Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100289
Drew J. Braet MD , Moritz Lindquist Liljeqvist MD, PhD
{"title":"Toward the “slope of enlightenment”: The role of adiposity in abdominal aortic aneurysms","authors":"Drew J. Braet MD , Moritz Lindquist Liljeqvist MD, PhD","doi":"10.1016/j.jvssci.2025.100289","DOIUrl":"10.1016/j.jvssci.2025.100289","url":null,"abstract":"","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100289"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100293
Nicasius Tjahjadi MD , Carlos Campello Jorge MD , Prabhvir S. Marway MD , Taeouk Kim MSc , Timothy Baker PhD , Constantijn Hazenberg MD, PhD , Joost A. van Herwaarden MD, PhD , C. Alberto Figueroa PhD , Himanshu J. Patel MD , Nicholas S. Burris MD
Objective
We utilized vascular deformation mapping (VDM) to assess ascending aortic motion, regional stiffness and growth in patients who underwent zone 2/3 thoracic endovascular aortic repair (TEVAR) to quantify changes in ascending aorta biomechanics after endograft implantation.
Methods
Multi-planar, multi-directional aortic motion, aortic strain, and three-dimensional aortic growth was extracted by VDM from electrocardiography-gated computed tomography angiograms. Aortic displacement and strain were compared between patients who underwent TEVAR (both pre- and post-procedure) and in patients with dilated ascending aorta (>4.0 cm) and a non-dilated control group.
Results
One hundred twenty subjects were included for analysis. Between pre-TEVAR and post-TEVAR, total displacement decreased (4.87 ± 1.52 mm vs 4.13 ± 1.43 mm; P = .03). Ascending aortic cross-sectional area strain at the sinuses (SVS), mid-ascending (MA), and proximal arch (PA) were lower in the pre-TEVAR group (SVS, 8.3% ± 4.7%; MA, 6.2% ± 3.2%; PA, 6.3% ± 3.0%; all P < .001) compared with non-dilated controls (SVS, 14.0% ± 6.6%; MA, 14.9% ± 6.6%; PA, 14.9% ± 6.9%). TEVAR increased aortic strain at the MA (pre-TEVAR, 6.2% ± 3.2%; post-TEVAR, 8.5% ± 4.6%; P < .001) and PA (pre-TEVAR, 6.3% ± 3.0%; post-TEVAR, 9.0% ± 4.6%; P < .001). A moderate, negative correlation (R = −0.57; P = .007) between MA aortic growth rate and aortic strain was observed post-TEVAR.
Conclusions
Zone 2/3 TEVAR introduces changes in ascending aortic biomechanics. Patients with lower post-TEVAR strain, suggesting higher aortic stiffness, may be at highest risk of progressive growth. Imaging-based assessment of aortic biomechanics may help improve risk stratification for long-term outcomes post-TEVAR.
{"title":"Three-dimensional characterization of ascending aortic strain, motion and growth in patients undergoing thoracic endovascular aortic repair","authors":"Nicasius Tjahjadi MD , Carlos Campello Jorge MD , Prabhvir S. Marway MD , Taeouk Kim MSc , Timothy Baker PhD , Constantijn Hazenberg MD, PhD , Joost A. van Herwaarden MD, PhD , C. Alberto Figueroa PhD , Himanshu J. Patel MD , Nicholas S. Burris MD","doi":"10.1016/j.jvssci.2025.100293","DOIUrl":"10.1016/j.jvssci.2025.100293","url":null,"abstract":"<div><h3>Objective</h3><div>We utilized vascular deformation mapping (VDM) to assess ascending aortic motion, regional stiffness and growth in patients who underwent zone 2/3 thoracic endovascular aortic repair (TEVAR) to quantify changes in ascending aorta biomechanics after endograft implantation.</div></div><div><h3>Methods</h3><div>Multi-planar, multi-directional aortic motion, aortic strain, and three-dimensional aortic growth was extracted by VDM from electrocardiography-gated computed tomography angiograms. Aortic displacement and strain were compared between patients who underwent TEVAR (both pre- and post-procedure) and in patients with dilated ascending aorta (>4.0 cm) and a non-dilated control group.