Expression of High Mobility Group Protein B1 in Cardiac Tissue of Elderly Patients with Coronary Artery Disease with or without Inflammatory Rheumatic Disease.

BACKGROUND: It is known from clinical practice and observational studies that elderly patients with a diagnosis of inflammatory rheumatic diseases (IRD) bear a significantly increased risk for cardiovascular diseases such as coronary artery disease (CAD) and heart failure. The molecular mechanism, however, is still not known. Recently, high mobility group protein B1 (HMGB1), a ubiquitous, highly conserved single polypeptide expressed in all mammal eukaryotic cells, has been identified to mediate myocardial dysfunction in vitro once released from the nuclei of cardiomyocytes. OBJECTIVE: To investigate whether HMGB1 and its receptors are expressed in cardiac muscles of elderly patients with CAD with or without IRD. METHODS: HMGB1 and its 3 well-known receptors, receptor for advanced glycation end products, Toll-like receptor 2 (TLR2), and TLR4, were examined by immunohistochemistry on myocardial biopsy specimens from 18 elderly patients with CAD (10 with IRD, 8 without IRD). Furthermore, total HMGB1 protein levels were measured by Western blot from the cardiac biopsies in 5 patients with and 5 without IRD. RESULTS: Pathologic cytosolic HMGB1 in cardiomyocytes was massively recorded in all patients with IRD, but only slightly expressed in 1 patient without IRD. Total HMGB1 levels were also consistently lower in myocardial muscle biopsies of patients with IRD compared to those without IRD. Furthermore, all 3 HMGB1 receptors were expressed in cardiomyocytes of all patients. CONCLUSION: The increased cytosolic expression of HMGB1 in cardiomyocytes and the lower total amount of HMGB1 in the cardiac specimens of IRD patients is consistent with a greater release of HMGB1 from the myocardial nuclei in IRD than non-IRD individuals. Thus, the HMGB1 signaling pathways may be more easily activated in elderly CAD patients with concomitant IRD and trigger a detrimental inflammatory process causing severe cardiovascular problems. Therefore, targeting HMGB1 in IRD patients might reduce the risk for cardiovascular events.

Plasma complement and vascular complement deposition in patients with coronary artery disease with and without inflammatory rheumatic diseases.

PURPOSE: Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients. METHODS: We examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry. RESULTS: IRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (ρ, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA). CONCLUSION: The independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies.

Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD) via mechanisms that have not yet been defined. Inflammatory pathways, in particular within the vascular adventitia, are implicated in the pathogenesis of primary CVD but could be amplified in RA at the local tissue level. The aim of this study was to examine the aortic adventitia of coronary artery disease (CAD) patients with or without RA to determine the cytokine profile contained therein. METHODS: Aortic adventitia and internal thoracic artery biopsy specimens obtained from 19 RA patients and 20 non-RA patients undergoing coronary artery bypass graft surgery were examined by immunohistochemistry. RESULTS: Interleukin-18 (IL-18), IL-33, and tumor necrosis factor (TNF) were expressed in aortic adventitia biopsy specimens from both groups, and expression of these cytokines was significantly higher in RA patients. In RA patients, IL-33 expression in endothelial cells correlated positively with the number of swollen joints, suggesting a link between the systemic disease state and the local vascular tissue microlesion. CONCLUSION: The presence of the proinflammatory cytokines IL-18, IL-33, and TNF may play a role in the inflammatory process within the adventitia that contributes to plaque formation and destabilization. In theory, the amplified expression of these cytokines may contribute to the known increased occurrence and severity of CAD in patients with RA.

Bacteria in the adventitia of cardiovascular disease patients with and without rheumatoid arthritis.

The incidence of atherosclerosis is significantly increased in rheumatoid arthritis (RA). Infection is one factor that may be involved in the pathogenesis of both diseases. The cause of RA and atherosclerosis is unknown, and infection is one of the factors that may be involved in the pathogenesis of both diseases. The aims of this study were to identify bacteria in the aortic adventitia of patients with cardiovascular disease (CVD) in the presence and absence of RA, and to determine the effect of identified candidate pathogens on Toll-like receptor (TLR)-dependent signalling and the proinflammatory response. The aortic adventitia of 11 CVD patients with RA (RA+CVD) and 11 CVD patients without RA (CVD) were collected during coronary artery bypass graft surgery. Bacteria were detected in four samples from CVD patients and three samples from RA+CVD patients and identified by 16S rRNA gene sequencing. Methylobacterium oryzae was identified in all three RA+CVD samples, representing 44.1% of the bacterial flora. The effect of M. oryzae on TLR-dependent signalling was determined by transfection of HEK-293 cells. Although mild TLR2 signalling was observed, TLR4 was insensitive to M. oryzae. Human primary macrophages were infected with M. oryzae, and a TLDA qPCR array targeting 90 genes involved in inflammation and immune regulation was used to profile the transcriptional response. A significant proinflammatory response was observed, with many of the up-regulated genes encoding proinflammatory cytokines (IL-1α, IL-1ß, IL-6, TNF-α) and chemokines (CCR7, IL-8). The aortic adventitia of CVD patients contains a wide range of bacterial species, and the bacterial flora is significantly less diverse in RA+CVD than CVD patients. M. oryzae may stimulate an proinflammatory response that may aggravate and perpetuate the pathological processes underlying atherosclerosis in RA patients.

