Risk factors for 1-year mortality after postoperative deep sternal wound infection.

BACKGROUND AND AIMS: A deep sternal wound infection is a life-threatening complication after cardiac surgery. This study was conducted to describe the mortality associated with postoperative deep sternal wound infections after cardiac surgery and to find risk factors linked to increased mortality in 1 year follow-up. MATERIAL AND METHODS: A total of 7973 open-heart surgeries were performed at Tampere University Hospital. Deep sternal wound infection patients were identified, their 1-year mortality status was recorded, and the related risk factors were analyzed. RESULTS: We detected a total of 129 (1.6%) postoperative deep sternal wound infection patients. The 1-year mortality associated with a postoperative deep sternal wound infection was 20.2%. No preoperative or perioperative, statistically significant factors associated with increased 1-year mortality were found. A prolonged stay in an intensive care unit after surgery as well as stroke, delirium, wound secretion, and co-infection were associated with increased 1-year mortality. CONCLUSION: The risk factors found for increased 1-year mortality were all postoperative. The quality of surgical treatment as well as precise postoperative care and evaluation remain the most important factors to decrease later mortality due to deep sternal wound infections.

The effect of postoperative complications on health-related quality of life and survival 12 years after coronary artery bypass grafting - a prospective cohort study.

BACKGROUND: Despite the steady improvements in survival and operative safety, postoperative complications still remain a significant cause of morbidity and mortality after coronary artery bypass grafting (CABG). However, less is known on the impact of postoperative complications on health-related quality of life (QoL). The main objective of our study was to investigate the impact of postoperative complications on long-term QoL and survival after CABG surgery. METHODS: Data of 508 patients, who underwent isolated CABG was prospectively collected. The RAND-36 Health Survey (RAND-36) was used to evaluate patients' QoL status preoperatively, 1 year and 12 years after the surgery. Predefined postoperative complications were reported during primary and secondary hospital stay. QoL and survival analysis were performed primarily on three patient groups: patients with and without complications and patients with major adverse cardiac and cerebrovascular events (MACCE). RESULTS: In total 205(40%) of 508 patients had at least one postoperative complication and 73 (14%) experienced MACCE. Patients' thirty-day, 1-year and 10-year survival rates were, 99, 98, 84% without complications, 97, 95, 72% with complications, and 90, 89, 64% with MACCE, respectively (log-rank p < 0.001). Patients without complications showed significant(p < 0.05) improvements in seven and patients with complications in five out of eight RAND-36 QoL dimensions. All patient groups showed significant improvements in RAND-36 summary scores compared with preoperative values. Patients with complications and especially with MACCE had more profound decline in their RAND-36 summary scores while patients without complications maintained their health status best. CONCLUSIONS: Despite the constant deterioration, both patients with and without complications showed improvements even 12 years after CABG compared with preoperative state. Postoperative complications and especially MACCE were associated with impaired long-term QoL.

Diabetics have Inferior Long-Term Survival and Quality of Life after CABG.

A prevalence of diabetes is increasing among the patients undergoing coronary artery bypass grafting (CABG). Data on whether health-related quality of life improves similarly after CABG in diabetics and nondiabetics are limited. We assessed long-term mortality and changes in quality of life (RAND-36 Health Survey) after CABG. Seventy-four of the 508 patients (14.6%) operated on in a single institution had a history of diabetes and were compared with nondiabetics. The RAND-36 Health Survey was used as an indicator of quality of life. Assessments were made preoperatively and repeated 1 and 12 years later. Thirty-day mortality was 2.7 versus 1.6 ( p = 0.511) in the diabetics and nondiabetics. One- and 10-year survival rates in the diabetics and nondiabetics were 94.6% versus 97.0% ( p = 0.287) and 63.5% versus 81.6% ( p < 0.001), respectively. After 1 year, diabetics improved significantly ( p < 0.005) in seven, and nondiabetics ( p < 0.001) in all eight RAND-36 dimensions. Despite an ongoing decline in quality of life over the 12-year follow-up, an improvement was maintained in four out of eight dimensions among diabetics and in seven dimensions among nondiabetics. Physical and mental component summary scores on the RAND-36 improved significantly ( p < 0.001) in both groups after 1 year, and at least slight improvement was maintained during the 12-year follow-up time. Diabetics have inferior long-term survival after CABG as compared with nondiabetics. They gain similar improvement of quality of life in 1 year after surgery, but they have a stronger decline tendency over the years.

