A.J. Pedroza

All Publications

• A top-down approach to perfusing the dissected aorta. The Annals of thoracic surgery Pedroza, A. J., Woo, Y. J. 2026

  View details for DOI 10.1016/j.athoracsur.2025.12.043

  View details for PubMedID 41577318

• Ross after David: Management of the fused plane between the prior reimplantation valve-sparing aortic root replacement and the pulmonary autograft JTCVS TECHNIQUES Pedroza, A. J., Shou, B., Bustos, M., Liou, K., Woo, Y. 2025; 34: 84-87

  View details for DOI 10.1016/j.xjtc.2025.08.017

  View details for Web of Science ID 001630141800001

• Ross after David: Management of the fused plane between the prior reimplantation valve-sparing aortic root replacement and the pulmonary autograft. JTCVS techniques Pedroza, A. J., Shou, B., Bustos, M., Liou, K., Woo, Y. J. 2025; 34: 84-87

  View details for DOI 10.1016/j.xjtc.2025.08.017

  View details for PubMedID 41368402

  View details for PubMedCentralID PMC12683042

• Single Cell and Spatial Transcriptomics Identify Novel Immune-Stromal Interactions in Cardiac Allograft Vasculopathy. Research square Owen, M. C., Li, D. Y., Shin, H., Gu, W., Parvathaneni, A., Kadyrov, F. F., Wang, X., Sticco-Ivins, M., Bonnici, G., Nelson, S. L., Dun, H., Hyacinth, S., Cain, M. T., Pedroza, A., Dalal, A., Sallam, K., Boyd, J., Woo, J., Amrute, J. M., Cheng, P., Lavine, K. J., Kopecky, B. J. 2025

  Abstract

  Cardiac allograft vasculopathy (CAV) is the leading cause of mortality in heart transplant recipients. Despite the prevalence of CAV, there are no targeted therapeutic options to prevent or reverse disease progression, and patients ultimately require retransplant. CAV is defined by progressive neointimal hyperplasia in donor heart coronary arteries, leading to luminal obliteration and ultimately allograft failure or sudden cardiac death. Although immune and stromal cell interactions are believed to play a key role in CAV pathogenesis, the specific cellular players and molecular signals driving disease remain undefined. In this study, we leverage single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to transcriptionally characterize CAV and define the neointimal microenvironment. We compare arteries with CAV to atherosclerotic coronary artery disease and non-disease controls to identify a unique CAV transcriptional signature. Integration of single-cell RNA sequencing and spatial transcriptomic datasets revealed that modulated vascular smooth muscle cells and macrophage subsets dominate the CAV neointima and suggest that these cells interact to propagate type 1 interferon (IFN)-mediated inflammation. In a mouse CAV model, we demonstrate that interferon blockade with Ruxolitinib significantly reduced the incidence of CAV and prolonged allograft survival. Collectively, this study offers a novel and detailed characterization of the unique cellular and transcriptional landscape of CAV and identify a candidate pathway that may underly CAV pathogenesis, which could serve as a new therapeutic target for this devastating disease.

  View details for DOI 10.21203/rs.3.rs-7812112/v1

  View details for PubMedID 41333445

  View details for PubMedCentralID PMC12668176

• The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci Weldy, C., Kundu, S., Monteiro, J., Gu, W., Pedroza, A., Dalal, A., Worssam, M., Li, D., Palmisano, B., Zhao, Q., Sharma, D., Nguyen, T., Kundu, R., Fischbein, M., Engreitz, J., Kundaje, A., Cheng, P., Quertermous, T. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1161/circ.152.suppl_3.4358524

  View details for Web of Science ID 001613911000034

• A cell and transcriptome atlas of human arterial vasculature. Cell genomics Zhao, Q., Pedroza, A., Sharma, D., Gu, W., Dalal, A., Weldy, C., Jackson, W., Li, D. Y., Ryan, Y., Nguyen, T., Shad, R., Palmisano, B. T., Monteiro, J. P., Worssam, M., Berezwitz, A., Iyer, M., Shi, H., Kundu, R., Limbu, L., Kim, J. B., Kundaje, A., Fischbein, M., Wirka, R., Quertermous, T., Cheng, P. 2025: 101034

  Abstract

  Arterial segments show differing disease propensities, yet mechanisms remain unknown. We compiled a transcriptomic and spatial atlas of healthy human arterial cells across multiple segments to understand these differences. Arteries demonstrated a stereotyped pattern of cell-specific, segmental heterogeneity not captured by common marker genes. Arterial identities are encoded in fibroblast and smooth muscle cell (SMC) transcriptomes. Differentially expressed genes enrich for disease loci. Fibroblast gene expression enriches for a disproportionate number of disease loci, highlighting an underrecognized role for fibroblasts in disease risk. Cells of different segments cluster more by embryonic origin than anatomy. Global analysis of disease regulons in fibroblasts and SMCs identified developmental transcription factors that persist into adulthood, suggesting a functional role of these factors in disease. Lastly, the heterogeneity of non-coding transcriptomes rivals that of protein-coding transcriptomes. Differentially expressed lncRNAs enrich for genetic signals for vascular diseases, suggesting a role for lncRNAs in vascular disease.

  View details for DOI 10.1016/j.xgen.2025.101034

  View details for PubMedID 41086809

• Ex vivo optimization of a bicuspid pulmonary valve using the resequenced composite autograft Ross technique. JTCVS techniques Pedroza, A. J., Shou, B., Woo, Y. J. 2025; 33: 75-78

  View details for DOI 10.1016/j.xjtc.2025.07.005

  View details for PubMedID 41112433

  View details for PubMedCentralID PMC12529671

• Ex vivo optimization of a bicuspid pulmonary valve using the resequenced composite autograft Ross technique JTCVS TECHNIQUES Pedroza, A. J., Shou, B., Woo, Y. 2025; 33: 75-78

  View details for DOI 10.1016/j.xjtc.2025.07.005

  View details for Web of Science ID 001588856200015

• Epigenomic landscape of single vascular cells reflects developmental origin and disease risk loci. Molecular systems biology Weldy, C. S., Kundu, S., Monteiro, J., Gu, W., Pedroza, A. J., Dalal, A. R., Worssam, M. D., Li, D., Palmisano, B., Zhao, Q., Sharma, D., Nguyen, T., Kundu, R., Fischbein, M. P., Engreitz, J., Kundaje, A. B., Cheng, P. P., Quertermous, T. 2025

  Abstract

  Vascular sites have distinct susceptibility to atherosclerosis and aneurysm, yet the epigenomic and transcriptomic underpinning of vascular site-specific disease risk is largely unknown. Here, we performed single-cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of mouse vascular tissue from three vascular sites. Through interrogation of epigenomic enhancers and gene regulatory networks, we discovered key regulatory enhancers to not only be cell type, but vascular site-specific. We identified epigenetic markers of embryonic origin including developmental transcription factors such as Tbx20, Hand2, Gata4, and Hoxb family members and discovered transcription factor motif accessibility to be vascular site-specific for smooth muscle, fibroblasts, and endothelial cells. We further integrated genome-wide association data for aortic dimension, and using a deep learning model to predict variant effect on chromatin accessibility, ChromBPNet, we predicted variant effects across cell type and vascular site of origin, revealing genomic regions enriched for specific TF motif footprints-including MEF2A, SMAD3, and HAND2. This work supports a paradigm that cell type and vascular site-specific enhancers govern complex genetic drivers of disease risk.

