Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.

BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis. METHODS: We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis. RESULTS: SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant KrasG12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. CONCLUSIONS: Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.

Bridge to Weight Loss: A Case Series.

Durable left ventricular assist devices (LVADs) are a well-established therapeutic option for patients with advanced heart failure. These devices are often used to "bridge" patients to an orthotopic heart transplantation (HT). Unfortunately, many patients on LVAD support with a body mass index (BMI) above a certain value are not eligible for HT due a lack of suitable donors and the association between obesity and poor outcomes after HT. This case series describes three individuals on LVAD support who were able to successfully lose enough weight to qualify to be listed for an HT. We highlight a systematic, multidisciplinary approach to implementing guideline-driven weight loss strategies, including some aggressive methods (ie, meal replacements, weight loss medications, and bariatric surgery). In addition to describing the weight loss outcomes, we also discuss barriers and medical challenges during weight loss that are unique to this population.

Atherosclerosis is a smooth muscle cell-driven tumor-like disease.

Atherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC "phenotypic switching" plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenic KrasG12D accelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.

Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human.

BACKGROUND: Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive. METHODS: To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro. RESULTS: We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed "SEM" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability. CONCLUSIONS: Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.

Curative treatment for low-grade arteriovenous malformations.

BACKGROUND: Spetzler-Martin (SM) grade I-II (low-grade) arteriovenous malformations (AVMs) are often considered safe for microsurgery or radiosurgery. The adjunctive use of preoperative embolization to reduce surgical risk in these AVMs remains controversial. OBJECTIVE: To assess the safety of combined treatment of grade I-II AVMs with preoperative embolization followed by surgical resection or radiosurgery, and determine the long-term functional outcomes. METHODS: With institutional review board approval, a retrospective analysis was carried out on patients with ruptured and unruptured SM I-II AVMs between 2002 and 2017. Details of the endovascular procedures, including number of arteries supplying the AVM, number of branches embolized, embolic agent(s) used, and complications were studied. Baseline clinical and imaging characteristics were compared. Functional status using the modified Rankin Scale (mRS) before and after endovascular and microsurgical treatments was compared. RESULTS: 258 SM I-II AVMs (36% SM I, 64% SM II) were identified in patients with a mean age of 38 ± 17 years. 48% presented with hemorrhage, 21% with seizure, 16% with headache, 10% with no symptoms, and 5% with clinical deficits. 90 patients (68%) in the unruptured group and 74 patients (59%) in the ruptured group underwent presurgical embolization (p = 0.0013). The mean number of arteries supplying the AVM was 1.44 and 1.41 in the unruptured and ruptured groups, respectively (p = 0.75). The mean number of arteries embolized was 2.51 in the unruptured group and 1.82 in the ruptured group (p = 0.003). n-Butyl cyanoacrylate and Onyx were the two most commonly used embolic agents. Four complications were seen in four patients (4/164 patients embolized): two peri-/postprocedural hemorrhage, one dissection, and one infarct. All patients undergoing surgery had a complete cure on postoperative angiography. Patients were followed up for a mean of 55 months. Good long-term outcomes (mRS score ≤ 2) were seen in 92.5% of patients with unruptured AVMs and 88.0% of those with ruptured AVMs. Permanent neurological morbidity occurred in 1.2%. CONCLUSIONS: Curative treatment of SM I-II AVMs can be performed using endovascular embolization with microsurgical resection or radiosurgery in selected cases, with very low morbidity and high cure rates. Compared with other published series, these outcomes suggest that preoperative embolization is a safe and effective adjunct to definitive surgical treatment. Long-term follow-up showed that patients with low-grade AVMs undergoing surgical resection or radiosurgery have good functional outcomes.

Epidemiology of cavernous malformations.

Cavernous malformations, accounting for approximately 5-15% of all vascular abnormalities in the central nervous system, are angiographically occult lesions which most often present with seizures, rather than acute hemorrhage. Widely variable across populations, the incidence of cavernous malformations has been reported to be 0.15-0.56 per 100 000 persons per year, with an annual hemorrhage rate of 0.6-11% per patient-year. Seen in 0.17-0.9% of the population, up to one-half are familial, and at least three gene loci have been associated with a familial form, more common among Hispanic Americans. Most cavernous malformations are supratentorial, with 10-23% in the posterior fossa, and approximately 5% found in the spine.

A Review and Survey of Neurosurgeon-Hospital Relationships: Evolution and Options.

As healthcare delivery shifts from fee-for-service, episodic care to pay for performance and population health, both hospitals and physicians are looking for new forms of integration. A number of regulations and restrictions govern physician relationships with hospitals. In this paper, we review the legal basis for such relationships and the options available. We also survey neurosurgeons and hospital executives to gain their perspective on the current situation and likely future. Two series of structured interviews were conducted with 10 neurosurgeons who work in a range of situations in diverse markets, and with Memorial Hermann Healthcare System senior executive leadership. Their responses form the basis for the subsequent discussion. Neurosurgeons can be independent, join a confederation such as an Independent Physician Association or another type of "clinically integrated" network, or be employed by a hospital, medical school, or physician group. With varying levels of integration comes the strength of size, management expertise, negotiating leverage, economies of scale, and possibly financial advantages, but with impact on autonomy and independence. Constructive alignment can lead to a win-win situation for both the individual physician and the organization, but options vary widely due to heterogeneous local conditions. This paper reviews possible relationships, moving along a spectrum from no financial integration to full integration. Concepts such as physician leasing, professional service agreements, "clinical integration," and employment are presented. This paper offers a practical reference that might be useful to a new graduate, independent neurosurgeon considering integration, or employed physicians considering alternatives.

