title: Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension.
abstract: OBJECTIVE
  Arterial stiffening and endothelial dysfunction are hallmarks of aging, and advanced glycation endproducts (AGE) may contribute to these changes. We tested the hypothesis that AGE crosslink breakers enhance endothelial flow-mediated dilation (FMD) in humans and examined the potential mechanisms for this effect.
  
  
  METHODS
  Thirteen adults (nine men, aged 65 +/- 2 years) with isolated systolic hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure < 90 mmHg or pulse pressure > 60 mmHg) on stable antihypertensive therapy were studied. Subjects received placebo (2 weeks) then oral alagebrium (ALT-711; 210 mg twice a day for 8 weeks). Subjects and data analyses were blinded to treatment. Arterial stiffness was assessed by carotid augmentation index (AI) and brachial artery distensibility (ArtD) using applanation tonometry and Doppler echo, and endothelial function by brachial FMD. Serum markers of collagen metabolism and vascular inflammation were assessed.
  
  
  RESULTS
  Alagebrium reduced carotid AI by 37% (P = 0.007) and augmented pressure (16.4 +/- 10 to 9.6 +/- 9 mmHg; P < 0.001). Heart rate, arterial pressures, and ArtD, were unchanged. FMD increased from 4.6 +/- 1.1 to 7.1 +/- 1.1% with alagebrium (P < 0.05), and was unrelated to altered shear stress or regional arterial distensibility. However, FMD change was inversely related to markers of collagen synthesis, p-selectin and intracellular cell adhesion molecule (all P < 0.05). Alagebrium-associated changes in plasma nitrite plus nitrate was inversely correlated with plasma matrix metalloproteinase 9 and type I collagen (P = 0.007).
  
  
  CONCLUSIONS
  Alagebrium enhances peripheral artery endothelial function and improves overall impedance matching. Improved endothelial function correlates better with reduced vascular fibrosis and inflammation markers than with vessel distensibility. AGE-crosslink breakers may reduce cardiovascular risk in older adults by reduced central arterial stiffness and vascular remodeling.
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. azieman@jhmi.edu
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Zieman
authors.forename: Vojtech
authors.initials: V
authors.lastname: Melenovsky
authors.forename: Lia
authors.initials: L
authors.lastname: Clattenburg
authors.forename: Mary C
authors.initials: MC
authors.lastname: Corretti
authors.forename: Anne
authors.initials: A
authors.lastname: Capriotti
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects; D004548:Elasticity / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008365:Manometry; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D016037:Single-Blind Method; D013844:Thiazoles / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D017127:Glycation End Products, Advanced; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; C406794:alagebrium; D020780:Matrix Metalloproteinase 9