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Objective: Red blood cell distribution width (RDW), is a measurement of the size variation as well as an erythrocyte heterogeneity index (i.e., anysocytosis). used in combination with the mean corpuscular volume for anemia diagnosis. However, it is emerging as an useful predictor biomarker of mortality and morbidity of cardiovascular diseases. However, until now no literature data there are about the RDW role in predicting mortality after aortic valve replacement (AVR). Thus, in this pilot study biological significance of elevated RDW values in early outcome following AVR was evaluated Methods: We enrolled 75 patients (mean age 73.5 ±7.9 years) subjected to AVR and/ or not co temporally to other surgical procedures . Demographics, comorbidities, clinical presentations, and laboratory parameters were collected. The RDW values were considered elevated when more high than 48 fL. Multivariable and univariable examinations were performed in determine associations between preoperative high RDW values and postoperative outcome. Results: Preoperative higher RDW values had a prevalence of 41% (31 patients) in AVR cases studied. These 31 patients were older (76 ± 5.5 years vs 71.6± 8.9 years, p-value=0,02 ), low weight (69.7 vs. 74.1 Kg, p-value= 0,12) with higher platelet levels (p-value 0,005) than the other 44 cases. In addition, they represented the patients that should have likely required renal replacement therapy (13% vs 0%, p-value = 0.026), and prolonged ventilation (16% vs 0%, p-value =0.01). Multivariable adjustment analysis also demonstrated significant associations between higher preoperative RDW values with high BMI values (p-value= 0.05) and renal failure (p-value= 0,06 and p-value=0,02). Conclusions: Increased RDW values seem to be a good predictor biomarker of early outcome after AVR, particularly in patients with high BMI, renal impairment and postoperative prolonged ventilation

Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovascular disease, as well as Alzheimer's disease (AD), all characterized by chronic inflammatory status. On the other hand, extensive abnormalities in insulin and insulin-like growth factor I (IGF-I) and IGF-II signaling mechanisms in brains with AD have been demonstrated, suggesting that AD could be a third form of diabetes. The Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) has an important role in the insulin pathway because its over-expression causes impairment of insulin/IGF-1 signaling. Because some single-nucleotide polymorphisms (SNP) of the gene encoding SHIP2 were significantly associated in T2DM patients with metabolic syndrome and some related conditions, we decided to conduct a case-control study on this gene, analyzing AD and T2DM subjects as cases and young, old, and centenarians as controls. Our results suggest a putative correlation between the the rs144989913 SNP and aging, both successful and unsuccessful, rather than age-related diseases. Because this SNP is an insertion/deletion of 28 bp, it might cause an alteration in SHIP2 expression. It is noteworthy that SHIP2 has been demonstrated to be a potent negative regulator of insulin signaling and insulin sensitivity. Many studies demonstrated the association of the insulin/IGF1 pathway with aging and longevity, so it is tempting to speculate that the found association with SHIP2 and aging might depend on its effect on the insulin/IGF-1 pathway.

Background: We have previously reported the increase of IgD-CD27- (Double Negative, DN) B cell population in the aged. These memory B cells have short telomeres and poor abilities to proliferate in vitro. Here, we investigated whether the low ability of DN B cells to proliferate depends on the expression levels of the CD307d and CD22 inhibitory receptors or whether DN B cells can proliferate and reactivate telomerase by the engagement of both innate and adaptive immune receptors. Methods: Phenotypic analyses were made by using flow cytometry. Quantitative analysis of telomerase activity was made by using a TRAP and a photometric enzyme immunoassay in young, healthy elderly, centenarian offspring (CO), and Alzheimer’s disease patients (AD). Results: We show that CD307d and CD22 expression levels are not related with the different ability of DN to be activated in the young and elderly. Moreover, CpG/α-IgG/α-CD40 (and not CpG or α-IgG/α-CD40) stimulation induces DN B cell proliferation in both young and elderly subjects. Furthermore, DN B cell telomerase activity in young, elderly, CO and AD patients, mirrors the age and health status of the subjects studied. Indeed, young donors show the highest levels of RTA, whereas AD patients the lowest. Healthy elderly and CO show lower levels than young, with a slight increase of activity in CO vs. elderly. Conclusions: Our present data add new information to our knowledge of DN B cells during aging. We demonstrate that the low ability of DN cells to proliferate depends on RTA and not on the expression of inhibitory receptors.

Background: Degenerative forms of mitral valve diseases (MVDs) are complex pathologies. Thus, it is difficult to make generalizations about MVD pathways or genetic risk factors. However, a key role of metalloproteinases (MMPs) in their pathophysiology is emerging. Thus, we performed a study to assess eventual associations of some functional SNPs in MMP-2 and MMP-9 genes with MVD risk, symptom severity and short- and long-term (4.8 years) complications. Methods: For this purpose, 90 patients and two control groups were genotyped for MMP-2 and MMP-9 gene SNPs, and systemic levels of proatrial natriuretic peptide (ANP), and two enzymes were quantified and correlated to the MMP-2 and MMP-9 SNPs. In addition, associations between these SNPs and symptom severity and short- and long-term complications were evaluated. Results: Interestingly, rs3918242 MMP-9 and rs2285053 MMP-2 SNPs were significantly represented in cases compared to two control groups, and were associated with a higher MVD risk. Cases stratified for New York Heart Association (NYHA) symptoms, and particularly NYHA III+IV, with rs3918242 CT+TT MMP-9 and rs2285053CT+TT genotypes also showed higher severity related to significant higher systemic levels of MMP enzymes and pro-ANP at enrollment and 4.8-year follow-up times. In addition, cases with these genotypes, and particularly NYHAIII+IV, had a very significant percentage of complications, particularly at the 4.8-year follow-up. Surprisingly, 20% of patient controls developed MVD at 4.8- year follow-up and were carriers of these genotypes. Conclusions: The associations observed seem to suggest that the two SNPs might represent useful biomarkers and targets for preventing and monitoring MVDs, leading to a more appropriate management and outcome