The effect of obesity on long-term survival and health-related quality of life after coronary artery bypass grafting: a 12-year follow-up.

OBJECTIVE: The proportion of obese patients undergoing coronary artery bypass graft (CABG) surgery is increasing. In this study, our main objective was to assess the effect of obesity on long-term mortality and changes in quality of life (QoL) after GABG. MATERIALS AND METHODS: Data of 508 patients who underwent isolated GABG were prospectively collected. RAND-36 Health Survey (RAND-36) was used as an indicator of QoL. BMI was used to assess obesity, and the analysis was based primarily on two patient groups: BMI less than 30 kg/m (408 patients) and BMI of at least 30 (100 patients). All assessments were made preoperatively and repeated 1 and 12 years after CABG surgery. The follow-up of the cohort was complete in 95 and 84% of the alive patients at 1 and 12 years, respectively. RESULTS: Thirty-day, 1-year, and 10-year survival rates were 99.0, 97.0, and 78.0%, respectively, in the obese and 98.0, 96.8, and 79.2%, respectively, in the nonobese group. Obese showed significant (P<0.05) improvements only in four and nonobese in seven of eight RAND-36 dimensions of QoL. In both obese and nonobese patients, improved RAND-36 physical component summary and mental component summary scores were seen in comparison with the preoperative values. Yet, obese patients had a more pronounced diminution in their physical component summary and mental component summary scores, whereas nonobese patients maintained their physical and mental health status better. CONCLUSION: Despite an on-going decline in 12 years after the CABG, both patient groups showed improvements in their health status in comparison with preoperative values. Obese patients gained less benefit in terms of QoL dimension, but there was no significant difference in overall mortality in the long-term follow-up.

Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm - The Tampere Vascular Study.

Ascending thoracic aortic aneurysm (ATAA) is a multifactorial disease with a strong inflammatory component. Surgery is often required to prevent aortic rupture and dissection. We performed gene expression analysis (Illumina HumanHT-12 version 3 Expression BeadChip) for 32 samples from ATAA (26 without/6 with dissection), and 28 left internal thoracic arteries (controls) collected in Tampere Vascular study. We compared expression profiles and conducted pathway analysis using Ingenuity Pathway Analysis (IPA) to reveal differences between ATAA and a healthy artery wall. Almost 5000 genes were differentially expressed in ATAA samples compared to controls. The most downregulated gene was homeobox (HOX) A5 (fold change, FC = -25.3) and upregulated cadherin-2 (FC = 12.6). Several other HOX genes were also found downregulated (FCs between -25.3 and -1.5, FDR < 0.05). 43, mostly inflammatory, canonical pathways in ATAA were found to be significantly (p < 0.05, FDR < 0.05) differentially expressed. The results remained essentially the same when the 6 dissected ATAA samples were excluded from the analysis. We show for the first time on genome level that ATAA is an inflammatory process, revealing a more detailed molecular pathway level pathogenesis. We propose HOX genes as potentially important players in maintaining aortic integrity, altered expression of which might be important in the pathobiology of ATAA.

Differentially expressed genes and canonical pathway expression in human atherosclerotic plaques - Tampere Vascular Study.

Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) < 0.05. 787 genes were significantly differentially expressed in atherosclerotic plaques. The most up-regulated genes were osteopontin and multiple MMPs, and the most down-regulated were cell death-inducing DFFA-like effector C and A (CIDEC, CIDEA) and apolipoprotein D (FC > 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds.

The long-term effect of perioperative myocardial infarction on health-related quality-of-life after coronary artery bypass grafting.

