Costs of endovascular and open repair of thoracic aortic aneurysms.

BACKGROUND: Repair of thoracic aortic aneurysms with either endovascular repair (TEVAR) or open surgical repair (OSR) represents major surgery, is costly and associated with significant complications. The aim of this study was to establish accurate costs of delivering TEVAR and OSR in a cohort of UK NHS patients suitable for open and endovascular treatment for the whole treatment pathway from admission and to discharge and 12-month follow-up. METHODS: A prospective study of UK NHS patients from 30 NHS vascular/cardiothoracic units in England aged ≥18, with distal arch/descending thoracic aortic aneurysms (CTAA) was undertaken. A multicentre prospective cost analysis of patients (recruited March 2014-July 2018, follow-up until July 2019) undergoing TEVAR or OSR was performed. Patients deemed suitable for open or endovascular repair were included in this study. A micro-costing approach was adopted. RESULTS: Some 115 patients having undergone TEVAR and 35 patients with OSR were identified. The mean (s.d.) cost of a TEVAR procedure was higher £26 536 (£9877) versus OSR £17 239 (£8043). Postoperative costs until discharge were lower for TEVAR £7484 (£7848) versus OSR £28 636 (£23 083). Therefore, total NHS costs from admission to discharge were lower for TEVAR £34 020 (£14 301), versus OSR £45 875 (£43 023). However, mean NHS costs for 12 months following the procedure were slightly higher for the TEVAR £5206 (£11 585) versus OSR £5039 (£11 994). CONCLUSIONS: Surgical procedure costs were higher for TEVAR due to device costs. Total in-hospital costs were higher for OSR due to longer hospital and critical care stay. Follow-up costs over 12 months were slightly higher for TEVAR due to hospital readmissions.

Inequalities for women diagnosed with distal arch and descending thoracic aortic aneurysms: results from the Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) cohort study.

BACKGROUND: Women with thoracic aortic aneurysms within the arch or descending thoracic aorta have poorer survival than men. Sex differences in relative thoracic aortic aneurysm size may account for some of the discrepancy. The aim of this study was to explore whether basing clinical management on aneurysm size index (maximum aneurysm diameter/body surface area) rather than aneurysm size can restore equality of survival by sex. METHODS: The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA; ISRCTN04044627) study was a prospective, observational cohort study. Adults referred to National Health Service hospitals in England with new/existing arch or descending thoracic aorta aneurysms greater than or equal to 4 cm in diameter were followed from March 2014 to March 2022. Baseline characteristics and survival to intervention and overall were compared for men and women. Survival models were used to assess the association between all-cause survival and sex, with and without adjustment for aneurysm diameter or aneurysm size index. RESULTS: A total of 886 thoracic aortic aneurysm patients were recruited: 321 (36.2%) women and 565 (63.8%) men. The mean(s.d.) aneurysm diameter was the same for women and men (5.7(1.1) versus 5.7(1.2) cm respectively; P = 0.751), but the mean(s.d.) aneurysm size index was greater for women than for men (3.32(0.80) versus 2.83(0.63) respectively; P < 0.001). Women had significantly worse survival without intervention: 110 (34.3%) women and 135 (23.9%) men (log rank test, P < 0.001). All-cause mortality remained greater for women after adjustment for diameter (HR 1.65 (95% c.i. 1.35 to 2.02); P < 0.001), but was attenuated after adjustment for aneurysm size index (HR 1.11 (95% c.i. 0.89 to 1.38); P = 0.359). Similar results were found for all follow-up, with or without intervention, and findings were consistent for descending thoracic aorta aneurysms alone. CONCLUSION: Guidelines for referral to specialist services should consider including aneurysm size index rather than diameter to reduce inequity due to patient sex.

Aneurysm growth, survival, and quality of life in untreated thoracic aortic aneurysms: the effective treatments for thoracic aortic aneurysms study.