Chronic inflammatory diseases, such as cardiovascular diseases (CVDs), diabetes, Alzheimer’s disease (AD) and cancer, have a disproportionate prevalence with advancing age owing to the continuous growth in the aging population. This condition determines several medical, economic and social problems due to the dramatic increase in the number of affected individuals, who are not autonomous. Thus, research efforts are centred around reducing and/or delaying the onset and progression of these diseases by researching new strategies for early prevention and diagnosis. In this context, understanding the mechanisms involved in the tissue, organ protection and repair are imperative for the development of new preventive treatments. Accordingly, medical research is pursuing new ways of trying to face this imposing challenge, i.e. regenerative medicine with stem cells and progenitors, such as endothelial progenitor cells (EPCs). Since their discovery, EPCs have rapidly caught the attention of researchers for their ability to facilitate vascular repair in different ischemic tissues, by contributing to neovascularization in several tissue injury models. Interest has also heightened dramatically after evidence about their capacity to counteract related CVD endothelium dysfunction. In addition, recent studies, using different animal models of cancer, suggested the importance of bone marrow-derived EPCs (i.e. postnatal vasculogenesis) in tumor vascularization and growth. EPCs are present in the peripheral blood; their levels are increased in response to certain signals/cytokines; and they home into the neovascular bed of malignant tissues. Furthermore, at the clinical level, evidence is emerging that changes in EPC levels might predict the efficacy of anticancer drug combinations, such as anti-angiogenic agents. On the basis of these observations, EPCs have attractive potential diagnostic and therapeutic applications for malignant diseases. Additional recent evidence also suggests the possibility to adopt EPCs as prognostic biomarkers for AD. It has been observed that patients with AD have reduced circulating EPCs, suggesting that an anomalous capacity to regenerate endothelium is associated with AD. In the case of diabetes, numerous groups have detected decreased EPC numbers and functionality in affected patients, confirmed by decreased numbers of colony-forming units, decreased adhesion and migration and decreased tubule formation. In addition, it has been found that strategies based on ix the administration of statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and peroxisome-proliferator-activating-receptor-c agonists, up-regulate and enhance both the EPC number and functionality. Emerging evidence also indicates that transplantation of EPCs is beneficial for the recovery of ischemic cerebral injury. EPC-based therapy could open a new avenue for ischemic diseases. Currently, clinical trials for evaluating EPC transfusion in treating ischemic stroke are underway. However, much of the increasing evidence implicating progenitors in these diseases is contrasting. Thus, their real role remains uncertain. This is compounded by the necessity for a standardization of the different methodologies and protocols for characterizing, identifying and defining these cells, or their subsets. This problem represents one of the major consequences of the large heterogeneity that exists in data from the literature. In this monograph, some of these aspects are discussed using research to give clear indications regarding EPC functions and definitions, as well as evidence to support the problem of their characterization. In addition, recent findings on their role as disease biomarkers and exogenous or autologous cell therapy are provided. Certainly, limitations are also stressed. Based on these observations, this monograph, structured in 3 chapters, will describe, in the first chapter, the relevance of translational medicine (TM) as a new research approach to counteract the imposing challenge of age-related diseases. In particular, a considerable emphasis will be given to regenerative medicine (RegMed), a new branch of TM. RegMed can be used to improve health and quality of life, by restoring, maintaining or enhancing tissue and functions of organs. Of the diverse RegMed approaches, a particular focus will be given to stem/progenitor cell-based therapies, their benefits and disadvantages, as well as to the description of types of stem and progenitor cells considered for regenerative cell therapies, such as EPCs as emerging candidates for RegMed applications. To understand the value and potentiality of EPCs in this field, as well as the related limitations, in Chap. 1, the biological features, origins, sources and endogenous functions of EPCs will be reported. In addition, a critique of EPCs, namely relating to their characterization and definition, will be put forward, because they represent the real cause of the extensive heterogeneity of existing data in the literature on this topic, which creates more confusion than comprehension. Chapter 2 outlines the clinical relevance of EPCs as both potential predictors, and diagnostic and prognostic biomarkers of age-related diseases and therapeutic agents, by discussing the advantages, disadvantages and the conflicting data. To conclude, Chap. 3 will propose a potential roadmap for revising the findings obtained to date, reordering them and creating a clear puzzle of the valid data. It can facilitate understanding of important aspects, including firstly defining, isolating and characterizing EPCs by establishing a standardized criteria for EPC research, discrimination of appropriate sub-populations for cell therapy, timing, dosing, priming of cells, and delivery mode for different applications. Furthermore, influencing factors might also be identified with the aim to focus resources and efforts, and the problems linked to the local retention and fate of cells in the therapeutic target zone might be resolved. Finally, an overview of innovative strategies will be reported, which might improve x Preface the efficacy of cell therapy at all levels, including cell priming, bio-nanotechnology, and tissue engineering. They might be used as emerging tools, and, in particular, their combination might produce very advantageous results. Such descriptions and discussions address an extensive audience, including students, health care professionals, biologists, physicians and diverse scientific community. In particular, it will be a valuable resource for clinical scientists, researchers, university professors, health practitioners, gerontologists and geriatricians, students, and for all those who wish to broaden their knowledge in the allied field. Policy makers and agencies involved in implementing preventive policies might also use this monograph as an updated integral resource. All government and private organizations, including libraries at the college level, academic universities, and research institutions might benefit from it as resource for its current references. Palermo, Italy Carmela Rita Balistreri July 2016

