Impact of coronary artery bypass grafting (CABG) on coronary collaterals in patients with a chronic total occlusion (CTO).

Chronic total occlusions (CTO) are found commonly in patients with prior coronary artery bypass grafting (CABG). We sought to determine the effect of CABG on collateral robustness in patients with a CTO. Patients with a CTO diagnosed on coronary angiography between July 2010 and December 2019 were included in this study. Patients were classified as either CTO supplied by a functional graft, CTO supplied by collaterals from a non-grafted donor vessel (non-grafted) or a CTO supplied by collaterals from a grafted donor vessel (grafted). The degree of collateral robustness was determined by the Rentrop classification and collateral connection (CC) grade. Demographic, angiographic and clinical outcomes were recorded. A total of 2088 CTO lesions were identified, of which 878 (42.0%) were supplied by a functional graft, 994 (47.6%) CTOs were supplied by a non-grafted donor vessel and 216 (10.3%) CTOs were supplied by a grafted donor vessel. CTOs supplied by a grafted donor vessel had lower rates of robust collaterals (37.0% vs 83.0%, p < 0.0001) with less mature collaterals as determined by the Rentrop grade (p < 0.0001) and CC grade (p < 0.0001) as compared to CTOs supplied by a non-grafted donor vessel. In patients with a previous CABG, a grafted donor vessel results in less robust coronary collaterals with lower Rentrop and CC grade compared to an ungrafted donor vessel. This may be attributable to changes in coronary blood flow and shear stress, and may be a factor in the lower procedural success rates for CTO intervention in patients with prior CABG.

Both surgical and percutaneous revascularization improve prognosis in patients with a coronary chronic total occlusion (CTO) irrespective of collateral robustness.

The impact of surgical or percutaneous coronary revascularization on prognosis in patients with a chronic total occlusion (CTO) remains uncertain. Particularly, whether revascularization of those with robust coronary collaterals improves prognosis is unknown. The objective of this study was to determine the predictors and prognostic impact of revascularization of a CTO, and to determine the clinical impact of robust coronary collaterals. Patients with a CTO diagnosed on coronary angiography between Jul 2010 and Dec 2019 were included in this study. Management strategy of the CTO was defined as percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or medical management. The degree of collateral robustness was determined by the Rentrop grading classification. Demographic, angiographic and clinical outcomes were recorded. A total of 954 patients were included in the study, of which 186 (19.5%) patients underwent CTO PCI, 296 (31.0%) patients underwent CABG and 472 (49.5%) patients underwent medical management of the CTO. 166 patients (17.4%) had Rentrop grade zero or one collaterals, 577 (60.5%) patients had Rentrop grade two and 211 (22.1%) had Rentrop grade three collaterals. The independent predictors of medical management of the CTO were older age, greater stenosis in the donor vessel, an emergent indication for angiography, a non-LAD CTO and female sex. The degree of collateral robustness was not associated with long-term mortality, while patients who were revascularized either through CABG or PCI had a significantly lower mortality compared to medical management alone (p < 0.0001). In patients with a CTO, the presence of robust collaterals is not associated with prognosis, while both surgical and percutaneous revascularization is associated with improved prognosis. Further research into the optimal revascularization strategy for a CTO is required.

Relation of Obstructive Sleep Apnea in Patients With a Coronary Chronic Total Occlusion to Coronary Collaterals and Mortality.

A chronic total occlusion (CTO) is frequently identified in patients undergoing coronary angiography. The prognostic implications of intermittent hypoxia from obstructive sleep apnea (OSA) on patients with a CTO, and effects on collateral recruitment are unknown. The aim of this study was to determine the prevalence, vascular effects, and prognostic implications of the presence of OSA in patients with a CTO. Patients with a CTO between July 2010 and December 2019 were reviewed. Electronic medical records were accessed to determine documented patient history of OSA, demographics, and clinical course. Patients with robust collateral recruitment were defined as Rentrop grade 2 or 3. A total of 948 patients were included in the study, of which 127 (13.4%) had a documented history of OSA. These patients were younger (67.0 years vs 70.6 years, p < 0.01), had a higher body mass index (29.6 kg/m2 vs 26.7 kg/m2, p < 0.0001), higher rates of hypertension (91.3% vs 83.2%, p < 0.05), higher rates of smokers (63.3% vs 49.0%, p < 0.01) and more use of ß-blockers (79% vs 68.5%, p < 0.05) and statins (92.7% vs 82.1%, p < 0.01). A documented history of OSA was independently associated with robust collaterals (OR 3.0 95%CI 1.5 to 5.8, p < 0.01) and lower mortality (HR 0.3 95% CI 0.1 to 0.7, p < 0.01) with a mean survival of 10.8 years, as compared to 8.1 years (log rank p < 0.0001). In conclusion, in patients with a CTO, documented OSA is independently associated with more robust coronary collaterals and lower mortality. The possible cardioprotective implications of intermittent hypoxia in OSA, as well as treatment effect requires further investigation.

