FROM THE COVER: ‘FIRST’ STUDY TO IDENTIFY ENDOTHELIAL CELL-CELL COMMUNICATION VIA BIDIRECTIONAL SECRETION OF EXTRACELLULAR VESICLE CARGO WINS SVS FOUNDATION AWARD

are submitted by the applicant alongside an SVS senior collaborator, and on winning, are given the opportunity to present their research at VAM. Said to be “moving the needle on every front” by her mentor and collaborator Kathryn L. Howe, MD, PhD, at the University of Toronto, Toronto, Canada, Raju is set to present her research during the first plenary—William J. von Liebig session—on Wednesday June 14, 8–8:10 a.m. in Potomac A/B).

The research is founded on a central tenet—ECs can release extracellular vesicle (EV)-encapsulated miRNAs and proteins to mediate cell-cell communication. Seeking to expand on this, Howe and Raju hypothesized that EC-EV release is altered by activation state and drives functional changes in surrounding cells via bidirectional release.

In conversation with VS@VAM prior to her presentation, Raju reflects on how the research was borne out of a deficit in knowledge surrounding plaque burden and its progression. Approaching Howe who runs a laboratory focused on endothelial communication and carotid disease, Raju found that their interests blended, and they began investigating this question through an endothelial and vesicle perspective, specifically looking at the bidirectional interface where these cells communicate.

“The idea in both of our minds,” Howe tells VS@ VAM, “is that atherosclerosis does not form overnight—it is not a single moment in time, it takes decades to form. So, if you envision a cell that has lived at this interface for a time where it is constantly irritated or activated by non-laminar or turbulent flow, you can imagine how it may be constantly sensing and communicating back this distressed environment response.” With this information, Raju alongside Howe investigated what drives atherosclerosis and plaque build-up in target zones, considering what influences shifts in cell activation state from stable to vulnerable to rupture.

These activation states, Raju describes, can be “happy” or “angry”, denoting the either quiescent or inflammatory vesicle packages the EC contains. “We wanted to see how the EC modulates vesicle release in conditions that are quiet and happy—and in conditions where we have made them angry, as is seen in patients who have vascular diseases like atherosclerosis,” Raju outlines. Interestingly, when relevant cells are treated with EC-derived vesicles, they found that vesicles were able to modulate or change conditions in cells found in both the vessel wall and the blood, raising new questions on the mechanism behind this.

“We were the first to show that ECs can load specific cargo and secrete it in both the apical and basolateral directions”, Raju says, their findings uncovering the “critical interface” ECs reside in. “Not only are they able to sense what is going on in the environment, but they are able to change the vesicular cargo” said Raju, which can then continued from page 1 induce the happy or angry cell activation states. Importantly, they also found that ECs can polarize vesicle release bidirectionally, which may specifically govern functional changes in circulating and resident vascular cells.

Making continued progress, Raju is interested in exploring this from a biomarker perspective so that she can get ahead of plaque progression before a patient becomes symptomatic. “As vascular surgeons we operate on patients who have symptomatic carotid atherosclerosis which leads to stroke.” However, without a “good biomarker” to indicate plaque progression in asymptomatic patients, predicting and preventing later clinical events can be difficult.

“This has broad-ranging applications” Raju states, “although it builds on a fundamental principle of vascular biology—we know that these ECs are secreting vesicles that are going into the vessel wall and communicating with cells there. If we can find a way to harness and

Understanding the communication between ECs and progression to rupture or stroke formulates the translational aspect to Raju’s research, which is a key element in the Resident Research Award’s parameters. To explore this, Raju’s team have been collecting carotid plaques and plasma to see if this information can be corroborated with their patient cohort. From a therapeutic perspective, Raju states, they want to better understand the mechanism by which ECs are releasing vesicles in a basolateral direction and driving the biology of the disease, so that they can design therapeutics or small molecules that can “inhibit or enhance” the mechanism and find ways of reverting it into a quiescent phenotype. “I think we have unearthed a basic biological tenet that can be applied to several vascular pathologies, which is promising,” Raju concludes. “Beyond a vascular surgical viewpoint, it could also be applied to other areas such as cerebral aneurysms or cancer biology.”