AIMS: To observe, describe, and evaluate management and timing of intervention for patients with untreated thoracic aortic aneurysms. METHODS AND RESULTS: Prospective study of UK National Health Service (NHS) patients aged ≥18 years, with new/existing arch or descending thoracic aortic aneurysms of ≥4 cm diameter, followed up until death, intervention, withdrawal, or July 2019. Outcomes were aneurysm growth, survival, quality of life (using the EQ-5D-5L utility index), and hospital admissions. Between 2014 and 2018, 886 patients were recruited from 30 NHS vascular/cardiothoracic units. Maximum aneurysm diameter was in the descending aorta in 725 (82%) patients, growing at 0.2 cm (0.17-0.24) per year. Aneurysms of ≥4 cm in the arch increased by 0.07 cm (0.02-0.12) per year. Baseline diameter was related to age and comorbidities, and no clinical correlates of growth were found. During follow-up, 129 patients died, 64 from aneurysm-related events. Adjusting for age, sex, and New York Heart Association dyspnoea index, risk of death increased with aneurysm size at baseline [hazard ratio (HR): 1.88 (95% confidence interval: 1.64-2.16) per cm, P < 0.001] and with growth [HR: 2.02 (1.70-2.41) per cm, P < 0.001]. Hospital admissions increased with aneurysm size [relative risk: 1.21 (1.05-1.38) per cm, P = 0.008]. Quality of life decreased annually for each 10-year increase in age [-0.013 (-0.019 to -0.007), P < 0.001] and for current smoking [-0.043 (-0.064 to -0.023), P = 0.004]. Aneurysm size was not associated with change in quality of life. CONCLUSION: International guidelines should consider increasing monitoring intervals to 12 months for small aneurysms and increasing intervention thresholds. Individualized decisions about surveillance/intervention should consider age, sex, size, growth, patient characteristics, and surgical risk.

Association of Collagen, Elastin, Glycosaminoglycans, and Macrophages With Tissue Ultimate Material Strength and Stretch in Human Thoracic Aortic Aneurysms: A Uniaxial Tension Study.

Fiber structures and pathological features, e.g., inflammation and glycosaminoglycan (GAG) deposition, are the primary determinants of aortic mechanical properties which are associated with the development of an aneurysm. This study is designed to quantify the association of tissue ultimate strength and extensibility with the structural percentage of different components, in particular, GAG, and local fiber orientation. Thoracic aortic aneurysm (TAA) tissues from eight patients were collected. Ninety-six tissue strips of thickened intima, media, and adventitia were prepared for uni-extension tests and histopathological examination. Area ratios of collagen, elastin, macrophage and GAG, and collagen fiber dispersion were quantified. Collagen, elastin, and GAG were layer-dependent and the inflammatory burden in all layers was low. The local GAG ratio was negatively associated with the collagen ratio (r2 = 0.173, p < 0.05), but positively with elastin (r2 = 0.037, p < 0.05). Higher GAG deposition resulted in larger local collagen fiber dispersion in the media and adventitia, but not in the intima. The ultimate stretch in both axial and circumferential directions was exclusively associated with elastin ratio (axial: r2 = 0.186, p = 0.04; circumferential: r2 = 0.175, p = 0.04). Multivariate analysis showed that collagen and GAG contents were both associated with ultimate strength in the circumferential direction, but not with the axial direction (collagen: slope = 27.3, GAG: slope = -18.4, r2 = 0.438, p = 0.002). GAG may play important roles in TAA material strength. Their deposition was found to be associated positively with the local collagen fiber dispersion and negatively with ultimate strength in the circumferential direction.

Endovascular stent grafting and open surgical replacement for chronic thoracic aortic aneurysms: a systematic review and prospective cohort study.

