Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

Atherosclerosis is an Inflammatory Disease

WRITING GROUP MEMBERS Emelia J. Benjamin, MD, SCM, FAHA Michael J. Blaha, MD, MPH Stephanie E. Chiuve, ScD Mary Cushman, MD, MSc, FAHA Sandeep R. Das, MD, MPH, FAHA Rajat Deo, MD, MTR Sarah D. de Ferranti, MD, MPH James Floyd, MD, MS Myriam Fornage, PhD, FAHA Cathleen Gillespie, MS Carmen R. Isasi, MD, PhD, FAHA Monik C. Jiménez, ScD, SM Lori Chaffin Jordan, MD, PhD Suzanne E. Judd, PhD Daniel Lackland, DrPH, FAHA Judith H. Lichtman, PhD, MPH, FAHA Lynda Lisabeth, PhD, MPH, FAHA Simin Liu, MD, ScD, FAHA Chris T. Longenecker, MD Rachel H. Mackey, PhD, MPH, FAHA Kunihiro Matsushita, MD, PhD, FAHA Dariush Mozaffarian, MD, DrPH, FAHA Michael E. Mussolino, PhD, FAHA Khurram Nasir, MD, MPH, FAHA Robert W. Neumar, MD, PhD, FAHA Latha Palaniappan, MD, MS, FAHA Dilip K. Pandey, MBBS, MS, PhD, FAHA Ravi R. Thiagarajan, MD, MPH Mathew J. Reeves, PhD Matthew Ritchey, PT, DPT, OCS, MPH Carlos J. Rodriguez, MD, MPH, FAHA Gregory A. Roth, MD, MPH Wayne D. Rosamond, PhD, FAHA Comilla Sasson, MD, PhD, FAHA Amytis Towfighi, MD Connie W. Tsao, MD, MPH Melanie B. Turner, MPH Salim S. Virani, MD, PhD, FAHA Jenifer H. Voeks, PhD Joshua Z. Willey, MD, MS John T. Wilkins, MD Jason HY. Wu, MSc, PhD, FAHA Heather M. Alger, PhD Sally S. Wong, PhD, RD, CDN, FAHA Paul Muntner, PhD, MHSc On behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart Disease and Stroke Statistics—2017 Update

Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association

https://vascular.stanford.edu/content/dam/sm/vascular/documents/endovasc/guidelines/PIIS0741521406022968.pdf

Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)

Author(s): Writing Group Members; Mozaffarian, Dariush; Benjamin, Emelia J; Go, Alan S; Arnett, Donna K; Blaha, Michael J; Cushman, Mary; Das, Sandeep R; de Ferranti, Sarah; Despres, Jean-Pierre; Fullerton, Heather J; Howard, Virginia J; Huffman, Mark D; Isasi, Carmen R; Jimenez, Monik C; Judd, Suzanne E; Kissela, Brett M; Lichtman, Judith H; Lisabeth, Lynda D; Liu, Simin; Mackey, Rachel H; Magid, David J; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Muntner, Paul; Mussolino, Michael E; Nasir, Khurram; Neumar, Robert W; Nichol, Graham; Palaniappan, Latha; Pandey, Dilip K; Reeves, Mathew J; Rodriguez, Carlos J; Rosamond, Wayne; Sorlie, Paul D; Stein, Joel; Towfighi, Amytis; Turan, Tanya N; Virani, Salim S; Woo, Daniel; Yeh, Robert W; Turner, Melanie B; American Heart Association Statistics Committee; Stroke Statistics Subcommittee

Heart Disease and Stroke Statistics—2016 Update: A Report From the American Heart Association

A simulation curriculum for laparoscopic common bile duct exploration, balloon sphincterotomy, and endobiliary stenting: Associations with resident performance and autonomy in the operating room.

