Students' perceived research skills development and satisfaction after completion of a mandatory research project: results from five cohorts of the Sydney medical program.

BACKGROUND: Research activities undertaken during University studies contribute to preparation of medical students for practice of evidence-based medicine. This study aimed to understand medical students' experiences, perceived research skills development and satisfaction associated with completion of mandatory research projects. METHODS: An online survey was sent to five cohorts of students (n = 1375) from years 2017-2021 at the completion of their research projects. Univariate analysis was conducted to understand students' perception of research skills development, followed by linear regression modeling to explore factors influencing satisfaction with their research project. Manifest content analysis employing a framework approach was used to analyse qualitative data from responses to open ended questions. RESULTS: Response rate was 42%, with 513 (89%) returned surveys being complete and included in analysis. Whilst 37% of students felt they had requisite research skills before undertaking the research project, 84% reported they had these skills after completing the project (χ2 = 8.99, P = 0.02). Mean satisfaction score of the students was 5.0/10 (+/- 2.5, median = 6 (IQR = 3.0-7.0) with 59% of students reporting satisfaction scores higher than the average. Higher satisfaction scores were reported by those who perceived that: research methods and teaching was useful in preparing them for conducting research; the research project helped them acquire new skills; the project resulted in peer-reviewed publication; and, who felt supported by their supervisors. Responses to open ended questions offered important insights into student experience and emphasised the importance of supportive supervisors and the need for a dedicated research block in the busy medical program. CONCLUSIONS: The majority of students reported positive outcomes from the mandatory research project. Student satisfaction can be improved by ensuring supportive research environments and high-quality supervision, and inclusion of dedicated research time in the medical curriculum.

Rapid Rescoping and Adaptation: An Evaluation of the Impact of COVID-19 on Postgraduate Medical Student Research Projects.

The COVID-19 pandemic has adversely affected tertiary science and medical education, with significant impact on research-related activities. Research projects are a mandatory requirement of the Doctor of Medicine (MD) Program at the University of Sydney, and medical student projects are delivered across multiple sites in metropolitan and rural New South Wales, Australia. Several cohorts of medical students had projects that were affected by COVID-19. The aims of this study were to determine the impact of COVID-19 on medical student research projects and describe the measures taken to rescope projects, to support students in meeting the learning objectives of the program. Mandatory submission statements for all medical student research project scientific reports for 2020-2022 were examined for reports of the effect of COVID-19 on the project, including COVID-19 related delays, downsizing and the need to change research project types. During the study period, a total of 760 student reports were submitted, of which 217 (28.7%) were affected by COVID-19. About 50% were significantly delayed, 30% were downsized, and 6% required completely new projects. Rescoping arrangements implemented facilitated the successful completion of projects. Overall, the final student grades for the research projects were unaffected by COVID-19 or the related project rescoping. Whilst significantly impacted by COVID-19, medical student research projects were completed with provision of appropriate rescoping plans and academic support. Ensuring projects have a documented contingency plan secured projects as the pandemic progressed and will be a useful safeguard for all future project delivery.

Molecular Mechanisms in Genetic Aortopathy-Signaling Pathways and Potential Interventions.

Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-ß, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm.

Long-term outcomes in heritable thoracic aortic disease.