  View details for DOI 10.1038/s44320-025-00140-2

  View details for PubMedID 40931195

  View details for PubMedCentralID 3357908

• Loeys-Dietz syndrome subtypes exhibit distinct clinical behavior and aortic cellular transcriptomic profiles. JTCVS open Pedroza, A. J., Dalal, A. R., Kim, J., Duda, M., Tognozzi, E., Gilles, C., Miller, D. C., Fischbein, M. P. 2025; 26: 1-14

  Abstract

  Loeys-Dietz syndrome comprises genetically discrete subtypes of varying clinical severity. This study integrates longitudinal Loeys-Dietz syndrome clinical outcomes after aortic root replacement with transcriptomic analysis of aortic smooth muscle cell dysregulation to investigate mechanisms governing this subtype-specific aortic vulnerability.Single institutional experience with aortic root replacement for nondissected aneurysm in patients with Loeys-Dietz syndrome was reviewed for midterm survival and distal aortic events (subsequent aortic intervention, aneurysm, or dissection). Single-cell RNA sequencing was performed using fresh aortic aneurysm tissue to compare smooth muscle cell phenotypes between patients with TGFBR1/2 and SMAD3 variants.A total of 62 patients with Loeys-Dietz syndrome were identified, including 59 genetically confirmed (n = 36 TGFBR1/2, n = 16 SMAD3, and n = 7 TGFB2/TGFB3). Valve-sparing operations were performed in 54 patients, 8 patients underwent composite root replacement operations, and 19 patients underwent concomitant arch replacement. Median follow-up was 6.16 years (interquartile range, 2.88-10.82). Estimated 5- and 10-year survivals for TGFBR1/2 patients were 97% (99%-82%) and 86% (96%-61%), respectively, and estimated incidence of aortic events at 5- and 10-year follow-up was 17% (7%-36%) and 28% (14%-51%), respectively. For SMAD3 patients, estimated survival was 94% (99%-63%) at both 5 and 10 years, and estimated incidence of aortic events at both 5- and 10-year follow-ups was 0%. Single-cell RNA sequencing analysis (n = 3 TGFBR1/2, n = 5 SMAD3) demonstrated altered smooth muscle cell phenotype modulation patterns, with greater retention of contractile gene expression, enriched collagen, and integrin receptor expression in TGFBR1/2 smooth muscle cells, whereas SMAD3 patients showed activation of osteochondrogenic matrix components (TNFRSF11B, CYTL1) and inflammatory pathways.Loeys-Dietz syndrome subtypes may demonstrate variable clinical outcomes after aortic root replacement. Distinct gene dysregulation patterns suggest varying smooth muscle cell-extracellular matrix interactions may participate in clinical variation.

  View details for DOI 10.1016/j.xjon.2025.06.013

  View details for PubMedID 40923070

  View details for PubMedCentralID PMC12414420

• Comprehensive Analysis of Myocardial Reverse Remodeling Following HeartWare Ventricular Assist Device Implantation CLINICAL TRANSPLANTATION Kawai, Y., Farag, J. A., Nishiga, M., Liu, Y., Kawago, K., Koyano, T. K., Fong, R., Bilbao, M., Hiesinger, W., Shin, H., Pfrender, E. M., Dalal, A., Pedroza, A. J., Boyd, J. H., Woo, Y., Shudo, Y. 2025; 39 (8)

  View details for DOI 10.1111/ctr.70245

  View details for Web of Science ID 001537569900001

• Immature Acta2R179C/+ smooth muscle cells cause moyamoya-like cerebrovascular lesions in mice prevented by boosting OXPHOS. Nature communications Kaw, A., Majumder, S., Esparza Pinelo, J. E., Wu, T., Starosolski, Z., Zhou, Z., Pedroza, A. J., Duan, X., Kaw, K., Gonzalez, A. D., Sarkar, R., Fischbein, M. P., Lorenzi, P. L., Tan, L., Martinez, S. A., Mahmud, I., Devkota, L., Buja, L. M., Taegtmeyer, H., Ghaghada, K. B., Marrelli, S. P., Kwartler, C. S., Milewicz, D. M. 2025; 16 (1): 6105

  Abstract

  ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusions of the distal internal carotid arteries, but the mechanisms of pathogenesis are unknown and no preventive treatments exist. Here we show that Acta2R179C/+ smooth muscle cells (SMCs) fail to fully differentiate and maintain stem cell-like features, including increased migration and glycolytic flux compared to wildtype (WT) SMCs. Increasing mitochondrial respiration with nicotinamide riboside (NR) drives differentiation and decreases migration of Acta2R179C/+ SMCs. Carotid artery injury of Acta2SMC-R179C/+ mice leads to premature death, intraluminal SMC accumulation leading to MMD-like occlusive lesions, neurologic symptoms, and neuron loss, whereas injured WT mice have none of these phenotypes, and all are prevented by NR treatment in the Acta2SMC-R179C/+ mice. These data show that driving differentiation and quiescence of Acta2R179C/+ SMCs by altering cellular metabolism attenuates MMD-like disease in the Acta2SMC-R179C/+ mice, highlighting a role of immature and highly migratory SMCs in the pathogenesis of MMD.

  View details for DOI 10.1038/s41467-025-61042-3

  View details for PubMedID 40603847

  View details for PubMedCentralID PMC12223207

• Angiosarcoma Beneath a Bleeding Aneurysmal Veil. JACC. Case reports Fereydooni, A., George, E. L., Pedroza, A. J., Miller, D. C., Liang, D. H., Stern, J. R. 2025; 30 (13): 103548

  Abstract

  Angiosarcoma is a rare and aggressive vascular tumor that often presents diagnostic and therapeutic challenges. Its potential for misdiagnosis emphasizes the importance of a multidisciplinary approach.A 54-year-old man with Loeys-Dietz syndrome and a history of popliteal artery aneurysm treated with surgical exclusion and autologous vein bypass presented with a recurrent hemorrhage from the popliteal fossa. Despite repeated surgical resection and embolization, persistent bleeding led to diffuse alveolar hemorrhage and respiratory failure. Autopsy confirmed metastatic angiosarcoma with bilateral lung involvement.Angiosarcoma is often misdiagnosed due to nonspecific symptoms and overlapping features with benign vascular conditions. This report highlights the rarity, aggressive nature, metastatic potential, and clinically intricate management of popliteal angiosarcoma.This case underscores the importance of considering angiosarcoma in unusual cases of aneurysmal hemorrhage and the need for comprehensive pathology and a multidisciplinary approach for early detection and treatment.

