12_16VS14_9.qxp
9/2/2014
4:28 PM
1
Page 12
NEWS FROM SVS
SEPTEMBER 2014 • VASCULAR SPECIALIST
SVS RESEARCH NEWSLETTER
Introduction: Fostering Research and Innovation he vascular community has a lot to be proud of. Thanks to what we do, our patients enjoy a better quality of life than ever before. Progress in our field has transformed expectations about aging and recovering from illness at any stage in life. But the full promise of our field cannot be fulfilled without research moving us forward. Support for vascular research is critical to developing better treatments for our patients, and maintaining a prominent role for our specialty in defining vasDR. LAWRENCE cular care. Or, as Michael Conte writes succinctly in these pages, “Research is important to SVS because it is important to our patients.” I am pleased to introduce the first-ever SVS research newsletter. In this issue you will learn more about the vascular surgeon scientists who are hungry for answers that will lead to better patient care, the society’s commitment to research and multispecialty collaboration, and the opportunities available to all members of our community to share their research. My heartfelt appreciation to our community of scientists and the SVS members serving on the Research Council and its committees. Together, we are fostering research and innovation with the highest levels of scientific integrity.
T
Peter F. Lawrence, MD President, Society for Vascular Surgery
SVS Research Leadership Report the whole story. The profile of Scott Berceli offered here provides ample evidence of the incalCOUNCIL culable value of our K Program. P Endorsing the BEST-CLI Trial is a prime exhank you, SVS colleagues, for the opportunity ample of how SVS contributes to advancing clinto help fulfill our collective commitment to ical research for our field. Following the process scientific leadership. Those of us developed by the council, the BEST-CLI who serve on the Research Council and Trial was the first study to obtain an its three committees – Clinical and SVS endorsement. As Alik Farber and Comparative Effectiveness Research, Matt Menard attest further in this reOutcomes and Technology Assessment, port, they believe the endorsement was and Research and Education – are instrumental in convincing the NIH to pleased to confirm the vibrant state of approve $25 million to fund the BESTour society’s scientific initiatives. CLI Trial, by any measure a monumenResearch is important to SVS betal study. cause it is important to our patients. P For nearly 30 years, the Vascular ReOur field has made dramatic advances DR. CONTE search Initiatives Conference has enbut the burden of vascular disease recouraged interaction and collaboration mains great, and we still have many unmet scienamong new and established vascular surgeon intific needs – spanning from discovery science vestigators and scientists from other vascular bithrough translation and clinical investigation. Reology-related disciplines. Katherine Gallagher’s search also propels our specialty forward in every top-rated presentation from the 2014 VRIC, sumrelevant domain, giving us an authoritative and marized here, demonstrates the compelling work persuasive voice with public policy makers, indus- our members are doing in translational research. try, regulatory bodies, orFinally, we are Research propels our specialty forward in ganizations like the AHA, mindful of the pioand the NIH. neering vascular every relevant domain, giving us an SVS has made imporsurgeon-scientists authoritative and persuasive voice with tant contributions to sciwho have conentific advances – in tributed so much to policy makers, industry, regulatory bodies, basic/translational, clinithe science and organizations like the AHA, and the NIH. cal, and outcomes repractice of vascular search. Here are some medicine, and have key examples: distinguished themselves by the volume, breadth P The SVS Foundation/ NHLBI Mentored Caand depth of their work. For his lifetime of reer Development Award Program has proven ef- achievements as a vascular biologist, his decades fective in sustaining the pipeline of of leadership, and most importantly his mentorbasic/translational vascular research. Our recent- ship and inspiration to so many of us, I salute ly completed 15-year assessment shows that with Alec Clowes. His insightful remarks in our first $9.4 million in supplemental support from SVS, Research Newsletter reflect a unique perspective 29 K Award recipients went on to secure $45.1 on where we are in vascular research and where million in additional NIH and VA funding, a 4.8 we are going. return on investment. Further positive results inOn behalf of all my Research Council colclude prodigious scientific output and a signifileagues, thank you for your ongoing support of cant amplification of knowledge and skills this work. We welcome any comments you may through mentorship. Still, the report does not tell have on this report. B Y M I C H A E L S. C O N T E , M D