</div></div><div><h3>Results</h3><div>One hundred twenty subjects were included for analysis. Between pre-TEVAR and post-TEVAR, total displacement decreased (4.87 ± 1.52 mm vs 4.13 ± 1.43 mm; <em>P</em> = .03). Ascending aortic cross-sectional area strain at the sinuses (SVS), mid-ascending (MA), and proximal arch (PA) were lower in the pre-TEVAR group (SVS, 8.3% ± 4.7%; MA, 6.2% ± 3.2%; PA, 6.3% ± 3.0%; all <em>P</em> < .001) compared with non-dilated controls (SVS, 14.0% ± 6.6%; MA, 14.9% ± 6.6%; PA, 14.9% ± 6.9%). TEVAR increased aortic strain at the MA (pre-TEVAR, 6.2% ± 3.2%; post-TEVAR, 8.5% ± 4.6%; <em>P</em> < .001) and PA (pre-TEVAR, 6.3% ± 3.0%; post-TEVAR, 9.0% ± 4.6%; <em>P</em> < .001). A moderate, negative correlation (R = −0.57; <em>P</em> = .007) between MA aortic growth rate and aortic strain was observed post-TEVAR.</div></div><div><h3>Conclusions</h3><div>Zone 2/3 TEVAR introduces changes in ascending aortic biomechanics. Patients with lower post-TEVAR strain, suggesting higher aortic stiffness, may be at highest risk of progressive growth. Imaging-based assessment of aortic biomechanics may help improve risk stratification for long-term outcomes post-TEVAR.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100293"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100292
Leah M. Gober MD , Alan Dardik MD PhD
{"title":"Using computational modeling and four-dimensional computed tomography to predict type II endoleaks","authors":"Leah M. Gober MD , Alan Dardik MD PhD","doi":"10.1016/j.jvssci.2025.100292","DOIUrl":"10.1016/j.jvssci.2025.100292","url":null,"abstract":"","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100292"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144481307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100281
Benjamin J. Madden BSc , Camilo Polania-Sandoval MD , Ganesh P. Pujari MD , Kiran K. Mangalaparthi PhD , M. Cristine Charlesworth PhD, MS , Mercedes Prudencio PhD , Tania Gendron PhD , Sukhwinder J.S. Sandhu MD , Aziza Nassar MD, MPH , Leonard Petrucelli PhD , James F. Meschia MD , Akhilesh Pandey MD, PhD , Young Erben MD
Objective
Extracranial carotid artery pathology accounts for 15% to 20% of ischemic strokes. Advancements in magnetic resonance angiography (MRA) with vessel wall imaging (VWI) have enabled the identification of vulnerable plaques, aiding in risk stratification for neurovascular events. This pilot study aimed to identify proteins in plaques with and without vulnerable features on MRA with VWI.
Methods
Consecutive patients undergoing carotid endarterectomy were included in the study cohort with preoperative MRA with VWI. A retrospective chart review was conducted to extract pertinent clinical data including cardiovascular risk factors and medications. Proteomic analysis involved Tandem Mass Tag (TMTpro) labeling of peptides, basic pH high-performance liquid chromatography fractionation, and NanoLC-tandem mass spectrometry.
Results
Proteomic analysis revealed 23 proteins significantly elevated in vulnerable plaques, including Proteinase 3 (PRTN3), Phospholipid Transfer Protein (PLTP), and S100 Calcium-Binding Protein A12 (S100A12), with increased abundance exceeding two-fold changes or above (P < .001). Conversely, three proteins exhibited reduced abundance in vulnerable plaques including Dynamin-3 (DNM3), Transmembrane Protein 181 (TMEM181), and Adducin-3 (ADD3) (P < .05).
Conclusions
This study contributes to the understanding of protein biomarkers associated with carotid plaque vulnerability, offering insights into disease progression and stroke prevention. Proteins secreted by vulnerable plaques may offer not only the potential for early disease recognition; but can also become a target for future pharmacologic therapy prior to a devastating neurologic event. Further validation studies and multi-center trials will be needed to confirm the value of these potential biomarkers.
