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CLINICAL RESEARCH: VALVULAR HEART DISEASE

Endothelial Function, Carotid–Femoral Stiffness, and Plasma Matrix Metalloproteinase-2 in Men With Bicuspid Aortic Valve and Dilated Aorta

Nikolaos Tzemos, MD^_*, Erik Lyseggen, MD, PhD^_*, Candice Silversides, MD, SM^_*, Michal Jamorski, RDCS^_*, Jeffrey H. Tong, PhD, Paula Harvey, MBBS, PhD^_*, John Floras, MD, DPhil^_* and Samuel Siu, MD, SM^,_*

^_* Division of Cardiology, University Health Network, University of Toronto, Toronto, Ontario, Canada
Department of Biochemistry, University Health Network, University of Toronto, Toronto, Ontario, Canada
Division of Cardiology, University of Western Ontario, London, Ontario, Canada

Manuscript received April 8, 2009; revised manuscript received July 7, 2009, accepted August 6, 2009.

^_* Reprint requests and correspondence: Dr. Samuel Siu, C6-005, University Hospital, 339 Windermere Road, London, Ontario N6A 5A5, Canada (Email: Samuel.Siu{at}lhsc.on.ca).

Objectives: This study sought to examine the relationship between proximal aortic dilation and systemic vascular function in men with bicuspid aortic valve (BAV).

Background: Proximal aortic dilation in subjects with BAV is associated with structural and functional abnormalities in the ascending aorta.

Methods: We studied 32 men (median age 31 years [range 28 to 32 years]) with nonstenotic BAV categorized into 2 subgroups according to proximal ascending aorta dimensions (nondilated 35 mm and dilated 40 mm, respectively). Sixteen healthy men were studied as control subjects. Flow-mediated dilation in response to hyperemia (a marker of endothelial dysfunction) and carotid–femoral pulse wave velocity (an index of aortic stiffness) were assessed, and peripheral blood was sampled for matrix metalloproteinases (MMP-2 and -9) and their tissue inhibitors (TIMP-1 and -2), respectively. Cardiac chamber and aortic dimensions were assessed by echocardiography and cardiac magnetic resonance imaging, respectively.

Results: Despite the similar severity of aortic stenosis, left ventricular mass, and function, men with dilated aortas had blunted brachial flow-mediated vasodilation to hyperemia (5% [interquartile range (IQR) 4% to 6%] vs. 8% [IQR 7% to 9%] change, p = 0.001), higher carotid–femoral pulse wave velocity (9.3 cm/s [IQR 9 to 10 cm/s] vs. 7 cm/s [IQR 6.9 to 7.4 cm/s], p = 0.001), and significantly higher plasma levels of MMP-2 (1,523 [IQR 1,460 to 1,674] vs. 1,036 [IQR 962 to 1,167], p = 0.001) compared with men with BAV and nondilated aorta. Values for MMP-9, TIMP-1 and -2 levels, and nitroglycerin-induced (endothelium-independent) vasodilation were similar in all 3 groups.

Conclusions: Young men with BAV and dilated proximal aortas manifest systemic endothelial dysfunction, increased carotid–femoral pulse wave velocity, and higher plasma levels of MMP-2. These observations could introduce new targets for screening and perhaps for therapeutic intervention.

Key Words: aortic dilation • bicuspid valve • flow-mediated vasodilation • MMP-2 • pulse wave velocity

Abbreviations and Acronyms   BAV = bicuspid aortic valve   cf-PWV = carotid–femoral pulse wave velocity   CMR = cardiac magnetic resonance   eNOS = endothelial nitric oxide synthase   FMD = flow-mediated vasodilation   GTN = glyceryl nitrate   LV = left ventricle/ventricular   MMP = matrix metalloproteinase   NO = nitric oxide   RT3DE = real-time 3-dimensional imaging   TIMP = tissue inhibitor of matrix metalloproteinase

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