ON BEHALF OF THE SVS RESEARCH
T
Astride Science and Clinical Practice B Y A L E X A N D E R W. C L O W E S, M D
n invitation arrived from Mike Conte and Julie Anne Freischlag to share my thoughts on what I see on the horizon for vascular surgeons. How could I resist? As context, I speak as a career academic surgeon working at the interface between vascular biology and clinical practice, focused on what I would call the response to
A
injury, intimal hyperplasia, and stenosis/restenosis. It’s a big problem and it is the main reason for luminal narrowing in 1 in 3 reconstructions. With that in mind, here are five thoughts. One: Peripheral vascular surgery isn’t going away. Peripheral vascular disease is not on the decline. Risk factors have not diminished. First, diabetes has gotten worse; we don’t have an effec-
tive way of countering the toxic effects of diabetes on the build-up of plaque. Second, with an aging babyboom generation, there’s going to be a lot more aneurysmal disease. There are other kinds of diseases that need attention, but these two probably transcend everything else in magnitude and in importance for the future. Two: We have gaps to fill. We have a variety of tools for
opening blocked arteries and restoring circulation. What is missing are strategies that are sufficiently robust to guarantee that the repair of an artery is long-lasting. We’ve had some progress here, but need a lot more. Part of the answer is more clinical trials. Vascular surgeons have come late to this research method, but it is very important and SVS should champion this approach. We have also come
to recognize the importance of “bedside to bench” – carefully studying the disease and responses in humans because our animal models have many limitations. This is a unique opportunity for surgeon-scientists. Three: Researchers will need new tools and expertise. If I were starting today, I Continued on following page
12_16VS14_9.qxp
9/2/2014
4:28 PM
Page 13
NEWS NEWSFROM FRSVSSVS VQI REPORT
SEPTEMBER 2014 • VASCULARSPECIALISTONLINE.COM
2
SVS RESEARCH NEWSLETTER Continued from previous page
would train myself in two areas: genetics, because I really do think there is a genetic underpinning for vascular disease; and novel imaging devices that will let us go beyond death and limb loss, and look at natural history and outcomes of pharmacological interventions. Research teams of the future will need to include not only vascular surgeons, but also people who are skilled
at defining the progression and regression of disease; who understand the underlying biology; who are experts in endocrinology, cholesterol metabolism, diabetes, and other areas. Four: SVS is on the right path; keep going. SVS and its members are well situated to improve vascular care because we treat all aspects of occlusive and dilating diseases, and that makes us unique. It also makes us responsible.
Some of our colleagues have a huge desire to do the science needed to advance our field. The SVS should continue to select, train and support young academic investigators who are capable of being the bridge between the science and the clinical care. We need more translational research, yes, but we also need to encourage those few brave souls willing to go straight after basic science. And we certainly need to expand the cadre of
highly qualified and creative clinical investigators. Our K Award programs are doing just that. Five: Tune in to the enthusiasm of vascular investigators. I don’t think the SVS should be in the business of telling people what to research. Investigators should have their own ideas because there is no substitute for enthusiastic investigators driven heart and soul to dig into something they care about.
Dr. Clowes has been associated with the University of Washington School of Medicine since 1980. He was Chief of the Division of Vascular Surgery from 1995 to 2007. He has been funded for more than 30 years by the NIH and currently is investigating the role of a single nucleotide polymorphism (SNP) in the promoter of a critical cell cycle regulator, p27 Kip1. Nothing has given him more professional satisfaction than witnessing the success of his colleagues as they build their careers.