OBJECTIVES: To evaluate the long-term effect of perioperative myocardial infarction (PMI) on outcomes and health-related quality-of-life (QOL) after coronary artery bypass grafting (CABG). METHODS: Eighty of the 501 patients (16%) fulfilled electrocardiogram or cardiac enzyme criteria for PMI and were compared with patients with no PMI. The RAND-36 Health Survey was used as an indicator of QOL. Assessments were made preoperatively and repeated 1 year and 12 years later. RESULTS: Thirty-day mortality was adversely affected by PMI (6.3 vs 1.0%, P = 0.001). One-year survival rates for PMI and no-PMI patients were 92.5 and 97.6%, 10-year rates being 72.5 and 79.8%. One year after the surgery, PMI patients improved in seven and no-PMI patients in all the eight RAND-36 dimensions. In the 12-year follow-up, the scores showed a general decline tendency. PMI patients still maintained a significant improvement in four and no-PMI patients in seven of eight dimensions when compared with the baseline scores. A highly significant improvement was seen in the RAND-36 mental and physical component summary scores in the no-PMI group 1 year after CABG. PMI patients improved also significantly although the magnitude of change was lower. In the 12-year follow-up, there was a general decline tendency in the scores. Both groups showed similar freedom from anginal symptoms at 12 years. CONCLUSIONS: Although PMI has a negative impact on health-related QOL 1 year after CABG, this effect is only minor in the long term. PMI increases 30-day mortality but shows no effect on later mortality.

A 12-year follow-up on the changes in health-related quality of life after coronary artery bypass graft surgery.

OBJECTIVES: Improvement in quality of life (QoL) and survival benefit are the primary objectives of coronary artery bypass graft (CABG) surgery. The profile of patients undergoing isolated CABG has altered towards higher age with more preoperative comorbidities. Thus, the importance of QoL over the quantity of life among elderly patients is getting more emphasized. In this study, our main goal was to evaluate the long-term changes in QoL, overall performance status and symptomatic status after the CABG. METHODS: Comprehensive data of 508 patients who underwent isolated CABG in a single institution were prospectively collected. The RAND-36 Health Survey (RAND-36) was used as an indicator of QoL. Karnofsky dependency category was used to evaluate overall performance status, and symptomatic status was assessed using New York Heart Association (NYHA) class. All assessment were made preoperatively and repeated 1 year and 12 years later. The follow-up of the study cohort was complete in 95 and 84% of the alive patients at 1 year and 12 years, respectively. Analysis was based mainly on three age groups: ≤64 years (282 patients), 65-74 years (175 patients) and ≥75 years (51 patients). RESULTS: Thirty-day, 1-year and 10-year survival rates were 98, 97 and 79%, respectively. Twelve years after the surgery significant improvement (P<0.05) was seen in all but one RAND-36 dimensions of the QoL (general health, P=0.76) as well as in functional capacity (P<0.001) and NYHA class. All age groups showed improvements in RAND-36 physical component summary (PCS) and mental component summary (MCS) scores compared with the preoperative values. The youngest subgroup maintained their physical and mental health status best, whereas older subgroups had more pronounced decreases in their PCS and MCS scores. CONCLUSIONS: Despite an ongoing deterioration 12 years after the CABG, there was significant improvement in most dimensions of the QoL and functional capacity in comparison with the preoperative values. The elderly gain less long-term benefit from CABG regarding the QoL and survival.

Quality of life 12 years after on-pump and off-pump coronary artery bypass grafting.

