From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction.

PURPOSE OF REVIEW: Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. RECENT FINDINGS: Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward.

Sex-specific genetic architecture of blood pressure.

The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (Pfemale ≤ 5 × 10-8; Pmale > 5 × 10-8) and 142 were male-specific (Pmale ≤ 5 × 10-8; Pfemale > 5 × 10-8); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1. Analyses of gene-by-sex interactions and sexually dimorphic effects identified four genomic regions, showing female-specific associations with diastolic BP or pulse pressure, including the chromosome 13q34-COL4A1/COL4A2 locus. Notably, female-specific pulse pressure-associated loci exhibited enriched acetylated histone H3 Lys27 modifications in arterial tissues and a female-specific association with fibromuscular dysplasia, a female-biased vascular disease; colocalization signals included Chr13q34: COL4A1/COL4A2, Chr9p21: CDKN2B-AS1 and Chr4q32.1: MAP9 regions. Sex-specific and sex-biased polygenic associations of BP traits were associated with multiple cardiovascular traits. These findings suggest potentially clinically significant and BP sex-specific pleiotropic effects on cardiovascular diseases.

Clinical outcomes of patients referred for left atrial appendage exclusion who did and did not undergo the procedure.

BACKGROUND: Left atrial appendage exclusion (LAAE) is an effective alternative to long-term anticoagulation in patients with atrial fibrillation. Not all patients considered for LAAE undergo the procedure because of ineligibility, anatomic or medical constraints, and preference of the patient. OBJECTIVE: The objective of this study was to report on the management strategies and long-term clinical outcomes of patients referred to a dedicated multidisciplinary LAAE clinic, including all who subsequently did and did not undergo LAAE. METHODS: This was a retrospective analysis of prospectively acquired data from all patients referred to the comprehensive multidisciplinary LAAE clinic at the University of Michigan between 2016 and 2022. A consecutive 301 patients (age, 75 ± 8 years; 106 women) with atrial fibrillation were evaluated. LAAE was performed in 168 patients (56%) with use of the Watchman device in 146 (49%) and surgically in 22 (7%). LAAE was not performed in 133 patients (44%, no-LAAE group) because of ineligibility in 62 (21%), anatomic constraints in 23 (7%), and preference of the patient in 48 (36%). The CHA2DS2-VASc score (4.7 ± 1.5 vs 4.1 ± 1.6; P = .002) and HAS-BLED score (3.4 ± 1.0 vs 2.8 ± 1.1; P < .001) were higher in the LAAE groups. RESULTS: Anticoagulant therapy was discontinued in 137 of 146 (94%) and 61 of 133 (61%) in the Watchman and no-LAAE groups, respectively (P < .001). During a median follow-up of 2.2 years (interquartile range, 1.2-4.0 years), in the LAAE (n = 168) and no-LAAE (n = 133) groups, respectively, 39 (23%) vs 29 (22%) deaths, 13 (8%) vs 5 (4%) thromboembolic events, and 24 (14%) vs 23 (17%) bleeding complications occurred. Continued long-term anticoagulation was not a predictor of clinical outcomes. CONCLUSION: After a comprehensive evaluation in a multidisciplinary clinic, ∼50% of the patients referred for LAAE did not proceed with LAAE and resumed anticoagulation.

Long-term outcomes of patients with ventricular arrhythmias and negative programmed ventricular stimulation followed with implantable loop recorders: Impact of delayed-enhancement cardiac magnetic resonance imaging.

