Initial Outcomes of the Gore TAG Thoracic Branch Endoprosthesis for Endovascular Repair of Blunt Thoracic Aortic Injury.

BACKGROUND: Endovascular repair of blunt thoracic aortic injury (BTAI) has dramatically reduced the morbidity and mortality of intervention. Injuries requiring zone 2 coverage of the aorta traditionally require left subclavian artery (LSA) sacrifice or open revascularization. Furthermore, these injuries are associated with an increased risk of in-hospital mortality and long-term morbidity. Here we report 1-year outcomes of total endovascular repair of BTAI with the GORE® TAG® Thoracic Branch Endoprosthesis for LSA preservation. METHODS: Across 34 investigative sites, 9 patients with BTAI requiring LSA coverage were enrolled in a nonrandomized, prospective study of a single-branched aortic endograft. The thoracic branch endoprosthesis device allows for graft placement proximal to the LSA and incorporates a single side branch for LSA perfusion. RESULTS: This initial cohort included 8 male and 1 female patient with a median age of 43 (22, 76) and 12 months of follow-up. Five total years of follow-up are planned. All participants had grade 3 BTAI. All procedures took place between 2018 and 2019. The median injury severity score was 2 (0, 66). The median procedure time was 109 min (78, 162). All aortic injuries were repaired under general anesthesia and with heparinization. A spinal drain was used in one patient. Post-deployment balloon angioplasty was conducted in one case at the distal landing zone. There was one asymptomatic LSA branch occlusion 6 months after repair. It was attributed to the purposeful proximal deployment of the branch stent to accommodate an early vertebral takeoff. The occlusion did not require revascularization. There were no strokes, mortalities, or aortic adverse events (migration, endoleak, native aortic expansion, dissection, or thrombosis) through 12 months of follow-up. CONCLUSIONS: Initial cohort outcomes suggest that endovascular repair of zone 2 BTAI is feasible and has favorable outcomes using the thoracic branch device with LSA preservation. Additional cases and longer-term follow-up are required for a definitive assessment of the device's safety and durability in traumatic aortic injuries.

Comprehensive Integration of Multiple Single-Cell Transcriptomic Data Sets Defines Distinct Cell Populations and Their Phenotypic Changes in Murine Atherosclerosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome.

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

Blood transfusion in aortic root surgery impairs midterm survival.

Objective: To evaluate the effect of perioperative allogeneic packed red blood cell (RBC) transfusion during aortic root replacement. Method: 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. Results: 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). Conclusions: 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.

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.

BACKGROUND: The role of increased smooth muscle cell (SMC) integrin αv signaling in Marfan syndrome (MFS) aortic aneurysm remains unclear. Herein, we examine the mechanism and potential efficacy of integrin αv blockade as a therapeutic strategy to reduce aneurysm progression in MFS. METHODS: Induced pluripotent stem cells (iPSCs) were differentiated into aortic SMCs of the second heart field (SHF) and neural crest (NC) lineages, enabling in vitro modeling of MFS thoracic aortic aneurysms. The pathological role of integrin αv during aneurysm formation was confirmed by blockade of integrin αv with GLPG0187 in Fbn1C1039G/+ MFS mice. RESULTS: iPSC-derived MFS SHF SMCs overexpress integrin αv relative to MFS NC and healthy control SHF cells. Furthermore, integrin αv downstream targets (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment of MFS SHF SMCs with GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS NC SMCs and control SMCs, which normalized with 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) had reduced aneurysm growth, elastin fragmentation, and reduction of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. CONCLUSIONS: The integrin αv-FAK-AktThr308 signaling pathway is activated in iPSC 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.

Outcomes of Reoperative Aortic Root Replacement After Previous Acute Type A Dissection Repair.

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 postoperative 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.

Midterm Outcomes in Type A Aortic Dissection Repair With and Without Malperfusion in a Hybrid Operating Room.

Treatment approach to type A aortic dissection with malperfusion, immediate open aortic repair vs upfront endovascular treatment, remains controversial. From January 2017 to July 2021, 301 consecutive type A repairs were evaluated at our institution. Starting in 2019, all type A aortic dissections were performed in a fixed-fluoroscopy, hybrid operating room. Propensity score matching was used to control baseline patient characteristics between traditional and hybrid operating room approaches. There were 144 patients in the traditional group and 157 in the hybrid group. In the hybrid group, 41% (64/157) underwent intraoperative angiograms, and of those, 58% (37/64) received at least 1 endovascular intervention. Following propensity matching, 125 patients remained in each the traditional and hybrid groups. Thirty-day survival was significantly improved in the hybrid cohort at 96.7% (122/125) as compared to the traditional cohort at 87.2% (109/125) (P = 0.002). There were no significant differences in perioperative paralysis (1.6% vs 1.6%, P > 0.9), new hemodialysis (12% vs 9.6%, P = 0.5), fasciotomy (2.4% vs 5.6%, P = 0.20, and exploratory laparotomy (1.6% vs 4.8%, P = 0.3). The hybrid operating room approach to type A aortic dissection, provides the ability to immediately assess distal malperfusion and perform endovascular interventions at the time of open aortic repair, and is associated with significantly higher 30-day and 2-year survival when compared to a stepwise repair approach in a traditional operating room.

