ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels.

BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of Abcg2-expressing ECs to vessel development and regeneration, we developed Abcg2CreErt2;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2-expressing ECs. RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2-expressing CRECs (AbcCRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in AbcCRECs. In addition, various angiogenic genes, such as Notch2 and Hey2, are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in AbcCRECs. CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction.

The great vessel freeze-out: A meta-analysis of conventional versus frozen elephant trunks in aortic arch surgery.

BACKGROUND: The optimal treatment strategy for complex aortic arch and proximal descending aortic pathologies remains controversial. Despite the frozen elephant trunk (FET) technique's increasing popularity, its use over the conventional elephant trunk (CET) remains a matter of physician preference and outcomes are varied. METHODS: This meta-analysis of available comparative studies of FET versus CET sought to examine differences in survival, reintervention, and adverse events. The following databases were searched from inception-May 2020: Ovid MEDLINE, Ovid EMBASE, and The Cochrane Library. Studies retrieved were then screened for eligibility against predefined inclusion/exclusion criteria with a protocol registered on Open Science Framework at https://osf.io/hrfze/. RESULTS: The search identified 1911 citations, with five studies included. The resultant meta-analysis included 313 CET and 292 FET cases. FET had lower perioperative mortality (risk ratio [RR]: 0.50, 95% confidence interval [CI]: [0.42; 0.60], p < .001) and improved 1-year survival compared to CET (hazard ratio: 0.63, 95% CI: [0.42; 0.95], p = .03). There were no significant differences in rates of overall or open reinterventions following FET versus CET, but FET did yield a significantly higher rate of endovascular reintervention (RR: 2.32, 95% CI: [1.17; 4.61], p = .03). No significant differences were observed in the incidences of postoperative stroke, spinal cord injury, or renal failure between groups. CONCLUSIONS: The FET technique yields superior rates of perioperative and medium-term survival with no significant increase in overall reinterventions. There was no significant difference in the rate of spinal cord injury between groups, providing further large-scale evidence that the FET is an acceptable, safe alternative to the CET.

Endothelial reprogramming for vascular regeneration: Past milestones and future directions.

Endothelial cells are critical mediators of health and disease. Regenerative medicine techniques that target the endothelium hold vast promise for improving lifespan and quality of life worldwide. Regenerative therapies via induced pluripotent stem cells (IPSCs) have helped demonstrate disease mechanisms, but so far, concerns regarding their function, malignant potential, and expense have limited therapeutic potential. One alternative approach is direct reprogramming of somatic cells, which avoids the pluripotent state and allows for in vivo reprogramming. Transcription factors from endothelial development have yielded essential transcription factors and small molecules that induce endothelial cell fate. Most direct cell reprogramming strategies targeting endothelial cells use ETV2, a pioneer transcription factor to specify endothelial lineage via histone-modifying enzymes. Many different types of starting cells and strategies, including lentiviral transduction, inducing innate immunity, and small molecule signaling have been leveraged for reprogramming. However, so far therapeutic benefit of these strategies remains unproven. Future research will have to solve scalability, safety, and efficacy hurdles before being ready for the clinic. However, researchers have already discovered meaningful insights into disease mechanisms and development through direct reprogramming.

Impact of ascending aortic prosthetic grafts on early postoperative descending aortic biomechanics on cardiac magnetic resonance imaging.

