Research Study Applications

Name: Anna Louise Pouncey, a vascular trainee at Imperial College London

Email: a.pouncey@imperial.ac.uk
Mobile: 011447912651686

Institution: Imperial College London

Research Topic:
Assessment of sex-specific differences in thrombus burden and anatomical complexity, and association with post-operative outcomes, for patients undergoing abdominal aortic aneurysm repair.

Background:

Sex-specific disparity in AAA repair outcomes
Sex-specific differences in anatomical complexity of AAAs, (i.e. smaller vessel size and greater neck angulation) has previously meant women are less likely to be considered suitable for the less invasive endovascular repair (EVAR) (34% vs. 54%; OR0·44 [95% CI0·32–0·62])1,2. At present, one-third of women with an AAA in the UK are not offered repair, and as such women constitute only 1 in 7 elective repairs but 1 in 3 of AAA ruptures1,3,4.

For the women who are selected for AAA repair, shocking disparity in outcomes is observed. An updated systematic review and meta-analysis completed by our study group, examining sex-specific 30-day mortality and complications for AAA repair, [accepted for publication in EJVES], demonstrated a significantly higher 30-day mortality risk for women following OAR, with an increased risk differential for EVAR (OR 1.49 vs. OR 1.86 respectively). This disparity remained following multivariable risk factor adjustment and has not been ameliorated by modern practice.

Sex-specific differences varied with type of repair, allowing insight into the increased mortality risk differential for EVAR. For both OAR and EVAR, women were at increased risk of respiratory complications (OAR OR1.40, EVAR OR1.58), bowel ischaemia (OAR OR 1.54, EVAR OR 1.90) and need for blood transfusion (OAR OR 1.81, EVAR OR 2.18): no post-operative complication was more common in men and procedure times were similar for both sexes. Following EVAR, women were also at increased risk of cardiac (OAR OR 1.18) and renal complications (EVAR OR 1.45) as well as limb ischaemia (OR 2.11) and arterial injury (OR 3.02).

These findings raise questions regarding procedure specific causes for the inequalities observed, which may include increased risk of thromboembolism, or increased risk for operative injury secondary to sex-specific differences in anatomical complexity.

Emboli are an important factor in the pathogenesis of post-operative bowel (and renal) ischaemia, and as EVAR is associated with twice the number of emboli than OAR, an increased embolization in women could contribute to the greater risk differential observed for EVAR5–7. In addition, it is recognised that patients with severe aortic atherosclerosis carry a high risk of iatrogenic embolization during aortic procedures8, and a correlation between aortic wall thrombus scores, embolic events and solid organ infarction has been reported in patients undergoing fenestrated- EVAR5. In addition, EVAR access complications are associated with four times the odds of perioperative death, while conversion to open, rather than planned cutdown, is associated with a higher risk of major complication60. Therefore it is certainly possible an iatrogenic component may contribute to the increased mortality and complications risk for women observed, and present a target for quality improvement9.

Clearly, a better understanding of sex-specific anatomical differences, thrombus burden and operative complexity are needed to elucidate whether these factors contribute to sex-specific disparity in outcomes.

Hypothesis:
Sex-specific differences in thrombus burden and anatomical complexity contribute to the disparity in post-operative outcomes (mortality and complications) for aortic aneurysm repair.

Pilot study data
We have performed a 1:2 matched retrospective pilot study at our tertiary centre (144 elective AAA patients: 48 females, 96 males) examining sex-specific differences in vessel morphology and disease, in aortic thrombus type and burden and in clinical outcome.

Females were treated at smaller AAA-diameters (median, 56.25 vs 59.45 mm, P<0.01), but a higher aortic size index (ASI) (3.4 vs. 2.3, P=0.02). Females had more tortuous AAAs (1.09 vs. 1.04, P<0.01), greater neck angulation (137.0° vs. 150.5, P<0.01), a higher aortic wall thrombus score (P=0.03) and a higher percentage of AAA-thrombus (63.3% vs. 54.8%, P=0.02). Thrombus morphology was more commonly irregular amongst females (P=0.02)

Visceral and renal vessels were significantly smaller (minimum diameter (mm): coeliac 4.92 vs. 6.17, SMA 5.45 vs. 6.79, right renal 4.04 vs. 4.68, left renal 1.36 vs. 4.81, IMA 2.83 vs. 3.31, P<0.01) and more tortuous (P=0.01). No difference in disease burden (percent stenosis, calcium, and thrombus) was observed. For access-vasculature, females were smaller across all measures of diameter at common iliac, external iliac and common femoral arteries (P<0.01). Tortuosity of access vessels was lower in females (1.265 vs 1.325, P<0.01) but a higher prevalence of disease was observed (TASC II score A or above: 69.7% vs 50%, P= 0.03).

Within our matched cohort, 30-day mortality, bowel ischaemia and additional lower-limb interventions were more common in females, (10.42% vs 1.04%, P=0.02, 12.5% vs. 1.04%, P<0.01 and 12.5% vs 0%, P<0.01), respectively. Rates of lower limb ischemia were statistically significant for the unmatched cohort (14.0% vs. 1.94% P <0.01) but did not remain significant following matching (10.42% vs 4.17%, P=0.16).

Rationale for further study
This pilot study supports the hypothesis that sex-specific differences in thrombus burden and anatomical complexity could contribute to the disparity in post-operative outcomes for AAA repair. However, while this study was sufficiently powered to examine morphological difference, it was not of a sufficient size to examine association with adverse outcomes. Allowing for 2020 NVR reporting of individual (0.8-9.2%) and overall (8.5-26.4%) complication rates10, it is estimated 1000 patients are required to enable association with outcomes. This requires expansion of the data set, as per the planned research proposal outline below.

If significant differences are identified they would represent amenable targets for quality improvement in peri-operative care strategies (e.g. aggressive preventative treatment in those with severe atherosclerosis or adjustments to pre-operative planning); which has the potential to address sex-specific disparity in AAA repair outcomes and may be translated to further areas of aortic repair. More detailed delineation of anatomical differences will also highlight sex-specific differences in the technical challenges of endovascular repair, which may facilitate on-going technological advancement.