BACKGROUND: The management of chronic thoracic aortic aneurysms includes conservative management, watchful waiting, endovascular stent grafting and open surgical replacement. The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) study investigates timing and intervention choice. OBJECTIVE: To describe pre- and post-intervention management of and outcomes for chronic thoracic aortic aneurysms. DESIGN: A systematic review of intervention effects; a Delphi study of 360 case scenarios based on aneurysm size, location, age, operative risk and connective tissue disorders; and a prospective cohort study of growth, clinical outcomes, costs and quality of life. SETTING: Thirty NHS vascular/cardiothoracic units. PARTICIPANTS: Patients aged > 17 years who had existing or new aneurysms of ≥ 4 cm in diameter in the arch, descending or thoracoabdominal aorta. INTERVENTIONS: Endovascular stent grafting and open surgical replacement. MAIN OUTCOMES: Pre-intervention aneurysm growth, pre-/post-intervention survival, clinical events, readmissions and quality of life; and descriptive statistics for costs and quality-adjusted life-years over 12 months and value of information using a propensity score-matched subsample. RESULTS: The review identified five comparative cohort studies (endovascular stent grafting patients, n = 3955; open surgical replacement patients, n = 21,197). Pooled short-term all-cause mortality favoured endovascular stent grafting (odds ratio 0.71, 95% confidence interval 0.51 to 0.98; no heterogeneity). Data on survival beyond 30 days were mixed. Fewer short-term complications were reported with endovascular stent grafting. The Delphi study included 20 experts (13 centres). For patients with aneurysms of ≤ 6.0 cm in diameter, watchful waiting was preferred. For patients with aneurysms of > 6.0 cm, open surgical replacement was preferred in the arch, except for elderly or high-risk patients, and in the descending aorta if patients had connective tissue disorders. Otherwise endovascular stent grafting was preferred. Between 2014 and 2018, 886 patients were recruited (watchful waiting, n = 489; conservative management, n = 112; endovascular stent grafting, n = 150; open surgical replacement, n = 135). Pre-intervention death rate was 8.6% per patient-year; 49.6% of deaths were aneurysm related. Death rates were higher for women (hazard ratio 1.79, 95% confidence interval 1.25 to 2.57; p = 0.001) and older patients (age 61-70 years: hazard ratio 2.50, 95% confidence interval 0.76 to 5.43; age 71-80 years: hazard ratio 3.49, 95% confidence interval 1.26 to 9.66; age > 80 years: hazard ratio 7.01, 95% confidence interval 2.50 to 19.62; all compared with age < 60 years, p < 0.001) and per 1-cm increase in diameter (hazard ratio 1.90, 95% confidence interval 1.65 to 2.18; p = 0.001). The results were similar for aneurysm-related deaths. Decline per year in quality of life was greater for older patients (additional change -0.013 per decade increase in age, 95% confidence interval -0.019 to -0.007; p < 0.001) and smokers (additional change for ex-smokers compared with non-smokers 0.003, 95% confidence interval -0.026 to 0.032; additional change for current smokers compared with non-smokers -0.034, 95% confidence interval -0.057 to -0.01; p = 0.004). At the time of intervention, endovascular stent grafting patients were older (age difference 7.1 years; 95% confidence interval 4.7 to 9.5 years; p < 0.001) and more likely to be smokers (75.8% vs. 66.4%; p = 0.080), have valve disease (89.9% vs. 71.6%; p < 0.0001), have chronic obstructive pulmonary disease (21.3% vs. 13.3%; p = 0.087), be at New York Heart Association stage III/IV (22.3% vs. 16.0%; p = 0.217), have lower levels of haemoglobin (difference -6.8 g/l, 95% confidence interval -11.2 to -2.4 g/l; p = 0.003) and take statins (69.3% vs. 42.2%; p < 0.0001). Ten (6.7%) endovascular stent grafting and 15 (11.1%) open surgical replacement patients died within 30 days of the procedure (p = 0.2107). One-year overall survival was 82.5% (95% confidence interval 75.2% to 87.8%) after endovascular stent grafting and 79.3% (95% confidence interval 71.1% to 85.4%) after open surgical replacement. Variables affecting survival were aneurysm site, age, New York Heart Association stage and time waiting for procedure. For endovascular stent grafting, utility decreased slightly, by -0.017 (95% confidence interval -0.062 to 0.027), in the first 6 weeks. For open surgical replacement, there was a substantial decrease of -0.160 (95% confidence interval -0.199 to -0.121; p < 0.001) up to 6 weeks after the procedure. Over 12 months endovascular stent grafting was less costly, with higher quality-adjusted life-years. Formal economic analysis was unfeasible. LIMITATIONS: The study was limited by small numbers of patients receiving interventions and because only 53% of patients were suitable for both interventions. CONCLUSIONS: Small (4-6 cm) aneurysms require close observation. Larger (> 6 cm) aneurysms require intervention without delay. Endovascular stent grafting and open surgical replacement were successful for carefully selected patients, but cost comparisons were unfeasible. The choice of intervention is well established, but the timing of intervention remains challenging. FUTURE WORK: Further research should include an analysis of the risk factors for growth/rupture and long-term outcomes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04044627 and NCT02010892. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 6. See the NIHR Journals Library website for further project information.