OBJECTIVE: To assess whether the use of either the on-pump or the off-pump method affects changes in health-related quality of life (QOL) in the long term after coronary artery bypass graft (CABG) surgery. METHODS: Four hundred and fifty-two (89.0%) of the 508 patients in a single institution were operated on-pump and 56 (11.0%) were operated off-pump. The RAND-36 Health Survey (RAND-36) was used as an indicator of QOL. Assessments were performed preoperatively and repeated 1 year and 12 years later. Symptomatic status was estimated according to New York Heart Association class. RESULTS: After 1 year, on-pump patients improved significantly (P<0.001) in all eight RAND-36 dimensions. Also, in off-pump patients, positive changes were observed in all RAND-36 dimensions and these changes were statistically significant (P<0.05) in six dimensions. Despite an ongoing decrease in QOL over the 12-year follow-up, on-pump patients still maintained a significant (P<0.05) improvement in all and off-pump patients in seven out of eight RAND-36 dimensions. A highly significant (P<0.001) pattern of change after 1 year was observed in the RAND-36 Mental Component Summary and Physical Component Summary scores in both operative groups, and despite the general declining trend, significant improvement was maintained during the 12-year follow-up time. Both groups showed almost identical relief from anginal symptoms at 12 years. CONCLUSION: A majority of patients experience significant improvement in health-related QOL in the long term after CABG. Cardiopulmonary bypass has no impact on patients' subsequent health-related QOL.

Genes involved in systemic and arterial bed dependent atherosclerosis--Tampere Vascular study.

BACKGROUND: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). CONCLUSIONS: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds.

Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL.

BACKGROUND: Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave proproteins into mature end products. Previously, MBTPS1 and PCSK9 have been shown to regulate cholesterol metabolism and LDL receptor recycling, whereas FURIN and PCSK5 have been suggested to inactivate lipases and regulate inflammation in atherosclerosis. Here, we systematically analyzed the expression of PCSKs and their targets in advanced atherosclerotic plaques. METHODS AND RESULTS: Microarray and quantitative real-time PCR experiments showed that FURIN (42.86 median fold, p = 2.1e-8), but no other PCSK, is universally overexpressed in the plaques of different vascular regions. The mRNA expression screen of PCSK target proteins in plaques identified many known factors, but it also identified the significant upregulation of the previously overlooked furin-processed B cell activating cytokines APRIL (TNFSF13, 2.52 median fold, p = 3.0e-5) and BAFF (TNFSF13B, 2.97 median fold, p = 7.6e-6). The dysregulation of FURIN did not associate with its htSNPs or the previously reported regulatory SNP (-229, rs4932178) in the promoter. Immunohistochemistry experiments showed the upregulation of FURIN in the plaque lymphocytes and macrophages where it was co-expressed with BAFF/TNFSF13B and APRIL/TNFSF13. CONCLUSIONS: Our data unequivocally show that FURIN is the primary PCSK that is dysregulated in the immune cells of advanced human atherosclerotic plaques, which implies a role for this enzyme in plaque pathology. Therefore, drugs that inhibit FURIN in arteries may modulate the course of this disease.

Electrocardiographic presentation of left main disease in patients undergoing urgent or emergent coronary artery bypass grafting.

BACKGROUND: Widespread ST-segment depression with inverted T waves maximally in leads V4-V5 (ie, the global ischemia electrocardiogram [ECG] pattern) is a marker of adverse outcome in patients with non-ST-segment elevation acute coronary syndrome (ACS), perhaps because this pattern is indicative of left main stem stenosis. However, the prognostic value of this ECG pattern has not yet been established. OBJECTIVE: We studied the predictive value of a prespecified ECG pattern in patients who underwent urgent or emergent coronary artery bypass grafting (CABG). METHODS: We studied the sensitivity, specificity, and predictive values for the global ischemia ECG to predict angiographic left main coronary artery disease. Patients with a 12-lead ECG recorded during anginal symptoms before CABG were included. RESULTS: The global ischemia ECG pattern was found in 61 (76%) of 80 patients with and 12 (19%) of 65 patients without left main disease. The sensitivity, specificity, and positive and negative predictive values for left main coronary artery disease in patients with the global ischemia ECG pattern were 76%, 81%, 84%, and 74%, respectively. In multivariate analysis, the global ischemia ECG pattern was strongly associated with angiographic left main coronary artery disease after adjusting for age, gender, diabetes, hypertension, and smoking (hazard ratio, 16.0; 95% confidence interval, 6.5-39.5; P < 0.001). CONCLUSION: The global ischemia ECG pattern was strongly associated with angiographic left main coronary artery disease in patients who underwent urgent or emergent CABG.