OBJECTIVES: Among patients with ascending thoracic aortic aneurysms, prosthetic graft replacement yields major benefits but risk for recurrent aortic events persists for which mechanism is poorly understood. This pilot study employed cardiac magnetic resonance to test the impact of proximal prosthetic grafts on downstream aortic flow and vascular biomechanics. METHODS: Cardiac magnetic resonance imaging was prospectively performed in patients with thoracic aortic aneurysms undergoing surgical (Dacron) prosthetic graft implantation. Imaging included time resolved (4-dimensional) phase velocity encoded cardiac magnetic resonance for flow quantification and cine-cardiac magnetic resonance for aortic wall distensibility/strain. RESULTS: Twenty-nine patients with thoracic aortic aneurysms undergoing proximal aortic graft replacement were studied; cardiac magnetic resonance was performed pre- [12 (4, 21) days] and postoperatively [6.4 (6.2, 7.2) months]. Postoperatively, flow velocity and wall shear stress increased in the arch and descending aorta (P < 0.05); increases were greatest in hereditary aneurysm patients. Global circumferential strain correlated with wall shear stress (r = 0.60-0.72, P < 0.001); strain increased postoperatively in the native descending and thoraco-abdominal aorta (P < 0.001). Graft-induced changes in biomechanical properties of the distal native ascending aorta were associated with post-surgical changes in descending aortic wall shear stress, as evidenced by correlations (r = -0.39-0.52; P ≤ 0.05) between graft-induced reduction of ascending aortic distensibility and increased distal native aortic wall shear stress following grafting. CONCLUSIONS: Prosthetic graft replacement of the ascending aorta increases downstream aortic wall shear stress and strain. Postoperative increments in descending aortic wall shear stress correlate with reduced ascending aortic distensibility, suggesting that grafts provide a nidus for high energy flow and adverse distal aortic remodelling.

Cooperative ETS Transcription Factors Enforce Adult Endothelial Cell Fate and Cardiovascular Homeostasis.

Current dogma dictates that during adulthood, endothelial cells (ECs) are locked in an immutable stable homeostatic state. By contrast, herein we show that maintenance of EC fate and function are linked and active processes, which depend on the constitutive cooperativity of only two ETS-transcription factors (TFs) ERG and Fli1. While deletion of either Fli1 or ERG manifest subtle vascular dysfunction, their combined genetic deletion in adult EC results in acute vasculopathy and multiorgan failure, due to loss of EC fate and integrity, hyperinflammation, and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency cause rapid transcriptional silencing of pan- and organotypic vascular core genes, with dysregulation of inflammation and coagulation pathways. Vascular hyperinflammation leads to impaired hematopoiesis with myeloid skewing. Accordingly, enforced ERG and FLI1 expression in adult human mesenchymal stromal cells activates vascular programs and functionality enabling engraftment of perfusable vascular network. GWAS-analysis identified vascular diseases are associated with FLI1/Erg mutations. Constitutive expression of ERG and Fli1 uphold EC fate, physiological function, and resilience in adult vasculature; while their functional loss can contribute to systemic human diseases.

Valve-sparing root replacement in patients with bicuspid aortopathy: An analysis of cusp repair strategy and valve durability.

OBJECTIVE: Valve-sparing root replacement using reimplantation techniques is increasingly applied to bicuspid aortopathy. Long-term durability of cusp repair is unclear. We analyze midterm results using a conservative approach to cusp repair. METHODS: From 2006 to 2018, 327 patients underwent valve-sparing reimplantation, 66 with bicuspid valves. Leaflets were analyzed after reimplantation. A majority (51/66) required no cusp repair. Fifteen patients had cusp repair limited to closure of unfused raphe or central plication. Patients were followed by echocardiography. RESULTS: Mean age of patients was 44.7 ± 12.3 years. The cusp repair group had a higher incidence of preoperative moderate (10% vs 40%) or severe (4% vs 33.3%) aortic insufficiency (P < .001). There was no operative mortality or major complication. Mean follow-up was 51.6 ± 40.8 months. On postoperative echocardiography, incidence of none, trace, or mild aortic insufficiency was 41.3% (19/46), 43.5% (20/46), and 15.2% (7/46) in the no cusp repair group and 40% (6/15), 40% (6/15), and 20% (3/15) in the cusp repair group, respectively (P = .907). Few patients progressed in degree of aortic insufficiency. No patients required reoperation. At 5 years, freedom from any aortic insufficiency was 46.9% versus 15.8% (P = .013), and freedom from greater than trace aortic insufficiency was 59.1% versus 36.9% (P = .002) due to the higher rate of postoperative trace and mild aortic insufficiency with cusp repair. There was no difference in freedom from greater than mild aortic insufficiency (92.1% vs 100%; P = .33). CONCLUSIONS: Valve-sparing root replacement is reliably performed with bicuspid aortic valves whether or not cusp reconstruction is necessary. Few patients progress to greater than mild aortic insufficiency. Need for reoperation is rare in midterm follow-up.

