The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication?

BACKGROUND: It has been suggested that inflammation can have a role in the development of atrial arrhythmias after cardiac surgery and that a genetic predisposition to develop postoperative complications exists. This study was conceived to verify if a potential genetic modulator of the systemic inflammatory reaction to cardiopulmonary bypass (the -174 G/C polymorphism of the promoter of the Interleukin-6 gene) has a role in the pathogenesis of postoperative atrial fibrillation (AF). Patients and Results- In 110 primary isolated coronary artery bypass patients the -174G/C Interleukin-6 promoter gene variant was determined. Interleukin-6, fibrinogen and C-reactive protein plasma levels were determined preoperatively, 24, 48, and 72 hours after surgery and at discharge. Heart rate and rhythm were continuously monitored for the first 36 to 48 hours; daily 12-lead electrocardiograms were performed thereafter until discharge. GG, CT, and CC genotypes were found in 62, 38, and 10 patients, respectively. Multivariate analysis (which included genotype, age, sex, and classical risk factors for AF) identified the GG genotype as the only independent predictor of postoperative AF. The latter occurred in 33.9% of GG versus 10.4% of non-GG patients (hazard ratio 3.25, 95%CI 1.23 to 8.62). AF patients had higher blood levels of Interleukin-6 and fibrinogen after surgery (P<0.001 for difference between the area under the curve). CONCLUSIONS: The -174G/C Interleukin-6 promoter gene variant appears to modulate the inflammatory response to surgery and to influence the development of postoperative AF. These data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication.     

Prothrombotic Response to Coronary Angioplasty in Patients with Unstable Angina and Raised C-Reactive Protein

Background: To better understand the mechanisms linking C reactive protein (CRP) to the risk of coronary thrombosis, we investigated the relation between inflammatory state and hemostatic response to coronary angioplasty in patients with either stable or unstable angina. Methods: Plasma levels of von Willebrand factor (vWF) antigen, vWF collagen binding activity, vWF-cleaving-protease, CRP, and whole-blood platelet reactivity were measured before and 24 h after angioplasty in 18 patients with recent unstable angina and in 17 with stable angina. Each group was divided according to preprocedural CRP levels: 3 mg/l (in 9 unstable and 9 stable patients) or <3 mg/l (in 9 unstable and 8 stable patients). Results: Baseline hemostatic parameters did not differ significantly among the four subgroups of patients. After angioplasty, virtually all patients with unstable angina and raised preprocedural CRP showed increased vWF antigen (P = 0.01), vWF collagen-binding (P = 0.001), CRP (P = 0.008), and platelet reactivity (P = 0.0007) compared to baseline, whereas no significant change of these variables was seen within the other three sets of patients. In the overall population, the changes in vWF antigen and vWF-collagen-binding induced by angioplasty correlated with those in CRP levels (r = 0.47, P = 0.004 and r = 0.44, P = 0.008). Baseline levels of vWF cleaving protease and modifications of this enzyme with angioplasty did not differ significantly among subgroups. Conclusions: Our data suggest that high preprocedural levels of CRP predict a significant vWF rise after angioplasty in patients with unstable angina. The rise in vWF is associated with that in CRP and with enhanced platelet reactivity. Such changes may contribute to the worse prognosis of unstable patients with raised indices of inflammation.     

Retrognathic maxilla in “Habsburg jaw”: Skeletofacial analysis of Joanna of Austria (1547–1578)

Objective:To evaluate the dentoskeletal features of the “Habsburg jaw” by analyzing the skull of Joanna of Austria.Materials and Methods:The skull, the panoramic radiograph, and the lateral cephalogram of Joanna of Austria were analyzed. The cephalometric values of Joanna were compared to cephalometric standards for adult female subjects.Results:The analysis of the dentition on the dry skull and on the panoramic radiograph showed a generalized horizontal alveolar bone resorption with severe bone loss that was interpreted as a sign of severe periodontal disease with respect to the young age (31 years). The cephalometric analysis revealed the presence of a skeletal Class III disharmony associated with maxillary retrusion and normal sagittal position of the mandible. The maxilla exhibited a reduction in the sagittal dimension while the mandible presented with increased dimensions both in total mandibular length (Co-Gn) and in the mandibular body (Go-Gn). The skeletal open bite contributed to the lack of mandibular protrusion though in presence of increased mandibular sagittal dimensions.Conclusion:Joanna of Austria appeared to be affected by a peculiar type of “Habsburg jaw” as the Class III skeletal disharmony was due to a retrognathic maxilla rather than to a prognathic mandible.     

