Effectiveness of combination of losartan potassium and doxycycline versus single-drug treatments in the secondary prevention of thoracic aortic aneurysm in Marfan syndrome
| Autor: | Ada W.Y. Chung, H.H. Clarice Yang, Jong Moo Kim, Elliott Chum, Cornelis van Breemen |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Marfan syndrome
Time Factors Fibrillin-1 Aorta Thoracic Smad2 Protein 030204 cardiovascular system & hematology Marfan Syndrome Aortic aneurysm Mice 0302 clinical medicine Transforming Growth Factor beta Secondary Prevention Phosphorylation Antibacterial agent 0303 health sciences Microfilament Proteins Drug Synergism 3. Good health Vasodilation Losartan Matrix Metalloproteinase 9 Doxycycline cardiovascular system Matrix Metalloproteinase 2 Drug Therapy Combination Cardiology and Cardiovascular Medicine medicine.drug Losartan Potassium Pulmonary and Respiratory Medicine medicine.medical_specialty Urology Fibrillins Thoracic aortic aneurysm 03 medical and health sciences medicine.artery Internal medicine medicine Animals Protease Inhibitors 030304 developmental biology Aorta Aortic Aneurysm Thoracic business.industry medicine.disease Elastic Tissue Angiotensin II Mice Mutant Strains Mice Inbred C57BL Disease Models Animal Endocrinology Vasoconstriction Surgery business Angiotensin II Type 1 Receptor Blockers |
| Zdroj: | The Journal of Thoracic and Cardiovascular Surgery. (2):305-312.e2 |
| ISSN: | 0022-5223 |
| DOI: | 10.1016/j.jtcvs.2009.10.039 |
| Popis: | Objective Losartan potassium (INN losartan), an antihypertensive drug, has been shown to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of transforming growth factor β. Recently we reported that doxycycline, a nonspecific inhibitor of matrix metalloproteinases 2 and 9, normalized aortic vasomotor function and suppressed aneurysm growth. We hypothesized that a combination of losartan potassium and doxycycline would offer better secondary prevention treatment than would single-drug therapy to manage thoracic aortic aneurysm. Methods A well-characterized mouse model of Marfan syndrome (Fbn1 C1039G/+ ) was used. At 4 months of age, when aneurysm had established, mice (n = 15/group) were given doxycycline alone (0.24 g/L), losartan potassium alone (0.6 g/L), or combined (0.12-g/L doxycycline and 0.3-g/L losartan potassium) in drinking water. Littermate Fbn1 +/+ mice served as control. Thoracic aortas at 6 and 9 months were studied. Results At 9 months, aortic diameter in untreated group was increased by 40% relative to control. Losartan potassium or doxycycline reduced aortic diameter by 10% to 16% versus untreated aortas. Losartan potassium and doxycycline combined completely prevented thoracic aortic aneurysm and improved elastic fiber organization, also downregulating matrix metalloproteinases 2 and 9 and transforming growth factor β and normalizing aortic contractile and relaxation functions to control values. Conclusions Neither losartan potassium nor doxycycline alone completely restored vascular integrity and cell function when given during delayed treatment, indicating the importance of timed pharmacologic intervention. Combined, however, they synergistically offered better aneurysm-suppressing effects than did single-drug medication in the secondary prevention of thoracic aortic aneurysm. |
| Databáze: | OpenAIRE |
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