Effectiveness of combination of losartan potassium and doxycycline versus single-drug treatments in the secondary prevention of thoracic aortic aneurysm in Marfan syndrome
Received 29 March 2009; received in revised form 31 May 2009; accepted 25 October 2009. published online 02 March 2010.
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 (Fbn1C1039G/+) 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.
Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
Address for reprints: Ada W. Y. Chung, PhD, Cardiovascular Science, Room 2099, 950 28th W Ave, Vancouver, British Columbia, Canada V5Z 4H4.
Supported by an operating grant from Canadian Institutes of Health Research. A.W.Y.C. is the recipient of Michael Smith Foundation for Health Research/St Paul Hospital's Foundation Trainee Award. H.H.C.Y. is the recipient of Michael Smith Foundation for Health Research Junior Trainee Award and NSERC: Alexander Graham Bell Canada Graduate Scholarship.
ABSTRACT