Heritable aortic aneurysm is an increasingly recognized cause of morbidity and mortality. Whilst Marfan syndrome (MFS) is well-known, the clinical presentation and prognosis of more newly described genetic syndromes is less familiar to clinicians. There is a particular lack of knowledge regarding clinical outcomes for non-syndromal heritable aortic disease. This study investigated the presentation, clinical course and survival of patients with syndromal [Loeys-Dietz, aneurysm-osteoarthritis, and aneurysm-cerebral arteriopathy (ACTA2) syndrome] and non-syndromal heritable aortic disease in comparison to MFS. The study group includes 536 individuals (283 Marfan, 176 non-syndromal heritable aortopathy, 36 aneurysm-osteoarthritis, 32 Loeys-Dietz, and 9 ACTA2 aneurysm) enrolled in a longitudinal clinical follow-up between 1990 and 2022. Age at diagnosis differed between groups: Marfan = 22.0 ± 16.6; Loeys-Dietz = 29.6 ± 21.5; aneurysm-osteoarthritis = 36.4 ± 18.8; ACTA2 aneurysm = 43.4 ± 18.6; non-syndromal heritable aortopathy = 47.2 ± 16.6 years (p < 0.001). Aortic dissection was the presenting event in 8% individuals with Marfan compared to 27% with non-syndromal heritable aortopathy and 34% with Loeys-Dietz syndrome (p < 0.01). Mean follow-up duration for the group was 16.4 years (range 0.2-30 years) and 74 individuals died during follow-up (Marfan = 52, Loeys-Dietz = 6, aneurysm-osteoarthritis = 4, ACTA2 aneurysm = 1, heritable non-syndromal aortopathy = 11). At 10 years follow-up, actuarial mean survivals were: aneurysm-osteoarthritis = 77.5 ± 10.4%; Loeys-Dietz = 90.0 ± 6.8%; Marfan = 94.6 ± 1.4%; heritable non-syndromal aortopathy = 95.9 ± 2.1% (NS). There were 60 aortic dissections (24 Type A, 36 Type B) during follow-up. At 10 years, survival free of dissection was comparable between groups: aneurysm-osteoarthritis = 90.7 ± 6.4%; Loeys-Dietz = 94.4 ± 5.4%; Marfan = 96.1 ± 1.2%; heritable non-syndromal aortopathy = 93.9 ± 2.3%, with similar findings at 20 years. Prophylactic aortic surgery was a first event during follow-up for 196 individuals (ACTA2 aneurysm = 3; aneurysm-osteoarthritis = 10; Loeys-Dietz = 19; Marfan = 119; heritable non-syndromal aortopathy = 45). A second surgical intervention was required in 45 individuals and a third intervention in 21 individuals. At 10 years follow-up, survival free of surgery differed between groups: aneurysm-osteoarthritis = 68.5 ± 10.1%; Loeys-Dietz = 40.8 ± 11.2%; Marfan = 75.5 ± 2.7%; heritable non-syndromal aortopathy = 63.8 ± 4.7% (p < 0.001). At 20 years follow-up mean survival free of surgery was: aneurysm-osteoarthritis = 26.6 ± 14.7%; Loeys-Dietz = 9.1 ± 8.2%; Marfan = 57.2 ± 3.4%; heritable non-syndromal aortopathy = 41.6 ± 8.2% (p < 0.001). Diagnosis of newer syndromic and non-syndromal heritable aortopathies is delayed compared to MFS, with associated complications of presentation with aortic dissection. Survival of individuals enrolled in follow-up surveillance is comparable between different genetic aortopathies, however aortic dissections still occur and need for surgical intervention is high.

Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease.

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. RESULTS: Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-ß pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2;P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. CONCLUSIONS: Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.

Research supervisors' views of barriers and enablers for research projects undertaken by medical students; a mixed methods evaluation of a post-graduate medical degree research project program.

BACKGROUND: Medical degree programs use scholarly activities to support development of basic research skills, critical evaluation of medical information and promotion of medical research. The University of Sydney Doctor of Medicine Program includes a compulsory research project. Medical student projects are supervised by academic staff and affiliates, including biomedical science researchers and clinician-academics. This study investigated research supervisors' observations of the barriers to and enablers of successful medical student research projects. METHODS: Research supervisors (n = 130) completed an anonymous, online survey after the completion of the research project. Survey questions targeted the research supervisors' perceptions of barriers to successful completion of projects and sources of support for their supervision of the student project. Data were analysed by descriptive statistics and using manifest content analysis. Further quantitative investigation was made by cross-tabulation according to prior research supervision experience. RESULTS: Research supervisors reported that students needed both generic skills (75%) and research-based skills (71%) to successfully complete the project. The major barrier to successful research projects was the lack of protected time for research activities (61%). The assessment schedule with compulsory progress milestones enabled project completion (75%), and improved scientific presentation (90%) and writing (93%) skills. Supervisors requested further support for their students for statistics (75%), scientific writing (51%), and funding for projects (52%). Prior research supervision experience influenced the responses. Compared to novice supervisors, highly experienced supervisors were significantly more likely to want students to be allocated dedicated time for the project (P < 0.01) and reported higher rates of access to expert assistance in scientific writing, preparing ethics applications and research methodology. Novice supervisors reported higher rates of unexpected project delays and data acquisition problems (P < 0.05). Co-supervision was favoured by experienced supervisors but rejected by novice supervisors. CONCLUSIONS: Both generic and research-related skills were important for medical student research project success. Overall, protected research time, financial and other academic support were identified as factors that would improve the research project program. Prior research supervision experience influences perceptions of program barriers and enablers. These findings will inform future support needs for projects and research supervisor training for the research supervision role.