Bibliography
1 Ulug P, Sweeting MJ, Thompson SG, Powell JT. Morphological suitability for endovascular repair , non-intervention rates , and operative mortality in women and men assessed for intact abdominal aortic aneurysm repair : systematic reviews with meta-analysis. Lancet 2017;389(17):1–10. Doi: 10.1016/S0140-6736(17)30639-6.
2 Ayo D, Blumberg SN, Gaing B, Baxter A, Mussa FF, Rockman CB, et al. Gender Differences in Aortic Neck Morphology in Patients with Abdominal Aortic Aneurysms Undergoing Elective Endovascular Aneurysm Repair. Ann Vasc Surg 2016;30:100–4. Doi: 10.1016/j.avsg.2015.09.002.
3 Scott SWM, Batchelder AJ, Kirkbride D, Naylor AR, Thompson JP. Late Survival in Nonoperated Patients with Infrarenal Abdominal Aortic Aneurysm. Eur J Vasc Endovasc Surg 2016;52(4):444–9. Doi: 10.1016/j.ejvs.2016.05.008.
4 Waton S, Johal A, Heikkila K, Cromwell D, Loftus I. National Vascular Registry: 2015 Annual report. London; 2015.
5 Ribeiro M, Oderich GS, Macedo T, Vrtiska TJ, Hofer J, Chini J, et al. From the Society for Vascular Surgery Assessment of aortic wall thrombus predicts outcomes of endovascular repair of complex aortic aneurysms using fenestrated and branched endografts. J Vasc Surg 2017;66(5):1321–33. Doi: 10.1016/j.jvs.2017.03.428.
6 Dadian N, Ohki T, Veith FJ, Edelman M, Mehta M, Lipsitz EC, et al. Overt colon ischemia after endovascular aneurysm repair : The importance of microembolization as an etiology. J Vasc Surg 2001;34(6):986–96. Doi: 10.1067/mva.2001.119241.
7 Thompson MM, Smith J, Naylor AR, Smith G, Bell P. Microembolization during endovascular and conventional aneurysm repair. J Vasc Surg 1997;25(1):179–86. Doi: https://doi.org/10.1016/S0741-5214(97)70336-7.
8 Molisse TA, Tunick PA, Kronzon I. Complications of aortic atherosclerosis: atheroemboli and thromboemboli. Curr Treat Options Cardiovasc Med 2007;9(2):137–47. Doi: 10.1007/s11936-007-0007-4.
9 O’Donnell TFX, Deery SE, Boitano LT, Schermerhorn L, Siracuse JJ, Clouse WD, et al. The Long-Term Implications of Access Complications during EVAR. J Vasc Surg 2020;73(4):1253–60. Doi: 10.1016/j.jvs.2020.08.033.
10 Waton S, Johal A, Birmpili P, Li W, Cromwell D, Boyle J, Pherwani A OR. NATIONAL VASCULAR 2020 Annual Report. Healthc Qual Improv Partnership, 2020;(November).
11 CHAPAneurysmData n.d.
12 CARADU C, Spampinato B, Vrancianu AM, Bérard X, Ducasse E. Fully automatic volume segmentation of infra-renal abdominal aortic aneurysm CT images with deep learning approaches versus physician controlled manual segmentation. J Vasc Surg 2020. Doi: https://doi.org/10.1016/j.jvs.2020.11.036.

Brief synopsis of planned research proposal:

Study design:
Observational retrospective cohort study utilising multicentre tertiary centre data (collaboration for ~1000 patients) to analyse the anatomical complexity of elective AAA patients. Analysis will be in greater detail than previous studies with emphasis on whether aspects of anatomical complexity, extent of disease and thrombus type and burden differ between sexes. Where data are sufficient, association of anatomical risk factors with the incidence of peri-operative or technical complications will be explored.

Power calculations: Estimate 1000 required for association with outcomes allowing for 2020 NVR reporting of individual (0.8-9.2%) and overall (8.5-26.4%) complication rates in the AAA repair population10. (Pilot study – estimate,110 required for sex-differences in morphology based on characterisation of the human aorta project: external iliac artery diameter mean difference 1.67mm, SD 1.48mm, a=0.05, b=0.111.)

Inclusion criteria:
Elective primary open or endovascular AAA repair.
Patients with sufficient clinical data and/or computed tomography (CT) imaging.
Exclusion criteria:
Insufficient CT imaging quality or lack of CT within 1 year prior to AAA repair.
Thoracic aneurysm, secondary repair, rupture, dissection, connective tissue disorders.

Imaging analysis:
Quantitative assessment of relevant sex-specific differences in aneurysm and associated vascular morphology using a pre-specified protocol (i.e. standard aneurysm metrics, vessel diameters, percentage calcium, thrombus and stenosis, type of thrombus and density (Hounsfield units), vessel tortuosity and angulation)25. Award of funding will allow imaging analysis to be performed using PRAEVAorta12 (a new fully automated software that enables fast and robust detection of the aortic lumen and AAA characteristics including volumetric assessment of thrombus and thrombus density ), or would contribute to costs for recruitment of experienced technicians (for whom intra and inter-reliability has been assessed and validated) to perform assessments using TeraRecon software.

Clinical data:
Collection of patient demographics, risk factors, repair type and peri-operative complications from National Vascular Registry data (vessel injury, bowel ischaemia, limb ischaemia, renal injury and mortality)10.

Outcome measures:
Primary outcomes:
Sex-specific differences in:
a) aneurysm and metrics.
b) extent of disease (visceral, renal and iliacs)
c) thrombus type and burden

Secondary outcomes:
a) Sex-specific differences in peri-operative complications and adverse technical outcomes.
b) Association between anatomical risk factors and adverse outcomes

Statistical analysis: Intra and inter-assessor reliability has been assessed & quantified. Standard univariate & multivariate analysis, dependent on normality of data, with adjustment for confounding factors. Confounding factors: Timing of imaging in relation to aneurysmal growth – scan closest to operative-decision making will be utilized, to consider subgroup analysis stratified by size and/or ASI.

Anticipated Impact: Results of this study would be expected to contribute evidence for patient selection, pre-operative risk stratification and patient optimisation. A greater understanding of sex-specific anatomical challenges and disease burden could also to facilitate technical advancement in endovascular repair.

Opportunity for future investigation: Expansion and collaboration with COMPASS trial (ISRCTN85731188) (~2000 scans) to examine influence of anatomical factors on long term repair outcomes. International collaboration and expansion to include pan-aortic disease and repair outcomes.

