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(Circulation. 2008;118:1002-1010.)
© 2008 American Heart Association, Inc.

Heart Failure

Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines

Brian P. Shapiro, MD^*; Theophilus E. Owan, MD, MSc^*; Selma F. Mohammed, MBBS; Donna M. Meyer, AA; Lisa D. Mills, BS; Casper G. Schalkwijk, PhD; Margaret M. Redfield, MD

From the Cardiorenal Research Laboratory, Mayo Clinic, Rochester, Minn (B.P.S., T.E.O., S.F.M., D.M.M., L.D.M., M.M.R.); and Department of Internal Medicine, University Hospital Maastricht, Maastricht, the Netherlands (C.G.S.). Dr Owan’s current affiliation is Division of Cardiology, University of Utah, Salt Lake City.

Correspondence to Margaret M. Redfield, MD, Cardiorenal Research Laboratory, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail redfield.margaret{at}mayo.edu

Received March 6, 2008; accepted July 10, 2008.

Background— Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function.

Methods and Results— Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure–volume analysis and aortic pressure–dimension and pressure–flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs.

Conclusions— In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 979-980. [Extract] [Full Text]

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				J. W.L. Hartog, S. Willemsen, and A. A. Voors Letter by Hartog et al Regarding Article, "Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines" Circulation, March 17, 2009; 119(10): e233 - e233. [Full Text] [PDF]

				B. P. Shapiro, T. E. Owan, S. F. Mohammed, D. M. Meyer, L. D. Mills, M. M. Redfield, and C. G. Schalkwijk Response to Letter Regarding Article, "Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines" Circulation, March 17, 2009; 119(10): e234 - e234. [Full Text] [PDF]