  View details for DOI 10.1016/j.jaccas.2025.103548

  View details for PubMedID 40480758

• The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci. bioRxiv : the preprint server for biology Weldy, C. S., Kundu, S., Monteiro, J., Gu, W., Pedroza, A. J., Dalal, A. R., Worssam, M. D., Li, D., Palmisano, B., Zhao, Q., Sharma, D., Nguyen, T., Kundu, R., Fischbein, M. P., Engreitz, J., Kundaje, A. B., Cheng, P. P., Quertermous, T. 2025

  Abstract

  Vascular sites have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinning of vascular site-specific disease risk is largely unknown. Vascular tissues have different developmental origins that may influence global chromatin accessibility, and understanding differential chromatin accessibility, gene expression profiles, and gene regulatory networks (GRN) on single cell resolution may give key insight into vascular site-specific disease risk. Here, we performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular sites, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. Through a comprehensive analysis at single cell resolution, we discovered key regulatory enhancers to not only be cell type, but vascular site specific in vascular smooth muscle (SMC), fibroblasts, and endothelial cells. We identified epigenetic markers of embryonic origin with differential chromatin accessibility of key developmental transcription factors such as Tbx20, Hand2, Gata4, and Hoxb family members and discovered transcription factor motif accessibility to be cell type and vascular site specific. Notably, we found ascending fibroblasts to have distinct epigenomic patterns, highlighting SMAD2/3 function to suggest a differential susceptibility to TGFβ, a finding we confirmed through in vitro culture of primary adventitial fibroblasts. Finally, to understand how vascular site-specific enhancers may regulate human genetic risk for disease, we integrated genome wide association study (GWAS) data for ascending and descending aortic dimension, and through using a distinct base resolution deep learning model to predict variant effect on chromatin accessibility, ChromBPNet, to predict variant effects in SMC, Fibroblasts, and Endothelial cells within ascending aorta, carotid, and descending aorta sites of origin. We reveal that although cell type remains a primary influence on variant effects, vascular site modifies cell type transcription and highlights genomic regions that are enriched for specific TF motif footprints - including MEF2A, SMAD3, and HAND2. This work supports a paradigm that the epigenomic and transcriptomic landscape of vascular cells are cell type and vascular site-specific and that site-specific enhancers govern complex genetic drivers of disease risk.

  View details for DOI 10.1101/2022.05.18.492517

  View details for PubMedID 40655014

  View details for PubMedCentralID PMC12247710

• Concurrent aortic valve replacement and splenectomy for Q-fever endocarditis with massive splenomegaly and pancytopenia. JTCVS techniques Weininger, G., Pedroza, A. J., Shou, B. L., Forrester, J. D., Lin, Y. 2025; 30: 73-76

  View details for DOI 10.1016/j.xjtc.2025.01.021

  View details for PubMedID 40242106

  View details for PubMedCentralID PMC11998301

• Chemokine (C-C Motif) Ligand 2 Expressing Adventitial Fibroblast Expansion During Loeys-Dietz Syndrome Aortic Aneurysm Formation. Arteriosclerosis, thrombosis, and vascular biology Dalal, A. R., Pedroza, A. J., Kim, J., Gilles, C., Gu, W., Kusadokoro, S., Shad, R., Mitchel, O., Jackson, W., Hiesinger, W., Berry, G., Gallo MacFarlane, E., Quertermous, T., Cheng, P., Fischbein, M. P. 2025

  Abstract

  Loeys-Dietz syndrome (LDS), caused by mutations in the TGF-β (transforming growth factor-β) signaling cascade, leads to aggressive thoracic aneurysms. While vascular smooth muscle cell (SMC) phenotype modulation has been implicated in thoracic aneurysm formation, we sought to characterize the role of cell state transitions in LDS aneurysm pathogenesis.We performed single-cell transcriptomic characterization of aortic root/ascending aorta from a murine LDS model (Tgfbr2G357W/+ versus littermate WT [wild-type] control) at 8 weeks, 24 weeks, and aortic root/ascending aortic samples from human LDS surgical specimens (n=5 LDS [TGFBR1/2] and n=2 donor control) to understand cell state transitions and transcriptomic alterations in LDS. Select cell markers were spatially localized with RNA in situ hybridization, immunofluorescence, and immunohistochemistry. Single-cell RNA sequencing of murine and human LDS samples (>30 000 cells) revealed unique SMC, fibroblast, and macrophage transcriptomic profiles in LDS.Instead of SMC phenotypic modulation seen in Marfan syndrome, transcriptomic alterations observed in LDS are most prominent in the adventitial fibroblast in the Tgfbr2G357W/+ mouse model. While a distinct modulated SMC cluster does not appear in Tgfbr2G357W/+, SMCs transcriptomically differ from WT counterparts. Adventitial fibroblasts were activated into a proinflammatory state associated with increased macrophage recruitment (Ccl2, Il6, Ccl7, and Cxcl2) and fibrotic response genes (Col1a1, Col1a2, and Col3a1), with a 6-fold increase in aortic wall macrophage content in Tgfbr2G357W/+ compared with WT. Similar findings were also observed in human LDS aortic samples with increased proinflammatory adventitial fibroblast transcriptomic program in parallel with heightened macrophage recruitment.Despite phenotypic similarities in aneurysm formation, the dominant cellular and molecular mechanism of Marfan syndrome and LDS aneurysms are distinct. LDS mouse and human adventitial fibroblasts transcriptomically modulate into a proinflammatory state. Adventitial fibroblasts, in addition to SMCs, are another important pathological cell population during LDS aneurysm formation to consider for targeted therapy to potentially impede LDS aneurysm formation.

  View details for DOI 10.1161/ATVBAHA.124.322069

  View details for PubMedID 40109260

• Heart and heart-lung transplantation with orthotopic pulmonary artery reconstruction to reverse Lecompte maneuver. JTCVS techniques Reed, A. K., Pedroza, A. J., Woo, Y. J. 2025; 29: 91-93

  View details for DOI 10.1016/j.xjtc.2024.10.017

  View details for PubMedID 39991277

  View details for PubMedCentralID PMC11845384

• Heart and heart-lung transplantation with orthotopic pulmonary artery reconstruction to reverse Lecompte maneuver JTCVS TECHNIQUES Reed, A. K., Pedroza, A. J., Woo, Y. 2025; 29: 91-93

  View details for DOI 10.1016/j.xjtc.2024.10.017

  View details for Web of Science ID 001417008600001

• Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model. Nature cardiovascular research Bramel, E. E., Espinoza Camejo, W. A., Creamer, T. J., Restrepo, L., Saqib, M., Bagirzadeh, R., Zeng, A., Mitchell, J. T., Stein-O'Brien, G. L., Pedroza, A. J., Fischbein, M. P., Dietz, H. C., Gallo MacFarlane, E. 2024

  Abstract

  Loeys-Dietz syndrome (LDS) is a connective tissue disorder caused by mutations that decrease transforming growth factor-β signaling. LDS-causing mutations increase the risk of aneurysm throughout the arterial tree, yet the aortic root is a site of heightened susceptibility. Here we investigate the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1M318R/+ LDS mice by single-cell transcriptomics to identify molecular determinants of this vulnerability. Reduced expression of components of the extracellular matrix-receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4-expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human single-cell RNA sequencing dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired transforming growth factor-β signaling.