The aorta is the main artery that carries oxygen-rich blood from the heart to the body. An aneurysm is a swelling or bulging in a blood vessel, which usually occurs where the wall has become weak and has lost its elastic properties, which means that it does not return to its normal shape after the blood has passed through. A thoracic aortic aneurysm, or TAA for short, is an aneurysm in the section of the aorta in the chest (www.bhf.org.uk/informationsupport/conditions/thoracic-aortic-aneurysms). The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) study aimed to investigate aneurysm growth rates, patient outcomes, quality of life and costs, including those from surgery. Surgical treatments include open heart surgery, in which the section of the aorta that contains the aneurysm is removed and replaced by a new aorta made from a synthetic material, and stent grafting, in which tubes are inserted into arteries to allow blood to flow freely, using less invasive 'keyhole' surgery. The existing research evidence was reviewed, but data comparing the effectiveness of these two approaches were sparse or of limited quality, and outdated. Between 2014 and 2018, clinical experts were surveyed and 886 NHS patients with chronic thoracic aortic aneurysms (≥ 4 cm in diameter) were observed to monitor aneurysm growth and patient outcomes. If patients were unfit or unwilling to have surgery, they had conservative management with medication and lifestyle changes. For small aneurysms, experts recommended watchful waiting, with regular monitoring, until the aneurysm grew to about 6 cm in diameter. Open surgery was preferred for larger arch aneurysms and for descending aneurysms in patients with genetic disorders. Otherwise, stent grafting was preferred. The observational study recruited 321 women and 565 men with an average age of 71 years from 30 English hospitals. A total of 489 patients underwent watchful waiting and 112 received conservative management. Without surgery, death rates were higher for women and older patients, while the risk of dying doubled for each centimetre of aneurysm diameter at baseline. Of the remaining patients, 150 underwent stent grafting and 135 had open surgery. One-year overall survival was 83% after stent grafting and 79% after open surgery but the difference could be due to chance. The factors affecting survival after stent grafting or open surgery were aneurysm location, age, breathlessness and time waiting for a procedure. Small aneurysms are low risk, so blood pressure management and smoking cessation are recommended. For larger aneurysms, it is important that surgery is not delayed, as a longer waiting time to surgery means that outcomes are poorer. Only about half of patients who had surgery were considered suitable for both stent grafting and open surgery, which limited the ability to determine the best use of NHS resources. No comparative cost-effectiveness analysis was feasible. The main cost in a stent grafting procedure was the stent graft, and the main cost in an open surgery procedure was days in an intensive care unit.

Systematic review of endovascular stent grafting versus open surgical repair for the elective treatment of arch/descending thoracic aortic aneurysms.

OBJECTIVE: To review comparisons of the effectiveness of endovascular stent grafting (ESG) against open surgical repair (OSR) for treatment of chronic arch or descending thoracic aortic aneurysms (TAA). DESIGN: Systematic review and meta-analysis DATA SOURCES: MEDLINE, EMBASE, CENTRAL, WHO International Clinical Trials Routine data collection, current controlled trials, clinical trials and the NIHR portfolio were searched from January 1994 to March 2020. ELIGIBILITY CRITERIA FOR SELECTIVE STUDIES: All identified studies that compared ESG and OSR, including randomised controlled trials (RCTs), quasi-randomised and non-RCTs, comparative cohort studies and case-control studies matched on main outcomes were sought. Participants had to receive elective treatments for arch/descending (TAA). Studies were excluded where other thoracic aortic conditions (eg, rupture or dissection) were reported, unless results for patients receiving elective treatment for arch/descending TAA reported separately. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one reviewer and checked by another. Risk of Bias was assessed using the ROBINS-I tool. Meta-analysis was conducted using random effects. Where meta-analysis not appropriate, results were reported narratively. RESULTS: Five comparative cohort studies met inclusion criteria, reporting 3955 ESG and 21 197 OSR patients. Meta-analysis of unadjusted short-term (30 day) all-cause mortality favoured ESG (OR 0.75; 95% CI 0.55 to 1.03)). Heterogeneity identified between larger and smaller studies. Sensitivity analysis of four studies including only descending TAA showed no statistical significance (OR 0.73, 95% CI 0.45 to 1.18)), moderate heterogeneity. Meta-analysis of adjusted short-term all-cause mortality favoured ESG (OR 0.71, 95% CI 0.51 to 0.98)), no heterogeneity. Longer-term (beyond 30 days) survival from all-cause mortality favoured OSR in larger studies and ESG in smaller studies. Freedom from reintervention in the longer-term favoured OSR. Studies reporting short-term non-fatal complications suggest fewer events following ESG. CONCLUSIONS: There is limited and increasingly dated evidence on the comparison of ESG and OSR for treatment of arch/descending TAA. PROSPERO REGISTRATION NUMBER: CRD42017054565.

Carotid artery diameter, plaque morphology, and hematocrit, in addition to percentage stenosis, predict reduced cerebral perfusion pressure during cardiopulmonary bypass: a mathematical model.