Novel insights into bicuspid aortic valve (BAV) aortopathy: Long non-coding RNAs TUG1 and MIAT are differentially expressed in BAV ascending aortas.

BACKGROUND: Whilst a combination of genetically mediated vulnerability and hemodynamic insult is suspected to contribute to bicuspid aortic valve (BAV) aortopathy, the underlying pathophysiological mechanisms are poorly understood. METHODS: Utilizing RT-qPCR, we compared the expression of 28 potentially relevant long non-coding RNA (lncRNA) in aortic tissue from BAV patients undergoing aortic surgery for aortopathy, to healthy controls. Relative lncRNA expression was measured using ΔΔCT, with fold-change calculated as RQ=2-ΔΔCT. RESULTS: When comparing samples from BAV patients (n=29, males n=25; median age 58 years, Q1-Q3 51-65, maximum aortic dimension 50±5 mm) with healthy controls (n=7; males n=4, P=.12; median age 39 years, Q1-Q3 18-47, P=.001), there were two differentially expressed lncRNA: TUG1 expression was significantly lower in BAV aortic tissue (RQ 0.59, 95% CI 0.50-0.69, P=.02), whilst MIAT expression was significantly higher (RQ 2.87, 95% CI 1.96-4.20, P=.01). Sensitivity analysis including only patients with normal BAV function showed similar trends of differential expression of TUG1 (RQ 0.69, 95% CI 0.50-0.90, P=.29) and MIAT (RQ 2.55, 95% CI 1.21-5.36, P=.29) compared to controls. CONCLUSIONS: LncRNA TUG1 and MIAT are differentially expressed in BAV aortopathy compared to healthy controls, independent of BAV hemodynamics. Aberrant lncRNA expression may be involved in the pathogenesis of BAV aortopathy.

Models of cardiovascular surgery biobanking to facilitate translational research and precision medicine.

Biobanking in health care has evolved over the last few decades from simple biological sample repositories to complex and dynamic units with multi-organizational infrastructure networks and has become an essential tool for modern medical research. Cardiovascular tissue biobanking provides a unique opportunity to utilize cardiac and vascular samples for translational research into heart failure and other related pathologies. Current techniques for diagnosis, classification, and treatment monitoring of cardiac disease relies primarily on interpretation of clinical signs, imaging, and blood biomarkers. Further research at the disease source (i.e. myocardium and blood vessels) has been limited by a relative lack of access to quality human cardiac tissue and the inherent shortcomings of most animal models of heart disease. In this review, we describe a model for cardiovascular tissue biobanking and databasing, and its potential to facilitate basic and translational research. We share techniques to procure endocardial samples from patients with hypertrophic cardiomyopathy, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, in addition to aortic disease samples. We discuss some of the issues with respect to data collection, privacy, biobank consent, and the governance of tissue biobanking. The development of tissue biobanks as described here has significant scope to improve and facilitate translational research in multi-omic fields such as genomics, transcriptomics, proteomics, and metabolomics. This research heralds an era of precision medicine, in which patients with cardiovascular pathology can be provided with optimized and personalized medical care for the treatment of their individual phenotype.

Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities.

Background: The primary objective of this review was to explore the contribution of oxidative stress to the pathogenesis of genetically-triggered thoracic aortic aneurysm (TAA). Genetically-triggered TAAs manifest substantial variability in onset, progression, and risk of aortic dissection, posing a significant clinical management challenge. There is a need for non-invasive biomarkers that predict the natural course of TAA and therapeutics that prevent aneurysm progression.Methods: An online systematic search was conducted within PubMed, MEDLINE, Scopus and ScienceDirect databases using keywords including: oxidative stress, ROS, nitrosative stress, genetically triggered thoracic aortic aneurysm, aortic dilatation, aortic dissection, Marfan syndrome, Bicuspid Aortic Valve, familial TAAD, Loeys Dietz syndrome, and Ehlers Danlos syndrome.Results: There is extensive evidence of oxidative stress and ROS imbalance in genetically triggered TAA. Sources of ROS imbalance are variable but include dysregulation of redox mediators leading to either insufficient ROS removal or increased ROS production. Therapeutic exploitation of redox mediators is being explored in other cardiovascular conditions, with potential application to TAA warranting further investigation.Conclusion: Oxidative stress occurs in genetically triggered TAA, but the precise contribution of ROS to pathogenesis remains incompletely understood. Further research is required to define causative pathological relationships in order to develop therapeutic options.

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms.

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.

