Calogera Pisano

Role of TGF-β Pathway Polymorphisms in Sporadic Thoracic Aortic Aneurysm: rs900 TGF-β2 Is a Marker of Differential Gender Susceptibility

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-β pathway 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-β isoforms 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.

Long-Term Results After Repair of Type A Acute Aortic Dissection According to False Lumen Patency

BACKGROUND Late survival and freedom from retreatment on the descending aorta was evaluated after ascending aortic repair for type A acute aortic dissection (TAAAD). METHODS Between March 1992 and January 2006, 189 TAAAD patients (mean age, 52 +/- 11; range, 17 to 83 years) were included; of these, 58 had a patent false lumen, and 49 had Marfan syndrome. The descending aorta was evaluated postoperatively with computed tomography (CT). Late outcomes were assessed by Cox regression analysis and actuarial survival and freedom from retreatment by the Kaplan-Meier method. Mean follow-up was 88 +/- 44 months. RESULTS There were 38 (20%) late deaths. At 10 years, survival was 89.8% +/- 2.1% for patients with an occluded false lumen and 59.8% +/- 3.5% for patients with a patent false lumen (p = 0.001), and freedom from retreatment on the descending aorta was 94.2% +/- 3.1% for an occluded false lumen and 63.7% +/- 2.6% for a patent false lumen (p < 0.0001). Descending aortic rupture (p = 0.002) and a patent false lumen (p = 0.001) were predictors for late death. Patent false lumen (p = 0.0001), Marfan syndrome (p = 0.03), and descending aortic diameter 4.5 cm or larger (p = 0.002) were predictors for retreatment. CONCLUSIONS A patent false lumen was a predictor for late death and retreatment on the descending aorta. Marfan syndrome and aortic size exceeding 4.5 cm were predictors for late retreatment. These patients require very close follow-up and a plan for retreatment on the descending aorta to prevent sudden rupture and late death.

Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives.

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.

Histological and genetic studies in patients with bicuspid aortic valve and ascending aorta complications

OBJECTIVES Aneurysm diameter and growing rate does not represent a definite parameter for operation in bicuspid aortic valve (BAV), ascending aortic aneurysm and normal root patients. Thus, we investigated histological and immunohistochemical aspects of different segments of ascending aorta (precisely, aortic root without dilatation, aneurysmatic tubular portion, dissected ascending aorta) and genetic features of patients with BAV and ascending aorta complication (aneurysm or dissection). METHODS Aorta tissue samples of 24 BAV patients were examined. The patients comprised of 18 men and 6 women; the mean age was 54.2 ± 14.3 years. All patients underwent composite aortic root replacement (button Bentall operation). Multiple histological sections were prepared from each aortic specimen. The evaluated features included elastic fibre fragmentation, cystic medial change, smooth muscle cell necrosis, medial fibrosis, and the markers of medial apoptosis and the metalloproteinases. Furthermore, genetic risk factors were also investigated. RESULTS The same medial degenerative lesions in tissue samples of different aorta segments (precisely of aortic root without dilatation, and aneurysmatic ascending aorta portion) were observed. More significant associations between single nucleotide polymorphisms (-786T/C endothelial nitric oxide synthase enzyme, D/I angiotensin-converting enzyme, -1562C/T metalloproteinase-9 and -735C/T metalloproteinase-2) and aneurysm risk were detected in BAV patients than in controls. CONCLUSIONS Based on our histological and genetic data, we underline that a surgical approach in patients with BAV, ascending aortic aneurysm and normal root, should consider not only the diameter of the aneurysmatic aortic portion but also the histological features of the whole ascending aorta and the genetic risk profile.

Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: clinical implications of a pilot study

