الفهرس 
Introduction
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Abstract
AF is the most frequent cardiac arrhythmia in clinical field and will become an ever greater problem in an increasingly aged population. The main vulnerability of AF as a clinical condition is that it remains a major independent risk factor for thromboembolism and stroke, particularly in old patients. AF accounts for about 15% of all strokes and 20 % of acute cerebral infarctions, where approximately one in three patients with AF not receiving anticoagulants will develop an ischemic stroke throughout his life.
The pathogenesis of thrombus formation in AF is multifactorial and is not only connected to stasis of blood in poorly contractile LA. More than 150 years ago, Rudolf Virchow proposed a triad of events desired for thrombus formation in AF, including: endothelial/endocardial damage or dysfunction, abnormal blood stasis and abnormal haemostasis, platelets and fibrinolysis. Although rheumatic heart disease is observed in only 15% of Western AF patients, rheumatic mitral disease is the most frequent underlying condition in AF in developing countries, where the risk of stroke increases 17-fold in presence of VAF versus 2-7 fold in case of nonvalvular AF.
CECs are considered to be mature cells that had been detached from the intimal mono layer of vascular wall in response to endothelial injury, with limited growth capability. Quantification of CECs may perhaps serve as a new precise marker of vascular injury that is capable of discriminating endothelial activation from damage. PMPs are procoagulant small membranous vesicles that are released from platelets following activation. In addition, the adhesion molecule P-selectin (CD62P) is of interest as another well known marker of platelet activation and is believed to be elevated in patients with AF.
In the last few years, plentiful studies have established that estimation of OxLDL plasma level is a useful marker of CVDs and may serve as a potential prognostic marker for future health events. The CD40 and its ligand (CD40L) signaling system is a pathway which is thought to play a pivotal link among platelet activation, inflammation, endothelial dysfunction and, ultimately, thrombosis.
The present study aimed to:
1) Asses the abnormality of CECs and OxLDL as indices of endothelial damage/dysfunction in patients with AF, together with CD40 as an inflammatory marker.
2) Clarify the importance of estimating platelet activation biomarkers such as PMPs and P-selectin as predictive of thrombo-embolic risk factors in AF patients.
3) Correlate the abnormality of endothelial damage/dysfunction and platelet activation biomarkers in patients with AF.
This analytic cross sectional study was carried out on 58 patients with rheumatic heart disease (20 men and 38 women), 30 patients with AF and 28 in NSR. Rheumatic patients attending the Outpatient Cardiac Clinic and Cardiac Catheter Unit from July 2011 to February 2012 were invited to participate in the study and classified into two groups, group I: included 30 patients with VAF (MS and/or MR) but without LA or LAA thrombus, or with past history of previous thromboembolic events but without criteria of prothrombotic states by SEC. Group IІ: included 28 patients with rheumatic valve disease (MS and/or MR) and in NSR. In addition, a third group of 20 apparently healthy, age matched volunteers were included in this study as controls (14 men and 6 women). All patients and controls were below 50 year.
Patients were subjected to medical history taking, physical examination and ECG/echocardiograpic evaluations. Subsequently, determination of CECs numbers and PMPs percentages as well as levels of OxLDL, P-selectin and CD40 were performed. CECs numbers and PMPs percentages were determined by flow cytometric analysis in Flow Cytometry Unit, Clinical Pathology Department, South Egypt Cancer Institute, while, OxLDL, P-selectin and CD40 levels were estimated by ELISA kits in Medical Biochemistry Department.
The results of our study demonstrated that there were considerably elevated CECs numbers, CD40 and OxLDL levels in diseased groups (VAF and RNAF) compared to HC and in VAF patients in comparison with RNAF. Similarly, P-selectin and PMPs were significantly elevated in rheumatic patients (VAF and RNAF) compared to HCs, but without significant difference in between. Moreover, PMPs percentages as well as mean levels of P-selectin and OxLDL were markedly decreased with regular drug therapies. Although, numbers of CECs and CD40 levels were higher in patients not receiving drugs than those receiving medication, the differences were insignificant.
Regarding correlations between the various studied parameters and risk factors, our results showed that the CECs numbers, CD40 and OxLDL levels were positively correlated with the diastolic blood pressure; however, there were significant positive correlations between PMPs percentages and systolic blood pressure. In addition, PMPs percentages were positively correlated with the MVS and negatively with the MVA. Once more, increased levels of P-selectin were positively correlated with MVS and negatively with MVA. Furthermore, a positive correlation was observed between OxLDL and MVS. In addition, Spearman correlation coefficient established that the older the age, the higher the levels of both CD40 and OxLDL. Studying correlations between various parameters verified that: significant positive correlations were observed between CECs and CD40, and between PMPs and P-selectin in VAF, RNAF and in diseased group as whole. In addition, OxLDL levels were positively correlated with both CECs and CD40.
from the ROC curve, our data suggested that CECs estimation could be considered as a sensitive and reliable marker of endothelial injury or damage that could replace the traditional markers of endothelium. In addition, CECs assessment may represent a prognostic indicator that perhaps reflects the severity of the insult(s) toward the endothelium. Moreover, PMPs may possibly serve as biomarkers of platelet activation and promising new targets for anti-platelet drugs.
In conclusion, severe endothelial damage, as assessed by increased numbers of CECs and augmented OxLDL levels appears to be a prominent feature of AF, but levels are certainly higher in the presence of associated cardiac disease (e.g. rheumatic valve), that more contributes to an enhanced prothrombotic state. Also, increased CD40 levels indicate a possible role of inflammation in the pathogenesis of AF and its thrombotic complications. Accordingly, estimation or these biomarkers may help in the prediction of thrombogenic tendencies of AF.
Moreover, there is evidence of platelet activation in AF disease revealed by increased PMPs percentages and P-selectin levels, but this is likely to be due to underlying cardiovascular diseases (rheumatic heart disease in our study) rather than arrhythmia as such. Also, although platelets are activated in AF patients, it may not be directly related to thrombus formation but may perhaps play a more indirect role in rendering AF hypercoagulable. However, our results could outcome from peripheral rout sampling rather than central routs and/or sampling at different times of disease activity, consequently, further studies are needed to clarify this point.