The RNA-binding fragile-X mental retardation protein and its role beyond the brain.

It is well-established that variations of a CGG repeat expansion in the gene FMR1, which encodes the fragile-X mental retardation protein (FMRP), cause the neurocognitive disorder, fragile-X syndrome (FXS). However, multiple observations suggest a general and complex regulatory role of FMRP in processes outside the brain: (1) FMRP is ubiquitously expressed in the body, suggesting it functions in multiple organ systems; (2) patients with FXS can exhibit a physical phenotype that is consistent with an underlying abnormality in connective tissue; (3) different CGG repeat expansion lengths in FMR1 result in different clinical outcomes due to different pathogenic mechanisms; (4) the function of FMRP as an RNA-binding protein suggests it has a general regulatory role. This review details the complex nature of FMRP and the different CGG repeat expansion lengths and the evidence supporting the essential role of the protein in a variety of biological and pathological processes.

Familial Aortopathies - State of the Art Review.

Aortopathies are conditions that result in aortic dilatation, aneurysm formation and dissection. Familial aortopathies (perhaps better known as heritable thoracic aortic aneurysm and dissection, h-TAAD, as not all have a positive family history) are recognised to have an underlying genetic cause and affect the aorta, predisposing it to the above pathologies. These conditions can also affect the extra-aortic vasculature, particularly large elastic arteries and other body systems. Mutations in a number of genes have been associated with h-TAAD. However, not all affected families have a pathogenic gene variant identified-highlighting the importance of a three-generational family history and the likely role of both environmental factors and future gene discoveries in furthering knowledge. Survival has improved over the last few decades, essentially due to surgical intervention. The benefit of identifying affected individuals depends upon a regular surveillance program and timely referral for surgery before complications such as dissection. Further research is required to appreciate fully the effects of individual gene variants and improve evidence for prophylactic medical therapy, as well as to understand the effect of h-TAAD on quality of life and life choices, particularly around exercise and pregnancy, for affected individuals. This will be complemented by laboratory-based research that seeks to understand the tissue pathways that underlie development of arterial pathology, ideally providing targets for novel medical therapies and a means of non-invasively identifying individuals at increased vascular risk to reduce dissection, which remains a devastating life-threatening event.

Age-related changes of shape and flow dynamics in healthy adult aortas: A 4D flow MRI study.

BACKGROUND: Abnormal flow dynamics play an early and causative role in pathologic changes of the ascending aorta. PURPOSE: To identify: 1) the changes in flow, shape, and size that occur in the ascending aorta with normal human ageing and 2) the influence of these factors on aortic flow dynamics. STUDY TYPE: Retrospective. SUBJECTS: In all, 247 subjects (age range 19-86 years, mean 49 ± 17.7, 169 males) free of aortic or aortic valve pathology were included in this study. Subjects were stratified by youngest (18-33 years; n = 64), highest (>60 years, n = 67), and the middle two quartiles (34-60 years, n = 116). FIELD STRENGTH/SEQUENCE: Subjects underwent a cardiac MRI (3T) exam including 4D-flow MRI of the aorta. ASSESSMENT: Aortic curvature, arch shape, ascending aortic angle, ascending aortic diameter, and the stroke volume normalized by the aortic volume (nSV) were measured. Velocity, vorticity, and helicity were quantified across the thoracic aorta. STATISTICAL TESTS: Univariate and multivariate regressions were used to quantify continuous relationships between variables. RESULTS: Aortic diameter, ascending aortic angle, shape, and curvature all increased across age while nSV decreased (all P < 0.0001). Systolic vorticity in the mid arch decreased by 50% across the age range (P < 0.0001), while peak helicity decreased by 80% (P < 0.0001). Curvature tightly governs optimal flow in the youngest quartile, with an effect size 1.5 to 4 times larger than other parameters in the descending aorta, but had a minimal influence with advancing age. In the upper quartile of age, flow dynamics were almost completely determined by nSV, exerting an effect size on velocity and vorticity >10 times that of diameter and other shape factors. DATA CONCLUSION: Aortic shape influences flow dynamics in younger subjects. Flow conditions become increasingly disturbed with advancing age, and in these conditions nSV has a more dominant effect on flow patterns than shape factors. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:90-100.

Epigenetic influences on genetically triggered thoracic aortic aneurysm.

