analyses. Methods: We obtained flash-frozen cardiac tissue from patients with HCM undergoing surgical myectomy/septal reduction therapy for relief of left ventricular outflow tract obstruction. RNA-sequencing (RNAseq) was performed using paired-end index reading on 97 myectomy tissues (44 female [45%]; mean age at surgery of 47 ± 18 years) and 23 control tissues (10 female [43%]; mean age at death of 43 ± 12 years) to identify differentially expressed genes (DEGs) using edgeR and pathways in HCM using Ingenuity Pathway Analysis. Additionally, genome sequencing (GS) was performed and HCM patients were divided into genotype-based subgroups to compare the transcriptional profile across different genotypes. Results: Overall, 43% had a pathogenic, HCM-associated variant including 23% with MYBPC3-HCM and 15% with MYH7-HCM. Among the 15,634 genes expressed in the cardiac tissue,1,246 genes (8%) were upregulated and 738 genes (3%) were downregulated significantly in HCM vs. controls. Pathway analysis showed alterations in 126 pathways with downregulation of 44 pathways and upregulation of 1 pathway. There were notable transcriptional alterations of most canonical, pro-hypertrophic pathways, including statistically and biologically significant downregulation of five pathways [-log (BH p-value)≥ 1.3; Z-score≤ -2]: ERK/MAPK, p38 MAPK, ERK5, IL6, and NF-κB signaling. Far less DEGs were observed between genotypic subgroups, with only 37 DEGSs identified between sarcomere positive- and genotype negative-HCM. Conclusions: At the time of surgical myectomy, the ventricular myocardium’s transcriptome, independent of genotype, reveals widespread downregulation of pro-hypertrophic pathways. Whether these counter regulatory measures can be targeted therapeutically warrants further investigation.

Background Intracranial aneurysms are reported in 6%–10% of patients with bicuspid aortic valve (BAV), and routine intracranial aneurysm surveillance has been advocated by some. We assessed the prevalence and features of the most important patient‐outcome: aneurysmal sub‐arachnoid hemorrhage (aSAH), as compared with controls without aSAH, and tricuspid aortic valve (TAV) with aSAH. Methods and Results Adult patients with accurate diagnosis of aSAH and at least one echocardiogram between 2000 and 2019 were identified from a consecutive prospectively maintained registry of aSAH admissions. Controls without a diagnosis of SAH were age‐ and sex‐matched. BAV prevalence was confirmed echocardiographically. Severity of aSAH was categorized using modified Fisher and World Federation of Neurological Scale. Neurologic outcome was assessed using modified Rankin score. A total 488 aSAH cases and 990 controls were identified and BAV status was confirmed. Prevalence of BAV in patients with aSAH was 1.2% (6/488) versus 3.5% (35/990) in controls, P =0.01. BAV+aSAH were noted to be younger than TAV+aSAH (56±11 versus 68±14; P =0.03) with smaller aneurysms (5±2 versus 7±4; P =0.31). The severity of aSAH was lesser in BAV+aSAH than TAV (modified Fisher grade>2 50% versus 74%; P =0.19, World Federation of Neurological Scale grade>3 17% versus 36%; P =0.43). BAV+aSAH had less severe neurologic disability (modified Rankin score 3%–6 33% versus 49% in TAV; P =0.44) and comparable in‐hospital mortality rates ( P =0.93). BAV had lower odds for aSAH on multivariate analysis (odds ratio 0.23[CI 0.08–0.65]; P =0.01). Conclusions Prevalence of BAV was 3 times lower in the aSAH registry than in controls without aSAH. BAV+aSAH had clinically smaller aneurysms, clinically smaller bleeds, and better neurologic outcome as compared with TAV+aSAH, which needs to be confirmed in larger studies. These findings argue against routine surveillance for intracranial aneurysms in patients with BAV without aortic coarctation.