  View details for DOI 10.1038/s44161-024-00562-5

  View details for PubMedID 39567770

  View details for PubMedCentralID 4131122

• Intrinsic Gata4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model. Research square Bramel, E. E., Camejo, W. A., Creamer, T. J., Restrepo, L., Saqib, M., Bagirzadeh, R., Zeng, A., Mitchell, J. T., Stein-O'Brien, G. L., Pedroza, A. J., Fischbein, M. P., Dietz, H. C., MacFarlane, E. G. 2024

  Abstract

  Loeys-Dietz syndrome (LDS) is an aneurysm disorder caused by mutations that decrease transforming growth factor-β (TGF-β) signaling. Although aneurysms develop throughout the arterial tree, the aortic root is a site of heightened risk. To identify molecular determinants of this vulnerability, we investigated the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1 M318R/+ LDS mice by single cell and spatial transcriptomics. Reduced expression of components of the extracellular matrix-receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4-expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human scRNAseq dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired TGF-β signaling.

  View details for DOI 10.21203/rs.3.rs-4420617/v1

  View details for PubMedID 38883722

  View details for PubMedCentralID PMC11177966

• Comprehensive Integration of Multiple Single-Cell Transcriptomic Datasets Defines Distinct Cell Populations and Their Phenotypic Changes in Murine Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology Sharma, D., DeForest Worssam, M., Pedroza, A. J., Dalal, A. R., Alemany, H., Kim, H. J., Kundu, R., Fischbein, M., Cheng, P., Wirka, R., Quertermous, T. 2023

  Abstract

  The application of single-cell transcriptomic (single-cell RNA sequencing) analysis to the study of atherosclerosis has provided unique insights into the molecular and genetic mechanisms that mediate disease risk and pathophysiology. However, nonstandardized methodologies and relatively high costs associated with the technique have limited the size and replication of existing data sets and created disparate or contradictory findings that have fostered misunderstanding and controversy.To address these uncertainties, we have performed a conservative integration of multiple published single-cell RNA sequencing data sets into a single meta-analysis, performed extended analysis of native resident vascular cells, and used in situ hybridization to map the disease anatomic location of the identified cluster cells. To investigate the transdifferentiation of smooth muscle cells to macrophage phenotype, we have developed a classifying algorithm based on the quantification of reporter transgene expression.The reporter gene expression tool indicates that within the experimental limits of the examined studies, transdifferentiation of smooth muscle cell to the macrophage lineage is extremely rare. Validated transition smooth muscle cell phenotypes were defined by clustering, and the location of these cells was mapped to lesion anatomy with in situ hybridization. We have also characterized 5 endothelial cell phenotypes and linked these cellular species to different vascular structures and functions. Finally, we have identified a transcriptomically unique cellular phenotype that constitutes the aortic valve.Taken together, these analyses resolve a number of outstanding issues related to differing results reported with vascular disease single-cell RNA sequencing studies, and significantly extend our understanding of the role of resident vascular cells in anatomy and disease.

  View details for DOI 10.1161/ATVBAHA.123.320030

  View details for PubMedID 38152886

• Augmenting Mitochondrial Respiration in Immature Smooth Muscle Cells with anACTA2Pathogenic Variant Mitigates Moyamoya-like Cerebrovascular Disease. Research square Kaw, A., Wu, T., Starosolski, Z., Zhou, Z., Pedroza, A. J., Majumder, S., Duan, X., Kaw, K., Pinelo, J. E., Fischbein, M. P., Lorenzi, P. L., Tan, L., Martinez, S. A., Mahmud, I., Devkota, L., Taegtmeyer, H., Ghaghada, K. B., Marrelli, S. P., Kwartler, C. S., Milewicz, D. M. 2023

  Abstract

  ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusion of the distal internal carotid arteries. A smooth muscle cell (SMC)-specific knock-in mouse model (Acta2SMC-R179C/+) inserted the mutation into 67% of aortic SMCs, whereas explanted SMCs were uniformly heterozygous. Acta2R179C/+ SMCs fail to fully differentiate and maintain stem cell-like features, including high glycolytic flux, and increasing oxidative respiration (OXPHOS) with nicotinamide riboside (NR) drives the mutant SMCs to differentiate and decreases migration. Acta2SMC-R179C/+ mice have intraluminal MMD-like occlusive lesions and strokes after carotid artery injury, whereas the similarly treated WT mice have no strokes and patent lumens. Treatment with NR prior to the carotid artery injury attenuates the strokes, MMD-like lumen occlusions, and aberrant vascular remodeling in the Acta2SMC-R179C/+ mice. These data highlight the role of immature SMCs in MMD-associated occlusive disease and demonstrate that altering SMC metabolism to drive quiescence of Acta2R179C/+ SMCs attenuates strokes and aberrant vascular remodeling in the Acta2SMC-R179C/+ mice.

  View details for DOI 10.21203/rs.3.rs-3304679/v1

  View details for PubMedID 37886459

• Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation NATURE CARDIOVASCULAR RESEARCH Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X., Kernell, C., Wang, C., Pinelo, J., Bowen, M., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., Milewicz, D. M. 2023; 2 (10): 937-+

  View details for DOI 10.1038/s44161-023-00337-4

  View details for Web of Science ID 001125047300009

• Nuclear Smooth Muscle α-actin Participates in Vascular Smooth Muscle Cell Differentiation. Nature cardiovascular research Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X. Y., Kernell, C., Wang, C., Pinelo, J. E., Bowen, M. S., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., Milewicz, D. M. 2023; 2 (10): 937-955

  Abstract

  Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult-onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by diverse childhood-onset vascular diseases. Here we show that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors. The ACTA2 p.R179 αSMA variant shows decreased nuclear localization. Primary SMCs from Acta2 SMC-R179C/+ mice are less differentiated than WT SMCs in vitro and in vivo and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neuroectodermal progenitor cells to SMCs, and single-cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue show increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.

  View details for DOI 10.1038/s44161-023-00337-4

  View details for PubMedID 38919852

  View details for PubMedCentralID PMC11198982

• Blood transfusion in cardiac surgeries - Toward a personalized protocol. American journal of surgery Min, Y., Dalal, A. R., Pedroza, A. J., Pham, T. D., Panigrahi, A. K., Goldstone, A. B., MacArthur, J. W., Woo, Y. J., Baiocchi, M., Fischbein, M. P. 2023

  View details for DOI 10.1016/j.amjsurg.2023.07.035

  View details for PubMedID 37558518

• Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome. The Journal of thoracic and cardiovascular surgery Pedroza, A. J., Cheng, P., Dalal, A. R., Baeumler, K., Kino, A., Tognozzi, E., Shad, R., Yokoyama, N., Nakamura, K., Mitchel, O., Hiesinger, W., MacFarlane, E. G., Fleischmann, D., Woo, Y. J., Quertermous, T., Fischbein, M. P. 2023

  Abstract

  Loeys-Dietz syndrome (LDS) patients demonstrate heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement (VSARR). This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in LDS and characterizes smooth muscle cell (SMC) phenotype in LDS aneurysmal and normal-sized downstream aorta.Patients with genetically confirmed LDS (n=8) underwent prophylactic aortic arch replacement during VSARR. 4D flow magnetic resonance imaging (MRI) studies were performed in n=4 LDS patients (VSARR+arch) and compared with both contemporary Marfan syndrome patients (VSARR only, n=5) and control patients (without aortopathy, n=5). Aortic tissues from n=4 LDS patients and n=2 organ donors were processed for anatomically segmented single-cell RNA sequencing (scRNAseq) and histologic assessment.LDS VSARR+arch patients had no deaths, major morbidity, or aortic events in median 2.00 years follow-up. 4D-MRI demonstrated altered flow parameters in post-operative aortopathy patients relative to controls, but no clear deleterious changes attributable to arch replacement. Integrated analysis of aortic scRNAseq data (>49,000 cells) identified a continuum of abnormal SMC phenotypic modulation in LDS defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These 'modulated SMCs' populated the LDS tunica media with gradually reduced density from the overtly aneurysmal root to the non-dilated arch.LDS patients demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant VSARR+arch operations. Abnormal SMC-mediated aortic remodeling occurs within the normal diameter, clinically at-risk LDS arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in LDS.