Vascular Surgery Leads in Definitive Guidance for CLI BEST-CLI Trial: 2,100 patients, 120 centers, 4 years, 26-month minimum follow-up, $25 million n October 2007, SVS members Alik Farber, MD, Boston Medical Center, and Matthew Menard, MD, Brigham and Women’s Hospital, Boston, decided to collaborate on a large-scale study to provide definitive guidance on how to best treat patients with CLI. They expected a long path. They were right. Countless conversations, hundreds of documents, dozens of consultations with researchers and clinicians in vascular surgery and other disciplines, two NIH grant cycles, and seven years later, their application for a $25 million R01 grant to support the BEST-CLI Trial was approved. Now the work begins.
I
Defining practice for CLI The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) Trial will compare treatment efficacy, functional outcomes, and costs for 2,100 patients age 35+ undergoing best open surgical or best endovascular revascularization. “It won’t be easy,” Dr. Farber said, “but the prospect of giving clinicians better guidance on how to effectively treat CLI, and offer patients optimal outcomes has been an ongoing motivator.” Dr. Menard agreed. “We understand the challenges of such an ambitious trial, but the support and enthusiasm we have seen from those who understand CLI and who share our desire for substantive progress given the current lack of data has been compelling.”
CLI: A top-three clinical research priority In 2010, the SVS named CLI one of the top-three unmet clinical research needs. Known to affect 500 to 1,000 per million U.S. patients every year,
DR. FARBER
DR. MENARD
the CLI rate is expected to continue to escalate. Currently, unless affected limbs can be successfully revascularized, as many as 40% will be amputated, and the associated annual mortality rate exceeds 20%.* “The CLI population is an exceptionally complex and challenging group of patients to treat. By looking at both functional outcomes and the cost-effectiveness of open and endovascular treatment options, we hope to provide the evidence-based guidelines that are currently needed,” Dr. Menard said. Unique on many levels The study is unique in several important ways, among them its pragmatic trial design, its use of novel endpoints, the inclusion of a robust costeffectiveness component, and its collaborative approach. The BEST-CLI Trial is also one of the few large-scale, multispecialty
clinical trials with vascular surgery roots and leadership. In addition to principal investigators Drs. Menard and Farber, who serve as two of the three trial chairs, vascular surgeons Dr. Michael S. Conte and Dr. Richard J. Powell serve on the seven-member executive committee. Dr. Conte cochairs the executive committee with Dr. Chris White, an interventional cardiologist. At the same time, the BEST-CLI Trial includes all specialists who treat patients with CLI: vascular surgeons, interventional cardiologists, interventional radiologists, and vascular medicine physicians. Drs. Farber and Menard acknowledge there has not always been perfect harmony among specialists treating CLI, but they have been encouraged by the extent to which those involved have worked to move beyond those differences to achieve the goals of the trial. “The BEST-CLI Trial is an opportunity for everyone treating patients with CLI to get away from bias and convictions that are not validated by science,” Dr. Farber said. “If we’re going to define practice, we have to involve everyone.” “The trial will provide a unique opportunity for interdisciplinary collaboration between all of the subspecialties providing care to CLI patients,” Dr. Menard added. “Dr. Ken Rosenfield, who represents the interventionalist community on the PI team, and his colleagues on the executive committee have been instrumental in involving a diversity of endovascular clinicians.” Endorsed by the SVS, other societies and the FDA Drs. Menard and Farber acknowledge the support provided to them and the