Neurosurgical Education in a Changing Healthcare and Regulatory Environment: A Consensus Statement from 6 Programs.

The purpose of neurosurgical education is to teach the clinical knowledge and surgical skills necessary to become a neurosurgeon. Another goal is to inculcate the principles of the scientific method. However, increasing expectations about attending involvement during surgery, duty hour requirements, and new curricular mandates have put programs under stress to ensure adequate training, in less time, in an environment of limited resident independence. More recently, the Accreditation Council for Graduate Medical Education has developed a new tracking process based on "milestones" or defined educational outcomes. At the same time, our healthcare system is undergoing a rapid socioeconomic transition in organization and payment models, which traditionally has not been a focus of formal teaching. A 2008 survey conducted by the Council of State Neurosurgical Societies found that graduating residents felt inadequately prepared in areas like contract negotiation, practice evaluation, and management.

New York City at the dawn of neurological surgery.

Although there are many cities that can claim to have been the incubator of modern neurological surgery, the rise of this surgical subspecialty in New York City in the late 19th and early 20th century mirrors what was occurring around the world. The first confirmed brain tumor operation in the US was performed there in 1887. The author describes the role of several pioneers in the development of neurological surgery. Charles Elsberg was the first dedicated neurological surgeon in New York City and was instrumental in the development of the Neurological Institute and the careers of several other notable neurosurgeons.

Arteriovenous malformations and headache.

Brain arteriovenous malformations (AVM) are complex vascular lesions commonly associated with chronic headache. An occipital location appears to increase the risk of concurrent migraine-like headaches in AVM patients. We have experienced great success in treating these headaches through a multidisciplinary approach to eradicate cerebral AVM. However, the specific clinical characteristics of AVM-associated headaches and the most effective treatment strategies for these patients remain unclear. Here, we provide a comprehensive review of the literature on AVM-associated headaches. We detail the history, classification, epidemiology, presentation, pathophysiology, treatment options, and outcomes for this poorly described condition. Additionally, we illustrate our approach to the management of patients with occipital AVM and associated intractable headaches.

Making Milestones: Development and Implementation of a Formal Socioeconomic Curriculum in a Neurosurgical Residency Training Program.

BACKGROUND: Improved training in the socioeconomic aspects of medicine is a priority of the Accreditation Council for Graduate Medical Education and the American Board of Neurological Surgeons. There is evidence that young neurosurgeons feel ill equipped in these areas and that additional education would improve patient care. OBJECTIVE: To present our experience with the introduction of a succinct but formal socioeconomic training course to the residency curriculum at our institution. METHODS: A monthly series of twelve 1-hour interactive modules was designed to address the pertinent Accreditation Council for Graduate Medical Education-American Board of Neurological Surgeons outcomes-based educational milestones. Slide-based lectures provided a comprehensive overview of social, legal, and business issues, and a monthly forum for open discussion allowed residents to draw on their applied experience. Residents took a 20-question pre- and postcourse knowledge assessment, as well as feedback surveys at 6 and 12 months. RESULTS: Residents were able to participate in the lectures, with an overall attendance rate of 91%. Residents felt that the course goals and objectives were well defined and communicated (4.88/5) and rated highly the content, quality, and relevance of the lectures (4.94/5). Performance on the knowledge assessment improved from 58% to 66%. CONCLUSION: Our experience demonstrates the feasibility of including a formal socioeconomic course in neurosurgical residency training with positive resident feedback and achievement of outcomes-based milestones. Extension to a 2-year curriculum cycle may allow the course to cover more material without compromising other residency training goals. Online modules should also be explored to allow for wider and more flexible participation. ABBREVIATIONS: ABNS, American Board of Neurological SurgeonsACGME, Accreditation Council for Graduate Medical Education.

Number and location of draining veins in pediatric arteriovenous malformations: association with hemorrhage.