Cerebral complications after cardiac surgery are a significant cause of morbidity, mortality, and financial cost. Numerous risk factors have been proposed to explain the risk of cerebral damage. Carotid artery disease has an important role. Percentage carotid artery stenosis is the only measure of carotid artery disease that is used by cardiac surgeons to determine the need for either a carotid endarterectomy and/or a higher pump perfusion pressure. Identification of patients through their carotid plaque morphology who might benefit from higher pump perfusion pressures or concomitant carotid endarterectomy may reduce cerebral morbidity and mortality. A mathematical model using finite element analysis was created to model the carotid artery vessel and its stenotic plaque. Analysis showed that the degree of carotid artery stenosis, the length of the carotid artery plaque, the diameter of the carotid artery, and the blood hematocrit all independently significantly affect the required pump perfusion pressure to maintain adequate cerebral perfusion during cardiopulmonary bypass (CPB). The results from a mathematical model showed that carotid artery diameter, carotid artery plaque length, and hematocrit, in addition to percentage stenosis, should be included in any thought process involving carotid artery stenosis and cardiac surgery. Estimating cerebral risk during CPB should no longer rely on only the percentage stenosis.

Effect of foreign surface pacification with albumin, aprotinin, propofol, and high-density lipoprotein.

Foreign surface pacification may significantly reduce the detrimental effects of the cardiopulmonary bypass (CPB) circuit. To date, albumin is the only intervention consistently shown to be beneficial. The cationic physical properties of aprotinin and the known negative charge on the plastic CPB circuit mean that aprotinin binds to the CPB circuit and membrane oxygenator. A previously validated model involving a parallel plate glass slide technique was used. The effects of albumin, aprotinin, propofol, and high-density lipoprotein (HDL) were assessed by the ability to inhibit platelet adhesion to the glass slide surface. The experiment was repeated with collagen-coated glass slides to reproduce the clinical effect of endothelial denudation. The interventions were repeated on membrane oxygenators that are used for CPB. Aprotinin resulted in a minimal reduction in platelet adhesion to uncoated or collagen-coated glass slides. HDL significantly reduced platelet adhesiveness to uncoated or collagen-coated glass slides. Human albumin solution (HAS) and propofol produced an intermediary inhibitory effect on platelet adhesion on both collagen-coated and uncoated glass slides. The same effect was seen with membrane oxygenators that are used during CPB. HDL produced a significant reduction of neutrophil activation when used to coat a membrane oxygenator. Foreign surface pacification with HDL may have beneficial effects as assessed by platelet adhesiveness in a parallel plate assay. Aprotinin had minimal effect, and propofol had an intermediate effect. The same results were obtained using membrane oxygenators, confirming the validity of the parallel plate technique as clinically valid.

Bayesian Inference-Based Estimation of Normal Aortic, Aneurysmal and Atherosclerotic Tissue Mechanical Properties: From Material Testing, Modeling and Histology.

OBJECTIVE: Mechanical properties of healthy, aneurysmal, and atherosclerotic arterial tissues are essential for assessing the risk of lesion development and rupture. Strain energy density function (SEDF) has been widely used to describe these properties, where material constants of the SEDF are traditionally determined using the ordinary least square (OLS) method. However, the material constants derived using OLS are usually dependent on initial guesses. METHODS: To avoid such dependencies, Bayesian inference-based estimation was used to fit experimental stress-stretch curves of 312 tissue strips from 8 normal aortas, 19 aortic aneurysms, and 21 carotid atherosclerotic plaques to determine the constants, C1, D1, and D2 of the modified Mooney-Rivlin SEDF. RESULTS: Compared with OLS, material constants varied much less with prior in the Bayesian inference-based estimation. Moreover, fitted material constants differed amongst distinct tissue types. Atherosclerotic tissues associated with the biggest D2, an indicator of the rate of increase in stress during stretching, followed by aneurysmal tissues and those from normal aortas. Histological analyses showed that C1 and D2 were associated with elastin content and details of the collagen configuration, specifically, waviness and dispersion, in the structure. CONCLUSION: Bayesian inference-based estimation robustly determines material constants in the modified Mooney-Rivlin SEDF and these constants can reflect the inherent physiological and pathological features of the tissue structure. SIGNIFICANCE: This study suggested a robust procedure to determine the material constants in SEDF and demonstrated that the obtained constants can be used to characterize tissues from different types of lesions, while associating with their inherent microstructures.

Aggressive zero balance ultrafiltration on CPB in patients with renal failure may cause cerebral edema: a theoretical analysis.