On winning the award, Raju reflects on the “motivation and inspiration” gaining this recognition has instilled: “It is great that the committee thought this work deserving of the award, I am very grateful for this international platform to showcase my research and establish international collaborations with fellow vascular surgeons and scientists to advance some of these questions together.”

On her involvement in research projects of the future, Raju details that in the year before she returns to residency, she hopes to dedicate time to the translational side of the current research. “I hope to stay involved in this project as it progresses and develops, and use this skill set to ask vascular biology related questions as a future surgeon-scientist in my own independent lab—that would be the dream.” change that communication to make it happier, then we can hopefully circumvent, reverse or rescue some of the negative cell-cell communication happening in disease states to mitigate plaque progression.”

Looking ahead to Raju’s presentation at VAM 2023, Howe believes it is an exciting chance to “lift the lid” on the progressions being made in research and “bring this into the space of the clinician.” gent mixed-methods study which included the use of cross-sectional surveys following the 2020 ABS In-Training Examination (ABSITE) and Vascular In-Training Examination (VSITE). This survey looked at eight domains of the learning environment and resident wellness, while multivariable logistic regression models were used to compare thoughts of attrition between postgraduate year (PGY) 1–3 residents in general and vascular surgery across 57 institutions. Focus groups were also conducted at last year’s VAM. expressed that early specialization and a smaller, more invested faculty allows for an apprenticeship model” that facilitates “frequent feedback, and thus early skill acquisition” as well as “closer relationships with co-residents and faculty.” This relationship in turn allowed vascular trainees to be more comfortable in reporting mistreatment.

Today’s program will feature the presentation of an abstract by R. Debbie Li, MD, Loyola University Medical Center, Chicago, on the divergent perceived experiences of the shared learning environment by vascular and general surgery residents.

T he research, led by Dawn M. Coleman, MD, Duke University Medical Center, Durham, North Carolina, and Malachi Sheahan III, MD, on behalf of the Vascular Arm of the SECOND Trial was carried out in the belief that “an enriching learning environment is integral to resident wellness” per the abstract. The study team aimed to identify differences in the experience of vascular and general surgery residents with a view to finding “practical levers for change” in improving resident wellness and addressing rates of attrition.

Li and colleagues conducted a conver-

In total, 205 vascular residents and 1,198 general surgical residents responded, with general residents found to be more likely to experience mistreatment and consider leaving their program. Coleman, Li and colleagues highlight the qualitative data they collected, stating: “Vascular trainees

These differences, the study authors suggest, may be the result of “intrinsic features of the integrated training paradigm that are not easily replicated” by larger surgical training programs. Li et al say they are “thrilled” with these results, and propose in conclusion that “optimization of differential aspects of the learning environment is crucial to continue to enhance the next generation of our surgical workforce.” —

Benjamin Roche

not just for what providers care about, but for what patients care about as well.

VS: and efficacy findings of the study?

By Jamie Bell Misty Humphries

EARLIER THIS YEAR, RESEARCHERS debuted single-center experiences indicating that intravascular lithotripsy (IVL) may be able to expand transcarotid artery revascularization (TCAR) into patients with traditionally prohibitive calcific disease.

With a multicenter case series now further suggesting IVL’s utility, but also revealing potential safety concerns versus conventional TCAR or carotid endarterectomy (CEA), principal investigator Misty Humphries, MD, MAS, associate professor of surgery at UC Davis in Sacramento, California, gives VS@VAM the lowdown on these findings.

VS: Could you very briefly outline the motives behind this research?

MH: TCAR has been shown to be highly effective and safe, but there are still anatomic exclusion criteria—specifically, severe calcification. There are also many patients who are just not a candidate for traditional CEA for various reasons. The use of IVL has the potential to open TCAR technology up to more patients.

VS: How do these more recent, multicentric findings build on your publication from earlier in the year?

MH: With our initial presentation, we discussed how we do the procedure. That presentation was our own institutional data. When we analyzed our own experience, we had no complications, and the technology appeared safe. But, in this larger, multicenter cohort, we see a risk of transient ischemic attack (TIA) post-procedure that was not present. Multicenter studies like this demonstrate what can happen when technology is expanded to more practitioners of various skill levels.

VS: Why was freedom from stroke/TIA selected as the study’s primary safety endpoint?

