Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations.
OBJECTIVE
Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.


METHODS
The effects of 8 weeks of treatment with either vitamin D₂ at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg⁻¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function.


RESULTS
Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment.


CONCLUSIONS
Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor.
Department of Medicine, Vascular Disease and Therapeutics Research Group, Basil Hetzel Institute, The Queen Elizabeth Hospital, The University of Adelaide, South Australia, Australia.
Doan Tm
DT
Ngo
Irene
I
Stafford
Aaron L
AL
Sverdlov
Weier
W
Qi
Ronald D
RD
Wuttke
Yuan
Y
Zhang
Darren J
DJ
Kelly
Helen
H
Weedon
Malcolm D
MD
Smith
Jennifer A
JA
Kennedy
John D
JD
Horowitz
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000502:physiology; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000097:blood; D004872:Ergocalciferols / Q000627:therapeutic use; D006801:Humans; D008297:Male; D011817:Rabbits; D017257:Ramipril / Q000494:pharmacology*; D014815:Vitamins / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D004872:Ergocalciferols; C486715:TXNIP protein, human; D014815:Vitamins; C018524:N,N-dimethylarginine; D001120:Arginine; D017257:Ramipril