Cerebral protection strategies in aortic arch surgery: A network meta-analysis.

OBJECTIVE: Cerebral protection for aortic arch surgery has been widely studied, but comparisons of all the available strategies have rarely been performed. We performed direct and indirect comparisons of antegrade cerebral perfusion, retrograde cerebral perfusion, and deep hypothermic circulatory arrest in a network meta-analysis. METHODS: After a systematic literature search, studies comparing any combination of antegrade cerebral perfusion, retrograde cerebral perfusion, and deep hypothermic circulatory arrest were included, and a frequentist network meta-analysis was performed using the generic inverse variance method. The primary outcomes were postoperative stroke and operative mortality. Secondary outcomes were postoperative transient neurologic deficits, myocardial infarction, respiratory complications, and renal failure. RESULTS: A total of 68 studies were included with a total of 26,968 patients. Compared with deep hypothermic circulatory arrest, both antegrade cerebral perfusion and retrograde cerebral perfusion were associated with significantly lower postoperative stroke and operative mortality rates: antegrade cerebral perfusion (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.51-0.75; and OR, 0.63, 95% CI, 0.51-0.76, respectively) and retrograde cerebral perfusion (OR, 0.66; 95% CI, 0.54-0.82; and OR, 0.57; 95% CI, 0.45-0.71, respectively). Antegrade cerebral perfusion and retrograde cerebral perfusion were associated with similar incidence of primary outcomes. No difference among the 3 techniques was found in secondary outcomes. At meta-regression, circulatory arrest duration correlated with the neuroprotective effect of antegrade cerebral perfusion and retrograde cerebral perfusion compared with deep hypothermic circulatory arrest. Unilateral or bilateral antegrade cerebral perfusion and arrest temperature did not influence the results. CONCLUSIONS: Antegrade cerebral perfusion and retrograde cerebral perfusion are associated with better postoperative outcomes compared with deep hypothermic circulatory arrest, and the relative benefit increases with the duration of the circulatory arrest. No differences between antegrade cerebral perfusion and retrograde cerebral perfusion were found for all the explored outcomes.

Pulmonary artery aneurysms: Preoperative, intraoperative, and postoperative findings.

BACKGROUND: Pulmonary artery aneurysms (PAAs) are a rare but potentially lethal cardiovascular pathology. PAAs tend to develop in young patients with no gender discrepancy; they are most often associated with congenital heart disorders but also with systemic infections, vasculitis, pulmonary arterial hypertension, chronic pulmonary embolism, and malignancies. Dissection and rupture carry significant morbidity and mortality, thus patients require careful management, especially those with associated pulmonary hypertension. Given the rarity of this condition, physicians have yet to establish standard treatment guidelines. Most studies published to date are case reports with one or two patients; here, we describe our experience with six cases of large PAAs treated surgically at our institution. METHODS: We identified and retrospectively analyzed clinical data for patients who underwent surgery for PAAs between 2009 and 2017. RESULTS: The average age at surgery was 59.73 years, five patients were females, and 83.3% had baseline hypertension. Systolic murmurs were the most common clinical finding. The average aneurysmal size was 65.0 mm. We repaired the PAA with a woven Dacron graft (22-26 mm) in four patients. We performed concomitant pulmonary valve procedures on five patients: four replacements and one repair. Mean pump and cross-clamp times were 108.5 and 65 minutes. Operative and 30-day mortality was 0%. Average length of stay was 10.5 days. CONCLUSIONS: Postoperative mortality was 0%; all patients showed improvement of symptoms after surgery. These findings confirm that PAA repair has an acceptable risk profile in select patients.

Sinus of Valsalva aneurysm repairs: Operative technique and lessons learned.

