Cumulative patient effective dose and acute radiation-induced chromosomal DNA damage in children with congenital heart disease

Background The seventh Committee on "Biological Effects of Ionizing Radiation" (BEIR VII, 2006) underlines "the need of studies of infants who are exposed to diagnostic radiation because catheters have been placed in their hearts". Objective To determine the lifetime attributable risk (LAR) of cancer associated with the estimated cumulative radiological dose in 59 children (42 male, age 2.863.2 years) with complex congenital heart disease, and to assess chromosomal DNA damage after cardiac catheterisation procedures. Methods In all patients, the cumulative exposure was estimated as effective dose in milliSievert (mSv), and LAR cancer was determined from the BEIR VII report. In a subset of 18 patients (13 male, age 5.265.7 years) micronucleus as a biomarker of DNA damage and longterm risk predictor of cancer was assayed before and 2 h after catheterisation procedures. Doseearea product (Gy cm2) was assessed as a measure of patient dose. Results The median life time cumulative effective dose was 7.7 mSv per patient (range 4.6e41.2). Cardiac catheterisation procedures and CT were responsible for 95% of the total effective dose. For a 1-year-old child, the LAR cancer was 1 in 382 (25th to 75th centiles: 1 in 531 to 1 in 187) and 1 in 156 (25th to 75th centiles: 1 in 239 to 1 in 83) for male and female patients, respectively. Median micronucleus values increased significantly after the procedure in comparison with baseline (before 6&vs after 9&, p?0.02). The median doseearea product value was 20 Gy cm2 (range 1e277). Conclusion Children with congenital heart disease are exposed to a significant cumulative dose. Indirect cancer risk estimations and direct DNA data both emphasise the need for strict radiation dose optimisation in children

Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2genes in familial cases of bicuspid aortic valve

BACKGROUND: The purpose of our study was to investigate the potential contribution of germline mutations in NOTCH1, GATA5 and TGFBR1 and TGFBR2 genes in a cohort of Italian patients with familial Bicuspid Aortic Valve (BAV). METHODS: All the coding exons including adjacent intronic as well as 5(′) and 3(′) untranslated (UTR) sequences of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes were screened by direct gene sequencing in 11 index patients (8 males; age = 42 ± 19 years) with familial BAV defined as two or more affected members. RESULTS: Two novel mutations, a missense and a nonsense mutation (Exon 5, p.P284L; Exon 26, p.Y1619X), were found in the NOTCH1 gene in two unrelated families. The mutations segregated with the disease in these families, and they were not found on 200 unrelated chromosomes from ethnically matched controls. No pathogenetic mutation was identified in GATA5, TGFBR1 and TGFBR2 genes. CONCLUSIONS: Two novel NOTCH1 mutations were identified in two Italian families with BAV, highlighting the role of a NOTCH1 signaling pathway in BAV and its aortic complications. These findings are of relevance for genetic counseling and clinical care of families presenting with BAV. Future studies are needed in order to unravel the still largely unknown genetics of BAV

Genetic stress echocardiography: role of A2a receptors polymorphism in modulating coronary flow reserve response in non-ischemic dilated cardiomyopathy

Background: Vasodilator stress imaging is based on coronary A2a receptor stimulation via endogenous adenosine (with dipyridamole administration), exogenous adenosine, or selective A2a receptor stimulation (with binodenoson).The recognized inter-individual variability in response to adenosine might be in part determined by genetic polymorphism in A2a adenosine receptors. Aim: to assess whether A2a receptor (263 C>T and 1976 C>T) polymorphism affects the coronary flow reserve (CFR) response in patients with non-ischemic dilated cardiomyopathy (DCM). Methods: we evaluated 44 DCM patients 34 males; age 62?9 years) by transthoracic dipyridamole (0.84 mg/kg) stress echocardiography. All patients had an ejection fraction <40% (mean 21.1?16.3%) and angiographically normal coronary arteries with NYHA class <3. CFR was assessed on left anterior descending coronary artery using Doppler as the ration of maximal peak vasodilation (dipyridamole) to rest diastolic flow velocity. All patients underwent peripheral blood sampling and A2a receptor genotyping with PCR and enzyme restriction analysis. Results: CFR was 2.1?0.6 (range=1.5-4). There was no correlation between CFR and 263 C>T variant of A2a gene. However, patients with 1976 TT genotype had significantly lower values from 1976 CC patients (p<0.05). The 7 patients omozygous for 1976 TT had an OR=8.8 (95% CI, 1-81, p=0.04) for abnormal CFR. Conclusion: In DCM patients 1976 C>T polymorphism of the adenosine A2A receptor gene may affect CFR response. In particular, the 1976-TT variant of A2a gene blunts the coronary vasodilatory response

Expression level of CCR5 chemokine receptor on blood CD4+ and CD8+ T-cells plays an important role in the Ascending Aortic Aneurysm pathophysiology.