  View details for DOI 10.1016/j.jtcvs.2023.07.023

  View details for PubMedID 37500053

• Smooth Muscle Cell Klf4 Expression Is Not Required for Phenotype Modulation or Aneurysm Formation in Marfan Syndrome Mice. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Dalal, A. R., Shad, R., Yokoyama, N., Nakamura, K., Mitchel, O., Gilles, C., Hiesinger, W., Fischbein, M. P. 2023

  Abstract

  BACKGROUND: Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified Klf4 as a potential mediator of SMC plasticity in MFS.METHODS: MFS (Fbn1C1041G/+) mouse strains with an inducible vascular SMC fluorescent reporter (MFSSMC) with or without SMC-specific deletion of Klf4 exons 2 to 3 (MFSSMC-Klf4Delta) were generated. Simultaneous SMC tracing and Klf4 loss-of-function (Klf4Delta mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4-24 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing.RESULTS: MFS mice demonstrated progressive aortic root dilatation compared with control (WTSMC) mice regardless of Klf4 genotype (P<0.001), but there was no difference in aneurysm growth in MFSSMC-Klf4Delta versus MFSSMC (P=0.884). Efficient SMC Klf4 deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg, Myh11, Cnn1) and heightened expression of matrix genes (eg, Col1a1, Fn1) between Klf4 genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that Klf4 deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in MFSSMC-Klf4Deltamice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg, Cytl1, Tnfrsf11b).CONCLUSIONS: Klf4 is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.

  View details for DOI 10.1161/ATVBAHA.122.318509

  View details for PubMedID 37128911

• Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice. Arteriosclerosis, thrombosis, and vascular biology Nakamura, K., Dalal, A. R., Yokoyama, N., Pedroza, A. J., Kusadokoro, S., Mitchel, O., Gilles, C., Masoudian, B., Leipzig, M., Casey, K. M., Hiesinger, W., Uchida, T., Fischbein, M. P. 2023

  Abstract

  To delineate the effects of integrin αv signaling in Marfan syndrome (MFS) and examine the potential efficacy of integrin αv blockade as a therapeutic strategy for MFS aneurysms.Induced pluripotent stem cells were differentiated into aortic smooth muscle cells (SMCs) of the second heart field (SHF) and neural crest lineages, enabling in vitro modeling of thoracic aortic aneurysm in MFS. Fbn1C1039G/+ MFS mice treated with integrin αv antagonist (GLPG0187) confirmed the pathological role of integrin αv on aneurysm formation.Induced pluripotent stem cell-derived MFS SHF SMCs overexpress integrin αv relative to MFS neural crest and healthy control SHF cells. Furthermore, downstream targets of integrin αv (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity in MFS SHF back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS neural crest and control SMCs, which was then inhibited by GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin αv, p-AktThr308, and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6-14 weeks) resulted in reduced aneurysm growth, elastin fragmentation, and normalization of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing.The integrin αv-FAK-AktThr308 signaling pathway is activated in induced pluripotent stem cell SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-AktThr308 signaling in Fbn1C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

  View details for DOI 10.1161/ATVBAHA.122.318448

  View details for PubMedID 37078287

• Outcomes after concomitant arch replacement at the time of aortic root surgery. JTCVS open Krishnan, A., Dalal, A. R., Pedroza, A. J., Nakamura, K., Yokoyama, N., Tognozzi, E., Woo, Y. J., Fischbein, M., MacArthur, J. W. 2023; 13: 1-8

  Abstract

  Contemporary series of aortic arch replacement at the time of aortic root surgery are limited in number of patients and mostly address hemiarch replacement. We describe outcomes after aortic root and concomitant arch replacement, including total arch replacement.This single-institution retrospective review studied 1196 consecutive patients from May 2004 to September 2020 who underwent first-time aortic root replacement. Patients undergoing surgery for endocarditis were excluded (n = 68, 5.7%). Patients undergoing concomitant root and arch replacement were propensity matched with patients undergoing isolated root surgery based on indication, clinical and operative characteristics, demographics, medical history including connective tissue disorders, and urgency. Multivariable Cox proportional hazards and logistic regression modeling were used to assess the primary outcome of all-cause mortality and the secondary outcomes of prolonged ventilator use, postoperative blood transfusion, and debilitating stroke, adjusted for patient and operative characteristics.Among the 1128 patients who underwent aortic root intervention during the study period, 471 (41.8%) underwent concomitant aortic arch replacement. Most underwent hemiarch replacement (n = 411, 87.4%); 59 patients (12.6%) underwent total arch replacement (with elephant trunk: n = 23, 4.9%; without elephant trunk: n = 36, 7.7%). The mean follow-up time was 4.6 years postprocedure. Operative mortality was 2.2%, and total mortality over the entire study period was 9.2%. Propensity matching generated 348 matches (295 concomitant hemiarch, 53 concomitant total arch). Concomitant hemiarch (hazard ratio, 1.00; 95% confidence interval, 0.54-1.86, P = .99) and total arch replacement (hazard ratio, 1.60, 95% confidence interval, 0.72-3.57, P = .24) were not significantly associated with increased mortality. Rates of stroke were not significantly different among each group: isolated root (n = 11/348, 3.7%), root + hemiarch (n = 17/295, 5.8%), and root + total arch (n = 3/53, 5.7%) replacement (P = .50), nor was the adjusted risk of stroke. Both concomitant arch interventions were associated with prolonged ventilator use and use of postoperative blood transfusions.Hemiarch and total arch replacement are safe to perform at the time of aortic root intervention, with no significant differences in survival or stroke rates, but increased ventilator and blood product use.

