Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion.

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Cardiopulmonary exercise testing augments watchful waiting in asymptomatic severe primary mitral regurgitation.

INTRODUCTION: Our aim is to describe the use of cardiopulmonary exercise testing in watchful waiting for asymptomatic severe primary mitral regurgitation. METHODS: Between October 2016 and October 2017, ten patients with asymptomatic severe primary mitral regurgitation underwent watchful waiting in a single centre. Baseline assessment included history, physical examination, transthoracic echocardiogram and cardiopulmonary exercise testing. Patients were re-evaluated every 6 months with history, physical examination and transthoracic echocardiogram; and at 12 months with cardiopulmonary exercise testing. RESULTS: At 1 year follow up, five patients remained asymptomatic with no significant change in left ventricular ejection fraction (p = 0.18). This was associated with no significant change in cardiopulmonary exercise testing parameters. However, five patients developed early new symptoms or changes in echocardiographic parameters with a significant fall in left ventricular ejection fraction (p < 0.01). This was associated with a significant fall in anaerobic threshold (p = 0.04) and four of the five patients having an abnormal percentage predicted peak VO2 at 1 year follow up. CONCLUSIONS: Changes in symptomatic status or echocardiographic parameters during a watchful waiting approach for asymptomatic severe primary mitral regurgitation is associated with a significant reduction in cardiopulmonary exercise testing parameters.

A new integrative approach combining right heart catheterization and echocardiography to stage aortic stenosis-related cardiac damage.

Introduction: Although staging of the extent of aortic stenosis (AS)-related cardiac damages is usually performed via echocardiography, this technique has considerable limitations in assessing pulmonary artery and right chamber pressures. The present hypothesis-generating study sought to explore the efficacy of a staging system of cardiac damage based on echocardiographic and invasive [right heart catheterization (RHC)] hemodynamic parameters in patients undergoing transcatheter aortic valve implantation (TAVI). Methods: We studied 90 symptomatic patients with severe AS in whom echocardiographic and invasive evaluation by RHC was obtained prior to TAVI. Cardiac damage stages were defined as follows: no cardiac damage (stage 0), left ventricular (LV) damage (stage 1), left atrial or mitral valve damage (stage 2), pulmonary vasculature or tricuspid valve damage (stage 3), and right ventricular (RV) dysfunction or low-flow state (stage 4). With the integrative approach using RHC, pulmonary hypertension (PH) was defined as an mPAP ≥25 mmHg and the low-flow state corresponded to a cardiac index of <1.8 L/min/m2 and a right atrial pressure of >10 mmHg. Results: During follow-up (median: 2.9 years), 43 patients (47.8%) died. The integrative cardiac damage staging was associated with a significant increase in all-cause and cardiovascular mortality per each increase of cardiac damage stage, whereas the outcome was similar according to the echocardiographic staging. Conclusions: A staging system of cardiac lesion based on echocardiographic and invasive hemodynamic parameters in patients with severe AS undergoing TAVI predicts mortality. Patients with pre-existing PH, ≥ moderate tricuspid regurgitation and/or RV dysfunction, and a low-flow state had a markedly increased risk of death. Further larger studies are needed to validate our findings.

Detachable Aortic Clamp for Minimally Invasive Cardiac Surgery.