How the money would be spent:
Funding would enable the acquisition of quantitative data from ~1000 scans, which would be appropriately powered to examine association between anatomical risk factors and outcomes. It would enable use of PRAEVAorta12 – a new fully automated software that enables fast and robust detection of the aortic lumen and AAA characteristics including the presence of thrombus – (negotiated as a $5000 dollar sum for all scans). Alternatively, it would contribute towards recruitment of trained technicians to assist the applicant in data collection. At a rate of ~£20 per hour – average scan assessment time 40 minutes, it would fund around 250 hours of a total of 566 hours remaining collection time (~100 hours already performed during collection of pilot data). Study design, pre-processing of clinical data, data analysis and interpretation will be performed by the applicant, Miss Anna Louise Pouncey, a vascular trainee at Imperial College London as part of her PhD project entitled “Investigation into sex-specific discrepancies in peri-operative mortality and morbidity following elective abdominal aortic aneurysm repair: Are sex-specific pathways required to enable equality in delivery of care?”, with supervision by Mr Colin Bicknell and Professor Janet Powell.

Name: Anahita Dua MD MS MBA FACS

Email: anahitadua@gmail.com
Mobile: 2625658247

Institution: Massachusetts General Hospital

Research Topic:
Preventing Graft Thrombosis in Elderly Women through Delineation of Longitudinal Coagulation Profiles and Development of a Risk Prediction Tool

Background:

Peripheral artery disease (PAD), caused by atherosclerotic chronic arterial occlusion of the lower extremities, is endemic in the elderly female population, and its prevalence increases with age. Over 50% of elderly female patients are symptomatic, warranting extremity artery bypass or endovascular stenting to increase limb perfusion and relieve symptoms. Thrombosis of bypass grafts or stents that results in impaired blood flow to lower extremities is a leading cause of amputation in these elderly female patients (aged ≥60 years). The incidence rate of early graft/stent thrombosis after extremity bypass is significant, ranging from 5% to 17%, and up to 50% of patients die within one year of amputation. Therefore, accurate identification of elderly female patients that are high risk for graft/stent thrombosis is critical to inform targeted, early interventions that will prevent graft/stent loss and amputation. This study will identify a novel, objective, coagulation assay-based risk prediction tool to identify elderly female patients at risk of graft/sent thrombosis.
The most common etiology driving graft/stent thrombosis is hypercoagulability. Men and women differ in their coagulation profiles but the specific differences have never been quantified. Elderly female patients who develop graft/stent thrombosis demonstrate pronounced elevations of platelet reactivity and thrombin generation, with concomitant reductions in fibrinolysis and have worse outcomes in terms of reintervention and amputation rates than their male counterparts. Current strategies to prevent thrombosis rely on anti-platelet and anticoagulant medications but managing thromboprophylaxis in elderly female patients is highly challenging as this patient population carries dual high risks of both life-threatening thrombotic and hemorrhagic complications. Furthermore, this patient population has a myriad of factors associated with increased coagulation but the interplay between factors and the impact on the patient at a specific time point has not been studied. Targeted and timely anticoagulant prescribing is especially critical in the elderly female patient but without an objective delineation of the coagulation profile that synthesizes all factors associated with a hypercoagulative state it is not possible to precisely treat these patients. Also, after extremity revascularization surgery, hypercoagulability in such patients can be transient, such that anticoagulation initiated to combat temporary thrombotic propensity increases the likelihood of hemorrhagic events during post-procedure months. Thus, the current practice of a “one size fits all” anticoagulation approach to thromboprophylaxis in elderly female patients is inappropriate and dangerous. The key barrier to progress is our current lack of any way to accurately predict which elderly patients are at risk of graft/stent thrombosis at various time points after extremity revascularization surgery to guide targeted, post-surgical anticoagulation administration practices. The goal of this application is to define novel, objective, and individualized biometrics to identify elderly female patients at high risk of extremity bypass graft/stent thrombosis and guide thromboprophylaxis strategies to improve the care and safety of these elderly patients.

Brief synopsis of planned research proposal:

Our preliminary data from a prospective, observational pilot study demonstrate that utilizing point-of-care coagulation assays can identify hypercoagulability that is amplified among elderly female patients who develop extremity bypass graft/stent thrombosis. Specifically, we showed that whole blood thromboelastography (TEG) and platelet mapping (PM) coagulation assays were able to identify hypercoagulability prior to a thrombotic event by delineating the longitudinal coagulative state of individual patients thereby providing opportunity for therapeutic correction with antiplatelet/anticoagulant medication. These preliminary findings suggest we can advance the field beyond those of prior research by developing/implementing into clinical care a new risk-scoring tool that incorporates patient-specific longitudinal coagulation assay data and can enable accurate prediction of 1) which elderly female patients are at risk of graft thrombosis, 2) when they are at highest risk following extremity revascularization surgery, and 3) what aspect of the coagulation cascade should be targeted with thromboprophylaxis medications. When combined with clinical variables, such a tool would enable early, targeted anticoagulant-based intervention that can prevent clotting complications and risk of extremity amputation and death. Based on our promising preliminary data, we hypothesize that utilization of personalized, longitudinal coagulation assay data (TEG/PM) in conjunction with patient specific clinical variables in a risk prediction tool will identify elderly female patients at risk of extremity graft/stent thrombosis and guide individualized thromboprophylaxis therapy to mitigate thrombotic risk.
Specific Aim 1. Identify longitudinal, individual coagulability profiles among elderly female patients at risk of extremity graft/stent thrombosis. We will prospectively establish individualized coagulation profiles utilizing pre- and post-operative data from point of care coagulation testing (TEG/PM) at a minimum of ten time points over a 6-month period. We will determine how individual clinical and pharmacological factors impact these coagulation assays longitudinally to identify personalized patient coagulation trends over time. This will identify when in the post-operative course individual elderly female patients are at highest risk for graft/stent thrombosis and what coagulation assay cut-point values are associated with a thrombotic event.
Specific Aim 2. Develop and validate a novel and individualized risk prediction tool for extremity graft/stent thrombosis in elderly female patients. Using longitudinal coagulation testing and clinical variables, we will generate a personalized thrombosis risk prediction tool using multivariable analysis. We will test the validity of our model through bootstrap analysis by repeated, random resampling of the cohort and corroborate further in a prospectively collected external dataset.