OBJECTIVES The involvement of different factors in the onset of thoracic aortic aneurysm (TAA) in patients with a bicuspid aortic valve (BAV) vs those with a tricuspid aortic valve (TAV) is well recognized. However, the molecular, genetic and cellular mechanisms driving TAA remain unclear. The aim of this study was to identify the different mechanisms involved in TAA development in patients with BAV vs TAV. METHODS Aorta specimens and DNA samples were collected from 24 BAV (18 men and 6 women; mean age: 54.2 ± 14.39 years) and 110 TAV (79 men and 31 women, mean age: 66 ± 9.8 years) patients. A control group of 128 subjects (61 men and 67 woman, mean age: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunohistochemical analyses were performed, as well as genotyping of 10 polymorphisms. RESULTS In BAV-associated ascending aortas, significant severe plurifocal apoptosis of smooth muscle cells and matrix metalloproteinase-9 (MMP-9) amounts were detected. In contrast, TAV-associated ascending aortas were characterized by a significant severity of elastic fragmentation, cystic medial necrosis, medial fibrosis and inflammation. In addition, in BAV cases, the -1562TMMP-9 and -735TMMP-2 alleles represent independent risk factors for TAA. The effects of these genotypes combined with hypertension and smoking in BAV cases result in an increase in both the apoptosis (P = 0.0001) and levels of MMP-9 (P = 0.001). In TAV cases, the D angiotensin-converting enzyme and +896A Toll-like receptor-4 alleles seem to be the predictive factors for TAA risk. They, combined with hypertension and age, significantly increase both the microscopic lesions and inflammation. CONCLUSIONS Our data seem to suggest that TAA in BAV and TAV patients arises from different molecular, cellular and genetic mechanisms. They might help to identify the potential molecular and genetic biomarkers that are useful to detect BAV subjects at high TAA risk, to monitor and treat them differently from those with TAV, with approaches such as the complete removal of the ascending aorta, including the aortic root with or without dilatation.

Is the mean blood leukocyte telomere length a predictor for sporadic thoracic aortic aneurysm? Data from a preliminary study.

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.

Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

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.

Valve prosthesis-patient mismatch: hemodynamic, echocardiographic and clinical consequences

OBJECTIVES The purpose is to evaluate in vivo at rest and under stress conditions hemodynamic performance of the small size St. Jude Medical Regent (SJMR) prosthetic valve in patients with a body surface area (BSA) of 1.8 ± 0.11 m(2) and to define the role of valve prosthesis- patient mismatch on left ventricular mass regression following aortic valve replacement. METHODS We evaluated 25 cases (12 males and 13 females, mean age 65.2 ± 8 years) of aortic valve replacement (17 mm SJMR in three cases and 19 mm SJMR in 22 cases). All the patients underwent at rest Doppler echocardiography before and after surgery and both basal and dobutamine stress echocardiography (DSE) at follow-up. The mean duration of follow-up was 41.3 ± 24 months. RESULTS A significant reduction in mean and peak transaortic gradients and peak transaortic velocity over time following valve replacement has been identified. After surgery, there was a significant increase of ejection fraction. DSE significantly increased heart rate, ejection fraction, peak transaortic gradient and peak transaortic velocity. All patients passed DSE without complication. Even if a significant mismatch was present in 76% of cases, the left ventricular mass decreased significantly from preoperative value of 278.7 ± 51.1 g to 181.5 ± 52.73 g, respectively. CONCLUSION Aortic valve replacement with 17 mm SJMR or 19 mm SJMR prostheses appear to provide satisfactory clinical and hemodynamic results at rest and under DSE, even in those patients with BSA of 1.8 ± 0.11 m(2) where it was not possible to enlarge the aortic annulus. Prosthesis-patient mismatch is not associated with lesser regression of left ventricular mass. Dobutamine stress echocardiography should be a useful and effective means for evaluating prosthesis hemodynamic aspects.

A particular phenotype of ascending aorta aneurysms as precursor of type A aortic dissection

OBJECTIVES We aimed to identify a phenotype of ascending thoracic aortic aneurysm (TAA), which, more than others, evolves into type A dissection (TAD). METHODS Aortic specimens were obtained from patients undergoing surgical repair of TAA and TAD (108 and 26, respectively). Histopathological and immunohistochemical analyses were performed by using adequate tissue specimens, appropriate techniques and criteria. RESULTS We identified the three following TAA phenotypes: phenotype I (cystic medial degeneration balanced by a substitutive fibrosis, in absence of medial apoptosis and with a faint collagenase concentration), phenotype II (cystic medial degeneration of higher grade, respectively, than substitutive fibrosis, with focal medial apoptosis and moderate collagenase concentration), and phenotype III (elevated cystic medial degeneration without substitutive fibrosis, with plurifocal medial apoptosis and severe collagenase concentration). The same medial degenerative lesions of TAA phenotype III were observed in TAD tissue samples. CONCLUSIONS The morphological identity of medial lesions observed in both the TAA phenotype III and in TAD aortas might be assumed to be the precursor-and consequently the optimal biomarker- of dissection, independently of aneurysm diameter or valvular disorder. Identification of genetic risk factors, useful both in diagnostics and in developing more targeted treatment for individual patients, might also be needed.

Penn classification in acute aortic dissection patients.

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.