{"title":"Proteomic analysis of carotid artery plaques with and without vulnerable features on magnetic resonance angiography with vessel wall imaging: a pilot study","authors":"Benjamin J. Madden BSc , Camilo Polania-Sandoval MD , Ganesh P. Pujari MD , Kiran K. Mangalaparthi PhD , M. Cristine Charlesworth PhD, MS , Mercedes Prudencio PhD , Tania Gendron PhD , Sukhwinder J.S. Sandhu MD , Aziza Nassar MD, MPH , Leonard Petrucelli PhD , James F. Meschia MD , Akhilesh Pandey MD, PhD , Young Erben MD","doi":"10.1016/j.jvssci.2025.100281","DOIUrl":"10.1016/j.jvssci.2025.100281","url":null,"abstract":"<div><h3>Objective</h3><div>Extracranial carotid artery pathology accounts for 15% to 20% of ischemic strokes. Advancements in magnetic resonance angiography (MRA) with vessel wall imaging (VWI) have enabled the identification of vulnerable plaques, aiding in risk stratification for neurovascular events. This pilot study aimed to identify proteins in plaques with and without vulnerable features on MRA with VWI.</div></div><div><h3>Methods</h3><div>Consecutive patients undergoing carotid endarterectomy were included in the study cohort with preoperative MRA with VWI. A retrospective chart review was conducted to extract pertinent clinical data including cardiovascular risk factors and medications. Proteomic analysis involved Tandem Mass Tag (TMTpro) labeling of peptides, basic pH high-performance liquid chromatography fractionation, and NanoLC-tandem mass spectrometry.</div></div><div><h3>Results</h3><div>Proteomic analysis revealed 23 proteins significantly elevated in vulnerable plaques, including Proteinase 3 (PRTN3), Phospholipid Transfer Protein (PLTP), and S100 Calcium-Binding Protein A12 (S100A12), with increased abundance exceeding two-fold changes or above (<em>P</em> < .001). Conversely, three proteins exhibited reduced abundance in vulnerable plaques including Dynamin-3 (DNM3), Transmembrane Protein 181 (TMEM181), and Adducin-3 (ADD3) (<em>P</em> < .05).</div></div><div><h3>Conclusions</h3><div>This study contributes to the understanding of protein biomarkers associated with carotid plaque vulnerability, offering insights into disease progression and stroke prevention. Proteins secreted by vulnerable plaques may offer not only the potential for early disease recognition; but can also become a target for future pharmacologic therapy prior to a devastating neurologic event. Further validation studies and multi-center trials will be needed to confirm the value of these potential biomarkers.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100281"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100283
Alexandre Malta Brandão MD, PhD , Marcos Vinícius Melo de Oliveira MD, PhD , Gina Camillo Rocha Silvestre BS , Alexandre Queiroz Silva BS , Michele Alberto Marques BS , Suely Aparecida Pinheiro Palomino MSc , Maria de Lourdes Higuchi MD, PhD , Erasmo Simão da Silva MD, PhD
Objective
Adipose tissue plays a role in atherogenesis and degeneration of the vascular wall. However, the relationship between aortic abdominal aneurysm (AAA) and adipose tissue is controversial. This study aimed to correlate the biomechanical properties (elasticity and resistance), histology and immunohistochemistry findings of aortic tissue fragments from abdominal aortic aneurysms (AAAs) with the abdominal fat distribution determined by computed tomography scans.
Methods
This retrospective study analyzed data from biomechanical tests performed on fragments of the anterior wall of AAA obtained during open surgical repair. A uniaxial test was used to determine the tissue's failure tensile strength, tension, stress, and elasticity (strain). Preoperative computed tomography scans were used to quantify abdominal circumference at the L3-L4 and umbilical levels. Visceral and subcutaneous fat areas were quantified at these levels using tissue radiodensity. Univariate analysis and multiple regression models were used to correlate adiposity measures with biomechanical variables, considering factors such as hypertension, diabetes, and smoking status. Histological analysis (hematoxylin and eosin staining) was performed on twenty-five specimens, and immunohistochemical analysis (CD20, CD68, CD45, peroxisome proliferator activated receptor-γ [PPAR-γ], KLF5, and tumor necrosis factor-α) was performed on 13 specimens.
Results
The most common risk factors were hypertension (82%) and smoking (85%). Diabetes mellitus was present in 21.8%. No correlation was found between visceral fat area and biomechanical parameters or maximum AAA diameter. Predominance of visceral adipose tissue at L3-L4 and the umbilical level was associated with lower fibrosis in all layers of the abdominal wall (subcutaneous, 61% vs visceral, 41%), higher PPAR-γ expression in the tunica media (subcutaneous, 170.5-199.0 positive cells/mm2 vs visceral, 957.88-1038.50 positive cells/mm2; P = .033), and lower elastic fiber concentration in the tunica media. (subcutaneous, 40.5% vs visceral, 31.5%).