Background and aim: The CC chemokine receptor 5 (CCR5) is involved in the migration of circulating NK and Th1 cells towards inflammatory sites. CCR5 expression has also been demonstrated on endothelial cells, aortic smooth muscle cells and implicated in the development of abdominal aortic aneurysm. Thoracic aortic aneurysm (TAA) is a lethal disease burdened by complications such as aortic dissection/rupture. The risk of these acute events has been related to the severity of aortic enlargement. The aim of our study is to investigate a possible role of CCR5 expression on peripheral blood CD4+ and CD8+ T-lymphocytes in the pathogenesis of TAA. Methods: We have studied 14 patients (8 female, 6 male) with mean age of 67.35?7.70, undergoing isolated aortic valve replacement (AVR) and/or TAA surgery. Preoperatively, venous blood samples were obtained. A three colors flow cytometric analysis was performed by appropriate combinations of monoclonal antibodies directed against the following surface molecules: CD3, CD4, CD8, CCR5. Data are expressed in terms of percentage of positivity. Maximal aortic diameter (MAD) was determined by transesophageal echocardiography. For each patient we calculated the aortic size index (ASI), defined as MAD/BSA (mm/m2). Results: Aortic index was 21.52?3.14 mm/m2. Nine patients underwent isolated AVR (group 1) and five patients underwent TAA surgery (group 2). The percentage of CCR5+ on CD4+ was significantly higher in group 2 (17.03?3.08 vs 13.03?2.72, p=0.0269). A trend towards a higher percentage of CCR5+ on CD8+ was observed in group 2 (22.74?8,39 vs 16.26?3.75, p=0.0653). A significant correlation between aortic index and the percentage of CD4+ and CD8+ T-cells expressing CCR5 was observed (p=0.048, R2=0.287 and p=0.0067, R2=0.471 respectively). Conclusions: The correlation between the percentage of CD4+ and CD8+ T-cells expressing CCR5 and aortic index suggests the role of a T-cell immune-mediated cytotoxic mechanism in the progression of TAA disease

Ascending aortic aneurysm in a patient with bicuspid aortic valve, positive history of systemic autoimmune diseases and common genetic factors: a case report

The bicuspid aortic valve (BAV) and specific systemic autoimmune diseases are associated with cardiovascular manifestation, including aortic aneurysm. We reported a case of 64 year-old patient with BAV and a history of ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE), and who developed ascending thoracic aortic aneurysm. The patient presented also the homozygosity for genetic variants of MMP9, ACE, MTHFR and PAI-1 genes. Gene-environmental interactions may represent an additional pathogenetic dimension in the still challenging management of the abnormalities of the aortic wall, including dilatation, aneurysm and dissection

Health Risk and Biological Effects of Cardiac Ionising Imaging: From Epidemiology to Genes

Cardiac diagnostic or therapeutic testing is an essential tool for diagnosis and treatment of cardiovascular disease, but it also involves considerable exposure to ionizing radiation. Every exposure produces a corresponding increase in cancer risk, and risks are highest for radiation exposure during infancy and adolescence. Recent studies on chromosomal biomarkers corroborate the current radioprotection assumption showing that even modest radiation load due to cardiac catheter-based fluoroscopic procedures can damage the DNA of the cell. In this article, we review the biological and clinical risks of cardiac imaging employing ionizing radiation. We also discuss the perspectives offered by the use of molecular biomarkers in order to better assess the long-term development of health effects

Bilayered Fibrin-Based Electrospun-Sprayed Scaffold Loaded with Platelet Lysate EnhancesWound Healing in a Diabetic Mouse Model

The present study examined the effects of a bilayered fibrin/poly(ether)urethane scaffold loaded with platelet lysate by a combination of electrospinning and spray, phase-inversion method for wound healing. In particular, the poly(ether)urethane layer was obtained using by a spray phase-inversion method and the fibrin fibers network were loaded with platelet lysate by electrospinning. The kinetics release and the bioactivity of growth factors released from platelet lysate-scaffold were investigated by ELISA and cell proliferation test using mouse fibroblasts, respectively. The in-vitro experiments demonstrated that a bilayered fibrin/poly(ether)urethane scaffold loaded with platelet lysate provides a sustained release of bioactive platelet-derived growth factors. The effect of a bilayered fibrin/poly(ether)urethane scaffold loaded with platelet lysate on wound healing in diabetic mouse (db/db) was also investigated. The application of the scaffold on full-thickness skin wounds significantly accelerated wound closure at day 14 post-surgery when compared to scaffold without platelet lysates or commercially available polyurethane film, and at the same level of growth factor-loaded scaffold. Histological analysis demonstrated an increased re-epithelialization and collagen deposition in platelet lysate and growth factor loaded scaffolds. The ability of bilayered fibrin/poly(ether)urethane scaffold loaded with platelet lysate to promote in-vivo wound healing suggests its usefulness in clinical treatment of diabetic ulcers