Total aortic arch replacement using a frozen elephant trunk device: Results of a 1-year US multicenter trial.

OBJECTIVE: In this prospective US investigational device exemption trial, we assessed the safety and 1-year clinical outcomes of the Thoraflex Hybrid device (Terumo Aortic) for the frozen elephant trunk technique to repair the ascending aorta, aortic arch, and descending thoracic aorta. METHODS: For the trial, which involved 12 US sites, 65 patients without rupture were recruited into the primary study group, and 9 patients were recruited into the rupture group. All patients underwent open surgical repair of the ascending aorta, aortic arch, and descending thoracic aorta in cases of aneurysm and/or dissection. The primary end point was freedom from major adverse events (MAE), defined as permanent stroke, permanent paraplegia/paraparesis, unanticipated aortic-related reoperation (excluding reoperation for bleeding), or all-cause mortality. RESULTS: In the primary study group, 2 patients were lost to follow-up at 1 year. Freedom from MAE at 1 year was 81% (51/63). Seven patients (11%) died (including 2 before 30 days or discharge), 3 patients (5%) suffered permanent stroke, and 3 (5%) developed permanent paraplegia/paraparesis. Twenty-six patients (41%) underwent planned extension procedures, including 22 endovascular procedures within a median of 122 (interquartile range, 64-156) days. In the aortic rupture group, 2 patients were lost to follow-up at 1 year. Freedom from MAE at 1 year was 71% (5/7). One patient (14%) died, 2 patients (29%) had permanent stroke, and none had permanent paraplegia/paraparesis. No extension procedures were performed in the rupture group. CONCLUSIONS: One-year results with the Thoraflex Hybrid device are acceptable. Long-term data are necessary to assess the durability of these repairs.

Angiogenic stem cell delivery platform to augment post-infarction neovasculature and reverse ventricular remodeling.

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.

Midterm Outcomes of Endovascular Repair of Aortic Arch Aneurysms with the Gore Thoracic Branch Endoprosthesis.

OBJECTIVE: Aortic aneurysms involving aortic arch vessels are anatomically unsuitable for standard thoracic endovascular repair (TEVAR) without cervical debranching of the arch vessels. Three year outcomes of a single branched thoracic endograft following previous publication of peri-operative and one year outcomes are reported. METHODS: This was a multicentre feasibility trial of the GORE TAG Thoracic Branch Endoprosthesis (TBE), a thoracic endovascular graft incorporating a single retrograde branch for aortic arch vessel perfusion. The first study arm enrolled patients with an intact descending thoracic aortic aneurysm extending to the distal arch with left subclavian artery (LSA) incorporation (zone 2). The second arm enrolled patients with arch aneurysms requiring incorporation of the left carotid or innominate artery (zone 0/1) and extra-anatomic surgical revascularisation of the remaining aortic arch vessels. Outcomes at three years are reported. RESULTS: The cohort comprised 40 patients (31 zone 2, nine zone 0/1). The majority were male (52%). Mean follow up was 1 408 ± 552 days in the zone 2 and 1 187 ± 766 days in the zone 0/1 cohort. During three year follow up there was no device migration, fracture, or aortic rupture in either arm. In the zone 2 arm, freedom from re-intervention was 97% at one and three years but there were two side branch occlusions. Two patients had aneurysm enlargement > 5 mm without documented endoleak or re-intervention. Freedom from death at one and three years was 90% and 84%. In the zone 0/1 arm there were no re-interventions, loss of branch patency, or aneurysm enlargement at three years. Cerebrovascular events occurred in three patients during follow up: two unrelated to the device or procedure, and one of unknown relationship. Two patients in this arm died during the follow up period, both unrelated to the procedure or the aneurysm. CONCLUSION: Initial three year results of the TBE device for endovascular repair of arch aneurysms show favourable patency and durability with low rates of graft related complications.

Evaluation of the Gore TAG thoracic branch endoprosthesis in the treatment of proximal descending thoracic aortic aneurysms.