OBJECTIVE: Sinus of Valsalva (SOV) aneurysms are rare and data on operative management are limited. They can cause right ventricular outflow tract or pulmonary artery compression, and rupture may be fatal. In this study, we describe our experience with the repair of 13 SOV aneurysms. METHODS: All patients who underwent SOV aneurysm repair from May 2001 to December 2017 at our single tertiary referral center were reviewed retrospectively. RESULTS: Thirteen patients (92% male) with a mean age of 60 years underwent repair of an SOV aneurysm; mean aneurysm diameter was 5.9 ± 0.8 cm and four patients (30.7%) presented with rupture into another cardiac chamber. Operative interventions included six Bentall procedures, five patch repairs (one with aortic valve replacement [AVR]), and two primary aneurysm closures both with concomitant AVR. There were no strokes, myocardial infarctions, re-explorations, or deaths in the postoperative period. After an average of 2.25 years, computed tomographic imaging in five patients demonstrated no aneurysm recurrence. CONCLUSIONS: Surgery is a safe option for both ruptured and nonruptured SOV aneurysms. A variety of repair strategies may be used. Larger studies are needed.

Quality metrics in coronary artery bypass grafting.

Studies on the association between care quality, case volume, and outcomes in coronary artery bypass grafting (CABG) have concluded that consistent adherence to quality measures improves mortality rates and outcomes. However, the quality metrics are not well-defined, and their significance to surgeons and healthcare providers remains uncertain. We review the concept of "quality and quality metrics" and discuss their importance in the context of CABG.

AngioVac for extraction of venous thromboses and endocardial vegetations: A meta-analysis.

BACKGROUND: AngioVac is a new device for filtering intravascular thrombi and emboli. Publications on the device are limited and underpowered to objectively estimate its safety and efficacy. We aimed to overcome this by performing a meta-analysis on the results of AngioVac for treating venous thromboses and endocardial vegetations. METHODS: A systematic literature review was performed to identify all articles reporting cardiac vegetation and/or thrombosis extraction using AngioVac. Endpoints were successful removal, operative mortality, conversion to open surgery, hospital stay, recurrent thromboembolism, and follow-up mortality. Random effect model was used, and pooled event rates (PERs) and incidence rate (IR) were calculated. RESULTS: A total of 42 studies with 182 patients (81 vegetation and 101 thrombosis) were included. Overall mean follow-up times were 3.1 and 0.7 years in vegetation and thrombosis patients, respectively. The PERs for successful removal were 74.5 (confidence interval [CI]: 48.2-90.2), 80.5 (CI: 70.0-88.0), and 32.4 (CI: 17.0-52.8) in vegetation, right atrial/caval venous thrombi, and pulmonary emboli (PE) patients, respectively. The PERs for operative mortalities were 14.6 (CI: 7.7-25.8), 14.8 (CI: 8.5-24.5), and 32.3 (CI: 15.1-56.3), respectively. The PERs for conversion to open surgery were 25.0 (CI: 9.3-51.9) and 12.3 (CI: 5.4-25.6) in vegetation and thrombosis patients, respectively. The IR of recurrent thromboembolism was 0.18 per person per year (PPY) (CI: 0.00-14.69) in vegetation and 0.19 PPY (CI: 0.08-0.48) in thrombosis patients. IR of follow-up mortality was 0.37 PPY (CI: 0.11-1.21) in thrombosis patients. CONCLUSIONS: AngioVac is a viable option for extracting right-sided vegetations and right atrial/caval venous thrombi. Rates of successful extraction and mortality are significantly worse for PE.

Technical Aspects of the Use of the Radial Artery in Coronary Artery Bypass Surgery.

BACKGROUND: The radial artery has been used for coronary artery bypass surgery for more than 25 years. The recent confirmation of the clinical benefits associated with the use of the artery is likely to drive a new interest toward this conduit in the next few years. METHODS: A group of surgeons with extensive experience in the systematic use of the radial artery summarize here the key technical aspects of the use of the conduit for coronary bypass operations. RESULTS: Preoperative evaluation of the ulnar collateral circulation and attention to the characteristics of the target vessel are keys for the successful use of the radial artery. Open or endoscopic harvesting can be used, preferentially with the aid of the harmonic scalpel. The use of vasodilatory and antispastic protocols is probably important but poorly supported by the current evidence. The radial artery can be used for multiple grafting strategies with a variable degree of technical complexity. CONCLUSIONS: With attention to few technical key points, the radial artery is a versatile conduit that can be easily introduced in the everyday practice of coronary artery bypass surgery.

