Ramipril Reduces Large-Artery Stiffness in Peripheral Arterial Disease and Promotes Elastogenic Remodeling in Cell Culture

Abstract

Abstract-Ramipril improves cardiovascular outcome in patients with peripheral arterial disease; however, the precise mechanisms of benefit remain to be elucidated. The effect of ramipril on large-artery stiffness in patients with peripheral arterial disease was examined. In addition, we determined the effect of ramiprilat on extracellular matrix from human aortic smooth muscle cell culture. Forty patients with peripheral arterial disease were randomized to receive ramipril, 10 mg once daily or placebo for 24 weeks. Arterial stiffness was assessed globally via systemic arterial compliance and augmentation index (carotid tonometry and Doppler velocimetry), and regionally via carotid-femoral pulse wave velocity. Angiotensin-converting enzyme inhibition increased arterial compliance by 0.10Ϯ0.02 mL/mm Hg, (PϽ0.001, all probability values relative to placebo) and reduced pulse wave velocity by 1.7Ϯ0.2 m/s (PϽ0.001), augmentation index by 4.1Ϯ0.3% (PϽ0.001), and systolic blood pressure by 5Ϯ1 mm Hg (PϽ0.001). Ramipril did not reduce mean arterial pressure significantly compared with placebo (Pϭ0.59). In cell culture, ramiprilat decreased collagen deposition by Ͼ50% and increased elastin and fibrillin-1 deposition by Ͼ3-and 4-fold respectively (histochemistry and immunohistochemistry). Fibrillin-1 gene expression was increased 5-fold (real-time reverse-transcriptase polymerase chain reaction). Ramiprilat also reduced gene and protein (Western) expression of both matrix metalloproteinase (MMP)-2 and MMP-3. In conclusion, ramipril promoted an elastogenic matrix profile that may contribute to the observed clinical reduction in large-artery stiffness and carotid pressure augmentation, which occurred independently of mean arterial blood pressure reduction in patients with peripheral arterial disease.

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