“The senescence status of somatic stem/progenitor cells contributes to ageing process”, and “an individual is as old as old are its stem cells”. These quotes represent the concepts, which are actually object of investigations of researchers involved in ageing studies.

Objective The objective of this study was to evaluate the effectiveness of the Penn classification in predicting in-hospital mortality after surgery in acute type A aortic dissection patients. Methods We evaluated 58 patients (42 men and 16 women; mean age 62.17 ± 10.6 years) who underwent emergency surgery for acute type A aortic dissection between September 2003 and June 2010 in our department. We investigated the correlation between the pre-operative malperfusion and in-hospital outcome after surgery. Results Twenty-eight patients (48%) were Penn class Aa (absence of branch vessel malperfusion or circulatory collapse), 11 (19%) were Penn class Ab (branch vessel malperfusion with ischaemia), 5 (9%) were Penn class Ac (circulatory collapse with or without cardiac involvement) and 14 (24%) were Penn class Abc (both branch vessel malperfusion and circulatory collapse). The number of patients with localized or generalized ischaemia or both, Penn class non-Aa, was 30 (52%). In-hospital mortality was 24%. In-hospital mortality was significantly higher in Penn class Abc and Penn class non-Aa. Intensive unit care stay, hospital ward stay and overall hospital stay was longer in Penn class non-Aa vs Penn class Aa. De Bakey type I dissection and type II diabetes mellitus were associated with in-hospital mortality. Conclusion Preoperative malperfusion is important for the evaluation of patients with acute aortic type A dissection. The Penn classification is a simple and quick method to apply and predict in-hospital mortality and outcomes. Keywords Type A dissection – Stanford classification – DeBakey classification – Penn classification.

Telomeres have been postulated as a universal clock that shortens in parallel with cellular aging. They are specialized DNA-protein structures at the ends of chromosome with remarkable functions--preventing their recognition as double-stranded DNA breaks, protecting their recombination and degradation, and avoiding a DNA damage cellular response. Telomere shortening is currently considered the best aging marker, but is also a predictor for age-related diseases, including cardiovascular diseases. Biological age clearly seems to be a better predictor of vascular risk rather than chronological age. This concept is supported by key assumptions that peripheral blood leukocyte telomere content accurately reflects that of the vascular wall and its decrease is associated with premature vascular disease. Thus, we are analyzing whether the mean of blood leukocyte telomere length might also be a predictor for sporadic thoracic aortic aneurysm (S-TAA). The preliminary results seem to be promising. Shorter telomeres were detected in patients than in controls. Thus, mean of blood leukocyte telomere length could contribute to identify individuals at S-TAA risk.

Coronary artery fistulas are rare anatomic abnormalities of the coronary arteries present in 0.002% of the general population and represent 14% of all anomalies of coronary arteries. Their clinical relevance focuses mainly on the mechanism of "coronary steal phenomenon”, causing myocardial functional ischemia even in the absence of stenosis, hence common symptoms are angina or dyspnea. Small size fistulas are mostly asymptomatic and have excellent prognosis if managed medically with regular follow-up consisting also in echocardiography every 2-5 years. Big-sized and symptomatic fistulas, on the contrary, should undergo invasive closure, either with a transcatheter approach or with surgical ligation, whose results are equivalent at long-term follow-up. However, in some cases, symptoms may not correspond with size. Larger fistulas may be asymptomatic and very small fistulas may cause symptoms like angina in our patient. Here, we are presenting an emblematic and very rare case with a complete literature review. Particularly, very didactic angiography images and then during surgery are shown.

Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for -765G/C PTGS2 and -1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the anti-inflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load.

This review discusses the role of estrogens as pro- or antiinflammatory players in immune-inflammatory responses. In particular, their role in Alzheimer’s disease (AD), an example of immune-inflammatory disease, is discussed briefly. AD is a progressive neurodegenerative disease, which in Western societies accounts for the majority of cases of clinical senile dementia. However, sexual dimorphism of diseases may also depend on factors independent of sex hormones (i.e., a gender effect), as demonstrated by our data on differential longevity in females and males. In fact, differences in mortality between men and women are not only a question of sex that refers to biological differences, but rather a question of ‘‘socially constructed sex,’’ a question of gender (i.e., the characteristics that a society or culture delineates as masculine or feminine). In gender medicine, we conclude that it is important to consider the role played both by hormones, customs, and educational levels regarding the different propensity of males and females to fall ill. So, in programming antiaging strategies, we have also to take these aspects into account

The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age-related diseases, atherosclerosis and Alzheimer's disease, suggesting a possible role of chemokine system on these diseases' pathophysiology. Finally, we review the data on the probable association between CCR5Delta32 deletion and cardiovascular diseases and Alzheimer's disease.

Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promotes wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, we summarize, in this chapter, related mechanisms involved, discuss on potentential treatment until now disposable, and suggest preventive measures.

Sporadic thoracic aortic aneurysms (TAA) and dissections are one of the major causes of morbidity and mortality worldwide, especially in those older than 65 years. The presentation of TAA is varied and often silent. Thus, sporadic TAA detection is often fortuitous, with identification occurring during a routine physical examination or during an unrelated medical evaluation. Once suspected, confirmation by imaging clinical approaches is needed to allow the choose of the unique treatments for TAA, namely the surgery procedures, including elective surgery or endovascular repair before the onset of catastrophic and fatal complications, such as dissection or rupture. At present, there are no biomarkers available to identify TAAs before visible symptoms. However, recent progresses in understanding of molecular and cellular mechanisms involved in the patho-physiology of sporadic TAA are suggesting different molecular pathways and their genetic variants as potential biomarkers, which might be applied into TAA clinical practice in the near future. Here, we report literature evidence on some disease pathways and their genetic variants on TAA susceptibility and compliances, and their translation as promising TAA preventive and prognostic biomarkers and targets for new personalized therapeutic treatments.

Advanced knowledge in the field of stem cell biology and their ability to provide a cue for counteracting several diseases are leading numerous researchers to focus their attention on “regenerative medicine” as possible solutions for cardiovascular diseases (CVDs). However, the lack of consistent evidence in this arena has hampered the clinical application. The same condition affects the research on endothelial progenitor cells (EPCs), creating more confusion than comprehension. In this review, this aspect is discussed with particular emphasis. In particular, we describe biology and physiology of EPCs, outline their clinical relevance as both new predictive, diagnostic, and prognostic CVD biomarkers and therapeutic agents, discuss advantages, disadvantages, and conflicting data about their use as possible solutions for vascular impairment and clinical applications, and finally underline a very crucial aspect of EPCs “characterization and definition,” which seems to be the real cause of large heterogeneity existing in literature data on this topic.

The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardiovascular diseases (CVD) and, subsequently, live longer if they do not become affected by serious infectious diseases. These results are in agreement with our other data demonstrating how genetic background may exert the opposite effect with respect to inflammatory components in CVD and longevity. In the present report, to validate this hypothesis, the levels of interleukin (IL)-6, a pro-inflammatory cytokine involved in atherosclerosis and longevity, were determined by an enzyme-linked immuno-sorbent assay (ELISA) in supernatants from a whole blood assay after stimulation with subliminal doses of lipopolysaccaride (LPS) from Escherichia coli (E. coli). The samples, genotyped for the ASP299GLY polymorphism, were challenged with LPS for 4, 24, and 48 h. What we found was that Il-6 values were significantly lower in carriers bearing TLR4 mutation. Therefore, the pathogen burden, by interacting with host genotype, determines the type and intensity of the immune-inflammatory responses accountable for pro-inflammatory status, CVD, and unsuccessful aging. On the other hand, our present data seem to explain the inconclusive results obtained in case-control studies taking into account the role of functional IL-6 polymorphisms in successful and unsuccessful aging. In fact, IL6 levels seem to depend, in addition, on IL-6 polymorphisms and on innate immunity gene polymorphisms as well.

The genetics of the interaction between host and microbes plays an essential role in the survival of the individual and attainment of longevity. The activation of toll-like receptor (TLR)4 plays a key role in natural and clonotypic immune responses. We evaluated whether TLR4 genotype is a component of genetic background protective versus rickettsiosis and whether this background influences longevity. We genotyped for +896A/G TLR4 polymorphism 78 patients affected by Boutonneuse fever, 78 age-matched controls and 78 advanced age individuals from Sicily. The +869G allele, that attenuates receptor signalling, was significantly overrepresented in patients in comparison with age-matched controls. By analyzing data according to gender, this allele was significantly higher in female patients when compared to advanced age women. Pro-inflammatory responses are programmed to resist fatal infections. So, it is not surprising that the genetic background of people that survive to an advanced age may be protective against infections. However, this seems to occur in women but not in men. In a previous study, the +896G TLR4 allele was overrepresented in advanced age men and underrepresented in men affected by myocardial infarction. Thus, previous and present results tend to agree with the suggestion that men and women may follow different trajectories to reach longevity. For men it might be more important to control atherogenesis, whereas for women it might be more important to control infectious diseases.

AGE6. Skin Ageing: Focus on the Role of Inflammatory Genetic Factors in Cutaneous Neoplasia C. M. Gambino1, F. Crapanzano1, G. Accardi1, A. Aiello1, C. Virruso1, G. Pistone1, M. R. Bongiorno1, D. Lio1, C. R. Balistreri1, G. Candore1 1University of Palermo, Palermo, Italy Background: Skin aging is a complex process that involves intrinsic and exogenous causes. Photo-oxidative damage caused by UV is the leading cause of extrinsic aging of the skin, known as photo-ageing. UV damages can be linked mostly to overproduction of ROS that induces a complex molecular cascade able to accelerate physiological aging, determining a typical dermal/epidermal inflammation with an increased risk of getting skin cancer. The skin response is strongly influenced by individual genetic background. Thus, polymorphisms in candidate inflammatory genes might play a role in photo-ageing and skin cancer. Methods: A total of 30 Sicilian subjects (12 females and 18 males; age range, 65–90 years) were enrolled. From histo-pathological data, 12 subjects showed skin cancer. Their blood samples have been used to obtain DNA samples and have been genotyped for TLR4 (+896 A/G; rs.4986790), TLR4 (+1196 C/T, rs.4986791), MMP2 (-1306 C/T, rs.243865) and MMP9 (-1562 C/T, rs.3918242) using a RFLP-PCR. Results: Allelic and genotypic frequencies of the SNPs analysed were evaluated by gene count. No significant differences in frequencies of these SNPs among cases and controls were observed. Conclusions: Our results are preliminary, so it is certainly necessary to increase the sample size of our study. In fact, the possible role of these SNPs in skin-ageing related neoplasia might open new perspectives for their analysis and prevention. However, it is imperative to underline the concept that functional effects of each SNP depend on the presence of one or different environmental causes (UV radiation, smoking, etc.).