Conclusions
No relationship was found between the biomechanical parameters of the AAA wall and visceral or subcutaneous fat areas. The predominance of visceral fat was associated with increased adipocyte cellularity and decreased elastic fiber concentration in the tunica media of the anterior AAA wall.
{"title":"Analysis of the relationship between central adiposity and biomechanical, histological, and immunohistochemical properties of the anterior wall of abdominal aortic aneurysms","authors":"Alexandre Malta Brandão MD, PhD , Marcos Vinícius Melo de Oliveira MD, PhD , Gina Camillo Rocha Silvestre BS , Alexandre Queiroz Silva BS , Michele Alberto Marques BS , Suely Aparecida Pinheiro Palomino MSc , Maria de Lourdes Higuchi MD, PhD , Erasmo Simão da Silva MD, PhD","doi":"10.1016/j.jvssci.2025.100283","DOIUrl":"10.1016/j.jvssci.2025.100283","url":null,"abstract":"<div><h3>Objective</h3><div>Adipose tissue plays a role in atherogenesis and degeneration of the vascular wall. However, the relationship between aortic abdominal aneurysm (AAA) and adipose tissue is controversial. This study aimed to correlate the biomechanical properties (elasticity and resistance), histology and immunohistochemistry findings of aortic tissue fragments from abdominal aortic aneurysms (AAAs) with the abdominal fat distribution determined by computed tomography scans.</div></div><div><h3>Methods</h3><div>This retrospective study analyzed data from biomechanical tests performed on fragments of the anterior wall of AAA obtained during open surgical repair. A uniaxial test was used to determine the tissue's failure tensile strength, tension, stress, and elasticity (strain). Preoperative computed tomography scans were used to quantify abdominal circumference at the L3-L4 and umbilical levels. Visceral and subcutaneous fat areas were quantified at these levels using tissue radiodensity. Univariate analysis and multiple regression models were used to correlate adiposity measures with biomechanical variables, considering factors such as hypertension, diabetes, and smoking status. Histological analysis (hematoxylin and eosin staining) was performed on twenty-five specimens, and immunohistochemical analysis (CD20, CD68, CD45, peroxisome proliferator activated receptor-γ [PPAR-γ], KLF5, and tumor necrosis factor-α) was performed on 13 specimens.</div></div><div><h3>Results</h3><div>The most common risk factors were hypertension (82%) and smoking (85%). Diabetes mellitus was present in 21.8%. No correlation was found between visceral fat area and biomechanical parameters or maximum AAA diameter. Predominance of visceral adipose tissue at L3-L4 and the umbilical level was associated with lower fibrosis in all layers of the abdominal wall (subcutaneous, 61% vs visceral, 41%), higher PPAR-γ expression in the tunica media (subcutaneous, 170.5-199.0 positive cells/mm<sup>2</sup> vs visceral, 957.88-1038.50 positive cells/mm<sup>2</sup>; <em>P</em> = .033), and lower elastic fiber concentration in the tunica media. (subcutaneous, 40.5% vs visceral, 31.5%).</div></div><div><h3>Conclusions</h3><div>No relationship was found between the biomechanical parameters of the AAA wall and visceral or subcutaneous fat areas. The predominance of visceral fat was associated with increased adipocyte cellularity and decreased elastic fiber concentration in the tunica media of the anterior AAA wall.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100283"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100282
Yukihiko Aoyagi MD , Andrew W. Schwartz BS , Zhuo Li MD, PhD , Hualong Bai MD, PhD , Luis Gonzalez PhD , Cayetana Lazcano Etchebarne BS , Yuichi Ohashi MD , Masaki Kano MD , Bryan Ho MD , Kathleen Martin PhD , Alan Dardik MD, PhD
Background
Vascular remodeling is a dynamic process characterized by changes in vascular identity that impact vessel structure and function. Molecular markers define cellular identity as arteries, veins, and lymphatic vessels: Ephrin-B2 and Notch determine arterial identity, EphB4 and COUP-TFII determine venous identity, and Prox1 determines lymphatic identity.
