| 1. |
- Hägg, Sara, 1977-, et al.
(författare)
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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
- 2009
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Ingår i: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Tidskriftsartikel (refereegranskat)abstract
- 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, cellular and lesion expression of LDB2, and 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.
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| 2. |
- Hägg, Sara, et al.
(författare)
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Molecular Phenotypes of Coronary Artery Disease : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUNDBy offering a comprehensive view of the molecular underpinnings of pathology, high-dimensional data have the potential to revolutionize the diagnosis and management of complex disorders such as coronary artery disease (CAD). To identify molecular phenotypes of CAD, we performed multi organ gene expression profiling of subjects enrolled in the Stockholm Atherosclerosis Gene Expression (STAGE) study.METHODSAtherosclerotic and unaffected arterial wall, liver, skeletal muscle, and mediastinal fat biopsies were obtained during coronary artery bypass grafting from 114 well-characterized CAD patients. RNA samples were isolated, and 278 transcription profiles were obtained using Affymetrix HG-U133_Plus_2 GeneChips.RESULTSThe most prominent molecular phenotype of the CAD patients was represented by 733 genes in mediastinal fat, which were involved in extracellular matrix organization, response to stress and regulation of programmed cell death. Other aspects of this phenotype were shared with liver (e.g., oxidoreductase activity), skeletal muscle (insulin-like growth factor binding), and atherosclerotic arterial wall (cell motility and adhesion, fatty acid metabolism). In addition, the activity of 400 genes exclusively in mediastinal fat was associated with the extent of coronary stenosis and atherosclerosis. Immune-cell activation in mediastinal fat defined CAD patients with poor blood glucose control and prolonged hospitalization.CONCLUSIONSThe molecular phenotype of mediastinal fat appears to be central in CAD and should be useful for early identification of CAD risk.
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| 3. |
- Lockowandt, Ulf
(författare)
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Endothelial function and dysfunction in coronary artery bypass grafting
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Nashef, Samer A. M., et al.
(författare)
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EuroSCORE II dagger
- 2012
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Ingår i: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 41:4, s. 734-745
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Sartipy, Ulrik, et al.
(författare)
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Cardiac rupture during vacuum-assisted closure therapy.
- 2006
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Ingår i: The Annals of thoracic surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 82:3, s. 1110-1
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Tidskriftsartikel (refereegranskat)abstract
- Vacuum-assisted closure therapy is a recently introduced technique for treatment of deep sternal wound infections after cardiac surgery. We present five cases of vacuum-assisted closure therapy-related major bleeding complications due to rupture of the right ventricle. This potentially lethal complication may be avoided by covering the heart with protective layers of paraffin gauze dressings.
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