Systematic preoperative CT scan is associated with reduced risk of stroke in minimally invasive mitral valve surgery: A meta-analysis.

BACKGROUND: Minimally invasive mitral valve surgery (MIMVS) is performed with increasing frequency. However, patients undergoing MIMVS might be at increased risk of perioperative stroke, mainly due to retrograde aortic embolization during femoral cardio-pulmonary bypass. Pre-operative computed tomography (CT) screening allows visualization of the aorta and femoro-iliac vessels and individualization of the surgical approach. In this meta-analysis, we aim to determine if systematic pre-operative CT screening is associated with decreased incidence of post-operative stroke and other complications following MIMVS. METHODS: A comprehensive review was performed in PubMed (inception-May 2018). Eligible studies included those which reported on MIMVS (mini-thoracotomy, port access or robotic approach) with retrograde arterial perfusion. Studies were separated into two subgroups: systematic pre-operative CT screening (CT-group) and no CT screening (Non-CT). Pooled event rates (PER) for operative mortality, post-operative stroke, perioperative myocardial infarction (MI), and new onset renal failure requiring dialysis were estimated and inter-group comparisons were performed. RESULTS: Data from 57 studies (13,731 patients) were analyzed (19 CT-group, 38 Non-CT). PER for post-operative stroke was 2.0% with a statistically significant difference between the groups (CT-group: 1.5% versus Non-CT: 2.2%, P = 0.03). PER for new dialysis was 1.9%, significantly lower in the CT-group (0.8% versus 2.3% in the Non-CT group, P = 0.02). PER for operative mortality was 1.4% with a trend towards better outcomes in the CT-group (0.8% versus 1.6% in the Non-CT group, P = 0.05). CONCLUSIONS: Systematic pre-operative CT screening is associated with lower risk of post-operative stroke and need for dialysis and a trend toward lower operative mortality after MIMVS.

Septuagenarians and Older Patients are at a Higher Risk of Mortality with Adrenal Metastasectomy: An Analysis of the HCUP-NIS Database From 1992 to 2011.

INTRODUCTION: Small institutional studies have shown that adrenalectomy to remove solitary metastases to the adrenal gland is safe and can improve overall survival for selective primary tumors. However, outcomes of adrenal metastasectomy have not been evaluated using large, national databases. MATERIALS AND METHODS: All cases of adrenal metastasectomies from 1992 to 2011 were identified in the HCUP-NIS database. The primary endpoint analyzed was death during the same hospitalization. Secondary outcomes included length of stay (LOS), blood loss requiring transfusion, surgical infection, cardiac complications, and respiratory complications. A sub-analysis of 428 patients stratified by primary tumor (where data were available) was also performed. Statistical analysis was performed using chi-square, ANOVA, and logistic regression using Stata software, significance was set at p value of 0.05. RESULTS: A total of 2,057 cases of adrenal metastasectomies were identified. Median age of the patients was 62 ± 13.2 years (49.9 % men, 69.7 % Caucasian). Over the study period, there was a general increase in the number of cases performed and the number performed by minimally invasive approaches. There was also a decrease in LOS and number of deaths. However, age ≥71 years predicted a significantly higher rate of mortality (OR = 6.0, CI 1.3-26.5) when controlled for race, procedure type, year of surgery, and primary tumor in multivariable analysis. This age group had a higher number of cardiac complications (5.4 %, p = 0.005) that potentially contributed to the higher mortality rate. In addition, there was no difference in surgical outcomes when stratified by primary tumor type for the entire cohort of patients. CONCLUSION: Adrenal metastasectomy is a safe procedure with decreasing same-hospitalization mortality from 1992 to 2011. However, age ≥71 years is a significant risk factor for same-hospitalization mortality. This increased risk should be considered when discussing adrenal metastasectomy in this age population.