Papers by Guglielmina Pepe
Autoimmune Diseases, 2013
PubMed, Feb 1, 2013
Improved knowledge of the structure and function of the aortic wall, as well as its pathophysiolo... more Improved knowledge of the structure and function of the aortic wall, as well as its pathophysiology and histopathology, will result in an increasing impact on clinical evaluation and treatment of thoracic aortic diseases. This opinion paper highlights the main "paradigmatic shifts" in this field, providing cardiologists with some novel clues for the clinical approach to patients with thoracic aortic disease.
Human Biology, 2005
Restriction fragment length polymorphisms are good anthropological markers for discriminating geo... more Restriction fragment length polymorphisms are good anthropological markers for discriminating geographically distinct populations at both the allele and the haplotype level. Two communities of African ancestry and ladinos, mestizos, and mulattoes living in the Esmeraldas province in northwestern Ecuador were analyzed for three RFLPs (EcoRI, RsaI, and MspI) of the COL1A2 gene. Also, the same markers were studied in a
PubMed, Dec 1, 2004
A growing body of evidence has shown a strong association between elevated plasma homocysteine (H... more A growing body of evidence has shown a strong association between elevated plasma homocysteine (Hcy) levels with vascular disease and thrombotic complications. Data available in literature also suggest a role of hyperhomocysteinemia in abdominal and thoracic aortic diseases. In particular, Hcy was investigated in patients with Marfan syndrome and it was demonstrated that Hcy levels were associated with the risk of severe cardiovascular manifestations or dissection. Hcy was significantly higher also in patients with abdominal aortic aneurysms and was associated with the size of aneurysms. It remains to be elucidated if this association is causal or simply an effect of the disease. A number of mechanisms may be evoked to explain these findings. Studies in animal models demonstrated that hyperhomocysteinemia could induce marked remodelling of the extracellular matrix of the arterial wall by inducing elastolysis through the activation of metalloproteinases. In addition, Hcy may directly affect fibrillin-1 or collagen by interfering with intra- and/or inter-molecular disulfide bonds through disulfide exchange, or binding to free sulphydryl groups. Further studies are needed to confirm the role of Hcy in aortic disease and the usefulness of including Hcy determination in the clinical evaluation of these patients.
Human Evolution, Jul 1, 1997
Assignement of the Fibronectin (FN1) gene to Pongo Pygmaeus (Orangutan) Chromosome 11. Using Fibr... more Assignement of the Fibronectin (FN1) gene to Pongo Pygmaeus (Orangutan) Chromosome 11. Using Fibronectin (F18) human cDNA probe, the FN geae was assigned to orangutan chromosome 11 by in situ hybridization. Our data confirm the homology between orangutan chromosome 11 and lhe long arm of human chromosome 2.
Cardiovascular Research, Oct 1, 2022
Background Timely diagnosis of patients with Heritable Thoracic Aortic Diseases (HTAD) is essenti... more Background Timely diagnosis of patients with Heritable Thoracic Aortic Diseases (HTAD) is essential to avoid (often fatal) aortic dissection. Experts of the HTAD rare disease working group of the European Reference Network of Rare Vascular diseases (vascern) aimed to propose a pathway to: (1) improve patient care by diminishing time to diagnosis; (2) facilitate the establishment of a correct diagnosis, using molecular genetics when possible, which may lead to a more personalized treatment; (3) exclude the diagnosis in unaffected persons (family screening); (4) avoid overuse of financial and personnel resources. Material and methods This pathway is a consensus at expert level. It was generated based on available guidelines when possible. Discussion items were listed and, where necessary, items were included in a questionnaire sent out for voting and discussion over monthly teleconference calls. Results and conclusions Pathway Elements include Thoracic aortic aneurysm – and dissection, Bicuspid Aortic Valve, Medium-sized artery aneurysms/dissection, Extravascular features and Family History. Recommendations for the evaluation of patients and family members are provided. This pathway is advised to implement standardisation of diagnostic workup and follow-up of patients with suspected HTAD and the screening of their relatives and it focuses on patients with heritable aortic diseases whether syndromic or not. It is subject to adjustment with better recognition of new entities, and with the technical progress and increased availability of genetic testing.