Methods
This is a review of experimental literature.
Results
These proteins determine identity during development before the first heartbeat. Hemodynamic changes in adulthood can also alter vascular identity. Changes in identity markers coincide with changes in vascular cell phenotype or disease and thus may play a role in regulating both normal and pathological vascular remodeling. Vascular diseases such as arteriovenous malformations and pulmonary hypertension are driven by changes in cell phenotype and vessel identity. Surgical interventions such as arteriovenous fistula (AVF) creation and arterial bypass using vein grafts induce alterations in identity; vein grafts lose their venous identity, but do not acquire arterial identity, whereas venous limbs of AVF gain arterial identity while retaining their venous identity. After patch angioplasty, vascular patches remodel in their environment. Patches in the venous environment acquire venous identity and patches in the arterial environment develop arterial identity. Interestingly, patches in the venous outflow of AVF gain a mixed venous-arterial phenotype.
Conclusions
Changes in vascular identity drive vascular remodeling in both physiological and pathological settings, with potential implications for therapeutic strategies targeting vascular diseases.
Clinical Relevance
Vascular remodeling is essential for both physiological and pathological vascular adaptation. Changes in vascular identity occur in response to hemodynamic forces and mediate vascular remodeling during development, in disease states, and after surgical and endovascular interventions. Alterations in arterial and venous molecular markers of identity regulate cellular phenotype, the extracellular matrix, and vessel wall structure, ultimately determining long-term vessel function. Understanding the molecular regulatory pathways controlling vascular identity provides insight into understanding the mechanisms of vascular remodeling and may identify potential therapeutic targets to treat vascular disease and improve outcomes after vascular interventions.
{"title":"Changes in vascular identity during vascular remodeling","authors":"Yukihiko Aoyagi MD , Andrew W. Schwartz BS , Zhuo Li MD, PhD , Hualong Bai MD, PhD , Luis Gonzalez PhD , Cayetana Lazcano Etchebarne BS , Yuichi Ohashi MD , Masaki Kano MD , Bryan Ho MD , Kathleen Martin PhD , Alan Dardik MD, PhD","doi":"10.1016/j.jvssci.2025.100282","DOIUrl":"10.1016/j.jvssci.2025.100282","url":null,"abstract":"<div><h3>Background</h3><div>Vascular remodeling is a dynamic process characterized by changes in vascular identity that impact vessel structure and function. Molecular markers define cellular identity as arteries, veins, and lymphatic vessels: Ephrin-B2 and Notch determine arterial identity, EphB4 and COUP-TFII determine venous identity, and Prox1 determines lymphatic identity.</div></div><div><h3>Methods</h3><div>This is a review of experimental literature.</div></div><div><h3>Results</h3><div>These proteins determine identity during development before the first heartbeat. Hemodynamic changes in adulthood can also alter vascular identity. Changes in identity markers coincide with changes in vascular cell phenotype or disease and thus may play a role in regulating both normal and pathological vascular remodeling. Vascular diseases such as arteriovenous malformations and pulmonary hypertension are driven by changes in cell phenotype and vessel identity. Surgical interventions such as arteriovenous fistula (AVF) creation and arterial bypass using vein grafts induce alterations in identity; vein grafts lose their venous identity, but do not acquire arterial identity, whereas venous limbs of AVF gain arterial identity while retaining their venous identity. After patch angioplasty, vascular patches remodel in their environment. Patches in the venous environment acquire venous identity and patches in the arterial environment develop arterial identity. Interestingly, patches in the venous outflow of AVF gain a mixed venous-arterial phenotype.</div></div><div><h3>Conclusions</h3><div>Changes in vascular identity drive vascular remodeling in both physiological and pathological settings, with potential implications for therapeutic strategies targeting vascular diseases.