Background Abdominal aortic aneurysms (AAA) are characterized by vascular inflammation and remodeling that can lead to aortic rupture resulting in significant mortality. Pannexin-1 channels on endothelial cells (ECs) can modulate ATP secretion to regulate the pathogenesis of AAA formation. Our hypothesis focused on potential of spironolactone to inhibit EC-mediated ATP release for the mitigation of AAA formation. Methods A topical elastase AAA model was used initially in C57BL/6 (wild-type; WT) male mice. Mice were administered either a vehicle control (saline) or spironolactone and analyzed on day 14. In a second chronic AAA model, mice were subjected to elastase and β-aminopropionitrile (BAPN) treatment with/without administration of spironolactone to pre-formed aneurysms starting on day 14 and analyzed on day 28. Aortic diameter was evaluated by video micrometry and aortic tissue was analyzed for cytokine expression and histology. ATP measurement and matrix metalloproteinase (MMP2) activity was evaluated in aortic tissue on days 14 or -28. In vitro studies were performed to evaluate the crosstalk between aortic ECs with macrophages or smooth muscle cells. Results In the elastase AAA model, spironolactone treatment displayed a significant decrease in aortic diameter compared to elastase-treated controls on day 14. A significant increase in smooth muscle α-actin expression as well as decrease in elastic fiber disruption and immune cell (macrophages and neutrophils) infiltration was observed in mice treated with spironolactone compared to saline-treated controls. Spironolactone treatment also significantly mitigated pro-inflammatory cytokine expression, MMP2 activity and ATP content in aortic tissue compared to controls. Moreover, in the chronic AAA model, spironolactone treatment of pre-formed aneurysms significantly attenuated vascular inflammation and remodeling to attenuate the progression of AAAs compared to controls. Mechanistically, in vitro data demonstrated that spironolactone treatment attenuates extracellular ATP release from endothelial cells to mitigate macrophage activation (IL-1β and HMGB1 expression) and smooth muscle cell-dependent vascular remodeling (MMP2 activity). Conclusion These results demonstrate that spironolactone can mitigate aortic inflammation and remodeling to attenuate AAA formation as well as decrease growth of pre-formed aneurysms via inhibition of EC-dependent ATP release. Therefore, this study implicates a therapeutic application of spironolactone in the treatment of AAAs.

/pdf/pharmacologic-inhibition-by-spironolactone-attenuates-3g1o946d.pdf

Pharmacologic inhibition by spironolactone attenuates experimental abdominal aortic aneurysms

