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.

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.

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.

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.

Blood lactate predicts mortality after surgical repair of type A acute aortic dissection.

BACKGROUND: Ischemia and malperfusion are strong predictors of poor postoperative outcomes in type A acute aortic dissection (TAAAD). Serum lactate is an accurate surrogate point-of-care marker of malperfusion. The aim of this study is to investigate the correlation between lactate, in-hospital outcomes, and 1-year survival following TAAAD repair. METHODS: One hundred and thirty-two patients underwent operative repair of TAAAD over a 4-year period at our institution 128 patients had serum lactate measurements at three stages peri-operatively-preoperatively, at the end of cardiopulmonary bypass (post-CPB) and 6 h postintensive care unit (ICU) admission. The primary outcomes were in-hospital mortality and 1-year survival. The secondary outcomes were the incidences of in-hospital morbidities. RESULTS: Patients were divided into two groups: 88 (68.8%) with normal lactate and 40 (31.2%) with elevated lactate (>2.2 mmol/L). Lactate measured preoperatively (odds ratio 1.52, 95% confidence interval 1.17-2.07, p < .01), post-CPB (1.34, 1.14-1.64, p < .01) and 6 h post-ICU admission (1.29, 1.08-1.55, p < .01) was an independent predictor of in-hospital mortality. Following adjustment for the Penn Classification, lactate continued to have a significant correlation with in-hospital mortality at all three timepoints. There was a higher incidence of complications in the elevated lactate group and especially hemofiltration (20% vs. 9.1%, p = .08). 1-year survival was similar in both groups (p = .23). CONCLUSIONS: There is a direct correlation between elevated serum lactate and postoperative mortality after TAAAD repair, which is independent of the Penn Classification status on admission.

Frozen elephant trunk procedure for complex aortic arch surgery: The Salerno experience with Thoraflex hybrid.

BACKGROUND AND AIM OF THE STUDY: To report early clinical outcomes of the frozen elephant trunk (FET) technique for the treatment of complex aortic diseases after transition from conventional elephant trunk. METHODS: A single-center, retrospective study of patients who underwent hybrid aortic arch and FET repair for aortic arch and/or proximal descending aortic aneurysms, acute and chronic Stanford type A aortic dissection with arch and/or proximal descending involvement, Stanford type B acute and chronic aortic dissections with retrograde aortic arch involvement. RESULTS: Between December 2017 and May 2020, 70 consecutive patients (62.7 ± 10.6 years, 59 male) were treated: 41 (58.6%) for emergent conditions and 29 (41.4%) for elective. Technical success was 100%. In-hospital mortality was 14.2% (n = 12, 17.1% emergent vs. 10.3% elective, P = NS); 2 (2.9%) major strokes; 1 (1.4%) spinal cord injury. Mean follow-up was 12.5 months (interquartile range, 3.7-22.3). Overall survival at 3, 6, 12, and 24 months was 90% (95% confidence interval [CI], 83.2-97.3), 85.6% (95% CI, 77.7-94.3), 79.1% (95% CI, 69.9-89.5), 75.6% (95% CI, 65.8-86.9) and 73.5% (95% CI, 63.3-85.3). There were no aortic re-interventions and no distal stent graft-induced new entry (dSINE); 5 patients with residual type B dissection underwent TEVAR completion. CONCLUSIONS: In a real-world setting, FET with Thoraflex Hybrid demonstrated feasibility and good clinical outcomes, even in emergent setting. Our implant technique optimize cerebral perfusion reporting good results in terms of neurological complications. Techniques to perfect the procedure and to reduce remaining risks, and consensus on considerations such as standardized cerebral protection need to be reported.

Frozen Elephant Trunk Technique in Acute Type A Aortic Dissection: Is It for All?

Acute type A aortic dissection (ATAAD) is an indisputable emergency with very poor outcomes without surgical treatment. Although the aortic arch is often involved in the aortic dissection, its optimal management during surgical therapy remains uncertain. A conservative tear-oriented approach has traditionally been adopted, limiting the procedure to the ascending aorta (or hemiarch) replacement. However, dilation of the residual dissected aorta and subsequent rupture may occur, requiring further intervention in the future. In the last two decades, the frozen elephant trunk (FET) technique has become a valid and attractive option to treat aortic disease when the arch and the thoracic aorta are involved, both in elective and in emergency settings. Here, we report a review of the contemporary literature regarding the short- and long-term outcomes of the FET technique in ATAAD repair.

Quantitative evaluation and comparison of coronary artery characteristics by 3D coronary volume reconstruction.

Non-atherosclerotic abnormalities of vessel calibre, aneurysm and ectasia, are challenging to quantify and are often overlooked in qualitative reporting. Utilising a novel 3-dimensional (3D) quantitative coronary angiography (QCA) application, we have evaluated the characteristics of normal, diabetic and aneurysmal or ectatic coronary arteries. We selected 131 individuals under 50 years-of-age, who had undergone coronary angiography for suspected myocardial ischaemia between 1st January 2011 and 31st December 2015, at the Bristol Heart Institute, Bristol, UK. This included 42 patients with angiographically normal coronary arteries, 36 diabetic patients with unobstructed coronaries, and 53 patients with abnormal coronary dilatation (aneurysm and ectasia). A total of 1105 coronary segments were analysed using QAngio XA 3D (Research Edition, Medis medical imaging systems, Leiden, The Netherlands). The combined volume of the major coronary arteries was significantly different between each group (1240 ± 476 mm3 diabetic group, 1646 ± 391 mm3 normal group, and 2072 ± 687 mm3 abnormal group). Moreover, the combined coronary artery volumes correlated with patient body surface area (r = 0.483, p < 0.01). Inter-observer variability was assessed and intraclass correlation coefficient of the total coronary artery volume demonstrated a low variability of 3D QCA (r = 0.996, p < 0.001). Dedicated 3D QCA facilitates reproducible coronary artery volume estimation and allows discrimination of normal and diseased vessels.