trial by the SVS. The society leadership at the time, including Drs. Richard P. Cambria, Anton Sidawy and Robert M. Zwolak, and Ronald L. Dalman provided a key endorsement at a critical early juncture. The endorsement cited the promise of the bringing “transformative power” to CLI care, and described trial results as being “of critical importance to patients and their vascular surgeon specialists.” “Strong endorsement from our national vascular surgery society, and the signal this sends to the NIH, was a very important component of our grant application,” Dr. Menard said. “We remain grateful for the ongoing investment in and support of the trial by the current SVS leadership, who have, throughout, shared our belief in the value of this effort to our collective patients.” Attesting to its broad multi-disciplinary backing, the BEST-CLI Trial is also endorsed by the FDA, the Society for Cardiovascular Angiography & Interventions (SCAI), the Society of Interventional Radiology (SIR), the Society of Vascular Medicine (SVM), the Vascular Disease Foundation (VDF), and Vascular InterVentional Advances (VIVA). Reflects realities of the care environment Unlike previous trials, the BEST-CLI Trial leaves the definition of “best therapy” to the individual investigator and allows use of all commercially available endovascular therapies, all surgical bypass techniques, and all types of conduit to be used. New and evolving therapies will be critically reviewed as the trial progresses; those found suitable will be added to Continued on following page
12_16VS14_9.qxp
9/2/2014
4:28 PM
3
Page 14
NEWS FROM SVS
SEPTEMBER 2014 • VASCULAR SPECIALIST
SVS RESEARCH NEWSLETTER Continued from previous page
the list of options. The dedicated focus of the trial on comparative effectiveness also reflects today’s economic realities. Dr. Farber described this aspect of the study as central to securing support from the NHLBI, the funding institute within the NIH. “Everyone recognizes the need to allocate the scarce resources of today’s tightened budgets as wisely as possible. We hope to provide a more objective, evidence-supported basis on which to do so,” he said. More than a conventional RCT Principal Investigators Dr. Menard,
Dr. Farber, and cardiologist Ken Rosenfield, MD, Massachusetts General Hospital, Boston, have always been interested in tapping the expertise offered at each of the 120 participating trial centers in the United States and inCanada. To do so, the investigators have championed a “CLI team” approach through which local site teams will collaborate over the course of the trial. Sites are on target to complete the first of several webinars scheduled this fall to orient investigators to the specific rules of the trial. This month, they hope to welcome the first of 2,100 randomized patients.
Bright outlook Asked how colleagues can help the Drs. Farber and Menard say their BEST-CLI Trial as it moves forward, SVS colleagues have been Dr. Farber said, “by joinnothing but supportive. ing in the effort to recruit from day one. “People patients.” understand the inherent Enrollment starts this challenges, but are motimonth. For more informavated by the potential for tion visit http://vsweb.org/ the level of data only a BESTCLI. randomized trial of this If interested in particikind can provide,” Dr. pating, please contact Dr. Menard said. Menard (mmenard@partAt the 2014 Vascular An- DR. ROSENFIELD ners.org ) or Dr. Farber nual Meeting, they de(Alik.Farber@bmc.org). scribed the investigators meeting to orient first-wave participants *Norgren, L., et al., Inter-Society Conand others still considering particisensus for the Management of Periphpation as “high attendance and high eral Arterial Disease (TASC II). J. energy.” Vasc. Surg. 2007. 45 Suppl S: p. S5-67.
The Best From 2014 VRIC: Highest-Rated Abstract Presentation Marrow-based epigenetic signatures and type 2 diabetic wounds ore than 100 investigators, students and trainees with an interest in science and cuttingedge translational research attended the April 30, 2014 Vascular Research Initiatives Conference in Toronto. The research abstract presented by Katherine A. Gallagher, MD, summarized below, was the highest-rated. Co-moderator for the VRIC session devoted to stem cells and tissue engi-
M
neering abstracts, Dr. Gallagher is a member of the SVS Research and Education Committee and an assistant professor of vascular surgery, University of Michigan, Ann Arbor, Michigan. ABSTRACT SUMMARY Bone-Marrow Chimeras Demonstrate That the Epigenetic Signature in the Bone Marrow Myeloid Cells Influences the Peripheral Wound M1-Dominant