MH: Stroke and TIA are the two outcomes patients care about most. We saw this with the CREST trial data that were analyzed. All of my research is patient-centered and, for me to use technology, I want to know that it is safe—

MH: be highly effective, allowing full stent ex pansion. The safety of the combined treat ment needs to be studied in a prospective trial. There are not a significant amount of known data on the risk of stroke and TIA in patients with severe calcium after carotid artery stenting (CAS) because these patients are typically excluded from trials. The best data we have were presented at the Society for Clinical Vascular Surgery (SCVS) meet ing earlier this year. In a review of Vascular Quality Initiative (VQI) patients who under went TCAR and CAS, patients with severe calcium had a higher risk of stroke/TIA than those who did not. This tells us that it is the disease process, and we need to learn more about this.

VS: technical success rate of 100% was achieved?

MH: can do the procedure. The real question is

Presenter Neeta Karani, MD, from Bronson Healthcare, Kalamazoo, Michigan, is set to elucidate findings that consider the incidence of carotid stent fractures and their impact on carotid stent durability during Plenary Session 2 (9:45–11 a.m.) in Potomac A/B. By Éva Malpass.

Research from Karani and colleagues—including senior author Robert Molnar, MD, from Michigan Vascular Center—comes against the backdrop of the recent approval of transcarotid artery revascularization (TCAR) for asymptomatic patients by the Centers for Medicare and Medicaid Services (CMS), which, by proxy, has increased the number of carotid artery stenting (CAS) procedures being performed today. Subsequently, Karani, alongside co- author Subbaiah Perla, a professor of statistics at Oakland University in Rochester, Michigan, identified a number of carotid stent fractures in their practice, and so set about investigating the prevalence of this condition and its influence on the efficacy of CAS.

Conducting a prospective trial, the researchers enrolled 200 patients who had undergone CAS between January 2002 and November 2021. Karani these patients for stent fractures via anterior-posterior (AP) and lateral cervical X-rays. These X-rays were independently reviewed by three vascular surgeons, who, upon complete consensus, identified those patients who had definitive stent fractures. Additionally, Karani and colleagues applied a modification to their study that allowed for a second X-ray to be obtained at a later date to assess the potential for late fracture development in their patient cohort.

Their primary outcome measure was defined as the incidence of carotid stent fracture, followed by a secondary measure which was an evaluation of the clinical implications associated with the condition upon confirmed identification.

In the 200 patients who consented and were enrolled in the study, a total of 227 stent procedures were performed over the duration of Karani and her team’s investigation. In the first wave of X-rays obtained by the team, they identified 18 stent fractures, amounting to a stent fracture rate of 7.9%. Karani will go on to report that 103 patients additionally received a second/delayed X-ray, which

1 The Venovo™ Venous Stent System was studied in the global VERNACULAR clinical trial, which was a prospective, multi-center, non-randomized, single-arm study of 170 patients. The primary effectiveness endpoint of the study was primary patency (PP) at 12 months post-index procedure, defined as: freedom from TVR and freedom from thrombus occlusion and stenosis > 50% as measured by DUS. Patients who received a Venovo™ Venous Stent had a weighted PP rate of 88.6%, demonstrating a statistically significant difference from a literature-derived performance goal (PG) of 74%. At 36 months, patients who received the Venovo Venous Stent had an unweighted PP of 79.5% (84.0% K-M) (N=141). The primary safety endpoint was freedom from major adverse events (MAE), including stent migration, through 30 days post-index procedure. Freedom from MAE was 93.5%, demonstrating a statistically significant difference from a literature-derived PG of 89%. Stents were evaluated at the 36-month follow-up for fracture analysis. An anteroposterior and lateral x-ray for each evaluated stent were sent to an independent core lab for analysis. 98 subjects’ x-rays were analyzed and no stent fractures were reported. Missing x-ray analyses were recorded as protocol deviations. Dake, Michael D, et al. “Three-Year Results from the Venovo Venous Stent Study for the Treatment of Iliac and Femoral Vein Obstruction.” Cardiovasc Intervent Radiol, vol. 44, no. 12, Dec. 2021, https://doi.org/10.1007/s00270-021-02975-2. Epub 2021 Sep 20.

The Venovo™ Venous Stent System is indicated for the treatment of symptomatic iliofemoral venous outflow obstruction. The Venovo™ Venous Stent System is contraindicated for use in patients with a known hypersensitivity to nitinol (nickel-titanium) and tantalum