T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for the 55.6%. Patients with A/A and A/G TLR4 genotypes showed significant differences in complication’s prevalence. In particular, AG carriers had higher risk prevalence for neuropathy (P=0.026), lower limb arteriopathy (P=0.013), and the major cardiovascular pathologies (P=0.017). Their cumulative risk was significant (P=0.01), with a threefold risk to develop neuropathy, lower limb arteriopathy, and major cardiovascular events in AG cases compared to AA cases. The adjusted OR for the confounding variables was 3.788 (95% CI: 1.642–8.741). Thus, the rs4986790 polymorphism may be an indicative of prevalence of complications in T2DM patients.

A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preliminary data, the mean of blood leukocyte telomere length, through use of terminal restriction fragment assay and in blood samples from sporadic TAA patients and controls, was examined. Telomerase activity was also analyzed in two groups. In addition, we verified the weight of genetic inflammatory variants and the major TAA risk factors in telomere/telomerase impairment. Aorta histopathological abnormalities and systemic inflammatory mediators were ultimately correlated with telomere/telomerase impairment. Data obtained demonstrated shorter telomeres and a reduced telomerase activity in TAA patients significantly associated with a genetic inflammatory risk profile, age, gender, smoking, hypertension, a histopathological phenotype, and higher levels of systemic inflammatory mediators than controls. In conclusion, telomere and telomerase activity’s detection might be used as predictor biomarkers of sporadic TAA. Their impairment also suggests a strong role of vascular ageing in sporadic TAA, evocated by both environmental and genetic inflammatory factors.

Thoracic aorta shows various changes with advancing age and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur. VR and MD are typical entities of sporadic thoracic aortic aneurysm (TAA), actually considered a common and serious health risk and a pathology by unclear mechanisms. Increased activity of the coagulation system, inflammation, activation of extracellular matrix remodeling and endothelial dysfunction pathways have been recently evidenced to have a key role in its onset. Thus, polymorphisms of the coagulation system [fibrinogen (rs1800790); Factor II ( rs1799963); Factor V (rs6025); Factor VII (rs121964926); tPA ( rs2020918); PAI-1 (rs1799768); TAFI (rs2146881)], inflammation [TLR4 (rs4986790); CCR5 (rs333)], extra-cellular matrix remodeling [MMP9 (rs3918242); MMP2 (rs243865)], endothelium dysfunction [eNOs (rs 1799983); ACE (rs1799752)] were analyzed. Methods: A total of 161 TAA individuals (127 men and 34 women; mean age: 63±10.7) and 128 controls (61 men and 67 women; mean age: 61.08±5.83 years) from Western Sicily were enrolled. Their DNA samples were genotyped for the selected polymorphisms. Results: Inconsistent associations of coagulation polymorphisms with TAA were observed while analysing preliminary data. More relevant results might be obtained when analysing their combined genotypes. Interestingly, we observed that the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA and it represents together with rs1799752 ACE, rs3918242 MMP-9 and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. Their combined risk genotype was also associated with TAA. Conclusions: Results obtained seem to suggest a new perspective for the diagnosis and prevention of sporadic TAA, utilizing genetic profiles as possible risk biomarkers.

Aging has a striking impact on the heart and the vascular system, particularly on the large elastic arteries (i.e., aorta), resulting in a multitude of changes at different structural and functional levels. As result, medial degeneration (MD) occurs. A characteristic example of MD is sporadic thoracic aortic aneurysm (S-TAA), whose patho-physiological mechanisms remain unclear. In this study, typical MD morphological phenotypes were researched in S-TAA cases and control aorta specimens by histopathological and immunohistochemical analyses. Three phenotypes (I, II, and III) were detected, but mainly the phenotype III was observed. Elevated cystic MD, plurifocal medial apoptosis, and increased metalloproteinase-9 amount characterize it. In addition, it was significantly correlated with the severity of elastic fragmentation, hypertension, and smoking, and particularly with advancing age. Thus, phenotype III might represent the typical MD phenotype associated with S-TAA in old people that have a major risk of aorta rupture and dissection independently on aneurysm diameter. This might permit the assumption that phenotype III with its typical histological abnormalities is an optimal biomarker of rupture and/or dissection in aged individuals and is useful both for applying different surgical approaches and providing appropriate surgical indications