The objective of this study was to determine the brain volume changes that occur secondary to hemofiltration during cardiopulmonary bypass in patients with renal failure. We hypothesized that in patients with elevated urea levels, quick aggressive hemofiltration could be associated with cerebral edema. We constructed a simple two-compartment model similar to the urea kinetic model developed by Depner. Intracellular urea exit was assumed to be minimal based on known urea redistribution times. Calculations were based on a 70-kg patient, with an intracellular volume of 25 L, extracellular volume of 15 L, and a preoperative urea of 40 mmol/L filtered to a post-procedure urea of 6 mmol/L. Analysis showed that a standard size 1500-mL human brain filtered from a preoperative urea of 40 to 6 mmol/L over a short period will expand by 59 mL secondary to the osmotic disequilibrium secondary to hemofiltration (p < .05). The higher the preoperative urea, the larger the fluid shift. This figure does not include the cerebral edema component that is known to arise secondary to cardiopulmonary bypass. Significant cerebral edema theoretically occurs secondary to hemofiltration during cardiopulmonary bypass. More detailed mathematical urea kinetic analysis and clinical correlation are needed.

Hypertonic cardiopulmonary bypass primes and endothelial damage.

The objective of this study was to investigate whether hypertonic hyperosmolar primes solution (HHPS), with an osmolarity of 2300 mOsmol/L, causes endothelial damage/loss. The bodies' normal osmolarity is -280 mOsmol/L. Aortic endothelial cells were cultured and plated to confluence, confirmed by light microscopy, on a 96-well plate. Serial dilutions of HHPS (n = 10) were incubated with the cells (n = 160) for 1 hour. The plates were agitated to simulate flow that occurs during cardiopulmonary bypass (CPB). One half the cells (n = 80) were stained with crystal violet to provide a visual analogue of cell survival. The second half of the cells had the HHPS removed and replaced with culture medium and were incubated overnight before being stained with crystal violet. Optical densities were measured using an optical plate reader set at 470 nm. Analysis of the endothelium after 1 hour showed that HHPS (2300 mOsmol/L) and water (positive control for 100% cell death) resulted in equal cell death, which was significantly higher (p < .05) than any of the other osmolarities tested for. There was no significant difference in the endothelial death rates for osmolarities between 260 and 400 mOsmol/L. Results of overnight incubation showed that cells in contact with a solution of osmolarity >320 mOsmol/L resulted in a significantly greater endothelial cell death rate (p < .05). Our results indicate that the endothelium can be irreversibly damaged by HHPS with osmolarities >320 mOsmol/L. The experimental protocol showed that this endothelial damage, which obviously occurs at the time of contact with the HHPS, may only become manifest 24 hours later.

The Use of Biophysical Flow Models in the Surgical Management of Patients Affected by Chronic Thromboembolic Pulmonary Hypertension.

Introduction: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) results from progressive thrombotic occlusion of the pulmonary arteries. It is treated by surgical removal of the occlusion, with success rates depending on the degree of microvascular remodeling. Surgical eligibility is influenced by the contributions of both the thrombus occlusion and microvasculature remodeling to the overall vascular resistance. Assessing this is challenging due to the high inter-individual variability in arterial morphology and physiology. We investigated the potential of patient-specific computational flow modeling to quantify pressure gradients in the pulmonary arteries of CTEPH patients to assist the decision-making process for surgical eligibility. Methods: Detailed segmentations of the pulmonary arteries were created from postoperative chest Computed Tomography scans of three CTEPH patients. A focal stenosis was included in the original geometry to compare the pre- and post-surgical hemodynamics. Three-dimensional flow simulations were performed on each morphology to quantify velocity-dependent pressure changes using a finite element solver coupled to terminal 2-element Windkessel models. In addition to transient flow simulations, a parametric modeling approach based on constant flow simulations is also proposed as faster technique to estimate relative pressure drops through the proximal pulmonary vasculature. Results: An asymmetrical flow split between left and right pulmonary arteries was observed in the stenosed models. Removing the proximal obstruction resulted in a reduction of the right-left pressure imbalance of up to 18%. Changes were also observed in the wall shear stresses and flow topology, where vortices developed in the stenosed model while the non-stenosed retained a helical flow. The predicted pressure gradients from constant flow simulations were consistent with the ones measured in the transient flow simulations. Conclusion: This study provides a proof of concept that patient-specific computational modeling can be used as a noninvasive tool for assisting surgical decisions in CTEPH based on hemodynamics metrics. Our technique enables determination of the proximal relative pressure, which could subsequently be compared to the total pressure drop to determine the degree of distal and proximal vascular resistance. In the longer term this approach has the potential to form the basis for a more quantitative classification system of CTEPH types.

Small vessel avulsion and acute aortic syndrome: a putative aetiology for initiation and propagation of blunt traumatic aortic injury at the isthmus.

