Preventing the aortic complications of Marfan syndrome: a case‐example of translational genomic medicine

• Published in: British journal of clinical pharmacology Vol. 72; no. 1; pp. 6 - 17
• Main Authors: Li‐Wan‐Po, Alain, Loeys, Bart, Farndon, Peter, Latham, David, Bradley, Caroline
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2011; Blackwell; Blackwell Science Inc
• Subjects: ACE inhibitors; ACEI; Adrenergic receptors; Angiotensin II; angiotensin II type I blockers; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Antimicrobial agents; Aorta; Aortic Aneurysm, Thoracic - etiology; Aortic Aneurysm, Thoracic - genetics; Aortic Aneurysm, Thoracic - prevention & control; Biological and medical sciences; Clinical trials; Connective tissue diseases; Doxycycline; Gelatinase A; Gelatinase B; genomics; Genomics - methods; Heart rate; Humans; Marfan Syndrome - complications; Marfan Syndrome - genetics; Marfan's syndrome; Matrix metalloproteinase; Medical sciences; Mutation; Pharmacogenetics; Pharmacology. Drug treatments; Pressure; Prophylaxis; Proteinase; Reviews; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Transforming growth factor- beta; Translation; Translational Medical Research - methods; translational research; Skin disease; Genomics; Peptide hormone; angiotensin II type I blockers; Marfan syndrome; Prevention; Octapeptide; Blood vessel; Systemic disease; ACEI; Genetics; Aorta; Complication; translational research; Antagonist; Angiotensin II; Connective tissue disease; Pharmacogenetics; Elastic tissue disease; Angiotensin I; Genetic translation; Artery; Genetic disease; Medicine; Renin angiotensin system; Circulatory system; Genome; ACE inhibitors; ACE inhibitor
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2011.03929.x

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 (AT1R) 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.