OBJECTIVE: Association between aortic aneurysm wall and risk of rupture or dissection. METHODS: Aortic specimens were obtained from 73 patients (51 men and 22 women, whose median age 61.7± 10.7 years) undergoing surgical repair of thoracic ascending aneurysm (TAA). Histopathological and immunohistochemical analyses were performed using adequate tissue specimens, appropriate techniques and criteria. Furthermore, genetic risk factors were also investigated. RESULTS: We identified three phenotypes of TAAs with different quality of aortic wall at the time of operation: phenotype I (normal wall); phenotype II (moderate wall thickness); phenotype III (thin and weak wall). No significant differences were detected in term of demographic and clinical data, co-morbidity conditions and pharmacological treatments. In contrast, significant statistical differences were observed by comparing abnormalities of extracellular matrix components among three phenotypes (fibrosis p

Thoracic aortic aneurysm (TAA) is a progressive disorder involving gradual dilation of ascending and/or descending thoracic aorta with dissection or rupture as complications. It occurs as sporadic or defined syndromes/familial forms.Genetic, molecular and cellular mechanims of sporadic TAA forms are poorly characterized and known. Thus, our interest has been focused on investigating the role of genetic variants of transforming growth factor-β(TGF-β) pathways in TAA risk. On the other hand, no data on the role of genetic variants of TGF-βpathway in sporadic TAA exist until now. In addition, other cytokines, including IL-10, orchestrate TAA pathophysiology. Their balance determines the ultimate fate of the aortic wall as healing atherosclerosis or aneurysm formation. Thus, in this paper it was analyzed the role of ten polymorphisms of genes encoding TGF-βisoforms and receptors, and IL-10 in sporadic TAA. Our study included cases affected by sporadic TAA and two control groups. The most relevant finding obtained allows us to propose that rs900 TGF-β2 SNP is associated with sporadic TAA in women. This might open new perspectives for the analysis of sporadic TAA susceptibility factors and prevention.

Ageing is a systemic condition leading to a gradual loss of molecular and cellular fidelity. A feature of ageing is immunosenescence, consisting in several modifications that increase morbidity and mortality in elderly. Environment, genetic background, immune system, and intestinal microbiota play a fundamental role in immunosenescence. The development of a chronic, low-grade, inflammatory status, known as “inflamm-ageing,” is a typical aspect of immunosenescence mostly due to the pro-inflammatory cytokine production linked to the chronic antigenic load. Nutrition can act on ageing, immunity, and health in general. Unbalanced diet with an insufficient intake of micro- and macronutrient and vitamins is a major nutritional problem among elderly, resulting in a dramatic change in gut microbiota. Calorie restriction and long-term adherence to Mediterranean diet could prevent or manage age-related diseases and immunosenescence.

Objectve: Metalloproteinases (MMPs) are endopeptidases involved in extracellular matrix remodelling, associated with both physiopatological processes of several human tissues and systems, such as vascular system. It is well known their involvement in mediating both beneficial and pathological aorta effects, such as abdominal orta aneurysms and its complcations. On the contrary, unclear data exist about their role in the pathophysiology of sporadic thoracic aneurysm (TAA) and its complications. Thus, the aim of this study was to nalyse the role of MMPs in TAA complications, i.e. rupture and dissection.Methods: Aortic specimens obtained from 73 patients (51 men and 22 women, age 61.7 years) affected by TAAs, 18 patients with type A aortic dissection (TAD) and 30 controls were utilised for histopathological and immne-histochemical analyses. In addition, a second group of 128 subjects (61men and 67 womem, age 61.7 years) was enrolled to examine the role of single nucleotide polymorphirms (SNPs) of MMP-9 and MMP-2 genes in disease risk. Results: Three different patterns of MMPs(extracellular, intracellular, and mixed) with different concentration (low, moderate, elevated) have been observed in case aorta samples. The pattern with elevated MMP amount in aorta samples from TAD cases was also characterised by increased cystic medial degeneration, whitout substitutive fibrosis, and plurifocal apoptosis. In the context of TAA aorta samples, we identified three phenotypes. In particular, the phenotype III mainly observed in case samples showed the same histological features of TAD with elevated MMP concentration with a mixed pattern. in addition, significant associations were obserbved between the -1562C/T MMP9, -735C/T MMP2 SNPs and the risk of both TAA and TAD. Conclusions: OUR data suggest a crucial role of both MMP-2 and -9 in both TAA and its complications. such as TAD. in future they might be considered as new criteria in TAA surgical indications.

AGE8. Is the Serum N Terminal Pro-Brain Natriuretic Peptide the Best Candidate Biomarker for Long-term Prognosis in Patients with Prosthesis-patient Mismatch after Mitral Valve Replacement? C. R. Balistreri1, C. Pisano1, R. Franchino1, S.R. Vacirca1, F. Crapanzano1, O. F. Triolo1, C. Palmeri1, G. Ruvolo1 1University Of Palermo, Palermo, Italy Background: Natriuretic peptides (NPs) are released from the heart in response to pressure and volume overload. Among these, B-NP and Nterminal- proBNP (NT-proBNP) have become important diagnostic tools for the management of heart failure. However, B-NP and NT-proBNP levels reflect complications of systolic and diastolic function as well as alteration of right ventricular and valvular function. In addition, their serum levels have a prognostic value in multiple clinical settings. Based on these observations, we sought to evaluate the relationship between prosthesis patient mismatch (PPM) and serum NT-pro-BNP levels after mitral valve replacement (MVR). PPM following MVR has been less investigated and it seems to mediate deleterious effects on long-term survival, even if contrasting opinions and data exist in the literature. Methods: A total of 100 patients that have undergone this surgical treatment will be enrolled, and opportune clinical data and peripheral blood samples will be collected. Blood samples are utilized to analyze clinical conditions and serum NT-proBNP levels. Evaluation of hemodynamic performances before or under dobutamine infusion is also being assessed. Results: The preliminary data on the serum NT-proBNP levels obtained seem to be interesting and promising, as well as their correlations with hemodynamic performances. Conclusions: The demonstration of negative effects on tricuspid valve and pulmonary hypertension and consequently on survival induced by PPM after MVR through the serum quantification of NT-proBNP levels might lead to consider it as an optimal biomarker to evaluate patients’ long-term prognosis and optimize surgical recommendations (i.e. tricuspid valve repair during mitral valve surgery in patients with moderate-severe mismatch).