Macrophage Phenotype Katherine A. Gallagher, Amrita Joshi, Emily Hogikyan, Dawn Coleman, William Carson, Steven Kunkel, University of Michigan, Ann Arbor, Michigan. Within the broad field of epigenetics, this work focused on the role of immune cells in Type 2 diabetic wound healing. Specifically, this research examined histone methylation changes in bone marrow stem cells and the associated transfer of information into more differentiated monocytes and macrophages at the wound level. The study hypothesized
Research and Publication Opportunities for Vascular Specialists Submit abstracts for meetings 2015 Vascular Research Initiatives Conference (San Francisco, CA) 2015 Vascular Annual Meeting (Chicago, IL) Apply for SVS Foundation Awards Mentored Clinical Scientist Research Career Development Award (K08) Mentored Patient-Oriented Research Career Development Award (K23) Clinical Research Seed Grant VRIC Trainee Travel Scholarship Resident Research Prize Student Research Fellowship EJ Wylie Traveling Fellowship SVS Foundation and Vascular Cures Wylie Scholar Award Submit manuscripts and articles for publication Journal for Vascular Surgery Journal of Vascular Surgery: Venous and Lymphatic Disorder Vascular Specialist
Deadline January 23, 2015
For more information vsweb.org/VRIC
February 10, 2015 Deadline October 12, 2014
VascularAnnualMeeting.org For more information vsweb.org/MentoredClinical
October 12, 2014
vsweb.org/MentoredPatient
Fall 2014 January 23, 2015 February 10, 2015 March 2, 2015 March 2, 2015 March 27, 2015
vsweb.org/SeedGrant vsweb.org/VRICscholarship vsweb.org/ResidentResearch vsweb.org/StudentResearch vsweb.org/WylieTravel vsweb.org/WylieScholar
Deadline Ongoing, published monthly Ongoing, published quarterly
For more information jvascsurg.org jvsvenous.org
Ongoing, published monthly
VascularSpecialistOnline.com
that the diabetic milieu in Type 2 diabetes generates cytokines and other growth factors that induce methylation changes at the bone marrow cell level, resulting in monocytes and peripheral macrophages which go to the wound “preprogrammed” to act as an M1 (pro-inflammatory) macrophage, and have trouble switching to an M2 (anti-inflammatory) phenotype for tissue repair. We found previously that a decreased level of H3K27 in mature macrophages at the IL12 promoter results in increased expression of the pro-inflammatory cytokine in wounds. In this study, we wanted to determine which epigenetic enzyme plays a role in driving this K27 methylation mark. We took macrophages from diabetic versus control wounds and found that one enzyme, Jmjd3, showed a 23-fold increase in diabetic macrophages versus control cells. That result did not surprise us, because Jmjd3 specifically demethylates for H3K27; it removes the methyl group, decreasing the level of H3K27. To assess whether this new result is functionally and biologically important, we exposed the diabetic macrophages to GSK-J4, a new dimethyl inhibitor specific for Jmjd3, and observed increased levels of H3K27 on
the IL12 promoter. Perhaps more importantly, when we looked at IL12 production, we saw a dose-dependent decrease corresponding with the inhibitor for Jmjd3. When we inhibit this epigenetic enzyme, we can control the levels of cytokine production coming from these diabetic macrophages, which is important from a therapeutic perspective. To look at our second goal, to assess the role of bone marrow in this process, we created chimeric mice. We took bone marrow from diabetic and non-diabetic mice and injected it into both irradiated diabetic and non-diabetic animals. We observed impaired wound healing in non-diabetic mice that received diabetic bone marrow. More importantly, their macrophages showed increased levels of Jmjd3 and IL12—as a result of diabetic bone marrow being injected into normal-diet mice. In summary, this study showed that bone marrow from diabetic mice can impair peripheral macrophages and negatively impair wound healing. Histone methylation changes in the cells appear to influence peripheral macrophage functions. Potentially, modulation of these enzymes may offer therapeutic benefits by modulating cytokine levels and perhaps dictating macrophage function.