Metoprolol versus amiodarone in the prevention of atrial fibrillation after cardiac surgery: a randomized trial.

BACKGROUND: Current guidelines recommend ß-blockers as the first-line preventive treatment of atrial fibrillation (AF) after cardiac surgery. Despite this, 19% of physicians report using amiodarone as first-line prophylaxis of postoperative AF. Data directly comparing the efficacy of these agents in preventing postoperative AF are lacking. OBJECTIVE: To determine whether intravenous metoprolol and amiodarone are equally effective in preventing postoperative AF after cardiac surgery. DESIGN: Randomized, prospective, equivalence, open-label, multicenter study. (ClinicalTrials.gov registration number: NCT00784316) SETTING: 3 cardiac care referral centers in Finland. PATIENTS: 316 consecutive patients who were hemodynamically stable and free of mechanical ventilation and AF within 24 hours after cardiac surgery. INTERVENTION: Patients were randomly assigned to receive 48-hour infusion of metoprolol, 1 to 3 mg/h, according to heart rate, or amiodarone, 15 mg/kg of body weight daily, with a maximum daily dose of 1000 mg, starting 15 to 21 hours after cardiac surgery. MEASUREMENTS: The primary end point was the occurrence of the first AF episode or completion of the 48-hour infusion. RESULTS: Atrial fibrillation occurred in 38 of 159 (23.9%) patients in the metoprolol group and 39 of 157 (24.8%) patients in the amiodarone group (P = 0.85). However, the difference (-0.9 percentage point [90% CI, -8.9 to 7.0 percentage points]) does not meet the prespecified equivalence margin of 5 percentage points. The adjusted hazard ratio of the metoprolol group compared with the amiodarone group was 1.09 (95% CI, 0.67 to 1.76). LIMITATIONS: Caregivers were not blinded to treatment allocation, and the trial evaluated only stable patients who were not at particularly elevated risk for AF. The withdrawal of preoperative ß-blocker therapy may have increased the risk for AF in the amiodarone group. CONCLUSION: The occurrence of AF was similar in the metoprolol and amiodarone groups. However, because of the wide range of the CIs, the authors cannot conclude that the 2 treatments were equally effective. PRIMARY FUNDING SOURCE: The Finnish Foundation for Cardiovascular Research and the Kuopio University EVO Foundation.

Activation of indoleamine 2,3-dioxygenase-induced tryptophan degradation in advanced atherosclerotic plaques: Tampere vascular study.

OBJECTIVE: We aimed to characterize the expression of indoleamine 2,3-dioxygenase (IDO) or IDO-induced tryptophan degradation-dependent pathways, which may lead to suppression of T cells and possible protection against atherosclerosis. METHODS AND RESULTS: Expression of IDO and IDO-related pathway components was analyzed in advanced human atherosclerotic plaques (n = 24) and in non-atherosclerotic arteries (n = 6). Up-regulation of IDO and genes related to the IDO pathway was found to be pronounced in atherosclerotic plaques. Immunohistochemistry demonstrated IDO protein in the atheromatous core and co-distribution with monocyte-macrophages (CD68-positive cells). In gene-set enrichment analysis, the IDO pathway revealed a significant (false discovery rate (FDR) = 0.07) regulatory T cell, fork-head box protein 3 (FoxP3)-initiated CD28-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-inducible T cell co-stimulator (ICOS)-driven pathway leading to activation of IDO expression in antigen-presenting cells (APCs). Expression of these IDO pathway genes varied between 2.1- and 16.8-fold as compared to control tissues (P < 0.05 for all). CONCLUSIONS: IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis offering new viable therapeutic targets for the development of antiatherogenic immunosuppressive therapies.

ADAM8 and its single nucleotide polymorphism 2662 T/G are associated with advanced atherosclerosis and fatal myocardial infarction: Tampere vascular study.