Genetically triggered thoracic aortic aneurysms (TAAs) account for 30% of all TAAs and can result in early morbidity and mortality in affected individuals. Epigenetic factors are now recognised to influence the phenotype of many genetically triggered conditions and have become an area of interest because of the potential for therapeutic manipulation. Major epigenetic modulators include DNA methylation, histone modification and non-coding RNA. This review examines epigenetic modulators that have been significantly associated with genetically triggered TAAs and their potential utility for translation to clinical practice.

Angiotensin, transforming growth factor ß and aortic dilatation in Marfan syndrome: Of mice and humans.

Marfan syndrome is consequent upon mutations in FBN1, which encodes the extracellular matrix microfibrillar protein fibrillin-1. The phenotype is characterised by development of thoracic aortic aneurysm. Current understanding of the pathogenesis of aneurysms in Marfan syndrome focuses upon abnormal vascular smooth muscle cell signalling through the transforming growth factor beta (TGFß) pathway. Angiotensin II (Ang II) can directly induce aortic dilatation and also influence TGFß synthesis and signalling. It has been hypothesised that antagonism of Ang II signalling may protect against aortic dilatation in Marfan syndrome. Experimental studies have been supportive of this hypothesis, however results from multiple clinical trials are conflicting. This paper examines current knowledge about the interactions of Ang II and TGFß signalling in the vasculature, and critically interprets the experimental and clinical findings against these signalling interactions.

Heart Valve Surgery Performed by Trainee Surgeons: Meta-Analysis of Clinical Outcomes.

BACKGROUND: Cardiac surgical units must balance trainee education with the duty to provide optimal patient care. This is particularly challenging with valvular surgery, given the lower volume and increased complexity of these procedures. The present meta-analysis was conducted to assess the impact of trainee operator status on clinical outcomes following valvular surgery. METHODS: Medline, Embase and CENTRAL databases were systematically searched for studies reporting clinical outcomes according to the training status of the primary operator (consultant or trainee). Data were extracted and meta-analysed according to pre-defined endpoints. RESULTS: Eleven observational studies met the inclusion criteria, reporting on five patient cohorts undergoing mitral valve surgery (n=3975), six undergoing aortic valve replacement (AVR) (n=6236) and three undergoing combined AVR and coronary artery bypass grafting (CABG) (n=3495). Perioperative mortality was not significantly different between trainee and consultant cases for mitral valve surgery (odds ratio [OR] 0.92; 95% confidence interval [CI], 0.62-1.37), AVR (OR 0.67; 95% CI, 0.37-1.24), or combined AVR and CABG (OR 1.07; 95% CI, 0.40-2.85). The incidences of perioperative stroke, myocardial infarction, arrhythmias, acute renal failure, reoperation or wound infection were not significantly different between trainee and consultant cases. There was a paucity of mid-term survival data. CONCLUSIONS: Valvular surgery cases performed primarily by trainees were not associated with adverse perioperative outcomes. These findings suggest the rigorous design of cardiac surgical trainee programs can sufficiently mitigate trainee deficiencies. However, studies with longer follow-up duration and echocardiographic data are required to assess long-term durability and safety.

ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype.

RATIONALE: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and reverse the disease phenotype. OBJECTIVE: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMCs), in the pathogenesis of TAA. METHODS AND RESULTS: Using human and mouse aortic samples, we report that ARHGAP18 levels were significantly reduced in the SMC layer of aortic aneurysms. Arhgap18 global knockout (Arhgap18-/-) mice exhibited a highly synthetic, proteolytic, and proinflammatory smooth muscle phenotype under basal conditions and when challenged with angiotensin II, developed TAA with increased frequency and severity compared with littermate controls. Chromatin immunoprecipitation studies revealed this phenotype is partly associated with strong enrichment of H3K4me3 and depletion of H3K27me3 at the MMP2 and TNF-α promoters in Arhgap18-deficient SMC. We further show that TAA formation in the Arhgap18-/- mice is associated with loss of Akt activation. The abnormal SMC phenotype observed in the Arhgap18-/- mice can be partially rescued by pharmacological treatment with the mTORC1 inhibitor rapamycin, which reduces the synthetic and proinflammatory phenotype of Arhgap18-deficient SMC. CONCLUSION: We have identified ARHGAP18 as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.

Management of aortic regurgitation and bilateral carotid occlusion in severe Takayasu arteritis.

We present a patient with Takayasu arteritis and severe aortic valve regurgitation and bilateral carotid artery occlusions, who underwent aortic valve replacement and aorto-bicarotid bypass. The management of the cardiovascular manifestations of Takayasu arteritis is reviewed.