Transforming Growth Factor-beta A Biomarker in Marfan Syndrome?
Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St Louis, Mo.Circulation (Impact Factor: 14.95). 08/2009; 120(6):464-6. DOI: 10.1161/CIRCULATIONAHA.109.883629
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ABSTRACT: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.International journal of cardiology 01/2011; 157(3):354-8. DOI:10.1016/j.ijcard.2010.12.070 · 6.18 Impact Factor
Article: Genetic biomarkers in aortopathy.[Show abstract] [Hide abstract]
ABSTRACT: The field of aortopathy, in common with other genomic disorders, is undergoing a revolution. This is largely driven by the implementation of newer forms of genetic sequencing (massively parallel or next-generation sequencing). Advantages conferred by this technology include reduced costs, reduced sequencing time and the ability to simultaneously test multiple genes. This has a significant advantage in the identification of genes disrupted in heritable aortopathies. These advances are enabling scientists and clinicians to identify key molecular pathways; translating fundamental genetic findings into a better understanding of disease mechanisms is ultimately leading to effective treatments. In outlining contemporary knowledge of genetic biomarkers in aortopathy we seek to demonstrate that the era of genomically orientated decision-making is here.Biomarkers in Medicine 08/2013; 7(4):547-63. DOI:10.2217/bmm.13.74 · 2.86 Impact Factor
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ABSTRACT: The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome. From the studies retrieved we then weaved an evidence-based description of progress. Marfan syndrome shows considerable heterogeneity in clinical presentation. It relies on defined clinical criteria with confirmation based on FBN1 mutation testing. Surgical advances have prolonged life in Marfan syndrome. First-line prophylaxis of complications with β-adrenoceptor blockers became established on the basis that reduction of aortic pressure and heart rate would help. Over-activity of proteinases, first suggested in 1980, has since been confirmed by evidence of over-expression of matrix metalloproteinases (MMP), notably MMP-2 and MMP-9. The search for MMP inhibitors led to the evaluation of doxycycline, and both animal studies and small trials, provided early evidence that this widely used antimicrobial agent was useful. Identification of the importance of TGF-β led to evaluation of angiotensin II type I receptor (AT(1) R) blockers with highly promising results. Combination prophylactic therapy would appear rational. Pharmacological and genomic research has provided good evidence that therapy with losartan and doxycycline would prevent the aortic complications of Marfan syndrome. If on-going well designed trials confirm their efficacy, the outlook for Marfan syndrome patients would be improved considerably.British Journal of Clinical Pharmacology 07/2011; 72(1):6-17. DOI:10.1111/j.1365-2125.2011.03929.x · 3.69 Impact Factor
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