Based on literature, clinical observation and the analysis of material properties of the aorta, we hypothesize that the aortic isthmus is intrinsically susceptible to blunt trauma because it has a higher density of tributary vessels than other elements of the aortic tree, the avulsion of which during trauma, is a contributory factor in the development of an acute aortic syndrome resulting from intra-mural haematoma, localized dissection and ultimately rupture. This hypothesis provides putative explanations for several aspects of the injury profile including: localized peri-isthmus injuries, inside out injury profiles and the concept of initiation versus propagation of blunt traumatic aortic injury.

An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death.

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-ß (TGF-ß) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-ß inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.

The ETTAA study protocol: a UK-wide observational study of 'Effective Treatments for Thoracic Aortic Aneurysm'.

INTRODUCTION: Chronic thoracic aortic aneurysm (CTAA) affecting the arch or descending aorta is an indolent but life-threatening condition with a rising prevalence as the UK population ages. Treatment may be in the form of open surgical repair (OSR) surgery, endovascular stent grafting (ESG) or best medical therapy (BMT). Currently, there is no consensus on the best management strategy, and no UK-specific economic studies that assess outcomes beyond the chosen procedure, but this is required in the context of greater demand for treatment and limited National Health Service (NHS) resources. METHODS AND ANALYSIS: This is a prospective, multicentre observational study with statistical and economic modelling of patients with CTAA affecting the arch or descending aorta. We aim to gain an understanding of how treatments are currently chosen, and to determine the clinical effectiveness and cost-effectiveness of the three available treatment strategies (BMT, ESG and OSR). This will be achieved by: (1) following consecutive patients who are referred to the teams collaborating in this proposal and collecting data regarding quality of life (QoL), medical events and hospital stays over a maximum of 5 years; (2) statistical analysis of the comparative effectiveness of the three treatments; and (3) economic modelling of the comparative cost-effectiveness of the three treatments. Primary study outcomes are: aneurysm growth, QoL, freedom from reintervention, freedom from death or permanent neurological injury, incremental cost per quality-adjusted life year gained. ETHICS AND DISSEMINATION: The study will generate an evidence base to guide patients and clinicians to determine the indications and timing of treatment, as well as informing healthcare decision-makers about which treatments the NHS should provide. The study has achieved ethical approval and will be disseminated primarily in the form of a Health Technology Assessment monograph at its completion. TRIAL REGISTRATION NUMBER: ISRCTN04044627.

Adrenalectomy for isolated metastasis from operable non-small-cell lung cancer.

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'in [patients with isolated adrenal metastasis from operable/operated non-small cell lung cancer] is [adrenalectomy] superior [to chemo/radiotherapy alone for achieving long-term survival]?' Altogether >160 papers were found using the reported search, of which 3 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that the body of evidence is small, retrospective and not formally controlled. As such interpretation is limited by selection bias in assignment of patients. These limitations notwithstanding, surgical resection is associated with prolonged survival for patients with isolated adrenal metastasis from non-small cell lung cancer (NSCLC). Patient selection is probably critical. Factors that are important are: otherwise early tumour, node (TN) status of the lung primary and R0 resection, long disease-free interval and confidence that there are no other sites of metastasis. Patients with ipsilateral adrenal metastasis may derive the greatest survival benefit from adrenalectomy, since spread to the ipsilateral gland may occur via direct lymphatic channels in the retroperitoneum. Involvement of the contralateral adrenal may signify haematogenous spread and therefore, a more aggressive process. Adrenalectomy must be accompanied by regional lymph node clearance to reduce the chance of further spread from the adrenal itself.

Mesenteric ischaemia following cardiac surgery: the influence of intraoperative perfusion parameters.