  View details for DOI 10.1016/j.xjon.2022.12.014

  View details for PubMedID 37063158

  View details for PubMedCentralID PMC10091289

• Blood transfusion in aortic root surgery impairs midterm survival. JTCVS open Dalal, A. R., Pedroza, A. J., Krishnan, A., Min, Y., Tognozzi, E., Yokoyama, N., Nakamura, K., Mitchel, O. R., Baiocchi, M., Woo, Y. J., MacArthur, J. W., Fischbein, M. P. 2023; 13: 9-19

  Abstract

  To evaluate the effect of perioperative allogeneic packed red blood cell (RBC) transfusion during aortic root replacement.We reviewed patients undergoing aortic root replacement at our institution between March 2014 and April 2020. In total, 760 patients underwent aortic root replacement, of whom 442 (58%) received a perioperative RBC transfusion. Propensity score matching was used to account for baseline and operative differences resulting in 159 matched pairs. All-cause mortality was assessed with Kaplan-Meier curves. Data were obtained from our institutional Society of Thoracic Surgeons database and chart review.After propensity score matching, the RBC-transfused and -nontransfused groups were similar for all preoperative characteristics. Cardiopulmonary bypass time, crossclamp time, and lowest operative temperature were similar between the transfused and nontransfused groups (standardized mean difference <0.05). RBC transfusion was associated with more frequent postoperative ventilation greater than 24 hours (36/159 [23%] vs 19/159 [12%]; P = .01), postoperative hemodialysis (9/159 [5.7%] vs 0/159 [0%]; P = .003), reoperation for mediastinal hemorrhage (9/159 [5.7%] vs 0/159 [0%]; P = .003), and longer intensive care unit and hospital length of stay (3 vs 2 days and 8 vs 6 days respectively; P < .001). Thirty-day operative mortality after propensity score matching was similar between the cohorts (1.9%; 3/159 vs 0%; P = .2), and 5-year survival was reduced in the RBC transfusion cohort (90.2% [95% confidence interval, 84.1%-96.7%] vs 97.1% [95% confidence interval, 92.3%-100%] P = .035).Aortic root replacement frequently requires RBC transfusion during and after the operation, but even after matching for observed preoperative and operative characteristics, RBC transfusion is associated with more frequent postoperative complications and reduced midterm survival.

  View details for DOI 10.1016/j.xjon.2023.01.006

  View details for PubMedID 37063152

  View details for PubMedCentralID PMC10091283

• Nuclear Smooth Muscle α-actin in Vascular Smooth Muscle Cell Differentiation. Research square Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X. Y., Kernell, C., Wang, C., Pinelo, J. E., Borthwick, M. S., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., Milewicz, D. M. 2023

  Abstract

  Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by childhood-onset diverse vascular diseases. Our data indicate that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors, and the ACTA2 p.R179 variant decreases nuclear localization of αSMA. SMCs explanted from a SMC-specific conditional knockin mouse model, Acta2SMC-R179/+, are less differentiated than WT SMCs, both in vitro and in vivo, and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neural crest cells to SMCs, and single cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue shows increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.

  View details for DOI 10.21203/rs.3.rs-1623114/v1

  View details for PubMedID 36909460

  View details for PubMedCentralID PMC10002808

• Outcomes of Reoperative Aortic Root Replacement After Previous Acute Type A Dissection Repair. Seminars in thoracic and cardiovascular surgery Pedroza, A. J., Dalal, A. R., Krishnan, A., Yokoyama, N., Nakamura, K., Tognozzi, E., Woo, Y. J., Macarthur, J. W., Fischbein, M. P. 2023

  Abstract

  Limited aortic root repair for acute type A dissection is associated with greater risk of proximal reoperations compared to full aortic root replacement. Surgical outcomes for patients undergoing reoperative root replacement after previous dissection repair are unknown. This study seeks to determine outcomes for these patients to further inform the debate surrounding optimal upfront management of the aortic root in acute dissection. Retrospective record review of all patients who underwent full aortic root replacement after a previous type A dissection repair operation at a tertiary academic referral center from 2004-2020 was performed. Among 57 cases of reoperative root replacement after type A repair, 35 cases included concomitant aortic arch replacements, and 21 cases involved coronary reconstruction (unilateral or bilateral modified Cabrol grafts). There were 3 acute post-operative strokes and 4 operative mortalities (composite 30-day and in-hospital deaths, 7.0%) . Mid-term outcomes were equivalent for patients who required arch replacement compared to isolated proximal repairs (81.8% vs. 80.6% estimated 5-year survival, median follow-up 5.53 years. Reoperative root replacement after index type A dissection repairs, including those with concomitant aortic arch replacement and/or coronary reconstruction is achievable with acceptable outcomes at an experienced aortic center.

  View details for DOI 10.1053/j.semtcvs.2023.02.001

  View details for PubMedID 36758660

• Angiogenic stem cell delivery platform to augment post-infarction neovasculature and reverse ventricular remodeling. Scientific reports Shin, H. S., Thakore, A., Tada, Y., Pedroza, A. J., Ikeda, G., Chen, I. Y., Chan, D., Jaatinen, K. J., Yajima, S., Pfrender, E. M., Kawamura, M., Yang, P. C., Wu, J. C., Appel, E. A., Fischbein, M. P., Woo, Y., Shudo, Y. 2022; 12 (1): 17605

  Abstract

  Many cell-based therapies are challenged by the poor localization of introduced cells and the use of biomaterial scaffolds with questionable biocompatibility or bio-functionality. Endothelial progenitor cells (EPCs), a popular cell type used in cell-based therapies due to their robust angiogenic potential, are limited in their therapeutic capacity to develop into mature vasculature. Here, we demonstrate a joint delivery of human-derived endothelial progenitor cells (EPC) and smooth muscle cells (SMC) as a scaffold-free, bi-level cell sheet platform to improve ventricular remodeling and function in an athymic rat model of myocardial infarction. The transplanted bi-level cell sheet on the ischemic heart provides a biomimetic microenvironment and improved cell-cell communication, enhancing cell engraftment and angiogenesis, thereby improving ventricular remodeling. Notably, the increased density of vessel-like structures and upregulation of biological adhesion and vasculature developmental genes, such as Cxcl12 and Notch3, particularly in the ischemic border zone myocardium, were observed following cell sheet transplantation. We provide compelling evidence that this SMC-EPC bi-level cell sheet construct can be a promising therapy to repair ischemic cardiomyopathy.

  View details for DOI 10.1038/s41598-022-21510-y

  View details for PubMedID 36266453

  View details for PubMedCentralID PMC9584918

• Mosaicism for the smooth muscle cell (SMC)-specific knock-in of the Acta2 R179C pathogenic variant: Implications for gene editing therapies. Journal of molecular and cellular cardiology Kaw, A., Pedroza, A. J., Chattopadhyay, A., Pinard, A., Guo, D., Kaw, K., Zhou, Z., Shad, R., Fischbein, M. P., Kwartler, C. S., Milewicz, D. M. 2022; 171: 102-104

  View details for DOI 10.1016/j.yjmcc.2022.07.004

  View details for PubMedID 35878552

• Embryologic Origin Influences Smooth Muscle Cell Phenotypic Modulation Signatures in Murine Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Dalal, A. R., Shad, R., Yokoyama, N., Nakamura, K., Cheng, P., Wirka, R. C., Mitchel, O., Baiocchi, M., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2022: 101161ATVBAHA122317381