Cardiology in the Young, 2020
Background:Marfan syndrome is an autosomal dominant disorder of the connective tissue, whose card... more Background:Marfan syndrome is an autosomal dominant disorder of the connective tissue, whose cardinal features affect eyes, musculoskeletal, and cardiovascular system. Despite prevalence and natural history of cardiovascular manifestation are well known in adults, little is known about children and young adult patients. The aim of this study was to describe a well-characterised cohort of consecutive children and young patients with marfan syndrome, looking at the impact of family history and presence of bicuspid aortic valve on disease severity.Methods:A total of 30 consecutive children and young patients with Marfan syndrome were evaluated. All patients underwent a comprehensive clinical–instrumental–genetic evaluation. Particular attention was posed to identify differences in prevalence of cardiovascular abnormalities between patients with and without family history of Marfan syndrome or bicuspid aortic valve.Results:Of these 30 patients, family history of Marfan syndrome and bicu...
Orphanet Journal of Rare Diseases, 2018
Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to ... more Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT is estimated to affect 85,000 European citizens, but most health care providers have limited prior HHT exposure or training. Outcome Measures were developed and implemented by the HHT Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN), in order to maximise the number of patients receiving good care. The measures specifically target areas where optimal management reduces morbidity and mortality in HHT patients, and were designed to be robust to emerging new evidence. Thresholds are the percentage of patients in particular settings who have been recommended screening, or provided with written advice. The 5 Outcome Measures cover (1) pulmonary AVM screening; (2) written nosebleed advice, (3) assessment of iron deficiency; (4) antibiotic prophylaxis prior to dental and surgical procedures for patients with pulmonary AVMs, and (5) written advice on pregnancy. They are not a blueprint for detailed HHT management, but are suitable for all clinicians to be aware of and implement. In summary, these 5 Outcome Measures provide metrics to identify healthcare providers of good care, and encourage care improvement by all healthcare providers.
Kardiologia Polska
This article is available in open access under Creative Common Attribution-Non-Commercial-No Deri... more This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.
Background In Systemic sclerosis (SSc), an imbalance of the fibrinolytic system was shown. In viv... more Background In Systemic sclerosis (SSc), an imbalance of the fibrinolytic system was shown. In vivo and in vitro studies suggest a role for Renin Angiotensin System in the regulation of fibrinolytic balance: Angiotensin II (Ang II) increases the plasminogen activator inhibitor?1 (PAI-1) production and secretion, and ACE reduces t-PA production. A polymorphism in the ACE gene consisting of an insertion or deletion (I/D) of 287 bp fragment in intron 16 was described. The D allele of ID polymorphism is associated with an increased level of ACE and ACE gene polymorphism may influence the production of Ang II. Objectives To investigate possible alterations in the fibrinolytic system and to examine the role of ACE I/D polymorphism in SSc. Methods PAI-1 activity, t-PA and D-Dimer plasma levels were measured in 61 SSc patients (36 limited, 25 diffuse) and 108 healthy controls. ACE I/D polymorphism was genotyped by PCR. PAI-1 activity and t-PA levels were assayed by chromogenic method and D-Dimer levels by ELISA. Results A significant difference in ACE genotype distribution (chi2 = 9.79 p = 0.007) and allele frequency was observed between patients and controls (0.64 vs 0.50 p = 0.009). In limited SSc a higher frequency of ACE D allele was found (0.68 vs 0.56 in diffuse SSc p = 0.23). By univariate analysis an association between ACE D allele and limited, but not diffuse SSc, was found (OR DD+ID/II = 6.44 95% CI 1.45-28.54 p = 0.005 and OR DD+ID/II = 1.91 95% CI 0.60-6.08 p = 0.31 respectively). Median values of PAI-1, t-PA and D-Dimer were 6.2 U/ ml (range 1-37.5),10.5 ng/mL (range 4.3-28.1) and 156 ng/mL (range 64-1064, respectively. Patients had higher t-PA and D-Dimer mean levels than controls (p = 0.000001 and p = 0.02, respectively). No difference was observed in PAI-1 plasma levels between patients and controls (p = 0.85). No association between high PAI-1, t-PA and D-Dimer plasma levels and ACE D allele was observed. Conclusion These data suggest that ACE D allele is highly associated with limited SSc. Thus, we could hypothesise that this allele may represent a risk factor for the development of limited SSc. Other mechanisms than the alterations of fibrinolytic system may have a role in determining the microvascular damage.
