Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10$^{−27and−30}$). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research

Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10−27and−30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research

Endothelial function and dysfunction in coronary artery bypass grafting

The integrity of the endothelium is of importance for short- and long-term results following coronary artery bypass grafting (CABG). In this thesis different factors of the endothelial role in the regulation of vascular tone in relation to various current aspects of CABG have been investigated. In study I, the time dependent effects of local ischaemia and reperfusion on the coronary vasoreactivity in the pig was evaluated. The model used was chosen because of its similarities to offpump CABG. It was shown that already short-term (10 min) interruption of the coronary blood flow caused marked effects on the endothelium-dependent vasodilator capacity. In study II, the cardiac outflow of vasoactive substances (Endothelin-1 (ET-1), Nitric oxide (NO) and prostacyclin (PGI2)), and the metabolic strain, in off-pump CABG was evaluated. An increased outflow of PG12 was observed, as well as a significant myocardial lactate release. In study III, the coronary vasoreactivity following on-pump CABG in patients with stable and unstable angina pectoris, and following off-pump CABG was studied. Endothelium-dependent vasodilator mechanisms were better preserved in off-pump CABG, while there was no difference in endothelium independent coronary vasodilatation in off- and on-pump CABG. In study IV, the tissue content of ET-1 in the internal mammary artery (IMA) and the radial artery (RA) was determined. Furthermore the in vitro functional effects of ET-1 on the IMA and the RA was investigated. The highest level of ETA was found in the distal RA, and followed in declining order by the proximal RA, the ascending aorta and the distal IMA. ETA acted as a potent vasoconstrictor of the IMA and the RA, through interaction with mainly ETA-receptors. ETA-blockers abolished this constriction. In study V, the influence of CABG on the plasma levels of ETA and Big ETA, as well as the pericardial levels of ETA and Big ET-1, in stable and unstable patients was determined. In addition, the tissue content of ETA and Big ETA in the IMA, and the in vitro functional effects of ETA and Big ETA on the IMA, in stable and unstable patients, were investigated. Unstable angina pectoris was associated with an increased ETA turnover, as indicated by higher Big ETA, but lower ETA circulating plasma levels. The pericardial levels of ETA was lower in the unstable patients. Revascularisation of the unstable patients caused a normalisation of Big ETA and ETA levels. ET-1 and Big ETA acted as potent vasoconstrictors of the IMA, through interaction with mainly ETAreceptors, in stable as well as unstable patients. In study VI, the myocardial metabolic disturbance during on-pump CABG, as well as the cardiac outflow of vasoactive substances (ET-1, NO and PGI2) following on-pump CABG, and local ET blockade, was determined. The coronary vasoreactivity following intracoronary infusion of ETblockers subsequent to CABG, and the effects of ET-receptor blockade on the coronary blood flow subsequent to CABG was also investigated. A myocardial lactate release, as well as an increased outflow of PG12 was observed. ET-receptor blockade after ischaemia did not improve endotheliumdependent vasodilatation. ET-receptor antagonists (ETA-blockade alone or combined with ETBblockade) did not influence cardiac outflow of ETA and did not improve immediate myocardial blood flow following CABG. Conclusions: Based on the present study it may be concluded that: (i) Off-pump CABG is less harmful compared to on-pump CABG in terms of cardiac endothelial and metabolic integrity; (ii) Unstable angina pectoris is associated with augmented ET-metabolism which is reversed by CABG; (iii) ET content, action and receptor activation are similar in arterial grafts commonly used in CABG; (iv) Coronary perfusion immediately following on-pump CABG is not dependent on ET-receptor activation

Mortality and reoperations in survivors operated on for acute type A aortic dissection and implications for catheter-based or hybrid interventions

ObjectiveThis study investigated late outcomes (mortality, reoperations) and their associated predictors after operations for acute type A aortic dissection. The role catheter-based and hybrid interventions is discussed.MethodsAll hospital survivors operated on for acute type A aortic dissection from 1990 through 2009 were reviewed, with cross-sectional follow-up. Mortality (overall and aortic) and freedom from reoperations (proximal and distal) were estimated using actuarial methods. Preoperative, intraoperative, and postoperative variables (n = 44) associated with late outcomes were analyzed with univariable and multivariable (Cox) statistical methods.ResultsOf 360 operated-on patients, 291 hospital survivors (81%) were monitored for a median of 5.5 years (1864 patient-years). Total late mortality was 30% (n = 86), with estimated (standard error) survival of 82% (3%), 64% (4%), and 48% (6%) at 5, 10, and 15 years, respectively. Aortic events accounted for at least 27% (up to 42% including unknown causes) of late deaths. In Cox analysis, variables independently related (hazard ratios [95% confidence limits]) to late mortality were increased age (1.6 per 10 years [1.3, 2.0]), earlier operation (<2005; 2.3 [1.2, 4.6]), permanent neurologic damage (2.6 [1.6, 4.2]), and respiratory insufficiency (3.4 [1.8, 6.4]). Thirty-four patients underwent 46 reoperations, 21 on the proximal and 25 on the distal aorta, up to 19 years after the primary operation; respective in-hospital reoperative mortality was 14% and 12%. Estimated freedom (standard error) from aortic reoperation was 95% (2%), 87% (4%), and 61% (5%) at 5, 10, and 15 years, respectively. In multivariable Cox analysis (hazard ratios [95% confidence limits]), use of surgical adhesive at the primary operation (4.2 [1.6, 11]) and temporary neurologic damage (3.2l [1.2, 8.9]) were independently related to proximal reoperation, and DeBakey type I dissection (10.5 [1.4, 80]) was related to late distal reoperation. Catheter-based (endovascular, percutaneous) or hybrid procedures were not used in any patients but could have been used in up to 74% of reoperations, including in four of six of those that resulted in in-hospital death and putatively in 10 of 17 patients who sustained lethal aortic events without reoperation.ConclusionsDespite close follow-up, aortic-related death after a successful operation for acute type A aortic dissection is prevalent, and overall mortality remains substantial. Reoperations are not uncommon, may be indicated very late as well as repeatedly in the same patient, and are associated with a significant mortality. Increased use of applicable but seemingly under-used catheter-based or hybrid treatment approaches could benefit this growing patient population by offering repeat intervention to more patients and as substitute for reoperative open surgery in selected cases