  Abstract

  BACKGROUND: Aortic root smooth muscle cells (SMC) develop from both the second heart field (SHF) and neural crest. Disparate responses to disease-causing Fbn1 variants by these lineages are proposed to promote focal aortic root aneurysm formation in Marfan syndrome (MFS), but lineage-stratified SMC analysis in vivo is lacking.METHODS: We generated SHF lineage-traced MFS mice and performed integrated multiomic (single-cell RNA and assay for transposase-accessible chromatin sequencing) analysis stratified by embryological origin. SMC subtypes were spatially identified via RNA in situ hybridization. Response to TWIST1 overexpression was determined via lentiviral transduction in human aortic SMCs.RESULTS: Lineage stratification enabled nuanced characterization of aortic root cells. We identified heightened SHF-derived SMC heterogeneity including a subset of Tnnt2-expressing cells distinguished by altered proteoglycan expression. MFS aneurysm-associated SMC phenotypic modulation was identified in both SHF-traced and nontraced (neural crest-derived) SMCs; however, transcriptomic responses were distinct between lineages. SHF-derived modulated SMCs overexpressed collagen synthetic genes and small leucine-rich proteoglycans while nontraced SMCs activated chondrogenic genes. These modulated SMCs clustered focally in the aneurysmal aortic root at the region of SHF/neural crest lineage overlap. Integrated RNA-assay for transposase-accessible chromatin analysis identified enriched Twist1 and Smad2/3/4 complex binding motifs in SHF-derived modulated SMCs. TWIST1 overexpression promoted collagen and SLRP gene expression in vitro, suggesting TWIST1 may drive SHF-enriched collagen synthesis in MFS aneurysm.CONCLUSIONS: SMCs derived from both SHF and neural crest lineages undergo phenotypic modulation in MFS aneurysm but are defined by subtly distinct transcriptional responses. Enhanced TWIST1 transcription factor activity may contribute to enriched collagen synthetic pathways SHF-derived SMCs in MFS.

  View details for DOI 10.1161/ATVBAHA.122.317381

  View details for PubMedID 35861960

• Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque. Nature cardiovascular research Cheng, P., Wirka, R. C., Kim, J. B., Kim, H. J., Nguyen, T., Kundu, R., Zhao, Q., Sharma, D., Pedroza, A., Nagao, M., Iyer, D., Fischbein, M. P., Quertermous, T. 2022; 1 (4): 322-333

  Abstract

  Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMC. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodelling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: a SMC phenotype that governs both vascular remodelling and recruitment of inflammatory cells, as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodelling, monocyte recruitment, and vascular calcification.

  View details for DOI 10.1038/s44161-022-00042-8

  View details for PubMedID 36246779

  View details for PubMedCentralID PMC9560061

• Acute Induced Pressure Overload Rapidly Incites Thoracic Aortic Aneurysmal Smooth Muscle Cell Phenotype. Hypertension (Dallas, Tex. : 1979) Pedroza, A. J., Shad, R., Dalal, A. R., Yokoyama, N., Nakamura, K., Hiesinger, W., Fischbein, M. P. 2022: HYPERTENSIONAHA12118640

  View details for DOI 10.1161/HYPERTENSIONAHA.121.18640

  View details for PubMedID 35124970

• The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci bioRxiv Weldy, C. S., Cheng, P. P., Pedroza, A. J., Dalal, A. R., Sharma, D., Kim, H., Shi, H., Nguyen, T., Kundu, R. K., Fischbein, M. P., Quertermous, T. 2022

  View details for DOI 10.1101/2022.05.18.492517

• Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells. Scientific reports Iosef, C., Pedroza, A. J., Cui, J. Z., Dalal, A. R., Arakawa, M., Tashima, Y., Koyano, T. K., Burdon, G., Churovich, S. M., Orrick, J. O., Pariani, M., Fischbein, M. P. 2020; 10 (1): 20392

  Abstract

  Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype-phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin alphaV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.

  View details for DOI 10.1038/s41598-020-77274-w

  View details for PubMedID 33230159

• Androgens Accentuate TGF-beta Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice. Journal of the American Heart Association Tashima, Y., He, H., Cui, J. Z., Pedroza, A. J., Nakamura, K., Yokoyama, N., Iosef, C., Burdon, G., Koyano, T., Yamaguchi, A., Fischbein, M. P. 2020; 9 (20): e015773

  Abstract

  Background Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced Erk (extracellular-signal-regulated kinase)/Smad activation, contributing to aneurysm progression in males. Methods and Results Aortic diameters in Fbn1C1039G/+ and littermate wild-type controls were measured at ages 6, 8, 12, and 16weeks. Fbn1C1039G/+ males were treated with (1) flutamide (androgen receptor blocker) or (2) vehicle control from age 6 to 16weeks and then euthanized. p-Erk1/2, p-Smad2, and matrix metalloproteinase (MMP) activity were measured in ascending/aortic root and descending aorta specimens. Fbn1C1039G/+ male and female ascending/aortic root-derived smooth muscle cells were utilized in vitro to measure Erk/Smad activation and MMP-2 activity following dihydrotestosterone, flutamide or transforming growth factor beta 1 treatment. Fbn1C1039G/+ males have increased aneurysm growth. p-Erk1/2 and p-Smad2 were elevated in ascending/aortic root specimens at age 16weeks. Corresponding with enhanced Erk/Smad signaling, MMP-2 activity was higher in Fbn1C1039G/+ males. In vitro smooth muscle cell studies revealed that dihydrotestosterone potentiates transforming growth factor beta-induced Erk/Smad activation and MMP-2 activity, which is reversed by flutamide treatment. Finally, in vivo flutamide treatment reduced aneurysm growth via p-Erk1/2 and p-Smad2 reduction in Fbn1C1039G/+ males. Conclusions Fbn1C1039G/+ males have enhanced aneurysm growth compared with females associated with enhanced p-Erk1/2 and p-Smad2 activation. Mechanistically, in vitro smooth muscle cell studies suggested that dihydrotestosterone potentiates transforming growth factor beta induced Erk/Smad activation. As biological proof of concept, flutamide treatment attenuated aneurysm growth and p-Erk1/2 and p-Smad2 signaling in Fbn1C1039G/+ males.

  View details for DOI 10.1161/JAHA.119.015773

  View details for PubMedID 33059492

• Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Tashima, Y., Shad, R., Cheng, P., Wirka, R., Churovich, S., Nakamura, K., Yokoyama, N., Cui, J. Z., Iosef, C., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2020: ATVBAHA120314670

  Abstract

  OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF (transforming growth factor)-beta-responsive genes correlated with SMC modulation in mouse and human data sets.CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-beta plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-beta signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

  View details for DOI 10.1161/ATVBAHA.120.314670

  View details for PubMedID 32698686

• Divergent effects of canonical and non-canonical TGF-beta signalling on mixed contractile-synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms. Journal of cellular and molecular medicine Pedroza, A. J., Koyano, T., Trojan, J., Rubin, A., Palmon, I., Jaatinen, K., Burdon, G., Chang, P., Tashima, Y., Cui, J. Z., Berry, G., Iosef, C., Fischbein, M. P. 2019

  Abstract

  Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF-beta driven via Smad (canonical) and ERK (non-canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF-beta-driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF-beta-dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF-beta-dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a 'mixed' contractile-synthetic phenotype in MFS aortic aneurysm;and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

  View details for DOI 10.1111/jcmm.14921

  View details for PubMedID 31886938

• Acute type A dissection causing impending rupture of abdominal aortic aneurysm previously treated with EVAR. Annals of vascular surgery Ogawa, Y., Watkins, A. C., Lee, A., Iwakoshi, S., Dua, A., Pedroza, A. J., Dake, M. D., Lee, J. T. 2019

  Abstract

  This report describes the rapid expansion of a previously excluded abdominal aortic aneurysm (AAA) following type A aortic dissection repair in a 74-year-old male. Following successful hemi-arch replacement, CT angiography (CTA) showed residual dissection throughout the thoracoabdominal aorta which had created a proximal endoleak at the prior endovascular stentgraft resulting in rapid growth of the residual AAA sac. Urgent thoracic endovascular aortic repair (TEVAR) did not fully obliterate false lumen flow allowing further unstable expansion of the AAA and abdominal pain. This was ultimately managed with an open replacement of the infrarenal neck with a Dacron interposition graft sewn to the prior EVAR. Post-op CTA showed resolution of the false lumen communication to the infrarenal AAA and no further endoleak. Open interposition AAA neck replacement is a possible treatment for new onset endoleak in patients with aortic dissection following prior infrarenal EVAR.