Since its first implementation, minimally invasive cardiac surgery has become more and more popular among surgeons. By avoiding a complete opening of the sternum, this surgery is traditionally associated with a faster recovery, less surgical pain and less postoperative bleeding and transfusions. With its growing popularity, the need for specifically designed surgical instrumentation is evident. Since 2008, the detachable-branch Glauber clamp (Cardiovision-Trytech, Tokyo, Japan) has been used to facilitate aortic cross-clamp during minimally invasive cardiac surgery, to optimize the intraoperative visualization field without the need for adjunctive incisions of the thorax. It has been specifically developed for limited single-access minimally invasive valve surgery. The clamp is introduced through the main access incision (mini-sternotomy or mini thoracotomy) by means of a specifically designed delivery system, which is subsequently removed, leaving inside the thorax only the detachable closed branches on the aorta. Since its first implementation, the clamp has been used in numerous patients at several cardiac surgery centers worldwide. Over the years, attempts have been made to improve its ergonomics and enhance its performance. The G2 detachable-branch Glauber clamp (USB Medical, Hatboro, PA, USA) occupies a smaller space inside the thorax, has a simplified gripping mechanism and comes with detachable arms that enhance versatility with up to 10 possible clamp configurations. This article describes the characteristics of detachable-branch aortic clamps and compares them to other aortic cross-clamps that are currently available for minimally invasive cardiac surgery.

Validation of the German Registry for Acute Aortic Dissection Type A Score in predicting 30-day mortality after type A aortic dissection surgery.

OBJECTIVES: No reliable scores are available to predict mortality following surgery for type A acute aortic dissection (TAAAD). Recently, the German Registry of Acute Aortic Dissection Type A (GERAADA) score has been developed. We aim to compare how the GERAADA score performs in predicting operative mortality for TAAAD to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. METHODS: We calculated the GERAADA score and EuroSCORE II in patients who underwent TAAAD repair at the Bristol Heart Institute. As there are no precise criteria to calculate the GERAADA score, we used 2 methods: a Clinical-GERAADA score, which evaluated malperfusion with clinical and radiological evidence, and a Radiological-GERAADA score, where malperfusion was assessed by computed tomography scan alone. RESULTS: 207 consecutive patients had surgery for TAAAD, and the observed 30-day mortality was 15%. The Clinical-GERAADA score showed the strongest discriminative power with an area under the curve (AUC) of 0.80 [95% confidence interval (CI) 0.71-0.89], while the Radiological-GERAADA score had an AUC of 0.77 (95% CI 0.67-0.87). EuroSCORE II showed acceptable discriminative power with an AUC of 0.77 (95% CI 0.67-0.87). CONCLUSIONS: Clinical GERAADA score performed better than the other scores and it is specific and easy to use in the context of a TAAAD. Further validation of the new criteria for malperfusion is needed.

MRI-based strain measurements reflect morphological changes following myocardial infarction: A study on the UK Biobank cohort.

In a porcine experimental model of myocardial infarction, a localised, layer-specific, circumferential left ventricular strain metric has been shown to indicate chronic changes in ventricular function post-infarction more strongly than ejection fraction. This novel strain metric might therefore provide useful prognostic information clinically. In this study, existing clinical volume indices, global strains, and the novel, layer-specific strain were calculated for a large human cohort to assess variations in ventricular function and morphology with age, sex, and health status. Imaging and health data from the UK Biobank were obtained, including healthy volunteers and those with a history of cardiovascular illness. In total, 710 individuals were analysed and stratified by age, sex and health. Significant differences in all strain metrics were found between healthy and unhealthy populations, as well as between males and females. Significant differences in basal circumferential strain and global circumferential strain were found between healthy males and females, with males having smaller absolute values for both (all p ≤ 0.001). There were significant differences in the functional variables left ventricular ejection fraction, end-systolic volume, end-systolic volume index and mid-ventricular circumferential strain between healthy and unhealthy male cohorts aged 65-74 (all p ≤ 0.001). These results suggest that whilst regional circumferential strains may be useful clinically for assessing cardiovascular health, care must be taken to ensure critical values are indexed correctly to age and sex, due to the differences in these values observed here.

Systematic total arch replacement with thoraflex hybrid graft in acute type A aortic dissection: A single centre experience.