Immediate rescue operations after failed diagnostic or therapeutic cardiac catheterization procedures.

OBJECTIVES: Although rare, life-threatening complications requiring emergency cardiac surgery do occur after diagnostic and therapeutic cardiac catheterization procedures. The operative mortality has been persistently reported to remain high. The purpose of this observational study was to evaluate and report the outcomes, with particular emphasis on early mortality, of these risky operations that were performed in a single highly specialized cardiac centre. METHODS: Between June 1997 and August 2007, 100 consecutive patients, 13 after diagnostic complicated cardiac catheterization (0.038% of 34,193 angiographies) and 87 after crashed percutaneous coronary intervention (PCI; 0.56% of 15,544 PCIs), received emergency operations at the Feiring Heart Center. In the same period, 10,192 other patients underwent open cardiac surgery. Early outcome data were analysed and compared between the cohorts. Follow-up was 100% complete. RESULTS: The preoperative status of the 100 patients was that 4 had ongoing external cardiac massage, 24 were in cardiogenic shock, 32 had frank enduring ST-segment infarction but without shock and 40 had threatened acute myocardial infarction. There was 1% (1 patient) 30-day mortality in the study group, which is equal (0.9%, P=0.60) to that of all other operations. Postoperative myocardial infarction and prolonged ventilator use were significantly higher in the crash group, whereas the rate of stroke, renal failure, reopening for bleeding and mediastinitis were similar between the groups. CONCLUSIONS: With rapid transfer to an operation room, minimizing the time of warm myocardial ischaemia, and by performing complete coronary revascularization, it is possible to obtain equally low operative mortality in patients with life-threatening cardiac catheterization-associated complications, as is the case with open cardiac operations in general.

Avoidance of noninfectious sternal dehiscence: figure-of-8 wiring is superior to straight wire closure.

OBJECTIVES: Comparison of figure-of-8 wiring or simple straight-wiring technique assessed by the frequency of early noninfectious sternal dehiscence. DESIGN: Observational register study with 7835 patients having sternal closure with figure-of-8 steel wires was compared with 2122 patients, where the sternotomy was closed by simple interrupted straight wires. The endpoint was the rate of early (within 30 days) sterile sternal dehiscence. RESULTS: Fourteen patients (0.66%) with single wires and five patients (0.06%) with figure-of-8 wires underwent re-operation for nonmicrobial sternal disruption (p < 0.0001). The median time-point for re-intervention was 6 days for both groups. In more than 6000 patients, the sternotomy was closed with five figure-of-8 wires without dehiscence in any of them. CONCLUSION: In a large cohort of consecutive cardiac operations, it was found that sternal closure with figure-of-8 wires is better than closure with simple interrupted wires.

Potassium-induced conversion of ventricular fibrillation after aortic declamping.

OBJECTIVES: The anti-fibrillatory effect of potassium is well recognized from experimental models. There have, however, been very few clinical reports on the use of potassium to convert ventricular fibrillation (VF) after cardioplegic arrest. METHODS: In total, 8465 adult patients undergoing cardiac operations on cardiopulmonary bypass (CPB) and with cold antegrade crystalloid cardioplegic arrest were consecutively enrolled in a database. Patients with VF after removal of the aortic clamp were given 20 mmol potassium, and if needed an extra 10 mmol, in the perfusion line and the conversion rate was registered. Preoperative and intraoperative factors possibly related to the occurrence of post-ischaemic VF were assessed. RESULTS: Of these, 1721 (20%) patients had VF and 1366 of these (79%) were successfully treated with potassium infusion. Only 355 (21%) patients (4% of all operations) had direct-current countershock. The need for pacing was lower in the treatment group compared with the non-treatment group (P <0.001). Multivariate analysis revealed as the main findings that age, gender, amount of cardioplegia related to body mass index (BMI), and blood transfusion during the time of CPB had a highly significant (P <0.001) impact on reducing the rate of post-arrest VF. Somewhat contrary to expectation, left ventricular hypertrophy (LVH) was not a significant factor (P = 0.32) for post-arrest VF. No conversion by potassium was significant for age (P <0.001), gender (P <0.001) and LVH (P <0.001), but not for blood transfusion during CPB (P = 0.38) and for the ratio of cardioplegia-BMI (P = 0.26). CONCLUSIONS: The results from this register study demonstrate that potassium infusion is an effective and convenient first-hand measure to convert post declamping VF on CPB.

Randomized prospective trial of saphenous vein harvest site infection after wound closure with and without topical application of autologous platelet-rich plasma.