</div></div><div><h3>Clinical Relevance</h3><div>Vascular remodeling is essential for both physiological and pathological vascular adaptation. Changes in vascular identity occur in response to hemodynamic forces and mediate vascular remodeling during development, in disease states, and after surgical and endovascular interventions. Alterations in arterial and venous molecular markers of identity regulate cellular phenotype, the extracellular matrix, and vessel wall structure, ultimately determining long-term vessel function. Understanding the molecular regulatory pathways controlling vascular identity provides insight into understanding the mechanisms of vascular remodeling and may identify potential therapeutic targets to treat vascular disease and improve outcomes after vascular interventions.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100282"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100295
Qunsheng Dai MD , Changxin Wan PhD , Yueyuan Xu PhD , Kaileen Fei MD , Lindsey A. Olivere MD , Hana Shafique BS, BA , Shaghayegh Sadeghmousavi MD , Camryn Johnson BS , Brianna Garrett MS , Leo Akers MS , Derek Peters MD, PhD , James Otto PhD , Christopher D. Kontos MD , Zhiceng Ji PhD , Yarui Diao PhD , Kevin W. Southerland MD
<div><h3>Background</h3><div>Skeletal muscle health and function are critical determinants of clinical outcomes in peripheral arterial disease. Chronic limb-threatening ischemia (CLTI), the most severe clinical manifestation of peripheral arterial disease, is associated with a 1-year amputation rate of 25%. In patients with CLTI, myosteatosis—the ectopic deposition of adipocytes—is independently associated with amputation. The mechanisms responsible for myosteatosis in patients with CLTI remain unknown. In this study, we aim to identify both the causal cellular population and the molecular mechanisms in patients with CLTI that promote myosteatosis.</div></div><div><h3>Methods</h3><div>To identify a candidate causal cell type and putative signaling axis that promotes myosteatosis, we performed single cell transcriptomic and chromatin accessibility profiling of ischemic muscle in a preclinical CLTI model. To assess the adipogenic potential for candidate subpopulations, we used an in vitro adipogenesis assay; myosteatosis was determined by Oil Red O (ORO), perilipin, and peroxisome proliferator-activated receptor gamma (PPAR-γ) staining. To determine the necessity of candidate transcriptional and epigenetic regulators, we used a small interfering RNA (siRNA). Finally, to assess the clinical significance of our findings, we used a publicly available human CLTI single cell RNA-sequencing dataset.</div></div><div><h3>Results</h3><div>Bulk-RNA sequencings and ORO staining reveal myosteatosis as a hallmark feature of the CLTI limb. Bioinformatic analyses reveal vascular adhesion molecule 1 (Vcam1)<sup>+</sup> fibro-adipogenic progenitors (FAPs) to be a proadipogenic cluster. Vcam1<sup>+</sup> FAPs display increased adipogenic potential compared with Vcam1<sup>−</sup> FAPs (ORO staining, <em>P</em> < .001; perilipin staining, <em>P</em> < .01; PPAR-γ staining, <em>P</em> < .05). Analyses of bulk and single cell RNA-sequencing datasets identify Sfrp1 as a regulator of Vcam1<sup>+</sup> FAP adipogenic differentiation. In vitro inhibition of Sfrp1 with a siRNA demonstrated impaired Vcam1<sup>+</sup> FAP adipogenic differentiation. Single cell ATAC sequencing identifies Nr3c1 as a candidate transcription factor that regulates Vcam1<sup>+</sup> FAP adipogenic differentiation. In vitro inhibition of Nr3c1 with a siRNA demonstrated decreased Sfrp1 expression (<em>P</em> < .01) and impaired adipogenic differentiation (ORO staining, <em>P</em> < .01; perilipin staining, <em>P</em> < .05; PPAR-γ, <em>P</em> < .001). Single cell transcriptomic profiling of paired nonischemic and ischemic muscle specimens from patients with CLTI displayed enriched gene expression of Vcam1 (<em>P</em> = 5.24e<sup>−166</sup>; log2FC = 0.89), Sfrp1 (<em>P</em> = 0; log2FC = 1.49) and Nr3c1 (<em>P</em> = .047; log2FC = 0.050) in ischemic CLTI muscle tissues. Altogether, these data reveal a candidate signaling axis, Nr3c1-Sfrp1, that regulates the differentiation of V