Study Population. The target population includes all elderly patients (males and females) with atherosclerosis undergoing revascularization at MGH/Harvard Medical School who meet the inclusion and exclusion criteria. Inclusion criteria are patients aged ≥60 years with a named vessel revascularization for atherosclerosis in the lower extremities (endovascular and/or open). Exclusion criteria are as follows: failure or refusal to provide written informed consent, aged <60 years or <50 kg in bodyweight if age is unknown, pregnant patients, and patients with contraindications to anticoagulation and/or antiplatelet agents. We aim to recruit 250 (200 sample cohort/50 external validation cohort) patients over a 10-month period including both genders and all ethnicities.
TEG/PM Collection and Analysis: After consent is obtained, all patients will have citrated tubes of blood drawn at each time point (pre-operative and the following times post-op: 6-h, 24-h, day 2, day 3, day 4, day 5, day 30, 3 months, 6 months, and at all readmissions) for the coagulation assays to establish an individual hypercoagulation profile pre- and post-operatively (up to 6 months) that integrates pre- and post-operative TEG, PM, and CAT (days 1–5, 3, 6 months and all readmissions) to determine when hypercoagulability peaks and when it trends to baseline. All PM samples will be analyzed on the TEG 6000s (Haemonetics®) machine using the platelet mapping cartridges. TEG samples will be analyzed in the principal investigator (PI) Dr Dua’s lab at MGH using TEG 6000s. Samples will be analyzed within 15 minutes of collection.
Study subjects will receive standard of care at the clinical site. All clinical variables will be collected and reported in accordance with Society of Vascular Surgery (SVS) guidelines for Peripheral Artery Disease reporting.
Power Analysis: There were 16.6% of all female subjects who experienced a thrombotic event in our preliminary data analysis. It is assumed that these values derived from the pilot study will also be observed in this investigation. With 80% power and two-sided alpha of 0.05, a sample size of 200 subjects will be required to detect a statistically significant difference between subjects with thrombotic events versus those without a thrombotic event. The model will be developed incorporating data from these 200 subjects and externally validated on a further 50 subjects for a total sample of 250 subjects. In our pilot study, we averaged 7 enrollments per week from 11 eligible subjects. Hence, in our enrollment period of 10 months, we anticipate prospective enrollment of all subjects needed for this proposed study accounting for a 10% subject attrition rate (7 × 40 weeks = 280).
Statistical Analysis: Normally distributed data will be summarized using means and SDs; non-normally distributed data will be explored using the median and interquartile range. Nominal t-tests will be used to determine differences in TEG/PM/CAT values at different time points for categorical variables. Categorical variables will be summarized using counts and percentages. Unadjusted logistic regression models will be utilized to determine the association and predictive probability of continuous covariates and TEG/PM/CAT values on thrombosis. The Expectation-Maximization (EM) algorithm will be used to obtain estimates of the variance-covariance matrix and model coefficients for logistic regression models predicting graft thrombosis. Simple associations of patient risk factors with presence of thrombosis will be tested by using logistic regression models. A sex-specific and ethnicity-specific comparative analysis will be performed to identify clinical and TEG-PM variables potentially uniquely associated with thrombosis within groups. Associations will be summarized by the odds ratio for thrombosis and associated 95% confidence intervals. The candidate variables, the 30 variables with the lowest univariable p-values, will be included in a multivariable logistic regression model with thrombosis event as the outcome. Stepwise selection will be performed to obtain a final model. Criteria to enter the model will be Pentry=0.20 and to exit the model will be Pstay=0.05. Cox regression will be implemented to determine the effect of time dependency on thrombosis prediction. All statistical analyses will be performed using STATA V.15.1.
Expected Outcomes: We predict our analysis of coagulation assay values (TEG/PM/CAT) will reveal that TEG mA, R, K, α-angle data, AA, and ADP inhibition/aggregation and/or time to peak thrombin generation data can predict which elderly female patients are at high risk of graft thrombosis.

How the money would be spent:
1) $3,500 would be utilized towards an out of hours data collection part time research assistant (weekends and night) as we are currently missing emergent/urgent add-on cases as we do not have coverage for blood draws 2) $1500 would be utilized for statistical analysis (specifically a PhD level statistician for statistics associated with predictive model development)

Name: tbd new person

Email: tbd@gmail.com
Mobile: 9025551212

Institution: Umass Memorial health, Worcester, MA

Research Topic:
Qualitative Analysis of the Gender Specific Impact of Chronic Limb Threatening Ischemia on Health-related Quality of Life

Background:

Peripheral artery disease (PAD) continues to be prevalent, with millions of individuals affected worldwide; this chronic health condition causes both physical disability and psychological distress. Patients with chronic limb threatening ischemia (CLTI) can be especially impacted, since they often have chronic wounds and are at high risk for major limb amputation. Studies of health-related quality of life (HR-QOL) among PAD patients identified five core areas of concern: treatment and diagnosis, symptoms, limitations in physical function, social function, and emotional function [Aitken SJ, et al. PMID: 31254902]. While surgeons have great familiarity with the first three, less is known about the impact of CLTI on social and emotional function. Unlike the other categories, there is potentially greater ability to positively change these domains of HR-QOL, partnering with health psychologists to develop targeted interventions for these issues.
It is well known that a lack of social and emotional support is associated with psychological disorders such as major depressive disorder. In turn, PAD patients with major depression have been shown to have greater risk of postoperative complications. They are also less likely to return home after limb revascularization. There is a critical unmet need for research on the differences in psychological symptoms between men and women with PAD. These findings would allow surgeons to partner with health psychologists for targeted counseling and coping strategies, ultimately improving HR-QOL.

Brief synopsis of planned research proposal:

This study is a prospective cohort study using qualitative analysis. Patients admitted to an academic tertiary care medical center for CLTI-related issues will be recruited to participate in semi-structured interviews. We will use purposive sampling to ensure an approximately equal proportion of men and women in the sample. Interviews will be recorded, and the audio transcribed verbatim. Transcripts of the interviews will be coded and analyzed for HR-QOL domain-specific themes. The interview questions will revolve around the participant’s physical health, as well as hobbies, family life, and mental health. We hypothesize that thematic analysis for HR-QOL domains will demonstrate differences in how CLTI impacts men versus women. We hypothesize that men will be more concerned with how their disease will affect their physical function, while female patients will be more concerned with their social and emotional function. These results will help clinicians develop interventions that help patients with CLTI develop effective coping skills.

