Per Bergman

Postoperative stroke in cardiac surgery is related to the location and extent of atherosclerotic disease in the ascending aorta

OBJECTIVES The aim of the study was to evaluate the risk from calcified atheromas in the ascending aorta, and the extent and topography of the disease in the development of stroke after cardiac surgery. BACKGROUND Postoperative stroke constitutes a serious problem in cardiac surgery, and atherosclerosis of the ascending aorta is an important risk factor. METHODS Before surgical manipulation epiaortic echocardiographic ultrasound was performed to evaluate the ascending aorta in 921 consecutive patients undergoing cardiac surgery. The presence of calcification, location of atheroma, extent of the disease and clinical variables including postoperative stroke were recorded prospectively. RESULTS A total of 26.2% of the patients had atherosclerosis of the ascending aorta, and in 44.4% of them more than one of 12 possible segments was involved. Logistic regression showed that atherosclerotic disease in the ascending aorta was the most important predictive factor for postoperative stroke. The incidence of stroke was 1.8% in patients without atherosclerotic disease of the ascending aorta, and 8.7% in patients with the disease (p < 0.0001). Diabetes mellitus was also a predictive factor (p = 0.04). A new and unique finding of this study was that the middle-lateral segment is an independent predictive factor for postoperative stroke, with a relative risk of 26% (p = 0.04). CONCLUSIONS Patients with atheromatosis in the ascending aorta had an 8.7% incidence of postoperative stroke, in spite of minor surgical modifications. The risk depended on the presence, location and extent of the disease. Randomized trials evaluating alternative surgical strategies in coronary surgery are urgently needed in high risk patients.

Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor.

BACKGROUND Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined. OBJECTIVE We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses. METHODS Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less. RESULTS Low concentrations of PGE2 (0.01-1 μmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 μmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure. CONCLUSION The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.

Atherosclerosis of the ascending aorta as a major determinant of the outcome of cardiac surgery

Epiaortic ultrasonography has high sensitivity for the detection of atherosclerosis. In several studies, the technique has identified atherosclerosis of the ascending aorta as the major risk factor for stroke after cardiac surgery. The level of risk depends on the presence, location and extent of disease when the ascending aorta is surgically manipulated. This knowledge enables clinicians to focus on the diagnostic and surgical technique and to consider the various options. Routine use of intraoperative epiaortic ultrasonography should be applied so that surgical manipulation of the ascending aorta can be reduced or, if possible, avoided in patients with atherosclerosis of the ascending aorta. Alternatively, if major manipulation such as clamping must be performed in the presence of severe atherosclerosis, the use of intra-aortic filters could be considered.

Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.

Taste-sensing type 2 receptors (TAS2Rs) have been implicated in extraoral functions. Airway smooth muscle expresses TAS2Rs and is strongly relaxed by TAS2R agonists. We hypothesised that TAS2R agonists might affect vascular smooth muscle as well. Moreover, the general pharmacological profile of TAS2R agonists, which are used to investigate the functions of TAS2R׳s, are undefined. The aim of this study was to pharmacologically characterise the effects of five prototype TAS2R agonists in vascular smooth muscle. Responses to the TAS2R agonists were investigated in guinea-pig aorta and taenia coli, mouse aorta (wild-type and caveolin-1-/- mice) and human pulmonary arteries. Chloroquine, denatonium, dextromethorphan, noscapine and quinine, agonists for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, induced strong endothelium-independent relaxations (responses between 82-96% of maximal relaxations) in phenylephrine pre-contracted guinea-pig aorta that persisted in the presence of L-type Ca2+ and KCa1.1-channel blockers. Experiments in guinea-pig taenia coli revealed that denatonium and quinine also inhibited relaxations to phenylephrine, indicating antagonism of α-adrenoceptors. Only chloroquine and noscapine mediated relaxations when the guinea pig aorta was pre-contracted by U-46619 or PGF2α. Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1-/- mice. Chloroquine and noscapine mediated relaxations of human pulmonary arteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the α1A adrenoceptor. Notwithstanding whether TAS2Rs are involved or not, TAS2R agonists have profound effects on vascular smooth muscle. Chloroquine and noscapine are of special interest as their effects cannot be accounted for by conventional pathways.