{"title":"Vascular adhesion molecule 1+ fibro-adipogenic progenitors mark fatty infiltration in chronic limb-threatening ischemia","authors":"Qunsheng Dai MD , Changxin Wan PhD , Yueyuan Xu PhD , Kaileen Fei MD , Lindsey A. Olivere MD , Hana Shafique BS, BA , Shaghayegh Sadeghmousavi MD , Camryn Johnson BS , Brianna Garrett MS , Leo Akers MS , Derek Peters MD, PhD , James Otto PhD , Christopher D. Kontos MD , Zhiceng Ji PhD , Yarui Diao PhD , Kevin W. Southerland MD","doi":"10.1016/j.jvssci.2025.100295","DOIUrl":"10.1016/j.jvssci.2025.100295","url":null,"abstract":"<div><h3>Background</h3><div>Skeletal muscle health and function are critical determinants of clinical outcomes in peripheral arterial disease. Chronic limb-threatening ischemia (CLTI), the most severe clinical manifestation of peripheral arterial disease, is associated with a 1-year amputation rate of 25%. In patients with CLTI, myosteatosis—the ectopic deposition of adipocytes—is independently associated with amputation. The mechanisms responsible for myosteatosis in patients with CLTI remain unknown. In this study, we aim to identify both the causal cellular population and the molecular mechanisms in patients with CLTI that promote myosteatosis.</div></div><div><h3>Methods</h3><div>To identify a candidate causal cell type and putative signaling axis that promotes myosteatosis, we performed single cell transcriptomic and chromatin accessibility profiling of ischemic muscle in a preclinical CLTI model. To assess the adipogenic potential for candidate subpopulations, we used an in vitro adipogenesis assay; myosteatosis was determined by Oil Red O (ORO), perilipin, and peroxisome proliferator-activated receptor gamma (PPAR-γ) staining. To determine the necessity of candidate transcriptional and epigenetic regulators, we used a small interfering RNA (siRNA). Finally, to assess the clinical significance of our findings, we used a publicly available human CLTI single cell RNA-sequencing dataset.</div></div><div><h3>Results</h3><div>Bulk-RNA sequencings and ORO staining reveal myosteatosis as a hallmark feature of the CLTI limb. Bioinformatic analyses reveal vascular adhesion molecule 1 (Vcam1)<sup>+</sup> fibro-adipogenic progenitors (FAPs) to be a proadipogenic cluster. Vcam1<sup>+</sup> FAPs display increased adipogenic potential compared with Vcam1<sup>−</sup> FAPs (ORO staining, <em>P</em> < .001; perilipin staining, <em>P</em> < .01; PPAR-γ staining, <em>P</em> < .05). Analyses of bulk and single cell RNA-sequencing datasets identify Sfrp1 as a regulator of Vcam1<sup>+</sup> FAP adipogenic differentiation. In vitro inhibition of Sfrp1 with a siRNA demonstrated impaired Vcam1<sup>+</sup> FAP adipogenic differentiation. Single cell ATAC sequencing identifies Nr3c1 as a candidate transcription factor that regulates Vcam1<sup>+</sup> FAP adipogenic differentiation. In vitro inhibition of Nr3c1 with a siRNA demonstrated decreased Sfrp1 expression (<em>P</em> < .01) and impaired adipogenic differentiation (ORO staining, <em>P</em> < .01; perilipin staining, <em>P</em> < .05; PPAR-γ, <em>P</em> < .001). Single cell transcriptomic profiling of paired nonischemic and ischemic muscle specimens from patients with CLTI displayed enriched gene expression of Vcam1 (<em>P</em> = 5.24e<sup>−166</sup>; log2FC = 0.89), Sfrp1 (<em>P</em> = 0; log2FC = 1.49) and Nr3c1 (<em>P</em> = .047; log2FC = 0.050) in ischemic CLTI muscle tissues. Altogether, these data reveal a candidate signaling axis, Nr3c1-Sfrp1, that regulates the differentiation of V","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100295"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jvssci.2025.100294
Kate Kosmac PhD , Jai K. Joshi BS , Mary M. McDermott MD , Jada C. Stewart BS , Dongxue Zhang MS , Shujun Xu MS , Karen J. Ho MD , Robert Sufit MD , Luigi Ferrucci MD , Charlotte A. Peterson PhD , Ahmed Ismaeel PhD
Objective
In people with peripheral artery disease (PAD), the Telmisartan Plus Exercise to Improve Functioning in Peripheral Artery Disease (TELEX) randomized clinical trial tested whether telmisartan (TEL), with or without exercise, significantly improved 6-minute walk distance at 6-month follow-up, compared with placebo (PLA). This study investigated the effects of TEL on exploratory muscle biopsy outcomes of muscle cellular characteristics (myofiber size, satellite cell content, capillary density, extracellular matrix, and collagen area) and molecular characteristics (cell-specific transcriptomics) in people undergoing supervised exercise in the TELEX Trial.