Aspirin Therapy in Primary Cardiovascular Disease Prevention : A Position Paper of the European Society of Cardiology Working Group on Thrombosis

Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding.     

Preoperative C-reactive protein level and outcome following coronary surgery.

OBJECTIVE: It has been suggested that a preoperative level of C-reactive protein (CRP)>5mg/l is predictive of postoperative complications in cardiac surgery patients. MATERIAL AND METHODS: Among 113 primary isolated coronary artery bypass patients, CRP was determined preoperatively and fibrinogen, interleukine 6, plasminogen activator inhibitor-1, prothrombin time, activated partial thromboplastin time, platelets and white blood cells count measured before surgery, 24, 48 and 72h thereafter and at hospital discharge. The clinical course of all cases was prospectively recorded. Data were then analysed according to the preoperative CRP level by dividing the patients into two groups (CRP>5mg/l or CRP<5mg/l). RESULTS: The in-hospital results were similar between the two patients groups. Even the postoperative haematic inflammatory markers did not significantly differ according to the preoperative CRP level. CONCLUSION: In this prospective study, a preoperative level of CRP>5mg/l did not predict in-hospital postoperative complications nor influence the extent of the inflammatory activation in primary isolated coronary bypass patients.     

New 2-arylpyrazolo[3,4-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies

This paper reports the study of some 2-arylpyrazolo[3,4-c]quinolin-4-ones, 4-amines, and 4-amino-substituted derivatives designed as human A3 adenosine receptor (AR) antagonists. Most of the herein reported compounds showed a nanomolar affinity toward the hA3 receptor subtype and different degrees of selectivity that resulted to be strictly dependent on the presence and nature of the substituent on the 4-amino group. Bulky and lipophilic acyl groups, as well as the benzylcarbamoyl residue, afforded highly potent and selective hA3 receptor antagonists. The selected 4-diphenylacetylamino-2-phenylpyrazoloquinoline (25) and 4-dibenzoylamino-2-(4-methoxyphenyl)pyrazoloquinoline (36), tested in an in vitro rat model of cerebral ischemia, prevented the irreversible failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. The observed structure-affinity relationships of this class of antagonists were also exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach.     

Update on phase II studies of erythropoietin in acute myocardial infarction. Rationale and design of Exogenous erythroPoietin in Acute Myocardial Infarction: New Outlook aNd Dose Association Study (EPAMINONDAS)

Erythropoietin (Epo) is a hematopoietic hormone produced mainly by the kidneys in response to hypoxia. Recent acquisitions in the fields of hematology, neurology, cardiology, and experimental medicine show cytoprotective, angiogenetic and antinflammatory effects of Epo. Exogenous erythroPoietin in Acute Myocardial Infarction: New Outlook aNd Dose Association Study (EPAMINONDAS, EudraCTno. 200500485386) is one of four ongoing randomized controlled trials, each testing the effects of Epo in ≥100 patients with STEMI. EPAMINONDAS is a multicenter, prospective, double-blind, placebo-controlled, dose-finding study assessing intravenous moderate doses of human recombinant Epo (epoietin-α, 100 or 200 IU/kg/die) versus placebo, given on the first 3 days, in 102 patients with first ST-segment elevation myocardial infarction. Initial dosing is within 12 h of primary percutaneous coronary revascularization. The primary endpoint is infarct size, quantified by CK-MB time–concentration curve, left ventricular wall motion score index, and pattern of contrast-enhanced magnetic resonance imaging. Secondary endpoints are ischemic recurrences, ventricular remodelling, and safety events, assessed in-hospital and at 12 months’ follow-up. The results of current phase II studies will help define the safety/efficacy profile of Epo for patients with STEMI.