Annals of the Rheumatic Diseases, Jun 1, 2014
treatment with regard to the patient and its quality of life along with positive impact on medica... more treatment with regard to the patient and its quality of life along with positive impact on medical system. Moreover the use of further investigation based on X-rays is prevented. Owing to this fact this program could turn out to be useful in order to help the doctor's assessment.
Seminars in Thrombosis and Hemostasis, Apr 1, 1997
Stimulated monocytes are involved in blood clotting and fibrin dissolution by synthesizing tissue... more Stimulated monocytes are involved in blood clotting and fibrin dissolution by synthesizing tissue factor (TF) and fibrinolytic components such as plasminogen activator inhibitor type 2 (PAI-2). Heparin interacts with smooth muscle cells, platelets, and endothelial cells and specifically binds to human monocytes. In endothelial and smooth muscle cells, heparin selectively inhibits collagenase and tissue plasminogen activator gene expression. To investigate (1) heparin's influence on the hemostatic system by its interactions with plasma factors and cellular elements and (2) to determine its effects on gene expression in blood circulating cells, we studied the effect of heparin on TF and PAI-2 protein and mRNA in human lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-stimulated monocytes. TF and PAI-2 proteins were investigated by ELISA and by assaying procoagulant activity. The mRNA study was carried out by an initial PCR screening followed by a Northern blot semiquantitative analysis. Heparin (0.5 U/mL) inhibited both TF and PAI-2 production and gene expression. The contemporaneous protein and mRNA decrease (TF and PAI-2 protein 22 and 42%, respectively; suggests that this action is, at least partially, at the transcriptional level. The effect is not specific for heparin and is not demonstrated by other glycosaminoglycans (chondroitin-4-sulfate or dermatan sulfate). This action may be relevant for the antithrombotic activity of heparin in cell-mediated blood clotting activation.
Minerva Cardioangiologica, 1999
Giornale italiano di cardiologia, Aug 1, 2004
Minerva Cardioangiologica, Dec 1, 1999
Nutrition Metabolism and Cardiovascular Diseases, 2017
Background: Severe hypertriglyceridemia (HTG) may result from mutations in genes affecting the in... more Background: Severe hypertriglyceridemia (HTG) may result from mutations in genes affecting the intravascular lipolysis of triglyceride rich lipoproteins. Objective and methods: The aim of this study was to investigate monogenic causes of severe HTG by a targeted Next Generation Sequencing (NGS) approach to capture the coding exons and intron/ exon boundaries of 18 genes affecting the main pathways of triglyceride synthesis and metabolism. Results: The targeted resequencing of candidate genes of severe HTG led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia. The mutation causes a C>G substitution in exon 9 (c.1380C>G), leading to a premature stop codon (W460X). The clinical and molecular familial cascade screening allowed the identification of two additional affected siblings and seven heterozygous carriers of the mutation. Homozygosity for the c.1380C>G mutation resulted in a severe HTG phenotype in the proband (II-2) while two other siblings (II-1 and II-4) showed mild to moderate HTG suggesting a different and variable pattern of penetrance among carriers of the same mutation of the LMF1 gene. None of them have suffered of acute pancreatitis or recurrent abdominal pain. Conclusions: We describe the third novel nonsense mutation of LMF1 gene (c.1380C>G-p.Y460X) identified by a customized NGS panel for targeted gene sequencing of 18 genes involved in hypertriglyceridemia. More studies are needed to understand the reasons of the phenotypic variability of the same molecular defect in the same family.