Methods
Baseline and 6-month follow-up muscle biopsies were obtained from 13 participants with PAD in the TELEX trial randomized to exercise + TEL (n = 6) or exercise + PLA (n = 7). Immunohistochemistry was used to measure muscle cellular characteristics, and the GeoMx digital spatial profiling system was used for transcriptomic analyses of alpha-smooth muscle actin (α-SMA)-positive and α-SMA-negative cells (primarily myofibers).
Results
Compared with exercise + PLA, exercise + TEL increased mean myofiber cross-sectional area (+2175 μm2; 95% confidence interval, −266 to 4615; P = .04) and the number of satellite cells associated with type II myofibers (+17; 95% confidence interval, −1 to 35; P = .03). In α-SMA-negative cells, exercise + TEL upregulated peroxisome proliferator-activated receptor gamma activation-related pathways, including nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling (P = .008), and fatty acid oxidation (P = .011). Exercise + TEL also reduced myostatin expression relative to exercise + PLA in α-SMA-negative cells (Log2fold-change = −1.24; false discovery rate = 0.010).
Conclusions
TEL may influence the effects of exercise on muscle in individuals with PAD by reducing myostatin expression, increasing myofiber size, and increasing activation of peroxisome proliferator-activated receptor gamma. Further study is needed to confirm these findings.
{"title":"Telmisartan modulates exercise responses in peripheral artery disease: Analyses of skeletal muscle from the TELEX Trial","authors":"Kate Kosmac PhD , Jai K. Joshi BS , Mary M. McDermott MD , Jada C. Stewart BS , Dongxue Zhang MS , Shujun Xu MS , Karen J. Ho MD , Robert Sufit MD , Luigi Ferrucci MD , Charlotte A. Peterson PhD , Ahmed Ismaeel PhD","doi":"10.1016/j.jvssci.2025.100294","DOIUrl":"10.1016/j.jvssci.2025.100294","url":null,"abstract":"<div><h3>Objective</h3><div>In people with peripheral artery disease (PAD), the Telmisartan Plus Exercise to Improve Functioning in Peripheral Artery Disease (TELEX) randomized clinical trial tested whether telmisartan (TEL), with or without exercise, significantly improved 6-minute walk distance at 6-month follow-up, compared with placebo (PLA). This study investigated the effects of TEL on exploratory muscle biopsy outcomes of muscle cellular characteristics (myofiber size, satellite cell content, capillary density, extracellular matrix, and collagen area) and molecular characteristics (cell-specific transcriptomics) in people undergoing supervised exercise in the TELEX Trial.</div></div><div><h3>Methods</h3><div>Baseline and 6-month follow-up muscle biopsies were obtained from 13 participants with PAD in the TELEX trial randomized to exercise + TEL (n = 6) or exercise + PLA (n = 7). Immunohistochemistry was used to measure muscle cellular characteristics, and the GeoMx digital spatial profiling system was used for transcriptomic analyses of alpha-smooth muscle actin (α-SMA)-positive and α-SMA-negative cells (primarily myofibers).</div></div><div><h3>Results</h3><div>Compared with exercise + PLA, exercise + TEL increased mean myofiber cross-sectional area (+2175 μm<sup>2</sup>; 95% confidence interval, −266 to 4615; <em>P</em> = .04) and the number of satellite cells associated with type II myofibers (+17; 95% confidence interval, −1 to 35; <em>P</em> = .03). In α-SMA-negative cells, exercise + TEL upregulated peroxisome proliferator-activated receptor gamma activation-related pathways, including nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling (<em>P</em> = .008), and fatty acid oxidation (<em>P</em> = .011). Exercise + TEL also reduced myostatin expression relative to exercise + PLA in α-SMA-negative cells (Log2fold-change = −1.24; false discovery rate = 0.010).</div></div><div><h3>Conclusions</h3><div>TEL may influence the effects of exercise on muscle in individuals with PAD by reducing myostatin expression, increasing myofiber size, and increasing activation of peroxisome proliferator-activated receptor gamma. Further study is needed to confirm these findings.</div></div>","PeriodicalId":74035,"journal":{"name":"JVS-vascular science","volume":"6 ","pages":"Article 100294"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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