chapter 36 – Endovascular Therapy

Background: Regulatory T cells (Tregs) suppress in ﬂ ammation in atherosclerosis, and therefore have the therapeutic potential to decrease the risk of myocardial infarction and stroke. However, there is currently no method to generate antigen speci ﬁ c Tregs that target atherosclerosis. We therefore engineered Tregs that express a chimeric antigen receptor (CAR) targeting malonaldehyde-modi ﬁ ed low-density lipoprotein cholesterol (MDA-LDL), the most common form of oxidized LDL and a key mo- lecular component of atherosclerosis. Methods: Novel single chain variable fragments (scFv) were synthesized using sequences from antibodies targeting human MDA-LDL. Oxidized-LDL speci ﬁ c CARs (ox-CARs) were subsequently engineered by fusing each scFv to an IgG4 hinge, CD28 transmembrane, and CD28/CD3z cyto-plasmic domains. CD4 + CD25 + CD127 low/ e Tregs were puri ﬁ ed from human blood via ﬂ uorescent activated cell sorting and lentivirally transduced to express the novel ox-CARs (ox-CAR-Tregs). Human atherosclerotic pla- ques were obtained from patients undergoing carotid endarterectomy. Autologous ox-CAR-Tregs were analyzed for activation after ex vivo co- culture with carotid endarterectomy samples. Results: A rationally designed panel of 42 ox-CARs were engineered us- ing scFv derived from 12 antibodies targeting MDA-LDL. We ﬁ rst assessed CAR expression and activation in Jurkat T cells to identify promising ox- CAR variants for further evaluation in human Tregs. After culture in the presence of MDA-LDL, six ox-CAR-Treg variants consistently showed sig- ni ﬁ cant activation, compared with controls, based on CD71 expression, cytokine expression, and proliferation in the absence of CD3/28 stimula- tion. Human atherosclerotic samples were identi ﬁ ed to have substantial amounts of MDA-LDL epitopes using immunohistochemistry. Autologous ox-CAR-Tregs showed a dose-dependent increase in CD71 expression after ex vivo co-culture with atherosclerotic plaque. Conclusions: An optimized CAR targeting MDA-LDL activates Tregs when cultured with human atherosclerotic plaque ex vivo Q10 . Biotherapeutics; Background: The critical role for chronic in ﬂ ammation in the develop- ment ofthoracic aortic aneurysmsand dissections (TAADs) has beenrecog-nized in both experimental and clinical settings. However, challenges remain on translating this knowledge to clinical applications. In this study, we tested the hypothesis that TLR-7 signaling triggered by self-RNAs sub- stantiates chronic in ﬂ ammation, promoting TAAD formation. Methods: A mouse TAAD model induced by SMC-speci ﬁ c deletion of Tgfbr1(Tgfbr1 TLR-7 ligand. Finally, treatment with the TLR-7 speci ﬁ c inhibitor, M5049, at a dose of 1.0 or 5.0 mg/kg/day via oral gavage prevented dilation of TAADs at four weeks compared with vehicle controls (9% vs 8% vs 23%; P < .001). Conclusions: Self-RNAs released from stressed and dying cells is associ- ated with chronically in ﬂ amed aortic tissue and promotes TAAD develop-ment via triggering TLR-7 signaling. Blocking TLR-7 signaling may represent a novel strategy to treat human TAADs. . Background: A central role of vascular smooth muscle cells (SMCs) in atherosclerosis has recently evolved that suggests causal genetic links to disease processes. Single cell sequencing studies of atherosclerotic plaques have identi ﬁ ed multiple mesenchymal transition cell populations within the plaques. Here, we correlated cell fractions from plaques to coronary artery disease (CAD) related gene polymorphisms to identify novel SMC targets and study their in ﬂ uence on SMC function in atherosclerosis. Methods: Deconvolution analysis was performed on bulk microarray data from carotid plaques in the Biobank of Karolinska Endarterectomies (BiKE; n ¼ 127) using single cell sequencing data from coronary plaques (n ¼ 5). CAD-associated genome-wide association studies loci associated with mesenchymal cell fractions were identi ﬁ ed, followed by functional analyses of these genes in SMC in vitro using migration, proliferation and apoptosis assays. Results: We identi ﬁ ed ﬁ ve mesenchymal cell-speci ﬁ c genetic variants associated with CAD, BiKE patient symptomatology, and gene expression quantitative trait loci in BiKE plaque tissue and GTex normal arteries. These variants were harbored in genetic loci of ARNTL, LDLR, MIA3, PAK1, and ARHGAP15. Microarray analysis revealed increased expression of ARHGAP15and PAK1and decreased levels of LDLRin carotid plaques compared with normal arteries (n ¼ 127 vs 10 respectively, Student ttest). Immunohistochemistry demonstrated increased expression of corre- sponding proteins in the ﬁ brous cap of plaques compared with normal arteries (n ¼ 5). To investigate their function in SMCs, the genes were silenced using small interfering RNAs followed by migration, proliferation, and apoptosis assays. Preliminary results indicated that silencing of MIA3, LDLR, and ARNTLinhibited SMC proliferation. Conclusions: The results of this project may reveal novel SMC-speci ﬁ c genetic links to the disease, which may serve as therapeutic targets to be explored for improved treatment of atherosclerosis. Disclosures: Narayanan: Quertermous: 22-VIRC-504-AHA-VD vesicles nano-sized RNAs, intercellular novel AAA therapies. EVs from human AAA tissue control aortic punch biopsies and pro ﬁ led EV content with microRNA (miRNA) sequencing to identify dysregulated pathways. Methods: The study was approved by the University Health Network Research Ethics Board. EVs were isolated from human AAA or aortic punch tissue and enriched using size exclusion chromatography (qEVoriginal columns 70 nm, Izon Science Ltd.) (n ¼ 3). EV size and concentration were determined using nanoparticle tracking analysis (NanoSight NS300, Malvern Panalytical Ltd.). EV-miRNA sequencing was performed with Illumina NextSeq (HTG Molecular Diagnostics Inc.) and analyzed using Partek Genomics Suite (v.10) and MIENTURNET (19-11-25). Results: Patients were selected for infrarenal AAA requiring surgical repair (AAA) or coronary artery disease requiring bypass graft surgery (control). EV size and concentration were con ﬁ rmed with nanoparticle tracking analysis. Principal components and gene set analyses revealed distinct clustering of tissue types with 901 and 687 miRNAs enriched in AAA and control samples, respectively. Pathway prediction using estab-lished AAA miRNAs (eg, miR-122, miR-146a, and miR-503) identi ﬁ ed sig- ni ﬁ cant interactions with proaneurysmal signaling pathways (eg, PI3K-AKT, JAK-STAT, and HIF-1) as well as cell senescence and adhesion pro- cesses (false discovery rate of < 0.05). EV-derived AAA tissue. Further investigation will explore EV-miRNAs as mediators of communication between distinct vascular cell populations that contribute to AAA development. with 11 lncRNAs being signi ﬁ cantly enriched in different smooth muscle cell clusters. We found all newly identi ﬁ ed lncRNAs conserved in our scRNA-seq datasets of genetically mutated (LDLR e / e ) Yucatan mini-pigs and the inducible carotid artery plaque rupture mice (ApoE e / e ). The cluster-de ﬁ ning genes from the human scRNA-seq data were then located in human carotid artery tissue sections using the hybridization-JVS