12_16VS14_9.qxp
9/4/2014
11:49 AM
Page 15
SEPTEMBER 2014 • VASCULARSPECIALISTONLINE.COM
NEWS NEWSFROM FRSVSSVS VQI REPORT
4
SVS RESEARCH NEWSLETTER
Dr. Scott Berceli Reflects on the Research and Career Value of the SVS Foundation K Award Program ach year, vascular surgeon-scientists awarded K08 or K23 career development grants compete for an SVS Foundation/NHLBI Mentored Career Development Award. In 2004, Scott Berceli, MD, PhD, succeeded, and received mentorship from a senior investigator and $75,000 per year in addition to NIH funding. Dr. Berceli said the supplemental funding is equally, if not more important than the K award itself. “My K08 award, allowed only $25,000 for supplies and other expenses—not enough if you want to innovate and move your research into a novel area,” he said. As it turned out, the SVS Foundation was crucial for Dr. Berceli. Understanding the biology of vein graft remodeling Going into his 2004-2009 K08 award, Dr. Berceli believed he would find one or two molecules that could be reprogrammed through drug therapy or some other means to help slow the progress of intimal hyperplasia so grafts would last longer. “Experiments showed that a variety of factors are involved, and a lot of interconnectedness. I needed to take my research in a completely new direction,” Dr. Berceli said. His background as a chemical engineer helped Dr. Berceli regroup under a systems biology approach. The new goal was a comprehensive understanding of the cell-to-cell signaling set off by the act of inserting a bypass graft into the arterial circulation. Following completion of work under the K award, Dr. Berceli secured a five-year R01 grant to keep the team intact and take the investigation further.
SVS
E
Dr. Scott Berceli (right), shown with his colleague and mentee, Dr. Salvatore Scali, is a prime example of the value of the SVS Foundation K Award Program.
The power of mathematical models Mathematical models revealed how specific genes signal cells to divide or die and reassemble to form scars, narrowing the vessel and changing the way the blood flows through the bypass. The team saw how genes could be turned on or off to change the vein remodeling cycle. They were able to quickly perform extensive experiments with various sets of genes and predict associated changes in vein graft geometry.
pices of the MultiScale Modeling Consortium. Funded by a $3.5 million U01 NIH grant, a multi-institutional research team is working with scientists at the NIH, National Science Foundation, Department of Energy, and Department of Defense. “Multiscale modeling says if we can predict how things will occur on a second-by-second basis at a molecular level, we can eventually understand how the whole hyperplastic process works,” Dr. Berceli explained. The team will define perhaps five genes with potential to improve bypass graft biology. Using high-throughput cell culture, they will run experiments on tens of thousands of different combinations of the target genes to validate previously developed predictions. Findings will be tested in the rabbit vein graft model that Dr. Berceli developed for his K Award study, after which the team can move on to tests in humans. When asked how novel this work is, Dr. Berceli said, “About a year ago, the head of the Bioengineering Directorate at the NIH asked me to present at a monthly seminar he hosts for his branch. He told me no one else he knows of is on our same path, linking engineering work and biology through multiscale modeling to develop a therapy.”
Circling back to in vivo models Today, one of three NIH studies that Dr. Berceli is leading is under the aus-
Changing lives through mentoring “No one outside my family has had a more profound influence on my
development, not only as a surgeon-scientist but as a person, than Dr. Frank LoGerfo and Dr. Alec Clowes, both giants in vascular re-
search,” Dr. Berceli said. As to the 30-plus lab trainees and vascular surgeons Dr. Berceli has mentored, “I’ve tried to create an environment where engineering grad students and surgery residents can cross-pollinate, flourish and move on,” he said. “I also mentor more senior people, like Dr. Salvatore Scali, our junior faculty member. Helping him plant good roots and succeed with his own K grant and SVS Foundation Award has been very rewarding.” More broadly, Dr. Berceli is concerned that research opportunities for vascular surgeons in training have all but disappeared. “It’s critical that we preserve opportunities for the motivated people who we think will lead the specialty going forward,” he said. “We need more investigative experiences, not just at the faculty level, but during training, when we can inspire people to choose a career that includes research.”
has not only a new look, but new features, with the goal of providing you the latest in vascular and medical news beyond the print edition.
4