How the money would be spent:
(1) password-protected audio recorders (approx. $50 x2); (2) the software package for transcription of the recordings and qualitative analysis (NVivo, QSR International, Burlington, MA), $2,000; (3) expenses for the research team to present their findings and publish them ($400)

Name: Oonagh Scallan

Email: oonagh.scallan@lhsc.on.ca
Mobile: 16478761954

Institution: Western University

Research Topic:
Anatomic morphology differences in women versus men presenting with type B aortic dissection

Background:

The pathophysiology of acute aortic dissection (AAD) involves a tear in the intimal aortic layer. Degeneration of the medial aortic layer is often the aetiology predisposing the aorta to dissection. The specific sequence of events leading to this tear are unclear, whether it is primarily a tear in the intima that leads to accumulation of blood in the media or if haemorrhage of the medial blood vessels leads to rupture of the intimal layer and creation of a false lumen. 1 Outcomes from AAD vary widely based on multiple factors including the anatomy of the tear, patient comorbidities, as well as accessibility to appropriate care, amongst other factors.1

Few studies have looked at diseases of the thoracic aorta and acute aortic dissection in the setting of gender differences. However, there is more literature that compares the presentation and outcomes by gender for other cardiovascular diseases, such as acute coronary syndromes (ACS) and abdominal aortic aneurysms (AAAs). 1 It is thought that the differential neurohormonal milieu is partially responsible for the difference in occurrence and outcomes of disease between the two genders, however the biological basis for the difference is not completely understood.1 Societal disparities in healthcare along with variable presentations between the two genders may also contribute to the different epidemiology and treatment of diseases.1

The management of women with aortic disease is mostly based on evidence from studies including only or mainly men.2 According to previous studies, women with aortic dissection are older than men at presentation.3–6 The IRAD consortium stated that women diagnosed with aortic dissection present to the hospital later, have worse clinical status at presentation and have higher surgical and total mortality.4 Likewise, the Oxford vascular study demonstrated higher 30-day and 5-year mortality in women compared to men.3 Some apparent sex differences were identified such as unchanged incidence in women compared to a decrease in men, a lower proportion of women admitted, fewer TEVAR-treated and a higher postoperative mortality in women even after adjusting for age. Tomographic findings suggestive of severe clinical/anatomical presentation or impending rupture, such as evidence of coronary artery compromise, pleural effusion, periaortic hematoma, and pericardial effusion, were more frequent among women, whereas lack of false lumen thrombosis was more frequent in men (p=0.007). 4

Aortic anatomic factors are known to affect procedural difficulty and patient selection for endovascular repair.7 In a review of 18 studies of predictors of aortic growth in uncomplicated type B aortic dissections (TBAD), aortic diameter ≥ 40 mm, proximal descending thoracic aorta false lumen diameter ≥ 22 mm, degree of fusiform dilation of the proximal descending aorta, elliptic shape of the true lumen, patency of the false lumen, partial thrombosis of the false lumen, saccular degeneration of the false lumen, presence of one entry tear, proximal entry tear ≥ 10 mm, location of the false lumen at the inner curvature of the aorta, and presence of ulcer-like projections were correlated with increasing aortic growth [4]. 7

It has been shown that women are less likely to undergo TEVAR than men for treatment of type B aortic dissection.2 The reasoning for this is not clear but several hypotheses exist, such as a response to clinically observed poorer outcomes in women undergoing surgery, or surgeons may be less willing to intervene in women with a type B aortic dissection when the likelihood of a favourable surgical outcome could be lower. These questions deserve further study and characterization, with the first step being the development of our understanding of the gender differences in type B aortic dissection morphology.

References

1. Siddiqi HK, Eagle KA. Acute aortic dissection in women: challenges and opportunities. Expert Rev Cardiovasc Ther. 2014;11(11):1527–39.
2. Smedberg C, Steuer J, Leander K, Hultgren R. Sex differences and temporal trends in aortic dissection: a population-based study of incidence, treatment strategies, and outcome in Swedish patients during 15 years. Eur Heart J. 2020;41(26):2430–8.
3. Howard DPJ, Banerjee A, Fairhead JF, Perkins J, Silver LE, Rothwell PM, et al. Population-Based Study of Incidence and Outcome of Acute Aortic Dissection and Premorbid Risk Factor Control. Circulation. 2013;127(20):2031–7.
4. Nienaber CA, Fattori R, Mehta RH, Richartz BM, Evangelista A, Petzsch M, et al. Gender-Related Differences in Acute Aortic Dissection. Circulation. 2004;109(24):3014–21.
5. Conway B, Stamou S, Kouchoukos N, Lobdell K, Hagberg R. Effects of Gender on Outcomes and Survival Following Repair of Acute Type A Aortic Dissection. Int J Angiology. 2014;24(02):093–8.
6. Zhou Y, Peng W, Yang G, Pan X, Ding N, Zhang H, et al. Gender Difference is Associated with Short-Term Outcomes in Non-Surgically Managed Acute Aortic Dissection Patients with Hypertension: A Retrospective Cohort Study. Risk Management Healthc Policy. 2021;14:323–30.
7. Chen S, Larion S, Ahanchi SS, Ammar CP, Brandt CT, Panneton JM. A novel anatomic severity grading score for acute Type B aortic dissections and correlation to aortic reinterventions after thoracic endovascular aortic repair. J Cardiothorac Surg. 2017;12(1):39.

Brief synopsis of planned research proposal:

This study would be a retrospective review of all patients with type B aortic dissections who presented to our centre, LHSC, over the last 20 years. Patient charts would be reviewed to collect the relevant patient characteristics, such as demographics, symptoms at the time of presentation, and blood pressure upon admission. CT of the thorax, abdomen and pelvis would be reviewed to collect anatomic morphologic details including measurements of the proximal landing zone, curvature and tortuosity, morphology of the true and false lumens, degree of calcification, and branch vessel location and patency. The recorded data will be based on the above mentioned anatomic factors that are known to affect aortic growth and remodelling. All patients over the age of 18 would be included, patients will be excluded if they do not have imaging adequate for detailed anatomic assessment. Collected anatomic data will then be analysed to determine whether there is a gender difference in the anatomic features of a type B aortic dissection at the time of presentation.