Guideline for resuscitation in cardiac arrest after cardiac surgery.

The Clinical Guidelines Committee of the European Association for Cardio-Thoracic Surgery provides this professional view on resuscitation in cardiac arrest after cardiac surgery. This document was created using a multimodal methodology for evidence generation including the extrapolation of existing guidelines from the International Liaison Committee on Resuscitation where possible, our own structured literature reviews on issues particular to cardiac surgery, an international survey on resuscitation hosted by CTSNet and manikin simulations of potential protocols. This protocol differs from existing generic guidelines in a number of areas, the most import of which are the following: successful treatment of cardiac arrest after cardiac surgery is a multi-practitioner activity with six key roles that should be allocated and rehearsed on a regular basis; in ventricular fibrillation, three sequential attempts at defibrillation (where immediately available) should precede external cardiac massage; in asystole or extreme bradycardia, pacing (where immediately available) should precede external cardiac massage; where the above measures fail, and in pulseless electrical activity, early resternotomy is advocated; adrenaline should not be routinely given; protocols for excluding reversible airway and breathing complications and for safe emergency resternotomy are given. This guideline is subject to continuous informal review, and when new evidence becomes available

EuroSCORE II dagger

To update the European System for Cardiac Operative Risk Evaluation (EuroSCORE) risk model. A dedicated website collected prospective risk and outcome data on 22 381 consecutive patients undergoing major cardiac surgery in 154 hospitals in 43 countries over a 12-week period (May-July 2010). Completeness and accuracy were validated during data collection using mandatory field entry, error and range checks and after data collection using summary feedback confirmation by responsible officers and multiple logic checks. Information was obtained on existing EuroSCORE risk factors and additional factors proven to influence risk from research conducted since the original model. The primary outcome was mortality at the base hospital. Secondary outcomes were mortality at 30 and 90 days. The data set was divided into a developmental subset for logistic regression modelling and a validation subset for model testing. A logistic risk model (EuroSCORE II) was then constructed and tested. Compared with the original 1995 EuroSCORE database (in brackets), the mean age was up at 64.7 (62.5) with 31% females (28%). More patients had New York Heart Association class IV, extracardiac arteriopathy, renal and pulmonary dysfunction. Overall mortality was 3.9% (4.6%). When applied to the current data, the old risk models overpredicted mortality (actual: 3.9%; additive predicted: 5.8%; logistic predicted: 7.57%). EuroSCORE II was well calibrated on testing in the validation data subset of 5553 patients (actual mortality: 4.18%; predicted: 3.95%). Very good discrimination was maintained with an area under the receiver operating characteristic curve of 0.8095. Cardiac surgical mortality has significantly reduced in the last 15 years despite older and sicker patients. EuroSCORE II is better calibrated than the original model yet preserves powerful discrimination. It is proposed for the future assessment of cardiac surgical risk

EACTS guidelines for the use of patient safety checklists

The Safety Checklist concept has been an integral part of many industries that face high-complexity tasks for many decades and in industries such as aviation and engineering checklists have evolved from their very inception. Investigations of the causes of surgical deaths around the world have repeatedly pointed to medical errors that could be prevented as an important cause of death and disability. As a result, the World Health Organisation developed and evaluated a three-stage surgical checklist in 2007 demonstrating that complications were significantly reduced, including surgical infection rates and even mortality. Together with the results from other large cohort studies into the utility of the surgical checklist, many countries have fully implemented the use of surgical checklists into routine practice. A key factor in the successful implementation of a surgical checklist is engagement of the staff implementing the checklist. In surgical specialties such as our own it was quickly seen that there were many important omissions in the generic checklist that did not cover issues particular to our specialty, and thus the European Association for Cardio-Thoracic Surgery embarked on a process to create a version of the checklist that might be more appropriate and specific to cardiothoracic surgery, including checks on preparations for excessive bleeding, perfusion arrangements and ICU preparations, for example. The guideline presented here summarizes the evidence for the surgical checklist and also goes through in detail the changes recommended for our specialty