Introduction: In the last two decades, a more aggressive approach has been encouraged to treat patients with acute type A aortic dissection (ATAAD), extending the repair to the aortic arch and proximal descending thoracic aorta with the frozen elephant trunk (FET) implantation. Here, we report our single-centre experience with the FET technique for the systematic treatment of emergency type A aortic dissection. Materials and methods: Between December 2017 and January 2022, 69 consecutive patients were admitted with ATAAD; of those, 66 patients (62.9 ± 10.2 years of age, 81.8% men) underwent emergency hybrid aortic arch and FET repair with the multibranched Thoraflex hybrid graft and were enrolled in the study. Primary endpoints were 30 days- and in-hospital mortality. Secondary endpoints were postoperative morbidity and follow-up survival. To better clarify the impact of age on surgical outcomes, we have divided the study population into two groups: group A for patients <70 years of age (47 patients), and group B for patients ≥70 years (19 patients). Time-to-event analysis has been conducted using the Log-rank test and is displayed with Kaplan-Meier curves. A multiple Cox proportional Hazard model was developed to identify predictors of long-term survival with a stepwise backward/forward selection process. Results: 30-days- and in-hospital mortality were 10.6 and 13.6%, respectively. Stroke occurred in three (4.5%) patients. Two (3.0%) patients experienced spinal cord ischemia. We did not find any statistically significant difference between the two groups in terms of main post-operative outcomes. The multivariable Cox proportional hazard model showed left ventricular ejection fraction (HR: 0.83, 95% CI: 0.79-0.92, p < 0.01), peripheral vascular disease (HR: 15.8, 95% CI: 3.9-62.9, p < 0.01), coronary malperfusion (HR: 0.10, 95% CI: 0.01-0.77, p =0.03), lower limbs malperfusion (HR: 5.1, 95% CI: 1.10-23.4, p = 0.04), and cardiopulmonary bypass time (HR: 1.02, 95% CI: 1-1.04, p = 0.01) as independent predictors of long term mortality. Conclusions: Frozen elephant trunk repair to treat emergency type A aortic dissection appears to be associated with good early and mid-term clinical outcomes even in the elderly.

The need for custom made frozen elephant trunk: when and where.

The frozen elephant trunk (FET) technique is an increasingly common procedure to treat complex extensive aortic disease both in elective and emergency setting. In a contemporary era, several prostheses are available to be used by surgeons performing such procedures, merging the advantages of endovascular and conventional surgery and preparing a more useful landing zone for second-stage downstream endovascular or open repair. Thoraflex hybrid (Terumo Aortic, Scotland) is a largely used hybrid vascular device merging a conventional surgical vascular graft made of gelatin-sealed woven polyester graft with a nitinol self-expanding stent graft. Since its release in 2012, this prosthesis has gained a large consensus, mainly for the plexus version, which allows for single reimplantation of the epiaortic vessels. In the last few years, new devices have come out to offer new specific weapons to be used by the surgical team in different clinical scenarios. In this context, the need of making the supra-aortic vessel debranching easier and more functional to our surgical technique has pushed our demand for a customization of a conventional Thoraflex hybrid. Here we report a modification to its standard design, the concept beyond the "Custom device" and its potential advantages with regards to our peculiar implantation technique and intraoperative cerebral perfusion during circulatory arrest time.

Development and Preliminary Testing of Porcine Blood-Derived Endothelial-like Cells for Vascular Tissue Engineering Applications: Protocol Optimisation and Seeding of Decellularised Human Saphenous Veins.

Functional endothelial cells (EC) are a critical interface between blood vessels and the thrombogenic flowing blood. Disruption of this layer can lead to early thrombosis, inflammation, vessel restenosis, and, following coronary (CABG) or peripheral (PABG) artery bypass graft surgery, vein graft failure. Blood-derived ECs have shown potential for vascular tissue engineering applications. Here, we show the development and preliminary testing of a method for deriving porcine endothelial-like cells from blood obtained under clinical conditions for use in translational research. The derived cells show cobblestone morphology and expression of EC markers, similar to those seen in isolated porcine aortic ECs (PAEC), and when exposed to increasing shear stress, they remain viable and show mRNA expression of EC markers similar to PAEC. In addition, we confirm the feasibility of seeding endothelial-like cells onto a decellularised human vein scaffold with approximately 90% lumen coverage at lower passages, and show that increasing cell passage results in reduced endothelial coverage.