Background: Genes coding for the cytochrome P450 (CYP) enzyme system implied in antineoplastic drug metabolism pathways are highly polymorphic. This may influence both carcinogen metabolism and drug pharmacodynamics modifying their therapeutic efficacy and side effects. Methods: We investigated the influence of genetic polymorphisms of CYP enzymes: rs1799853 (CYP2C9), rs35742686 (CYP2D), rs5030655 (CYP2D6/3), rs2740574 (CYP3A4/1) rs776746 (CYP3A5) on the response of chemotherapy and clinical outcomes, in a group of 56 patients affected by sporadic CRC, treated with the standard protocols. A total of 44 patients were in complete remission after treatment, 12 had persistence of the disease. Polymorphisms were typed using a competitive allele specific PCR assay (KASPar), developed by KBioscience. Statistical were analyzed using the χ2 test with Yates correction and Fisher's Exact Test. Significance was defined as p values

Analysis of Polymorphism C558T of MAL (TIRAP) in Mediterranean Spotted Fever M. Bova1, L. Scola1, C. Colomba1, L. Vaccarino1, P. Di Gangi1, G. Santini1, G. Giammanco1, C. R. Balistreri1, D. Lio1, L. Titone Lanza Di Scalea1 1University of Palermo, Palermo, Italy Background: In our previous studies, we have demonstrated that cytokine polymorphisms, such as IFNγ +874T/A or IL-17 SNP (7488T/C), might interfere with R. Conorii infection control. In addition, we have reported that +896A/G TLR4 SNP is a component of a genetic background that might influence the clinical outcome of Boutonneuse fever (Mediterranean spotted fever, MSF). The +869G allele, that attenuates receptor signaling, was actually significantly overrepresented in symptomatic patients. Rickettsial PAMPS recognised through TLR4 and TLR2, activates the MyD-88 signaling pathway, which is involved in the transcription activation of pro-inflammatory cytokine genes. In this pathway MAL (also known as TIRAP) plays a crucial role, therefore, TIRAP polymorphisms may influence the response to the pathogen. In particular, we analyzed C558T of TIRAP that seems to attenuate TLR signaling. Methods: A total of 70 Sicilian patients affected by MSF and 230 control subjects matched for age, gender, and geographic origin were typed for TIRAP SNP (C558T) according to our laboratory procedures. Results: No significant differences between the two groups were observed; therefore, the TIRAP C558T genotypes seem not to influence the susceptibility or protection against MSF. Conclusions: The results obtained suggest that the analyzed SNP on the gene coding for MAL does not seem relevant in determining increased susceptibility for the development of MSF. Nevertheless, it is appropriate to enlarge the casuistry and the number of SNPs involved in TLR signaling pathways to better define the genetic background that modulates the immune response against R. conorii infection and the consequential clinical outcome.

Background: Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews. Methods: We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls. Results: Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity. Conclusions: TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.

IMIN11. Cytokine Polymorphism in Takotsubo Cardiomyopathy P. Di Gangi1, L. Scola1, S. Giambanco1, M. Bova1, G. Santini1, L. Vaccarino1, C. R. Balistreri1, D. Lio1, P. Assennato1, S. Novo1, G. Novo1 1University of Palermo, Palermo, Italy Background: Takotsubo (TT) cardiomyopathy is characterised by an acute left ventricular dysfunction triggered by emotional or physical stresses. Clinically, the syndrome is characterised by acute symptoms mimicking acute infarction without relevant electrocardiographic and biochemical markers of myocardial damage changes. Stressful events inducing an excess catecholamine release and myocardial β-adrenergic receptors (β-AR) seem to play a major role in TT. Accordingly, we have reported that the L41Q polymorphism of the G protein-coupled receptor kinase 5 (GRK5), which, leads to β-arrestin recruitment and mediates β- AR desensitisation might play a role in TT susceptibility. Extended sympathetic activation may influence the pro-inflammatory cytokine secretion triggering b-adrenergic receptors of the immuno system cells. In turn, IL-1, IL-6, TNF-α stimulating the synthesis and release of CRH and norepinephrine might magnify the activation of the sympathetic system. In this view, we have analyzed the role that polymorphisms of inflammatory cytokines might play in the pathogenesis of TT. Methods: We analysed ADRB-1 (rs1801253), IL–1A (rs1800587), IL-1B (rs16944), (rs1143634), IL-6 (rs1800795), TNF-α(rs1800629), TGF- β(rs1800471), IL-10 (rs1800872), (rs1800871), (rs1800896), MAL (rs8177374) and TLR-4 polymorphisms in 25 TT patients and 100 controls using KASPar SNP genotyping method. Statistical analysis of data was performed using dominant, codominant, and recessive models. Results: Analysis of the genotypic and allelic frequencies does not allow the detection of relevant differences in polymorphism frequencies in TT patients. Conclusions: Because of the low number of patients, further studies are necessary to understand the role of cytokine polymorphisms in Takotsubo cardiomyopathy. Work is in progress to recruit and analyse a larger group of patients.

Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR=14.4,P=0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

Background: Dietary intervention and genetic alterations in gene encoding proteins involved in nutrient-sensing pathways can modulate lifespan, influencing longevity. It depends on under/over-expression of regulatory molecules that lead to different expression of homeostatic genes. Insulin/IGF-1 pathway was associated with longevity and lifespan modulation in model organisms. In humans, a key molecule in this pathway is FOXO3A that acts as a TF on homeostatic genes in response to decreased signaling increasing life span. Interestingly, other genes that increase lifespan interact with FOXO3A such as SIRT1, which modulates the oxidative stress response. Methods: We used meta-analytical and candidate-gene approaches to investigate the association of SNPs encoding proteins involved in Insulin/IGF-1 pathway with ageing and longevity. Results: Our study confirmed previous results related to the association between FOXO3A, IGF-1R, KLOTHO and longevity. No association was reported between IGF-1 and SIRT1 although all IGF-1 SNPs could affect its serum levels, known to modulate ageing and longevity. Moreover, we showed a new association between SHIP2 SNPs and longevity. Conclusions: Our results showed that specific SNPs of IGF-1R, FOXO3A, SHIP2 and KLOTHO influence ageing and longevity in different ethnic populations and that FOXO3A could be the most relevant gene in lifespan extension, particularly in males. Moreover, it could be speculated that a reduction of insulin signaling may decrease the activation of NF-kB slowing down inflammatory gene transcription. Thus, the intervention on ageing and longevity should be based both on nutrient-sensing and inflammatory pathways. The first simple step could be represented by the adherence to the Mediterranean diet with low glycaemic index and low animal proteins.

Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer in Western male populations. A complex interaction between genetic and environmental factors (i.e. infectious agents, dietary carcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronic inflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers exist until now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variants in genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able to modify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate in combination to create a 'risk profile'. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PC patients. Thus, their combinations might be used as promising biomarkers in a pre- and post-treatment clinical PC setting. Indeed, their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized in this report through the elucidation of literature data and the results of our studies.

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.

Atherosclerosis (AS) is a chronic, progressive, multifactorial disease mostly affecting large and medium-sized elastic and muscular arteries. It has formerly been considered a bland lipid storage disease. Currently, multiple independent pathways of evidence suggest this pathological condition is a peculiar form of inflammation, triggered by cholesterol-rich lipoproteins and influenced both by environmental and genetic factors. The Human Genome Project opened up the opportunity to dissect complex human traits and to understand basic pathways of multifactorial diseases such as AS. Population-based association studies have emerged as powerful tools for examining genes with a role in common multifactorial diseases that have a strong environmental component. These association studies often estimate the risk of developing a certain disease in carriers and non-carriers of a particular genetic polymorphism. Dissecting out the influence of pro-inflammatory genes within the complex pathophysiology of AS and its complications will help to provide a more complete risk assessment and complement known classical cardiovascular risk factors. The detection of a risk profile will potentially allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug or lifestyle modification; i.e. it will open the door to personalized medicine.

Cytokines act as pleiotropic polypeptides able to regulate inflammatory/immune responses and to provide important signals in physiological and pathological processes. Several cytokines (Th1, Th2, and Th17) seem to be involved in the pathophysiology of Behçet's disease, a chronic immune-mediated disease characterized by oral and genital lesions and ocular inflammation. Its individual susceptibility seems to be modulated by genetic variants in genes codifying these cytokines. Th1 and Th17 seem to be involved in the disease's active phases, and Th2 seems to affect the development or severity of the disease; however, contrasting data are reported. In this study, some genetic variants of the Th1/Th2 cytokine genes were investigated in Sicilian patients and age- and gender-matched controls. Three very significant associations with Behçet's disease were detected, and combined genotypes associated with increased disease risk were identified. Results obtained point to the key role of Th1/Th2 cytokine genetic variants in disease susceptibility.

Type A aortic dissection (TAAD) is a severe cardiovascular disease with high mortality rates. Current evidence suggests inflammation as the main mechanism of its complex pathophysiology. Accordingly, in this study the eventual presence of inflammatory cells in aorta specimens and any contribution of these cells in both apoptosis and metalloproteinase levels were assessed. The potential relationship between plasma inflammatory molecules and TAAD was also detected. In addition, implication in TAAD susceptibility of ten common and functional single nucleotide polymorphisms (SNP)s of six candidate genes (CCR5, TLR4, ACE, eNOs, MMP-9 and −2) was determined. Thus, histo-pathological and immunoistochemical aorta examination, TUNEL testing, genotyping of ten SNPs were performed. Levels of plasma inflammatory molecules were also determined using ELISA technique. A significant inflammatory infiltrate was observed in the examined aortas. Consistent with these data, significantly higher plasma levels of systemic inflammatory mediators characterized the cases. In addition, a high risk genotype significantly associated with TAAD susceptibility was identified. Thus, inflammation producing MMPs, cytokines and death mediators seem to be the shared pathological mechanism for TAAD in the population examined.