OBJECTIVES: Mesenteric ischaemia (MesI) remains a rare but lethal complication following cardiac surgery. Previously identified risk factors for MesI mortality (age, poor left ventricular (LV) function, cardiopulmonary bypass time and blood loss) are non-specific and cannot necessarily be modified. This study aims to identify potentially modifiable risk factors for MesI mortality through analysis of peri- and intraoperative perfusion data. METHODS: Patients who underwent cardiac surgery between 2006 and 2011 at Papworth Hospital were retrospectively divided into 3 outcome categories: death caused by MesI; death due to other causes and survival to discharge. A published MesI risk calculator was used to estimate risk of MesI for each patient and then to create 3 cohorts of matched patients from each outcome group. Pre-, intra- and postoperative variables were collected and conditional logistic regression methods were used to identify parameters associated specifically with MesI deaths after cardiac surgery. RESULTS: A total of 10 409 patients underwent cardiac surgery between 2006 and 2011. The incidence of MesI was 0.3% (30 patients). Two hundred and sixty-one patients died of non-MesI causes and 10 118 survived. It was possible to identify 25 patients in each group at equivalent risk of MesI. The following parameters were found to be associated with MesI mortality: recent myocardial infarction [odds ratio (OR) 4.98, 95% confidence interval (CI) 1.58-15.71, P = 0.01], standard EuroSCORE (OR 1.12, 95% CI 1.03-1.21, P = 0.01), vasopressor dose on bypass (OR 1.28, 95% CI 1.04-1.57, P = 0.02), metaraminol dose on bypass (OR 1.52, 95% CI 1.12-2.06, P = 0.01) and lowest documented mean arterial pressure (OR 0.90, 95% CI 0.83-0.97, P = 0.01). No other intraoperative perfusion-related parameters (e.g. flow, average activated clotting time or pressure) were associated with MesI mortality. CONCLUSIONS: Our study not only confirms previously known predictive factors, but also demonstrates a new association between intraoperative vasopressor use and MesI mortality.

The influence of endoscopic vein harvesting on outcomes after coronary bypass grafting: a meta-analysis of 267,525 patients.

In recent times, practice in cardiac surgery has shifted towards using endoscopic techniques to harvest the saphenous vein from the leg for use as a bypass graft. A paper published in the New England Journal of Medicine (NEJM) in 2009 raised concerns over increased graft occlusion rates in veins harvested endoscopically. This NEJM paper has been criticized, but has nonetheless been influential in guiding practice. We have undertaken this meta-analysis to provide evidence on the clinical outcomes of endoscopic vein harvesting (EVH), so that clinicians can make an informed judgement about whether this technique, popular as it is with patients, should still be offered. We systematically reviewed the global literature and performed a meta-analysis of clinical outcomes after endoscopic and open vein harvesting. In all outcomes, endoscopic harvesting appears to be equal, if not superior, to open harvesting. The suspicion of higher rates of vein graft occlusion was not borne out by randomized studies. When considering evidence from only randomized studies, there is no statistical difference in vein graft stenosis or occlusion between open and endoscopically harvested veins. In conclusion, EVH reduces pain and leg wound complications. At a median follow-up of 2.6 years, we found no significant difference in mortality, myocardial infarction, repeat revascularization, angina recurrence, vein graft stenosis or occlusion. Therefore, the authors support the ongoing use of endoscopic harvesting techniques.

Defining acute aortic syndrome after trauma: Are Abbreviated Injury Scale codes a useful surrogate descriptor?

BACKGROUND: The severity and location of injuries resulting from vehicular collisions are normally recorded in Abbreviated Injury Scale (AIS) code; we propose a system to link AIS code to a description of acute aortic syndrome (AAS), thus allowing the hypothesis that aortic injury is progressive with collision kinematics to be tested. METHODS: Standard AIS codes were matched with a clinical description of AAS. A total of 199 collisions that resulted in aortic injury were extracted from a national automotive collision database and the outcomes mapped onto AAS descriptions. The severity of aortic injury (AIS severity score) and stage of AAS progression were compared with collision kinematics and occupant demographics. Post hoc power analyses were used to estimate maximum effect size. RESULTS: The general demographic distribution of the sample represented that of the UK population in regard to sex and age. No significant relationship was observed between estimated test speed, collision direction, occupant location or seat belt use and clinical progression of aortic injury (once initiated). Power analysis confirmed that a suitable sample size was used to observe a medium effect in most of the cases. Similarly, no association was observed between injury severity and collision kinematics. CONCLUSION: There is sufficient information on AIS severity and location codes to map onto the clinical AAS spectrum. It was not possible, with this data set, to consider the influence of collision kinematics on aortic injury initiation. However, it was demonstrated that after initiation, further progression along the AAS pathway was not influenced by collision kinematics. This might be because the injury is not progressive, because the vehicle kinematics studied do not fully represent the kinematics of the occupants, or because an unknown factor, such as stage of cardiac cycle, dominates. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level IV.

Three strikes--don't die of a broken heart.

There are multiple layers of complexity in prevention of vehicle related blunt traumatic aortic rupture (BTAR), many of which are enshrined within government policy and car design. We present a 'layers of protection analysis' (LOPA) based loosely on original work by Professor John Doyle, which describes these attempts to 'design out' the risk of BTAR following a vehicle collision. We have modified this approach to include a physiological dimension suggesting that this may be a factor in susceptibility to aortic injury following trauma. Understanding processes involved in BTAR following vehicle collisions is key to designing preventative processes.