OBJECTIVE: Previously, we scanned all 23,000 human genes for differential expression between normal and atherosclerotic tissues and found the involvement of ADAM8. METHODS: We investigated the expression of ADAM8 mRNA and protein level in human atherosclerotic tissues and non-atherosclerotic internal thoracic arteries as well as the association of ADAM8 2662 T/G single nucleotide polymorphism (SNP) with the extent of coronary atherosclerosis and with the risk of fatal myocardial infarction. RESULTS: ADAM8 mRNA was up-regulated in carotid, aortic, and femoral atherosclerotic plaques (n=24) when compared with non-atherosclerotic arteries. ADAM8 protein expression was increased in advanced atherosclerotic plaques as compared to control vessels wherein it was localized to macrophages and smooth muscle cells The G allele carriers of the ADAM8 2662 T/G SNP had significantly larger areas of fibrotic, calcified, and complicated plaques in coronary arteries (P=0.027, P=0.011, and P=0.011, respectively) and significantly higher occurrence of myocardial infarction (MI) (P=0.004) and fatal pre-hospital MI (P=0.003) than did the TT homozygotes. CONCLUSION: ADAM8 is a promising candidate to be involved in atherosclerosis, and its 2662 T/G allelic variant significantly associates with advanced atherosclerotic lesion areas and MI.

ADAM-9, ADAM-15, and ADAM-17 are upregulated in macrophages in advanced human atherosclerotic plaques in aorta and carotid and femoral arteries--Tampere vascular study.

BACKGROUND AND AIMS: The expression of disintegrin and metalloprotease ADAM-9, ADAM-15, and ADAM-17 has been associated with cell-cell, cell-platelet, and cell-matrix interactions and inflammation. They are possibly implicated in the pathophysiology of atherosclerosis. METHODS AND RESULTS: Whole-genome expression array and quantitative real-time polymerase chain reaction (PCR) analysis confirmed that ADAM-9, ADAM-15, and ADAM-17 are upregulated in advanced human atherosclerotic lesions in samples from carotid, aortic, and femoral territories compared to samples from internal thoracic artery (ITA) free of atherosclerotic plaques. Western analysis indicated that the majority of these ADAMs were in the catalytically active form. ADAM-9, ADAM-15, and ADAM-17-expressing cells were shown to co-localize with CD68-positive cells of monocytic origin in the atherosclerotic plaques using immunohistochemistry and double-staining immunofluorescence analysis. Co-localization was demonstrated in all vascular territories. In the carotid territory, cells expressing the ADAMs co-distributed also with smooth muscle cells and, in femoral territory, with CD31-positive endothelial cells, indicating that the ADAM expression pattern depends on vascular bed territory. CONCLUSIONS: Present findings provide strong evidence for the involvement of catalytically active ADAM-9, ADAM-15, and ADAM-17 in advanced atherosclerosis, most notably associated with cells of monocytic origin.

The Impact of Adenosine Fast Induction of Myocardial Arrest during CABG on Myocardial Expression of Apoptosis-Regulating Genes Bax and Bcl-2.

Background. We studied the effect of fast induction of cardiac arrest with denosine on myocardial bax and bcl-2 expression. Methods and Results. 40 elective CABG patients were allocated into two groups. The adenosine group (n = 20) received 250 mug/kg adenosine into the aortic root followed by blood potassium cardioplegia. The control group received potassium cardioplegia in blood. Bcl-2 and bax were measured. Bax was reduced in the postoperative biopsies (1.38 versus 0.47, P = .002) in the control group. Bcl-2 showed a reducing tendency (0.14 versus 0.085, P = .07). After the adenosine treatment, the expression of both bax (0.52 versus 0.59, P = .4) and bcl-2 (0.104 versus 0.107, P = .4) remained unaltered after the operation. Conclusion. Open heart surgery is associated with rapid reduction in the expression of apoptosis regulating genes bax and bcl-2. Fast Adenosine induction abolished changes in their expression.

Human adaptation to ischemia by preconditioning or unstable angina: involvement of nuclear factor kappa B, but not hypoxia-inducible factor 1 alpha in the heart.