Is management of complex abdominal aortic aneurysms consistent? A questionnaire-based survey.

BACKGROUND: Complex abdominal aortic aneurysm (AAA) is a relatively common presentation to the vascular specialist. Despite this there is little consensus on how to manage the often comorbid group of patients. Recent advances in endovascular technology have led to the availability of multiple devices, many of which could be used to treat the same aneurysm. The aim of this study was to quantify this potential variability across vascular specialists from multiple countries. METHODS: An online survey was emailed to members of the Vascular Society for Great Britain and Ireland (VSGBI), the Canadian Society for Vascular Surgery (CSVS) and the Australian and New Zealand Society for Vascular Surgery (ANZSVS). The survey presented a vignette of a 63-year-old woman with significant respiratory comorbidity and a 54 mm juxtarenal AAA (7 mm neck). There were no other adverse morphological features for endovascular repair. The survey included images and questions related to management of the aneurysm. RESULTS: The survey received 238 responses; 61 from ANZSVS, 65 from CSVS and 112 from VSGBI. VSGBI specialists were significantly more likely to continue surveillance than both ANZSVS (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.61-7.65; P<0.001) and CSVS counterparts (OR 2.61, 95% CI: 1.29-5.47; P<0.01). ANZSVS specialists were significantly more likely to perform an endovascular repair than those from CSVS (OR 3.28, 95% CI: 1.50-7.40; P<0.01) and VSGBI (OR 3.65, 95% CI: 1.81-7.59; P<0.001). CSVS specialists were significantly more likely to manage the aneurysm with open surgery than colleagues from the VSGBI (OR 6.57, 95% CI: 2.58-18.46; P<0.001) and ANZSVS (OR 7.18, 95% CI: 2.22-30.79; P<0.001). CONCLUSIONS: Significant variation in the management of a juxtarenal AAA between countries was observed. The same patient would be more likely to have an endovascular repair in Australia and New Zealand, open surgery in Canada and continuing surveillance in the UK and Ireland. This variation reflects the lack of long-term evidence and international consensus on the optimal management of complex AAA.

A Comparison of Manual and Three-Dimensional Modalities in Predicting Nellix Polymer Volume.

PURPOSE: Achieving an effective seal with the Nellix endovascular aneurysm system is dependent on filling the stent bags with an appropriate volume of polymer. Calculating this volume preoperatively is essential and can be performed manually or using three-dimensional (3D) software. The aim of this project was to compare the accuracy of these two methods relative to the actual polymer volume used. MATERIALS AND METHODS: Consecutive patients undergoing Nellix aneurysm repair were included in this retrospective study. Operation notes were analysed for the polymer volume used intra-operatively. Predicted volumes for all patients had been calculated on picture archiving and communication system (PACS) using a manual 'segmental cylinder' method. Computed tomography angiograms were then re-analysed using the Synapse 3D PACS update. The difference between groups was assessed using a paired t-test. RESULTS: Twenty-eight patients were included in the analysis; 26 men (92.9%) and 2 women (7.1%); median age 80.9 years (interquartile range, 72.5-84.5 years). The mean volume of polymer used was 103 mL. The mean manual-derived prediction was 100.1 mL (P=0.365) and 3D-derived prediction 110.2 mL (P<0.001). Manual prediction led to an average 2.8% underestimate of polymer volume whilst 3D prediction led to an average 7.0% overestimate. CONCLUSION: Calculating predicted polymer volume for the Nellix system is more accurate using a manual approach then the 3D alternative. Whilst this method is more time-consuming, there is no significant difference when compared to the actual volume used. Quicker 3D software predictions can be utilised, but their tendency to overestimate should be recognized and taken into account during planning.

Smartphone learning as an adjunct to vascular teaching - a pilot project.