BACKGROUND: Thoracic endovascular aortic repair has radically transformed the treatment of descending thoracic aortic aneurysms. However, when aneurysms involve the aortic arch in the region of the left subclavian artery, branch vessel preservation must be considered. Branched aortic endografts have provided a new option to maintain branch patency. METHODS: Six investigative sites enrolled 31 patients in a nonrandomized, prospective investigational device exemption feasibility trial of a single branched aortic endograft for the management of aneurysms that include the distal aortic arch. The Gore TAG thoracic branch endoprosthesis (W. L. Gore & Associates, Inc, Flagstaff, Ariz), an investigational device, allows for graft placement proximal to the left subclavian artery and incorporates a single side branch for left subclavian perfusion. RESULTS: All 31 patients (100%) had undergone successful implantation of the investigational device in landing zone 2. Men slightly outnumbered women (51.6%). Their average age was 74.1 ± 10.4 years. The aneurysm morphology was fusiform in 12 and saccular in 19 patients, with a mean maximum aortic diameter of 54.8 ± 10.9 mm. The mean follow-up period for the cohort was 25.2 ± 11.1 months. We have reported the patient outcomes at 1 month and 1 year. At 1 month, the side branch patency was 100% and the freedom from core laboratory-reported device-related endoleak (types I and III) was 96.7%, without 30-day death or permanent paraplegia. One patient experienced a procedure-related stroke. Through 1 year, five patients had died; none of the deaths were related to the device or procedure (clinical endpoint committee adjudicated). One thoracic reintervention was required. No conversions were required, and no aneurysm growth (core laboratory) was reported. One case of the loss of side branch patency was diagnosed in the left subclavian artery in an asymptomatic individual from computed tomography at 6 months, with no reported subsequent adverse events due to loss of patency. Endoleaks were reported by the core laboratory in five patients at 12 months (two, type II; and three, indeterminate). CONCLUSIONS: The present investigational device exemption feasibility study has reported the preliminary results of the use of a single side branch endograft to treat patients with proximal descending thoracic aortic aneurysms.

Off-Pump Minithoracotomy Versus Sternotomy for Left Anterior Descending Myocardial Bridge Unroofing.

BACKGROUND: Myocardial bridge (MB) of the left anterior descending (LAD) coronary artery occurs in approximately 25% of the population. When medical therapy fails in patients with a symptomatic, hemodynamically significant MB, MB unroofing represents the optimal surgical management. Here, we evaluated minimally invasive MB unroofing in selected patients compared with sternotomy. METHODS: MB unroofing was performed in 141 adult patients by sternotomy on-pump (ST-on, n = 40), sternotomy off-pump (ST-off, n = 62), or minithoracotomy off-pump (MT, n = 39). Angina symptoms were assessed preoperatively and 6 months postoperatively using the Seattle Angina Questionnaire. Matching included all MT patients and 31 ST-off patients with similar MB characteristics, no previous cardiac operations or coronary interventions, and no concomitant procedures. RESULTS: MT patients tended to have a shorter MB length than ST-on and ST-off patients (2.57 vs 2.93 vs 3.09 cm, P = .166). ST-on patients had a longer hospital stay than ST-off and MT patients (5.0 vs 4.0 vs 3.0 days, P < .001), and more blood transfusions (15.2% vs 0.0% vs 2.6%, P = .002). After matching, MT patients had a shorter hospital stay than ST-off patients (3.0 vs 4.0 days, P = .005). No deaths or major complications occurred in any group. In all groups, MB unroofing yielded significant symptomatic improvement regarding physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life. CONCLUSIONS: We report our single-center experience of off-pump minimally invasive MB unroofing, which may be safely performed in carefully selected patients, yielding dramatic improvements in angina symptoms at 6 months after the operation.

Aortic growth and development of partial false lumen thrombosis are associated with late adverse events in type B aortic dissection.

BACKGROUND: Patients with medically treated type B aortic dissection (TBAD) remain at significant risk for late adverse events (LAEs). We hypothesize that not only initial morphological features, but also their change over time at follow-up are associated with LAEs. MATERIALS AND METHODS: Baseline and 188 follow-up computed tomography (CT) scans with a median follow-up time of 4 years (range, 10 days to 12.7 years) of 47 patients with acute uncomplicated TBAD were retrospectively reviewed. Morphological features (n = 8) were quantified at baseline and each follow-up. Medical records were reviewed for LAEs, which were defined according to current guidelines. To assess the effects of changes of morphological features over time, the linear mixed effects models were combined with Cox proportional hazards regression for the time-to-event outcome using a joint modeling approach. RESULTS: LAEs occurred in 21 of 47 patients at a median of 6.6 years (95% confidence interval [CI], 5.1-11.2 years). Among the 8 investigated morphological features, the following 3 features showed strong association with LAEs: increase in partial false lumen thrombosis area (hazard ratio [HR], 1.39; 95% CI, 1.18-1.66 per cm2 increase; P < .001), increase of major aortic diameter (HR, 1.24; 95% CI, 1.13-1.37 per mm increase; P < .001), and increase in the circumferential extent of false lumen (HR, 1.05; 95% CI, 1.01-1.10 per degree increase; P < .001). CONCLUSIONS: In medically treated TBAD, increases in aortic diameter, new or increased partial false lumen thrombosis area, and increases of circumferential extent of the false lumen are strongly associated with LAEs.