OBJECTIVE: Ischemic preconditioning reduces infarct size and improves hemodynamic function. Unstable angina may be a clinical analogue to ischemic preconditioning, and involve activation of gene programs. We hypothesized that preceding unstable angina and/or ischemic preconditioning activated genes regulated by nuclear factor kappa B (NFkappaB) or hypoxia-inducible factor 1 alpha in parallel to improved cardiac function. METHODS: Patients undergoing coronary artery bypass grafting with stable or unstable angina were subjected to ischemic preconditioning or sham treatment (n=10-11 in each group). Central hemodynamics were monitored. Left ventricular and atrial biopsies were harvested before cardioplegic arrest and after 25 min of reperfusion. Expression of heat shock protein 72 was evaluated by immunoblot, and activation of NFkappaB was detected by electrophoretic mobility shift assay. Real-time PCR was used to quantify expression of genes regulated by NFkappaB (inducible nitric oxide synthase, tumor necrosis factor-alpha, intercellular adhesion molecule 1) or by hypoxia-inducible factor 1 alpha (heme oxygenase-1, glucose transporter-1 and vascular endothelial growth factor-A). RESULTS: Ischemic preconditioning improved postoperative cardiac index and left ventricular stroke work index in both stable and unstable groups on the first postoperative day. Expression of hypoxia-inducible factor 1 alpha regulated genes was not influenced by cardioplegia and reperfusion, ischemic preconditioning or unstable angina. Expression of the NFkappaB-regulated genes increased after cardioplegia and reperfusion, but this was not influenced by ischemic preconditioning in stable patients. Inducible nitric oxide synthase and tumor necrosis factor expression were reduced after ischemic preconditioning in patients with unstable angina. There were no significant differences in gene expression between stable and unstable patients before cardioplegia and ischemic preconditioning. NFkappaB translocation at reperfusion was reduced in stable preconditioned and unstable control patients compared to stable controls. Heat shock protein 72 expression increased after preconditioning of unstable patients. CONCLUSION: Cardiac function was improved by ischemic preconditioning in both stable and unstable patients. Unstable angina per se had no effect. NFkappaB-regulated genes were influenced by ischemic preconditioning, but hypoxia-inducible genes were not.

Initial results of a clinical study: adenosine enhanced cardioprotection and its effect on cardiomyocytes apoptosis during coronary artery bypass grafting.

OBJECTIVE: Apoptosis has been considered as one of the mechanisms of cardiomyocyte loss during open heart surgery. Adenosine is cardioprotective against ischemia-reperfusion injury in experimental models. The aim of this study was to find out whether the administration of single dose adenosine added to blood cardioplegia is effective in decreasing the apoptosis process. METHODS: In a double-blinded randomized control intervention study, 40 patients were enrolled for elective coronary artery bypass grafting. In the adenosine group (n=20) patients received 250 microg/kg adenosine in the aortic root after cross-clamping followed by cold blood cardioplegia. In the control group (n=20) patients had only antegrade cardioplegia. Left ventricular tissue samples (from apex) were taken before and after the bypass. The apoptotic cells were identified by dUTP nick-end labeling (TUNEL) using an apoptosis detection kit. The number of TUNEL-positive cardiomyocytes was expressed as percentage of the total number of cardiomyocytes in histological tissue sections. RESULTS: The groups were closely identical in demographic data, cross-clamp time, cardiopulmonary bypass time and weaning time. The postoperative cardiac index and other hemodynamic parameters, including the patterns of CK-MB, did not show statistically significant differences. In the tissue samples there were an equal number of patients who developed apoptosis after the cross-clamp. Although the frequency of apoptosis in the control group was two times higher than in the adenosine group, this was statistically not significant. CONCLUSIONS: Adenosine enhanced blood cardioplegia could not prevent myocardial apoptosis completely. However, it seems to be that adenosine might influence the frequency of apoptosis and this needs to be considered in future investigations.

Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death.

BACKGROUND: Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314) and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD). METHODS: Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33-69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes. RESULTS: Whole genome expression profiling showed a significant (p = 0.02) down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07-6.71), compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant. CONCLUSION: The results suggest that the allelic variants (SREBF-2 1784G>C and SCAP 2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.