Dissertation committee:
Δημήτριος Ηλιόπουλος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Χρήστος Βερύκοκος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Δημητρούλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Κόντζογλου, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Τούτουζας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Σπυρίδων Δευτεραίος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνα Αγγέλη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Thoracic aortic aneurysms (TAA) often go undetected to the point where they strike brutally and cause terrible consequences. Aortic dissection and rupture account for 2%-7% of all sudden cardiac fatalities in the general population, which represents a significant mortality load. Up to 22% of patients who experience acute aortic events are pronounced dead before reaching the hospital. It is estimated that in the Unites States alone, aortic diseases account for about 13.000 deaths annually and act as a contributing factor in more than 16.415 deaths making them the 17th most common cause of mortality in people older than 50 years. Moreover, many thoracic aortic-related sudden deaths can be misdiagnosed as myocardial infarction. As such, it is possible that these data significantly underestimates the true burden of aortic diseases in the population. This evidence highlights the significance of timely detection of TAA since it is rampant but asymptomatic, hence termed “silent killer”.TAA can be categorized as either heritable or degenerative from an etiologic perspective. Less than 30% of all TAA cases are genetically triggered, whereas more than 70% are degenerative. Mutations in genes encoding proteins such as Smooth Muscle (SM) contractile proteins, Extracellular Matrix (ECM) proteins and proteins involved in Transforming Growth Factor beta (TGF-β) signaling are the main causes of genetically triggered TAA. Sporadic TAA are primarily linked to risk factors such as age, male sex, smoking and hypertension. In the context of aneurysmal diseases of the thoracic aorta, ascending (ATAA) and descending (DTAA) aneurysms behave as two distinct types of disorders. This could be explained due to the different embryologic origins of ascending and descending aortic vascular smooth muscle cells (VSMCs), which are in charge of secreting many of the proteolytic factors associated with aneurysm formation, including matrix metalloproteinase (MMP) and plasmin.Currently, the diagnosis of ATAA is largely based on imaging tests (echocardiography, computed tomography and magnetic resonance imaging), which are frequently performed for unrelated purposes; therefore the aneurysm is found by accident. However, ATAA in patients who are not subjected to those imaging studies remains undetected and complications, such as aortic dissection and rupture, might occur. There are no effective preventive strategies for TAA, thus, early detection, surveillance and treatment are critical to improving outcomes.The development of biomarkers that could be helpful in identifying individuals with thoracic aortic illness are investigated. However, to date, the majority of biomarkers are mostly successful in identifying aortic disease after an aortic dissection or rupture has taken place. Hence, in order to improve clinical care and outcomes for this fatal disease it is essential to establish new ways to help in the identification of people at risk of currently having or developing a thoracic aneurysm. Using a targeted proteomic approach, we sought to investigate the effect of the formation of an ascending thoracic aortic aneurysm on the proteomic profile in the serum of patients identified with ATAA in an effort to develop potential biomarkers for the detection of ATAA.In this study, 52 patients were divided into three groups depending on their ascending aorta diameter: 4.0-4.5 cm (N=23), 4.6-5.0 cm (N=20), and >5.0 cm (N=9). A total of 30 controls were in-house populations ethnically matched to cases without known or visible ATAA-related symptoms and had no ATAA familial history. Before the debut of our study, all patients provided medical history and underwent physical examination. Diagnosis was confirmed by echocardiography and angio-computed tomography (CT) scans. Targeted-proteomic analysis was conducted to identify possible biomarkers for the diagnosis of ATAA.Kruskal-Wallis test revealed that C-C motif chemokine ligand 5 (CCL5), defensin beta 1 (HBD1), intracellular adhesion molecule- 1 (ICAM1), interleukin-8 (IL8), tumor necrosis factor alpha (TNFα) and transforming growth factor-beta 1 (TGFB1) expressions are significantly increased in ATAA patients in comparison to control subjects with physiological aorta diameter (p<0.0001). The receiver-operating characteristic analysis showed that the area under the curve values for CCL5 (0.84), HBD1 (0.83) and ICAM1 (0.83) were superior to that of the other analyzed proteins.CCL5, HBD1 and ICAM1 are very promising biomarkers with satisfying sensitivity and specificity that could be helpful in stratifying risk for the development of ATAA. These biomarkers may assist in the diagnosis and follow-up of patients at risk of developing ATAA. This retrospective study is very encouraging; yet further in-depth studies may be worthwhile to investigate the role of these biomarkers in the pathogenesis of ATAA.
Keywords:
Aneurysm, Aorta, Biomarker, Diagnosis, Proteomics