Clinical Outcomes and OCT Analysis After Culotte Stenting With 2nd- and 3rd-Generation Everolimus-Eluting Stents: Two-Year Follow-Up of the CELTIC Bifurcation Study.

PURPOSE: The aim of this study was to provide 2-year clinical outcomes for patients with Medina 1,1,1 bifurcation lesions treated with a culotte technique, comparing Synergy and Xience drug eluting stent (DES) platforms. A sub-group analysis of 9-month Optical Coherence Tomography (OCT) was performed to assess stent healing. METHODS: A total of 170 patients with non-left main stem Medina 1,1,1 lesions, were randomized to treatment with Synergy or Xience DES. The primary outcome was a composite of death, myocardial infarction, stroke, target vessel failure, stent thrombosis and angiographic restenosis. Qualitative and quantitative analyses of 30 bifurcations were carried out on OCT images taken at 9-month follow-up. RESULTS: After 2 years, the primary outcome had occurred in 17.7% of patients in the Synergy group and 18.8% of patients in the Xience group. The non-inferiority test was met (p = 0.0055). MACCE occurred in 7.3% of all patients by 2 years. OCT analysis found smaller stent and lumen areas in patients treated with Synergy stents. There was a higher proportion of malapposed struts in patients treated with Xience stents. CONCLUSIONS: The first report of the CELTIC bifurcation study demonstrated a low MACCE rate after 9 months. There was little accrual of events after this timepoint. There was no difference in clinical outcomes between the platforms tested. OCT analysis demonstrated excellent healing of both platforms.

Hybrid coronary revascularization versus coronary artery bypass grafting for multivessel coronary artery disease: A systematic review and meta-analysis.

BACKGROUND: Hybrid coronary revascularization (HCR) combines the benefits of a left internal mammary artery to left anterior descending artery anastomosis, via a mini thoracotomy, with percutaneous coronary intervention (PCI) for other diseased coronaries. AIMS: The aim of this meta-analysis is to compare the short- and long-term outcomes of HCR with those of coronary artery bypass grafting (CABG) for multi-vessel coronary artery disease (MCAD). METHODS: We performed a meta-analysis with a primary outcome of short-term mortality and secondary outcomes of mid-term survival, length of hospital stay, stroke, renal failure and mid-term MACE rate. RESULTS: 3399 patients (HCR = 1164, CABG = 2235) were included, with no significant difference in short-term mortality between groups (OR = 1.50, 95% CI = [0.90,2.49], p = 0.11), although a higher mortality rate was seen in the HCR group (0.73% vs 0.64%). The average length of stay in intensive care unit was significantly shorter following HCR than CABG (mean difference = -15.52 h, CI = [-22.47,-8.59], p˂0.001) and overall hospital stay was also shorter in this group, although not statistically significant (mean difference = -3.15 days, 95% CI = [-6.55, 0.25], p = 0.07). HCR was associated with a reduced odds of blood transfusion (OR = 0.34, 95% CI = [0.22,0.54], p < 0.001). There was not a significant difference in mid-term survival (OR = 0.86, 95% CI = [0.62,1.21], p = 0.39) or MACE rate (OR = 0.82, 95% CI = [0.55,1.23], p = 0.34). No differences were found between HCR and CABG for post-operative stroke (OR = 1.36, 95% CI = [0.87, 2.13], p = 0.16) or renal failure (OR = 0.71, 95% CI = [0.43,1.16], p = 0.14). CONCLUSIONS: HCR has a higher incidence of short-term mortality compared to CABG in patients with MCAD, although this difference is not statistically significant. Similar rates of mid-term survival and other short term post-operative complications were found between the two groups. HCR has a shorter ICU stays and reduced requirement for blood transfusion.