Transplantation, Mar 1, 2001
Background. Long-term survival of renal transplant recipients seems to be influenced by the occur... more Background. Long-term survival of renal transplant recipients seems to be influenced by the occurrence of thromboembolic complications and cardiovascular disease. Preliminary data available in the literature found high levels of cysteine (Cy) as a risk factor for deep venous thrombosis independently of high homocysteine (tHcy) levels, but no data are available about Cy levels in renal transplant recipients. Methods. To investigate Cy, tHcy, and plasminogen activator inhibitor-1 (PAI-1) levels and the prevalence of 5,10-methylenetetrahydrofolate reductase (MTHFR) in renal transplantation, we studied 70 stable renal transplant recipients and 66 age-and sex-matched normal subjects as controls. Results. Cy, tHcy, and PAI-1 levels were significantly higher in renal transplant recipients with respect to controls (Cy: 254 mol/L [117-466] vs. 198 mol/L [99-331], P<0.
Neuromuscular Disorders, Dec 1, 2002
Bethlem myopathy (OMIM # 158810) is an early-onset benign myopathy characterized by proximal musc... more Bethlem myopathy (OMIM # 158810) is an early-onset benign myopathy characterized by proximal muscle weakness and multiple flexion contractures [1-3]. It is caused by dominant mutations in COL6A1 (OMIM # 120220), COL6A2 (OMIM # 120240) [4], and COL6A3 (OMIM # 120250) [5] genes. Seventeen active participants attended the International Workshop of the Consortium on Bethlem myopathy from six countries, including France, Italy, Japan, The Netherlands, Turkey, and the United Kingdom. Since Camacho Vanegas and co-workers [8] demonstrated the association of a second disease with COL6 genes, this second meeting on Bethlem myopathy included sections on Ullrich scleroatonic muscular dystrophy (UCMD) [6,7]-a subgroup associated with collagen type VI and other clinical entities overlapping with the above disorders in which the molecular bases are still unknown [9]. 2. Bethlem myopathy Cardiac and respiratory muscle involvements are wellknown complications in muscular dystrophies. Until now, in Bethlem myopathy, cardiac abnormalities have not been described, and pulmonary involvement is supposed to be rare. Anneke van der Kooi reported a study by the Dutch group and their collaborators on patients presenting with a phenotype compatible with Bethlem myopathy. Both frequency and nature of cardiac involvement were investigated in 121 Bethlem myopathy patients (59 males, 62 females) from 61 families. Patients were subdivided into two categories: genetically proven or possible. Cardiac involvement was assessed by electrocardiography (ECG), echocardiography (ECHO) and 24 h ECG (Holter). In addition, pulmonary investigations were performed. ECG was Neuromuscular Disorders 12 (2002) 984-993
BMC Medical Genetics, Feb 24, 2014
Background: Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with freque... more Background: Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined. Methods: Ten consecutive BAV patients [8 men, age range 24-42 years] without MFS were clinically characterized. BAV phenotype and function, together with evaluation of aortic morphology, were comprehensively assessed by Doppler echocardiography. Direct sequencing of each FBN1 exon with flanking intron sequences was performed on eight patients. Results: We detected three FBN1 mutations in two patients (aged 24 and 25 years) displaying aortic root aneurysm ≥50 mm and moderate aortic regurgitation. In particular, one patient had two mutations (p.Arg2726Trp and p.Arg636Gly) one of which has been previously associated with variable Marfanoid phenotypes. The other patient showed a pArg529Gln substitution reported to be associated with an incomplete MFS phenotype. Conclusions: The present findings enlarge the clinical spectrum of isolated BAV to include patients with BAV without MFS who have involvement of FBN1 gene. These results underscore the importance of accurate phenotyping of BAV aortopathy and of clinical characterization of BAV patients, including investigation of systemic connective tissue manifestations and genetic testing.
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Papers by Guglielmina Pepe