BACKGROUND: Programed ventricular stimulation (PVS) is a risk stratification tool in patients at risk for adverse arrhythmia outcomes. Patients with negative PVS may yet be at risk for adverse arrhythmia-related events, particularly in the presence of symptomatic ventricular arrhythmias (VA). OBJECTIVE: To investigate the long-term outcomes of real-world patients with symptomatic VA without indication for device therapy and negative PVS, and to examine the role of cardiac scaring on arrhythmia recurrence. METHODS: Patients with symptomatic VA, and late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR), and negative PVS testing were included. All patients underwent placement of implantable cardiac monitors (ICM). Survival analysis was performed to investigate the impact of LGE-CMR findings on survival free from adverse arrhythmic events. RESULTS: Seventy-eight patients were included (age 60 ± 14 years, women n = 36 (46%), ejection fraction 57 ± 9%, cardiomyopathy n = 26 (33%), mitral valve prolapse [MVP] n = 9 (12%), positive LGE-CMR scar n = 49 (62%), history of syncope n = 23 (29%)) including patients with primarily premature ventricular contractions (n = 21) or nonsustained VA (n = 57). Patients were followed for 1.6 ± 1.5 years during which 14 patients (18%) experienced VA requiring treatment (n = 14) or syncope due to bradycardia (n = 2). Four/9 patients (44%) with MVP experienced VA (n = 3) or syncope (n = 1). Baseline characteristics between those with and without adverse events were similar (p > 0.05); however, the presence of cardiac scar on LGE-CMR was independently associated with an increased risk of adverse events (hazard ratio: 5.6 95% confidence interval: [1.2-27], p = 0.03, log-rank p = 0.03). CONCLUSIONS: In a real-world cohort with long-term follow-up, adverse arrhythmic outcomes occurred in 18% of patients with symptomatic VA despite negative PVS, and this risk was significantly greater in patients with positive DE-CMR scar. Long term-monitoring, including the use of ICM, may be appropriate in these patients.

The clinical and genomic features of seizures in meningiomas.

Meningiomas are the most common central nervous system tumors. Although these tumors are extra-axial, a relatively high proportion (10%-50%) of meningioma patients have seizures that can substantially impact the quality of life. Meningiomas are believed to cause seizures by inducing cortical hyperexcitability that results from mass effect and cortical irritation, brain invasion, or peritumoral brain edema. In general, meningiomas that are associated with seizures have aggressive features, with risk factors including atypical histology, brain invasion, and higher tumor grade. Somatic NF2 mutated meningiomas are associated with preoperative seizures, but the effect of the driver mutation is mediated through atypical features. While surgical resection is effective in controlling seizures in most patients with meningioma-related epilepsy, a history of seizures and uncontrolled seizures prior to surgery is the most significant predisposing factor for persistent postoperative seizures. Subtotal resection (STR) and relatively larger residual tumor volume are positive predictors of postoperative seizures. Other factors, including higher WHO grade, peritumoral brain edema, and brain invasion, are inconsistently associated with postoperative seizures, suggesting they might be crucial in the development of an epileptogenic focus, but do not appear to play a substantial role after seizure activity has been established. Herein, we review and summarize the current literature surrounding meningioma-related epilepsy and underscore the interaction of multiple factors that relate to seizures in patients with meningioma.

Metastatic Phyllodes Tumor in a Patient With Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is an epigenetic disorder of imprinting on the chromosome 11p15 region that presents with clinical features, such as macroglossia, abdominal wall defects, neonatal hypoglycemia, hemihypertrophy, and embryonal tumors. Phyllodes tumors (PTs) are rare fibroepithelial tumors that account for 0.3% to 1% of breast tumors and present in women aged 35 to 55 years. Here we describe a rare case of metastatic malignant phyllodes tumor in a 27-year-old woman with BWS and uniparental disomy (UPD) of chromosome 11p15.5. To our knowledge, this is the first case report in literature to describe metastatic malignant phyllodes tumor in a woman with BWS.

Mortality from Aspiration Pneumonia: Incidence, Trends, and Risk Factors.