How the money would be spent:
The funds from this research proposal would be allocated towards statistical support and a small amount would be utilised for research coordinator support for data entry and administrative tasks such as ethics board submission. Thank you so much for the consideration.

Name: Katherine Hekman

Email: khekman@emory.edu
Mobile: 619-754-5405

Institution: Emory University

Research Topic:
Stem cell-based regenerative therapy for vascular disease

Background:

Peripheral vascular disease affects over 5 million people in the United States alone [1]. Chronic limb threatening ischemia, characterized by lower extremity rest pain and tissue loss, is a significant cause of morbidity, including major amputation, as well as mortality, and invariably necessitates endovascular or surgical treatment [2]. While treatment options have advanced in the past decade, many patients are not candidates for therapy due to anatomic constraints or co-morbidities, and many more patients fail these therapies either due to the nature of the disease or due to infectious complications. There remains a great need for improved therapeutic modalities to treat this population and to prevent limb loss with its associated morbidity.
Stem cells have emerged as a promising source to treat patients who cannot be treated with existing surgical therapies [3]. The advent of induced pluripotent stem cell (iPSC) technology allows for an infinitely reproducible source of patient-specific stem cells generated from adult tissues [4]. This technology was rendered applicable to vascular disease by establishing the ability to reliably perform directed differentiation of said stem cells to generate the myriad vascular cell types required for a functional blood vessel [5]. Deriving endothelial cells (ECs) from iPSCs, compared with other means of generating ECs, hold the advantage of iPSCs being infinitely renewable and scalable.
Our prior work addressed the premature senescence limitation seen during culture of these cells [6]. While this premature senescence phenotype has been overcome in healthy commercial iPSC lines, it is currently unknown (1) how sex, age, race, and co-morbidity status will affect the manifestation of this loss of mitophagy and early senescence phenotype and the resulting functionality of iPSC-ECs; (2) whether this loss of mitophagy is unique to iPSC-ECs or if it is a generalized feature of EC health; and (3) how to optimize production of iPSC-ECs with cells derived from patients with peripheral arterial disease and associated co-morbidities. Optimization of iPSC-ECs from diverse PAD patients with other associated chronic illnesses – such as diabetes, tobacco abuse, and end-stage renal disease – will be imperative in order to proceed with generating expanded clinical therapies for these patient populations to prevent major amputation.

Brief synopsis of planned research proposal:

Specific aim:
Generate and characterize EC function in iPSC-ECs from PAD patients, male and female, of differing age, race and co-morbidity status.

-Hypothesis:
We hypothesize that sex, age, race and co-morbidity status will affect the premature senescence phenotype and overall function of iPSC-ECs.
-Objective and Rationale:
Native endothelial cell dysfunction is a key element of PAD pathophysiology [7, 8]. In order to harness iPSC-based therapies to treat PAD, it will be imperative to characterize the function of iPSC-derived endothelial cells from PAD patients of different ages, races and co-morbidity statuses to optimize them for clinical applications.
-Experimental Approach:
We will utilize mesenchymal stem cells (MSCs) to generate iPSCs by drawing from the existing repository of over 84 PAD patient MSC lines that have been obtained from bone marrow during amputation surgeries under our ongoing IRB-approved project, Learning from Failure. We will also utilize our bank of 7 control MSC lines from healthy patients. We will generate iPSCs from these MSCs using the CytoTune 2.0 kit (Thermo Fisher A16517).
We will characterize these iPSCs for (1) pluripotent potential using the Human Pluripotent Stem Cell Functional Identification Kit (R&D SC027B); (2) pluripotent cell gene expression using the Scorecard kit (Thermo Fisher A15871); and (3) by karyotyping for chromosomal abnormalities (WiCell).
We will perform directed differentiation of these PAD patient-derived iPSCs to ECs using the protocol by Patsch et al [5]. We will characterize these PAD iPSC-ECs for mature endothelial cell function by (1) immunofluorescence staining (IF) and flow cytometry (FC) for cell surface markers CD144 (IF: Sigma V1514; FC: BD Biosciences 560410) and CD31 (IF: Abcam 187377; FC: BD Biosciences 560984); (2) quantifying nitric oxide synthase activity (Thermo Fisher D23842); (3) assessing tubule formation capacity on Matrigel (Fisher Scientific 08-774-552); and (4) quantifying proliferation with Edu labeling (Invitrogen C10214) and senescence with beta galactosidase staining (Thermo Fisher C10850) over serial passages.
We will compare these functional metrics in iPSC-ECs between male and female patients; patients with and without PAD; PAD patients under 75 and 75+ years old; African American and Caucasian PAD patients; PAD patients with or without diabetes; PAD patients with or without a history of tobacco abuse; and PAD patients with or without DM and end-stage renal disease combined. To detect a 30% reduction in proliferation with 80% power and 95% confidence, we will need 3 subjects in each category.
-Anticipated results, potential pitfalls and alternative approaches:
We anticipate (1) successfully reprogramming healthy and PAD patient MSCs to iPSCs; 2) successfully differentiating these patient iPSCs to ECs; and (3) observing a more severe premature senescence phenotype in cells from older patients and in patients with diabetes or end-stage renal disease. Potential pitfalls include limited capacity of MSCs from patients with the specified co-morbidities to be reprogrammed to iPSCs. Alternative approaches include using peripheral blood as a source material for patient cells to be reprogrammed. An additional potential pitfall is an inability to generate functional ECs from patient iPSCs in 2D culture. An alternative approach would be to generate 3D blood vessel organoids from patient iPSCs, containing endothelial cells and smooth muscle cells, which has been successfully done with samples from diabetic patients [9].