22-VIRC-451-AHA-VD A Chimeric Antigen Receptor Targeting Malonaldehyde-modi ﬁ ed Low-density lipoprotein Cholesterol Activates Regulatory T Cells in the Presence of Human Atherosclerotic Plaque Inhibition of TLR-7 Signaling Attenuates Thoracic Aortic Aneurysms and Dissection Formation

T here are a number of sources of funding available to surgical faculty to support research. Most research grants to the surgical faculty come from governmental funding agencies. Private industry, foundations, and professional societies form the bulk of additional sources of funding. Although clinical margins have decreased, research support generated from clinical revenue remains an important mechanism for research funding in most departments of surgery. Biomedical research in the United States is an approximately $100 billion a year enterprise. About two-thirds of biomedical research is performed by private industry. Governmental agencies and private foundations account for approximately one-third of biomedical research funding and foundations represent only about 5%. However, when compared to the healthcare market, biomedical research accounts for <5% of all health-related expenditures. In addition, less than one-tenth of 1% supports investigation into health services, comparative effectiveness, best practices, or quality outcomes, which is an area of investigation that surgeons can provide meaningful results.

Gilbert R. Upchurch

Papers

A simulation curriculum for laparoscopic common bile duct exploration, balloon sphincterotomy, and endobiliary stenting: Associations with resident performance and autonomy in the operating room.

Pharmacologic inhibition by spironolactone attenuates experimental abdominal aortic aneurysms

chapter 36 – Endovascular Therapy

22-VIRC-451-AHA-VD A Chimeric Antigen Receptor Targeting Malonaldehyde-modi ﬁ ed Low-density lipoprotein Cholesterol Activates Regulatory T Cells in the Presence of Human Atherosclerotic Plaque Inhibition of TLR-7 Signaling Attenuates Thoracic Aortic Aneurysms and Dissection Formation

Presidential Forum Discussion: Development of Surgical Scientists.