Aspiration pneumonia is a potentially preventable, aggressive type of pneumonia. Little is understood on the burden in mortality from aspiration pneumonia. Our objectives were to first examine the burden of mortality from aspiration pneumonia in the United States and second investigate comorbidities associated with aspiration pneumonia to understand risk factors. We conducted a case-control study of individuals who died of aspiration pneumonia matched to those who died of other causes. We analyzed all deaths in the United States using the Multiple Cause of Death Dataset from 1999 to 2017. Cases were matched with controls based on age, sex, and race. We calculated age-adjusted mortality rates, annual percentage changes in aspiration pneumonia mortality, and matched odds ratio comparisons. We identified a total of 1,112,944 deaths related to aspiration pneumonia from 1999 to 2017 or an average of 58,576 per year (age-adjusted mortality rate, 21.85 per 100,000 population; 95% confidence interval (CI) 21.78-21.92). Aspiration pneumonia was reported as the underlying cause of death in 334,712 deaths or an average of 17,616 deaths per year (30.1% of the total aspiration pneumonia-associated deaths). Individuals 75 years old or older accounted for 76.0% of aspiration pneumonia deaths and the age adjusted rate ratio was 161.0 (CI 160.5-161.5). Neurologic, upper gastrointestinal, and pulmonary conditions as well as conditions associated with sedative substances were more often associated with aspiration pneumonia-associated deaths. Aspiration pneumonia is the underlying cause or a cofactor in tens of thousands of deaths each year in the United States. Aspiration pneumonia-associated deaths are highly prevalent with advanced age and are associated with neurologic, upper gastrointestinal and pulmonary conditions.

Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Tick hypersensitivity and human tick-borne diseases.

Immune-mediated hypersensitivity reactions to ticks and other arthropods are well documented. Hypersensitivity to ixodid (hard bodied) ticks is especially important because they transmit infection to humans throughout the world and are responsible for most vector-borne diseases in the United States. The causative pathogens of these diseases are transmitted in tick saliva that is secreted into the host while taking a blood meal. Tick salivary proteins inhibit blood coagulation, block the local itch response and impair host anti-tick immune responses, which allows completion of the blood meal. Anti-tick host immune responses are heightened upon repeated tick exposure and have the potential to abrogate tick salivary protein function, interfere with the blood meal and prevent pathogen transmission. Although there have been relatively few tick bite hypersensitivity studies in humans compared with those in domestic animals and laboratory animal models, areas of human investigation have included local hypersensitivity reactions at the site of tick attachment and generalized hypersensitivity reactions. Progress in the development of anti-tick vaccines for humans has been slow due to the complexities of such vaccines but has recently accelerated. This approach holds great promise for future prevention of tick-borne diseases.

Associations of meningioma molecular subgroup and tumor recurrence.

BACKGROUND: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients. METHODS: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling. RESULTS: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence. CONCLUSION: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.

Clinical and genomic factors associated with seizures in meningiomas.

OBJECTIVE: The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients. METHODS: Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures. RESULTS: Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis. CONCLUSIONS: Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.

Description and Assessment of a Neurosurgery Shadowing and Research Program: A Paradigm for Early and Sustained Exposure to Academic Neurosurgery.

OBJECTIVE: To describe and assess the educational value of a functional neurosurgery clinical shadowing and research tutorial for pre-medical trainees. DESIGN: Program participants observed functional neurosurgery procedures and conducted basic science and clinical research in neurosurgery fields. Former participants completed a brief online survey to evaluate their perspectives and experiences throughout the tutorial. SETTING: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. PARTICIPANTS: 15 pre-medical and post-baccalaureate trainees participated in the tutorial. All former tutorial participants were emailed. RESULTS: 11/15 former participants responded to the survey. Survey results suggest that the tutorial program increased participants' understanding of and interest in neurosurgery and related fields in neuroscience. CONCLUSIONS: The functional neurosurgery medical tutorial provides valuable clinical and research exposure in neurosurgery fields for pre-medical trainees. Our work is a preliminary step in addressing the crucial challenge of training the next generation of neurosurgeon-scientists by providing a pedagogical paradigm for development of formal experiences that integrate original scientific research with clinical neurosurgery exposure.