BACKGROUND: M-learning is education using personal mobile electronic devices. Given the prevalence of these in society and amongst healthcare professionals, we aimed to assess their use and feasibility in improving the educational programme of a single vascular institution. METHODS: A weekly vascular departmental teaching programme was initiated with registrars giving 30-min presentations on a defined book chapter. Two multiple-choice questions (MCQ) per session were devised by a supervising consultant utilising the smartphone response system application, Polltogo. A separate investigator disseminated one pre-teaching and one post-teaching MCQ to the attending trainees via a WhatsApp group. Instant feedback of the correct answer was provided by the application. Participants' satisfaction was judged through a survey after 13 sessions. RESULTS: 11 junior doctors of varying seniority participated in the trial. The median number of session attendees was 5. 129 MCQ responses were received. The mobile engagement score (number of answers received divided by total possible answers) was 97.7%. The average correct score for pre-teaching MCQs was 39.4% and post-teaching MCQs 73.0% (p < 0.001). Satisfaction with the concept was high; 80% of responders agreed that it was a useful adjunct to the teaching programme whilst 90% found the system highly user-friendly. CONCLUSIONS: Smartphones can be utilised effectively and with high user satisfaction in assessing knowledge transfer throughout a departmental education programme. Trainees' responses to MCQs significantly improved after 30-min teaching sessions. This concept of m-learning could be developed further to assist with postgraduate examination revision or Deanery teaching programmes in larger cohorts.

Pulmonary Vein Isolation for Atrial Fibrillation Can Be Achieved With Low Radiation Exposure.

BACKGROUND: Atrial fibrillation is common and management by pharmacotherapy is limited by modest efficacy and significant toxicities. Pulmonary vein isolation (PVI) is a safe and effective alternative in select patients with atrial fibrillation. However, prolonged procedure time raises concerns of health risks from radiation exposure. This study aims to determine the significance of radiation exposure from PVI. METHODS: In this study, we retrospectively reviewed patient demographics, fluoroscopy time, entrance skin dose and dose area product in 80 cases of PVI, radiofrequency ablation for atrial flutter and diagnostic coronary angiogram performed in our institution. RESULTS: Compared to other procedures, patients who underwent PVI were younger (age, mean±standard error of mean, 59.4±1.1 years old, p<0.0001) and were more likely to be male (82%, p<0.001). Body mass index was similar between the three groups. The median (and interquartile range) fluoroscopy time was similar between PVI (20.8 and 13.1-30.7mins) and flutter ablation (17.6 and 11.1-26.1mins) but longer than diagnostic angiography (4.2 and 2.3-6.7mins, p<0.0001). Entrance skin dose was similar between PVI and flutter ablation groups but significantly higher in the diagnostic angiography group, with median and IQR for PVI vs. flutter ablation vs. diagnostic angiography, 100.4 (52.8-179.9) vs. 73.2 (37.0-142.1) vs. 393.5 (276.1-555.6) mGy (p<0.0001). Dose area product in PVI (1831.2 and 887.7-3460.8cGycm2) was higher than flutter ablation (1077.8 and 452.9-2410.2cGycm2, p<0.05) but lower than the diagnostic angiography group (3446.8 and 2341.9-5283.1cGycm2, p<0.0001). The fluoroscopy time and entrance skin dose for PVI decreased over time, likely due to increased operator experience. CONCLUSIONS: Despite prolonged procedure time, radiation exposure from PVI was comparable to, or lower than, other fluoroscopy-guided cardiac procedures.

VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.

Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A-VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor-ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.

Scavenger receptor structure and function in health and disease.

Scavenger receptors (SRs) are a 'superfamily' of membrane-bound receptors that were initially thought to bind and internalize modified low-density lipoprotein (LDL), though it is currently known to bind to a variety of ligands including endogenous proteins and pathogens. New family of SRs and their properties have been identified in recent years, and have now been classified into 10 eukaryote families, defined as Classes A-J. These receptors are classified according to their sequences, although in each class they are further classified based in the variations of the sequence. Their ability to bind a range of ligands is reflected on the biological functions such as clearance of modified lipoproteins and pathogens. SR members regulate pathophysiological states including atherosclerosis, pathogen infections, immune surveillance, and cancer. Here, we review our current understanding of SR structure and function implicated in health and disease.

VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.

Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell-cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform-specific stimulation of VCAM-1 gene expression, which controls endothelial-leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform-specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A-stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A-stimulated VCAM-1 expression and endothelial-leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial-leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways.

A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A.

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states.