OBJECT: The significance of draining vein anatomy is poorly defined in pediatric arteriovenous malformations (AVMs). In adult cohorts, the presence of fewer veins has been shown to lead to an increased rate of hemorrhage, but this phenomenon has not yet been studied in pediatric AVMs. This report analyzes the impact of draining vein anatomy on presentation and outcome in a large series of pediatric AVMs. METHODS: Eighty-five pediatric patients with AVMs were treated at the Columbia University Medical Center between 1991 and 2012. Charts were retrospectively reviewed for patient characteristics, clinical course, neurological outcome, and AVM angioarchitectural features identified on the angiogram performed at presentation. Univariate analyses were performed using chi-square test and ANOVA when appropriate; multivariate analysis was performed using logistic regression. RESULTS: Four patients were excluded due to incomplete records. Twenty-seven patients had 2 or 3 draining veins; 12 (44.4%) of these patients suffered from hemorrhage prior to surgery. Fifty-four patients had 1 draining vein; 39 (72.2%) of these 54 suffered from hemorrhage. Independent predictors of hemorrhage included the presence of a single draining vein (p = 0.04) and deep venous drainage (p = 0.02). Good outcome (modified Rankin Scale [mRS] score < 3) on discharge was found to be associated with higher admission Glasgow Coma Scale (GCS) scores (p = 0.0001, OR 0.638, 95% CI 0.40-0.93). Poor outcome (mRS score > 2) on discharge was found to be associated with deep venous drainage (p = 0.04, OR 4.68, 95% CI 1.1-19.98). A higher admission GCS score was associated with a lower discharge mRS score (p = 0.0003, OR 0.6, 95% CI 0.46-0.79), and the presence of a single draining vein was associated with a lower mRS score on long-term follow-up (p = 0.04, OR 0.18, 95% CI 0.032-0.99). CONCLUSIONS: The authors' data suggest that the presence of a single draining vein or deep venous drainage plays a role in hemorrhage risk and ultimate outcome in pediatric AVMs. Small AVMs with a single or deep draining vein may have the highest risk of hemorrhage.

Variability in outcome after elective cerebral aneurysm repair in high-volume academic medical centers.

BACKGROUND AND PURPOSE: Unruptured intracranial aneurysm repair is the most commonly performed procedure for the prevention of hemorrhagic stroke. Despite efforts to regionalize care in high-volume centers, overall results have improved little. This study aims to determine the effectiveness in improving outcomes of previous efforts to regionalize unruptured intracranial aneurysm repair to high-volume centers and to recommend future steps toward that goal. METHODS: Using data obtained via the New York Statewide Planning and Research Cooperative System, this study included all patients admitted to any of the 10 highest volume centers in New York state between 2005 and 2010 with a principal diagnosis of unruptured intracranial aneurysm who were treated either by microsurgical or endovascular repair. Mixed-effects logistic regression was used to determine the degree to which hospital-level and patient-level variables contributed to observed variation in good outcome, defined as discharge to home, between hospitals. RESULTS: Of 3499 patients treated during the study period, 2692 (76.9%) were treated at the 10 highest volume centers, with 2198 (81.6%) experiencing a good outcome. Good outcomes varied widely between centers, with 44.6% to 91.1% of clipped patients and 75.4% to 92.1% of coiled patients discharged home. Mixed-effects logistic regression revealed that procedural volume accounts for 85.8% of the between-hospital variation in outcome. CONCLUSIONS: There is notable interhospital heterogeneity in outcomes among even the largest volume unruptured intracranial aneurysm referral centers. Although further regionalization may be needed, mandatory participation in prospective, adjudicated registries will be necessary to reliably identify factors associated with superior outcomes.

The modified pterional keyhole craniotomy for open cerebrovascular surgery: a new workhorse?

BACKGROUND: The frontotemporal craniotomy is the most commonly used approach for vascular neurosurgery. However, this approach requires significant mobilization of overlying soft tissues, resulting in muscle atrophy and temporomandibular joint pain. We describe a modified pterional keyhole approach and its use in our initial clinical experience. PATIENTS AND METHODS: Eleven consecutive minimally invasive pterional keyhole approaches were used for 14 aneurysms. Patient demographics, aneurysm characteristics, and morbidities were prospectively collected. RESULTS: Mean aneurysm size was 6.5 mm, and all were in the anterior circulation. All aneurysms were successfully clipped, with no occurrence of intraoperative rupture or perforator occlusion. There were no incidences of frontalis nerve injury. No technical difficulties or limitation to aneurysm access were experienced. CONCLUSION: In carefully selected patients, a minimally invasive keyhole approach may be a safe and effective alternative to traditional pterional craniotomy for certain anterior circulation aneurysms.

Statins reduce neurologic injury in asymptomatic carotid endarterectomy patients.

BACKGROUND AND PURPOSE: Statins are neuroprotective in a variety of experimental models of cerebral injury. We sought to determine whether patients taking statins before asymptomatic carotid endarterectomy exhibit a lower incidence of neurological injury (clinical stroke and cognitive dysfunction). METHODS: A total of 328 patients with asymptomatic carotid stenosis scheduled for elective carotid endarterectomy consented to participate in this observational study of perioperative neurological injury. RESULTS: Patients taking statins had a lower incidence of clinical stroke (0.0% vs 3.1%; P=0.02) and cognitive dysfunction (11.0% vs 20.2%; P=0.03). In a multivariate regression model, statin use was significantly associated with decreased odds of cognitive dysfunction (odds ratio, 0.51 [95% CI, 0.27-0.96]; P=0.04). CONCLUSIONS: Preoperative statin use was associated with less neurological injury after asymptomatic carotid endarterectomy. These observations suggest that it may be possible to further reduce the perioperative morbidity of carotid endarterectomy. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00597883.