  View details for DOI 10.1016/j.avsg.2019.11.047

  View details for PubMedID 31863952

• Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation. Journal of cellular and molecular medicine Emrich, F., Penov, K., Arakawa, M., Dhablania, N., Burdon, G., Pedroza, A. J., Koyano, T. K., Kim, Y. M., Raaz, U., Connolly, A. J., Iosef, C., Fischbein, M. P. 2019

  Abstract

  Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin-enhanced chemiluminescence (LGCL), Verhoeff's elastin-Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1C1039G/+ AS- or DES-derived smooth muscle cells (SMC) were treated with anti-TGF-beta antibody, angiotensin II (AngII), anti-TGF-beta antibody+AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1C1039G/+ AS aorta, but absent in normal-sized DES aorta. Fbn1C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1C1039G/+ -derived AS SMC had increased NADPH activity compared to DES-derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF-beta dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF-beta dependent.

  View details for DOI 10.1111/jcmm.14587

  View details for PubMedID 31402541

• Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras-Induced ERK (Extracellular Signal-Regulated Kinase) Signaling Pathway JOURNAL OF THE AMERICAN HEART ASSOCIATION Sato, T., Arakawa, M., Tashima, Y., Tsuboi, E., Burdon, G., Trojan, J., Koyano, T., Young-Nam Youn, Penov, K., Pedroza, A. J., Shabazzi, M., Palmon, I., Nguyen, M., Connolly, A. J., Yamaguchi, A., Fischbein, M. P. 2018; 7 (21): e008543

  Abstract

  Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane-bound G-protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1C1039G/+ mice were treated with (1) pravastatin (HMG-CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A ( MA ; FPT inhibitor), (3) perillyl alcohol ( GGPT 1 and -2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal-regulated kinase) signaling. In vitro Fbn1C1039G/+ aortic smooth muscle cells were utilized to measure Ras-dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA -treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c-Raf and phosphorylated ERK 1/2 were significantly reduced in MA -treated mice (4-5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 signaling was elevated in Fbn1C1039G/+ smooth muscle cells (n=5 per group). Fbn1C1039G/+ smooth muscle cell Ras-dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin-treated mice. Conclusions Aneurysm reduction in Fbn1C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras-dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.

  View details for PubMedID 30571378

• Emergency valve-sparing aortic root replacement and coronary artery bypass grafting for giant left sinus of Valsalva aneurysm presenting as acute coronary syndrome JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Pedroza, A. J., Brewer, Z. E., Lee, A. M. 2018; 156 (2): E81–E84

  View details for DOI 10.1016/j.jtcvs.2018.03.009

  View details for Web of Science ID 000438731500004

• Emergency valve-sparing aortic root replacement and coronary artery bypass grafting for giant left sinus of Valsalva aneurysm presenting as acute coronary syndrome. The Journal of thoracic and cardiovascular surgery Pedroza, A. J., Brewer, Z. E., Lee, A. M. 2018

  View details for PubMedID 29615334

• Long-term miR-29b suppression reduces aneurysm formation in a Marfan mouse model. Physiological reports Okamura, H., Emrich, F., Trojan, J., Chiu, P., Dalal, A. R., Arakawa, M., Sato, T., Penov, K., Koyano, T., Pedroza, A., Connolly, A. J., Rabinovitch, M., Alvira, C., Fischbein, M. P. 2017; 5 (8)

  Abstract

  Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR-29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1(C1039G/+) Marfan mice. Herein, we sought to determine whether miR-29b suppression can reduce aneurysm formation long-term. Fbn1(C1039G/+) Marfan mice were treated with retro-orbital LNA-anti-miR-29b inhibitor or scrambled-control-miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1(C1039G/+) mice at 14.5 days post-coitum) (n = 8-10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8-10, each group). To determine if miR-29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4-6, each group). miR-29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA-anti-miR-29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR-29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR-29b inhibition significantly reduces aneurysm development long-term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR-29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.

  View details for DOI 10.14814/phy2.13257

  View details for PubMedID 28455451

• Long-term miR-29b suppression reduces aneurysm formation in a Marfan mouse model PHYSIOLOGICAL REPORTS Okamura, H., Emrich, F., Trojan, J., Chiu, P., Dalal, A. R., Arakawa, M., Sato, T., Penov, K., Koyano, T., Pedroza, A., Connolly, A. J., Rabinovitch, M., Alvira, C., Fischbein, M. P. 2017; 5 (8)

  View details for DOI 10.14814/phy2.13257

  View details for Web of Science ID 000400380800012

• Enhanced Caspase Activity Contributes to Aortic Wall Remodeling and Early Aneurysm Development in a Murine Model of Marfan Syndrome ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Emrich, F. C., Okamura, H., Dalal, A. R., Penov, K., Merk, D. R., Raaz, U., Hennigs, J. K., Chin, J. T., Miller, M. O., Pedroza, A. J., Craig, J. K., Koyano, T. K., Blankenberg, F. G., Connolly, A. J., Mohr, F. W., Alvira, C. M., Rabinovitch, M., Fischbein, M. P. 2015; 35 (1): 146-154

  Abstract

  Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs.Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.

  View details for DOI 10.1161/ATVBAHA.114.304364

  View details for PubMedID 25359856

• Endovascular Aortic Repair After Proximal Stent Graft Migration of a Modified Frozen Elephant Trunk. Innovations (Philadelphia, Pa.) Dalal, A. R., Pedroza, A. J., Iwakoshi, S. n., Lee, J. T., Fleischmann, D. n., Watkins, A. C. ; 15 (2): 169–72

  Abstract

  We describe the endovascular repair for a proximal endograft migration following a modified frozen elephant trunk (mFET) repair for a retrograde type A dissection (retro-A AD). A 40-year-old man presented with a type B aortic dissection that progressed to a retro-A AD. He was emergently taken to the operating room for an mFET repair. Computed tomography (CT) angiogram on the day of discharge revealed that the proximal end of the endograft migrated through the primary intimal tear resulting in obstruction of true lumen flow. The patient returned to the catheterization lab for endovascular repair utilizing a through-and-through wire to extend the endograft proximally and a left carotid-subclavian artery bypass. This complication highlights the importance of postoperative CT surveillance and the endovascular technique utilized to restore aortic true lumen flow.

  View details for DOI 10.1177/1556984520902839

  View details for PubMedID 32352908