Aortic atheroma is related to number of particulates captured by intra-aortic filtration in CABG

OBJECTIVE Intra-aortic filtration during coronary artery bypass grafting (CABG) has the potential to harvest all particles embolized into the aorta proximal to the filter. The aim of this study was to determine risk factors for embolization of particles during CABG. METHODS Forty consecutive patients undergoing conventional multi-vessel CABG were included in the study. Plaques of the ascending aorta were determined by epiaortic ultrasonography prior to aortic manipulation. Intra-aortic filters (Embol-X, Mountain View, CA) were inserted before removal of the aortic cross-clamp and extracted after end of cardiopulmonary bypass. Filters underwent histologic analysis at a core lab (Stanford University, Stanford, CA). RESULTS The average number of proximal anastomoses was 2.2 (SD 0.55, range 1-3). All patients had particles in the filters. The average number of particles per filter was 10.5 (SD 5.4, range 2-23) with a mean surface area of 8.1mm(2) (SD 9.3, range 0.3-51.1). Fibrous atheroma was extracted from 85% (34/40) of the filters. Logistic regression explained 46% (r(2)=0.46, P<0.001) of the number of particles harvested by the filters. The most important independent risk factors for particles were number/grade of atheromas in the ascending aorta (P<0.01), obesity (P<0.02), hypertension (P<0.02) and number of proximal anastomoses (P<0.02). CONCLUSIONS Atheroma in the ascending aorta is the most important risk factor for particle embolization during CABG. The number of particles correlated with the extent of atheromatous disease in the ascending aorta and logistic regression identified hypertension, obesity and the number of proximal anastomoses to have significant influence on the number of captured particulates.

A novel method for sample preparation of fresh lung cancer tissue for proteomics analysis by tumor cell enrichment and removal of blood contaminants

BackgroundIn-depth proteomics analyses of tumors are frequently biased by the presence of blood components and stromal contamination, which leads to large experimental variation and decreases the proteome coverage. We have established a reproducible method to prepare freshly collected lung tumors for proteomics analysis, aiming at tumor cell enrichment and reduction of plasma protein contamination. We obtained enriched tumor-cell suspensions (ETS) from six lung cancer cases (two adenocarcinomas, two squamous-cell carcinomas, two large-cell carcinomas) and from two normal lung samples. The cell content of resulting ETS was evaluated with immunocytological stainings and compared with the histologic pattern of the original specimens. By means of a quantitative mass spectrometry-based method we evaluated the reproducibility of the sample preparation protocol and we assessed the proteome coverage by comparing lysates from ETS samples with the direct lysate of corresponding fresh-frozen samples.ResultsCytological analyses on cytospin specimens showed that the percentage of tumoral cells in the ETS samples ranged from 20% to 70%. In the normal lung samples the percentage of epithelial cells was less then 10%. The reproducibility of the sample preparation protocol was very good, with coefficient of variation at the peptide level and at the protein level of 13% and 7%, respectively. Proteomics analysis led to the identification of a significantly higher number of proteins in the ETS samples than in the FF samples (244 vs 109, respectively). Albumin and hemoglobin were among the top 5 most abundant proteins identified in the FF samples, showing a high contamination with blood and plasma proteins, whereas ubiquitin and the mitochondrial ATP synthase 5A1 where among the top 5 most abundant proteins in the ETS samples.ConclusionThe method is feasible and reproducible. We could obtain a fair enrichment of cells but the major benefit of the method was an effective removal of contaminants from red blood cells and plasma proteins resulting in larger proteome coverage compared to the direct lysis of frozen samples. This sample preparation method may be successfully implemented for the discovery of lung cancer biomarkers on tissue samples using mass spectrometry-based proteomics.

Preoperative computed tomography or intraoperative epiaortic ultrasound for the diagnosis of atherosclerosis of the ascending aorta

BACKGROUND Extensive atherosclerotic disease, usually first diagnosed intraoperatively, is the most important risk factor for postoperative stroke after cardiac surgery. The aim of this study was to investigate if preoperative computed tomography (CT) is comparable with intraoperative epiaortic ultrasound to diagnose severe atherosclerosis in the ascending aorta. METHODS The study included 20 consecutive patients who underwent elective coronary artery bypass surgery. Preoperative CT evaluation of the ascending aorta was compared with intraoperative epiaortic ultrasound findings. The ascending aorta was divided into 12 segments per patient, giving 240 segments to compare. RESULTS Epiaortic ultrasound detected atherosclerosis in 16.7% +/- 2.4% of the segments, a rate significantly higher than with CT ( P < or =.03). There was a low reliability between the 2 methods, indicated by kappa coefficients of 0.45 or lower. CONCLUSIONS The CT method is inferior to epiaortic ultrasound, todays gold standard, in diagnosing the extent and location of atherosclerosis of the ascending aorta. Other methods, possibly magnetic resonance imaging, should be considered.

A policy to reduce stroke in patients with extensive atherosclerosis of the ascending aorta undergoing coronary surgery.