References
1. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000. Circulation 2004;110(6):738-43.
2. Duff S, Mafilios MS, Bhounsule P, et al. The burden of critical limb ischemia: a review of recent literature. Vasc Health Risk Manag 2019;15187-208.
3. Fujita Y, Kawamoto A. Stem cell-based peripheral vascular regeneration. Adv Drug Deliv Rev 2017;12025-40.
4. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131(5):861-72.
5. Patsch C, Challet-Meylan L, Thoma EC, et al. Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol 2015;17(8):994-1003.
6. Hekman KK, K; Ivancic, DA; He, C; Wertheim, JA. The Role of Autophagy During Differentiation and in Enhancing the Longevity of Induced Pluripotent Stem Cell-Derived Endothelial Cells. Vascular Research Initiatives Conference. Virtual: JVS Vascular Science, 2020:254.
7. Chen L, Daum G, Chitaley K, et al. Vasodilator-stimulated phosphoprotein regulates proliferation and growth inhibition by nitric oxide in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2004;24(8):1403-8.
8. Zuckerbraun BS, Stoyanovsky DA, Sengupta R, et al. Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA. American journal of physiology Cell physiology 2007;292(2):C824-31.
9. Wimmer RA, Leopoldi A, Aichinger M, et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature 2019;565(7740):505-10.

How the money would be spent:
CytoTune 2.0 kit (Thermo Fisher A16517) – 1 kit = $3200 Human Pluripotent Stem Cell Functional Identification Kit (R&D SC027B) – 1 kit = $700 Scorecard kit (Thermo Fisher A15871) – 1 kit = $1100

Name: Laura Marie Drudi

Email: laura.drudi@umontreal.ca
Mobile: +1 5147718890

Institution: Centre Hospitalier de l’Université de Montréal

Research Topic:
Critical Limb Threatening Ischemia and Health Disparities in Quebec and Canada

Background:

Goal: To improve care for patients with critical limb threatening ischemia (CLTI) in Quebec and Canada

Context: Peripheral arterial disease (PAD) is widely prevalent, affecting approximately 800,000 Canadians and 12% to 29% of the elderly. CLTI, the most severe form of PAD, is associated with high rates of limb loss and accounts for over 80% of lower extremity amputations in Canada. Patients with CLTI are a unique group of patients with complex comorbidities who may also be socially vulnerable. Social determinants of health have been associated with disparities in access to care, clinical and surgical care, and post-operative outcomes. However, there is limited evidence on the impact of social determinants of health in patients with CLTI in Quebec and Canada.

Brief synopsis of planned research proposal:

Research Question:

What are the social determinants of health that impact patient-centred and clinical outcomes for patients with CLTI in Quebec and Canada?

Research Design: The study will be an exploratory sequential mixed methods research design. Multiple institutions across the province of Quebec and across Canada will be invited to participate.

Aim 1: Determine the patient-reported and provider-reported barriers to access to care and perceived risk factors related to limb loss through qualitative reporting. This study uses a community engaged research (CEnR) approach to assess the needs of stakeholders for improving limb salvage care related to CLTI. Techniques used will be purposeful sampling with maximum variations. Interviews will be done one-on-one using a semi-structured interview format. Patients with CLTI who have undergone limb salvaging interventions and amputations will be invited to participate in the interviews. Their caregivers will also be invited to participate. Providers who provide care for patients with CLTI will further be invited to participate. Interviews will be conducted in both English and French, and the help of a translator for those who don’t speak either language.

Aim 2: Evaluate the impact of biopsychosocial determinants of vulnerability on limb loss in patients with CLTI. A prospective cohort study of patients with CLTI will be developed. Important social determinants of health that were identified in Aim 1 will be incorporated into this prospective study. This prospective study will serve as a pre-implementation cohort of patients prior to the implementation of our intervention (Aim 3). This prospective cohort study will continue post-implementation of our intervention.

Aim 3: To develop a pilot amputation prevention program in Quebec and subsequently expand to provinces and territories in Canada. Using the information collected from Aim 1 and Aim 2, as well as feedback from our stakeholder group, we will develop and adapt an evidence-based amputation prevention program that will be feasible and adaptable to the diverse communities and populations in Quebec and Canada. Using the Consolidate Framework for Implementation Research (CFIR), the implementation of this program will be evaluated for the feasibility and acceptability of the implementation of this program.

How the money would be spent:
The money research from this grant will be used entirely for academic development at the Michigan Mixed Methods Design Workshop and S-SPIRE Workshop on Mixed Methods

Name: Kavya Sinha

Email: ksinha@houstonmethodist.org
Mobile: 8325965194

Institution: Houston Methodist Hospital

Research Topic:
Gender differences in the presentation & management of DVTs

Background:

Gender inequality within healthcare continues to be a major challenge. The incidence, risk factors, clinical presentation, and prognosis of cardiovascular diseases differ among men and women. Recognizing and managing these differences is important in an era of individualized and precision medicine. There has been a growing interest in the understanding of the presentation of DVTs in men and women(1), particularly during the Covid-19 pandemic. It is known that women are at higher risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE)(2). However, women typically use fewer health services and associated delays in the presentation of VTE can lead to poorer outcomes (3).
Optimal patient selection for the endovascular treatment of iliofemoral DVTs remains a significant clinical challenge though it is still recommended for patients that present within 14 days(4). Symptom onset is used as a gross surrogate for determining the composition of the clot to determine if a lesion is amenable to endovascular treatment. As the thrombus ages, collagen deposition increases and the bulk of fibrin within the thrombus becomes crosslinked and resistant to lysis(5). We have previously demonstrated that MRI using T2-weighted (T2W) and ultrashort echo time (UTE) sequences can accurately characterize collagen and thrombus with histologic validation(6). Symptom onset has a poor correlation with collagen content and is not a predictor of endovascular success(5,7,8).

Brief synopsis of planned research proposal:

The goal of this study is to relate MRI-defined clot composition to the presentation of the patients and understand how gender plays a role in the presentation and management of these patients. We plan to scan 20 patients, 10 male, and 10 female when they present with symptoms of a DVT in a 7T clinical MRI scanner. If the patients are candidates for a thrombectomy, we will use the retrieved clot for histological slicing and staining with Mason’s trichrome stain to determine the age of the clot and correlate it with the presenting symptoms as well as our MRI imaging. The preliminary data of 3 men and 5 women was submitted as an abstract for the Women’s vascular summit this year. The primary outcomes will be the management of the patient, either medically or via a thrombectomy, procedural success as well as the composition of the clots retrieved correlated with imaging and symptoms.
With this study, we will gain insights on gender inequality in VTE management and begin to elucidate the underlying pathophysiology for these differences so we can use the knowledge to optimize the current management of VTE.

