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We report a 9-year-old girl homozygous for a loss-of-function mutation in the PIEZO-2 gene. She showed generalized muscular hypotonia with severe scoliosis, joint deformities, deficient proprioceptive function and selective atrophy and signal alterations of both gastrocnemii on whole body MRI scan. Light microscopic and ultrastructural examination showed few atrophic fibres, abnormal mitochondria, focal myofibrillar disruption and endomysial capillary microangiopathy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case-control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Genetic variation in plasma fibrinogen and the platelet receptor GP IIIa locus has been independently associated with increased risks of ischaemic heart disease, but there have been few reports on the relationship with peripheral arterial disease. This study determined the risk of peripheral arterial disease and ischaemic heart disease associated with polymorphisms of fibrinogen T/G(+1689) and platelet glycoprotein Pl(A) genes and the effects of cigarette smoking and fibrinogen., Materials and Methods: In the 5-year follow-up phase of the Edinburgh Artery Study, 939 subjects (60-79 years) had DNA extracted from a venous blood sample. One hundred sixteen subjects were identified as having angina, 87 a myocardial infarction, 104 had intermittent claudication and 663 subjects comprised a healthy group., Results: Distribution of the fibrinogen genotype was similar across the disease and healthy groups. Logistic regression analyses found no significant association between fibrinogen genotype and ischaemic heart disease and peripheral arterial disease. A lower percentage of claudicants had the Pl(A2) allele (8.3% vs. 15.2%, p=0.025). After adjustment for age and sex, the risk of IC associated with the Pl(A2) was half that of the homozygous Pl(A1) genotype (OR 0.49, 95% CI 0.25, 0.88; p<==0.05). Adjustment for lifetime smoking and fibrinogen levels increased the odds slightly to nonsignificance., Conclusions: The Pl(A2) genotype was associated with a decreased risk of developing IC. There was no significant relationship between fibrinogen T/G(+1689) genotype and ischaemic and peripheral heart disease in this older population.

Objective: Vascular inflammation is a hallmark in the development of abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a novel vascular anti-inflammatory factor. A (GT)(n) dinucleotide repeat in the HO-1 gene promoter shows a length polymorphism that modulates the level of gene transcription. Short (< 25 GT) repeats are associated with an increased HO-1 upregulation in response to inflammatory stimuli than are longer repeats. We hypothesised that patients with AAA had less frequently short repeats in the HO-1 gene promoter compared to patients with coronary (CAD) or peripheral artery disease (PAD), or healthy controls., Methods: 70 consecutive patients with atherosclerotic AAA, each 70 age- and sex-matched patients with CAD and PAD as well as 61 unmatched healthy atherosclerosis-free controls for a total of 271 individuals were studied. The frequency of carriers of short repeats in the HO-1 gene promoter was determined and compared between the groups., Results: In the AAA group, 29 patients (41%) were carriers of short (GT)(n) repeats compared to 47 patients (67%) in the CAD group, 44 patients (63%) in the PAD group and 35 healthy controls (59%). Patients with AAA were less frequently carriers of short repeats compared to age- and sex-matched patients with CAD (OR = 0.38, p = 0.006) and PAD (OR = 0.35, p = 0.01). Healthy controls exhibited short alleles more frequently than patients with AAA (p = 0.04), but comparable to CAD (p = 0.3) and PAD patients (p = 0.7)., Conclusion: Patients with AAA were less frequently carriers of short (< 25 GT) repeats in the HO-1 gene promoter than patients with atherosclerosis or healthy subjects. This suggests that short alleles, and thus, facilitated upregulation of HO-1, may be a protective anti-inflammatory factor against the development of AAA., (Copyright 2002 Elsevier Science Ltd.)

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular diseases, such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy, for which no known effective therapy exists. The first human trial in cardiovascular disease was started in 1994 to treat peripheral vascular disease using vascular endothelial growth factor. In addition, therapeutic angiogenesis using the vascular endothelial growth factor gene was applied in the treatment of ischemic heart disease. The results from these clinical trials seem to exceed expectation. Improvement of clinical symptoms in peripheral arterial disease and ischemic heart disease has been reported. At least five different potent angiogenic growth factors have been tested in clinical trials to treat peripheral arterial disease or ischemic heart disease. In addition, another strategy for combating disease processes, to target the transcriptional process, has been tested in a human trial. Transfection of cis-element double-stranded oligodeoxynucleotides is an especially powerful tool in a new class of antigen strategies for gene therapy. Transfection of double-stranded oligodeoxynucleotides corresponding to the cis sequence will result in the attenuation of the authentic cis-trans interaction, leading to the removal of trans-factors from the endogenous cis-elements, with subsequent modulation of gene expression. Genetically modified vein grafts transfected with a decoy against E2F, an essential transcription factor in cell cycle progression, revealed apparent long-term potency in human patients. This review focuses on the future potential of gene therapy for the treatment of cardiovascular disease.