Since 1995 we have routinely used epiaortic scanning in cardiac surgery and since 1998 we have employed off-pump surgery for coronary revascularization. In patients with extensive atherosclerosis in the ascending aorta we tried to assess whether or not conversion from a planned on-pump to off-pump coronary surgery affects the incidence of postoperative stroke. We studied 28 consecutive patients with extensive atherosclerosis in the ascending aorta undergoing coronary surgery. Extensive atherosclerosis, detected by epiaortic ultrasound, was defined as involvement of 6 or more out of 12 segments. Since 1998 we have converted 15 patients with extensive atherosclerosis in the ascending aorta from on-pump to off-pump. Thirteen patients with similar disease who underwent on-pump before the introduction of off-pump were used as controls. The incidence of stroke in the off-pump group was 0% as compared with 31% in the coronary artery bypass grafting group (P=0.03). Y-grafts were used more often in the off-pump (47%) than in the on-pump group (0%, P<0.01). The non-touch technique of the ascending aorta was also more frequently used in the off-pump group (73 versus 0%, P<0.001). Off-pump reduces the incidence of stroke in patients with aortic atherosclerosis when the disease occupies 50% or more of the ascending aorta.

Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69−CD56dim cells

Background: In contrast to the extensive knowledge about human natural killer (NK) cells in peripheral blood, relatively little is known about NK cells in the human lung. Knowledge about the composition, differentiation, and function of human lung NK cells is critical to better understand their role in diseases affecting the lung, including asthma, chronic obstructive pulmonary disease, infections, and cancer. Objective: We sought to analyze and compare the phenotypic and functional characteristics of NK cells in the human lung and peripheral blood at the single‐cell level. Methods: NK cells in human lung tissue and matched peripheral blood from 132 subjects were analyzed by using 16‐color flow cytometry and confocal microscopy. Results: CD56dimCD16+ NK cells made up the vast majority of NK cells in human lungs, had a more differentiated phenotype, and more frequently expressed educating killer cell immunoglobulin‐like receptors compared with NK cells in peripheral blood. Despite this, human lung NK cells were hyporesponsive toward target cell stimulation, even after priming with IFN‐&agr;. Furthermore, we detected a small subset of NK cells expressing CD69, a marker of tissue residency. These CD69+ NK cells in the lung consisted predominantly of immature CD56brightCD16− NK cells and less differentiated CD56dimCD16+ NK cells. Conclusion: Here, we characterize the major NK cell populations in the human lung. Our data suggest a model in which the majority of NK cells in the human lung dynamically move between blood and the lung rather than residing in the lung as bona fide tissue‐resident CD69+ NK cells. Graphical abstract Figure. No Caption available.

Validation of the 7th TNM classification for non-small cell lung cancer: A retrospective analysis on prognostic implications for operated node-negative cases

Abstract Background. The 7th TNM staging system for non-small cell lung cancer (NSCLC) developed by the International Association for the study of Lung Cancer (IASLC) has been applied in Sweden since the beginning of the year 2010. The aim of this retrospective study was to evaluate the prognostic role of the 7th TNM staging system in a surgical Swedish patient cohort with node-negative NSCLC. Material and methods. We collected data from stage I patients (pT1-2 pN0, 6th TNM system) who underwent surgery for NSCLC at Karolinska University Hospital from 1987 to 2002. Tumors were restaged according to the 7th TNM version. Cox multivariate survival analysis was implemented in order to determine the prognostic impact of pathological stage when classified according to either the 6th or the 7th TNM systems. Results. The patient population consisted of 452 subjects. Tumor size was ≤ 3 cm in 51% of cases. The predominant histology was adenocarcinoma (53%) and lobectomy was the most common surgical procedure (82% of patients). The five-year survival rate in patients with stage IA vs. IB (6th TNM) was 62% vs. 51%, respectively (log-rank p = 0.036). Corresponding figures for the 7th TNM system were 70% in stage IA-T1a, 51% in stage IA-T1b, 54% in stage IB, 51% in stage IIA and 35% in stage IIB (log-rank p = 0.002). On multivariate analysis, adjusted by age, gender, histology, kind of surgery, grade of differentiation and smoking status, pathological stage was an independent prognostic factor if classified according to the 7th TNM version (p = 0.001), but not if scored according to the 6th TNM edition (p = 0.090). Conclusion. The 7th TNM classification system is a more accurate predictor of prognosis in stage I operated patients than the old classification. The new system should be implemented even on retrospective cohorts especially when investigating the prognostic implication of the expression of molecular biomarkers.