How the money would be spent:
We plan to use the money to scan 10 patients, 5 male, and 5 female when they present with symptoms of a DVT in a 7T clinical MRI scanner. If the patients are candidates for a thrombectomy, we will use the retrieved clot for histological slicing and staining with Mason’s trichrome stain to determine the age of the clot and correlate it with the presenting symptoms as well as our MRI imaging.

Name: Morgan Cox

Email: morgan.cox@surgery.ufl.edu
Mobile: 2193131032

Institution: University of Florida

Research Topic:
Evaluation of Performance Ratings and Perceived Autonomy of Vascular Surgery Trainees based on Gender

Background:

The field of vascular surgery continues to strive for increased race and gender diversity. Currently, 14% of practicing vascular surgeons are female with a higher proportion of women within vascular surgery training programs including 25% of traditional fellows and 30% of residents. Unfortunately, even with this increase in female representation amongst trainees, there is evidence that women within vascular surgery remain underrepresented in roles of leadership which is crucial to the continued professional development and recruitment to the field [1]. Additionally, a recent publication outlined patient outcomes are affected by the gender of their surgeon. Female patients treated by male surgeons had worse outcomes compared to female patients treated by female surgeons further demonstrating the importance of combating gender bias within the field of vascular surgery [2].

The time spent in training remains particularly formative for young vascular surgeons making the understanding of gender bias during this time of utmost importance. The perception of trainee autonomy has been investigated within general surgery programs where trainees, both male and female, perceive a lower level of autonomy compared to faculty raters [3,4]. Additionally, female trainees rated themselves as less autonomous compared to male trainees [4]. Prior investigations including a multicenter study utilizing the SIMPL app reported that female trainees had less autonomy in complex cases and lower self-assessments compared to their male counterparts although there was no difference in faculty performance assessments. However, this study included only two vascular surgery programs accounting for <1% of the evaluations included [5]. Additional data specific to general surgery trainees revealed similar findings with less surgical autonomy allotted to females [6]. A similar single center analysis within the field of urology noted no difference in autonomy or performance ratings between male and female trainees as well as no difference based on the gender of faculty raters [7]. No comparable analysis has been performed within vascular surgery.

Exploring the differences within vascular surgery training based on gender is the first step to identifying the root of gender bias in the work force that is seen throughout the academic hierarchy. By better outlining these differences, the field can continue to move forward with a better understanding to develop the programs and knowledge necessary to combat gender bias.

1. Humphries MD, Mikityuk A, Harris L, Simons JP, Aulivola B, Bush R, Freischlag JA, Reed AB. Representation of women in vascular surgery science and societies. J Vasc Surg. 2021 Aug;74(2S):15S-20S. doi: 10.1016/j.jvs.2021.03.056. PMID: 34303453.
2. Wallis CJD, Jerath A, Coburn N, Klaassen Z, Luckenbaugh AN, Magee DE, Hird AE, Armstrong K, Ravi B, Esnaola NF, Guzman JCA, Bass B, Detsky AS, Satkunasivam R. Association of Surgeon-Patient Sex Concordance With Postoperative Outcomes. JAMA Surg. 2022 Feb 1;157(2):146-156. doi: 10.1001/jamasurg.2021.6339. PMID: 34878511; PMCID: PMC8655669.
3. Chen JX, Chang EH, Deng F, Meyerson S, George B, Kozin ED, Gray ST. Autonomy in the Operating Room: A Multicenter Study of Gender Disparities During Surgical Training. J Grad Med Educ. 2021 Oct;13(5):666-672. doi: 10.4300/JGME-D-21-00217.1. Epub 2021 Oct 15. PMID: 34721795; PMCID: PMC8527937.
4. Kim GJ, Clark MJ, Meyerson SL, Bohnen JD, Brown KM, Fryer JP, Szerlip N, Schuller M, Kendrick DE, George B. Mind the Gap: The Autonomy Perception Gap in the Operating Room by Surgical Residents and Faculty. J Surg Educ. 2020 Nov-Dec;77(6):1522-1527. doi: 10.1016/j.jsurg.2020.05.023. Epub 2020 Jun 19. PMID: 32571692.
5. Meyerson SL, Teitelbaum EN, George BC, Schuller MC, DaRosa DA, Fryer JP. Defining the autonomy gap: when expectations do not meet reality in the operating room. J Surg Educ. 2014 Nov-Dec;71(6):e64-72. doi: 10.1016/j.jsurg.2014.05.002. Epub 2014 Jun 10. PMID: 24924583.
6. Meyerson SL, Odell DD, Zwischenberger JB, Schuller M, Williams RG, Bohnen JD, Dunnington GL, Torbeck L, Mullen JT, Mandell SP, Choti MA, Foley E, Are C, Auyang E, Chipman J, Choi J, Meier AH, Smink DS, Terhune KP, Wise PE, Soper N, Lillemoe K, Fryer JP, George BC; Procedural Learning and Safety Collaborative. The effect of gender on operative autonomy in general surgery residents. Surgery. 2019 Nov;166(5):738-743. doi: 10.1016/j.surg.2019.06.006. Epub 2019 Jul 17. PMID: 31326184; PMCID: PMC7382913.
7. Olumolade OO, Rollins PD, Daignault-Newton S, George BC, Kraft KH. Closing the Gap: Evaluation of Gender Disparities in Urology Resident Operative Autonomy and Performance. J Surg Educ. 2021 Nov 12:S1931-7204(21)00310-X. doi: 10.1016/j.jsurg.2021.10.010. Epub ahead of print. PMID: 34782271.

Brief synopsis of planned research proposal:

Our study team will perform a multi-center retrospective study using data from the SIMPL Registry to analyze and describe the differences in perceived autonomy and performance based on gender. We will perform comparative analyses based on trainee gender as well as faculty rater gender. Gender differences will also be explored within the different training paradigms including vascular surgery residents (5+0) and traditional vascular fellows (5+2) which will provide insight into autonomy and performance assessments based on level of training and over time. This study will be the first of its kind within vascular surgery and the basis for future studies to intervene and implement changes to mitigate, and hopefully eliminate, gender bias within vascular surgery training.

How the money would be spent:
The funds from this research grant will be used to support the effort of our statistical staff and education research fellow to work on this sub analysis of the vascular surgery SIMPL data.