OBJECTIVE: Wound infection is still a common problem after open long saphenous vein harvesting. Platelets are important for the healing process. The hypothesis was that spraying of the wounds with platelet-rich plasma might reduce the frequency of harvest site infections. METHODS: From January to October 2008, 140 patients undergoing first-time coronary artery bypass grafting were randomized into two groups of 70 patients. Both groups had standard surgical leg wound closure and care except topical application of platelet-rich plasma as adjunctive treatment in the active treatment group. End points were wound infection and cosmetic result at 6 weeks. RESULTS: The follow-up was 100% complete. Nine patients (13%) in the treatment group and eight (11%) in the control group experienced harvest site infection (p=0.80). The overall cosmetic result was also similar between the groups (p=0.34), but the top score was borderline and more frequent in the treatment group (p=0.050). CONCLUSION: Topical application of autologous platelet-rich plasma on vein harvest wounds did not reduce the rate of surgical site infection.

Mediastinitis after coronary artery bypass grafting risk factors and long-term survival.

BACKGROUND: Mediastinitis is a severe complication of coronary artery bypass grafting. The aim of the present study was to determine incidence of mediastinitis, its risk factors, and its effect on early and long-term survival. METHODS: The study has a dual design, a case-control, and a retrospective cohort, using a source population of 18,532 consecutive patients who underwent coronary artery bypass grafting from January 1989 to December 2000. The closing date was February 1, 2008. Median follow-up was 10.3 (range 8.1 to 18.9) years. Patients with mediastinitis were compared with a random control group without mediastinitis issued from the same source population in a ratio 1:4. The crude effect of mediastinitis was estimated using rate ratio and 95% confidence limits. Adjustment for multiconfounders was done with the Cox model. A logistic model was used to pinpoint risk factors of mediastinitis. Calibration and discrimination of a prognostic model was done. RESULTS: One hundred seven patients (0.6%) developed mediastinitis. Diagnosis was made 12 (9 to 19) days postoperatively. Independent risk factors of mediastinitis using the logistic model were advanced age, male gender, left main stenosis, body mass index 30 kg/m(2) or greater, chronic obstructive pulmonary disease, diabetes, and increased amount of blood transfusion. There was no increased risk of early mortality (odds ratio = 0.58; 95% confidence interval 0.13 to 2.61) (p = 0.48) but there was increased risk of morbidity (intraaortic balloon pump, ventricular and supraventricular arrhythmia, stroke, inotrope, and myocardial infarction). Follow-up had a median observation time of 10.3 years. Survival for patients with mediastinitis was 49.5 +/- 5.0% versus 71.0 +/- 2.2% for controls (p < 0.01). Analysis of specific death causes documented that cardiac deaths were significantly more frequent in mediastinitis patients than in control patients. When controlling for the confounding effect of the other variables (age, cardiopulmonary bypass time, body mass index, chronic obstructive pulmonary disease), the hazard ratio associated with mediastinitis on long-term mortality was 1.59, 95% confidence limits (1.16 and 2.70) (p = 0.003). CONCLUSIONS: The incidence of mediastinitis in 18,532 patients undergoing coronary artery bypass grafting surgery was low. The major preventable risk factor of mediastinitis was amount of blood transfusion. Mediastinitis had an excess risk of early morbidity and was associated with a significant reduced long-term survival. Most deaths were considered to be cardiac.

Inflammatory markers in patients with coronary artery disease with and without inflammatory rheumatic disease.

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRDs) have a higher morbidity and mortality from accelerated atherosclerosis than the general population. We hypothesized that patients with the combination of IRD and coronary artery disease (CAD) would have a certain inflammatory phenotype compared with CAD patients without this comorbidity. METHODS: Four groups of patients were included: patients with IRD, referred to coronary artery bypass grafting (CABG) (CAD-IRD, n = 67), patients without IRD, referred to CABG (CAD, n = 52), patients with IRD without CAD (IRD, n = 32) and healthy controls (n = 30). Plasma levels of several inflammatory markers were analysed by enzyme immunoassays. RESULTS: (i) Plasma levels of markers of endothelial cell activation [i.e. vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor] and osteoprotegerin (OPG) were significantly increased and plasma levels of CCL21 significantly decreased in CAD-IRD patients as compared with CAD patients without IRD. (ii) Within the CAD-IRD group, acute coronary syndrome was a significant predictor of OPG, suggesting an enhanced inflammatory response during plaque destabilization in CAD-IRD patients. (iii) Plasma levels of VCAM-1, OPG and CCL21, but not lipid parameters, IRD characteristics and several other inflammatory markers (e.g. CRP), were significant predictors of CAD-IRD as opposed to CAD in two logistic regression models. CONCLUSION: Our findings further support a role for inflammation in the accelerated form of atherosclerosis in IRD patients, and suggest that certain inflammatory pathways, such as the enhanced endothelial cell activation and the RANK ligand/RANK/OPG system, may be of particular importance.