Inhibition of collagen cross-linking: effects on fibrillar collagen and ventricular diastolic function.
The fibrillar collagen network is postulated to be a primary determinant of left ventricular diastolic stiffness. This hypothesis was tested by examining the structural and physiological effects of a reduction in fibrillar collagen content and cross-linking in the intact left ventricle. Collagen cross-linking was inhibited by treating five normal adult pigs with beta-aminopropionitrile (BAPN; 10 g/day po) for 6 wk; five normal untreated pigs served as controls. Left ventricular volume, mass, and function were determined by simultaneous echocardiography and catheterization. Chamber stiffness, defined by pressure vs. volume data, and myocardial stiffness, defined by stress vs. dimension data, were determined from variably loaded beats during dextran infusion. Collagen distribution (% area) and integrity (% confluence) were determined by light microscopy. Collagen content was measured by hydroxyproline assay, and collagen cross-linking was measured by salt extraction. BAPN decreased collagen distribution (% area decreased from 12 +/- 1% in control to 7 +/- 1% in BAPN, P < 0.05), collagen integrity (% confluence decreased from 8 +/- 1% in control to 4 +/- 1% in BAPN, P < 0.05), collagen content (from 36 +/- 2 mg/g dry wt in control to 27 +/- 2 mg/g dry wt in BAPN, P < 0.05), and collagen cross-linking (extractable collagen increased from 21 +/- 2% in control to 28 +/- 2% in BAPN, P < 0.05). BAPN decreased chamber stiffness (0.13 +/- 0.02 in control to 0.06 +/- 0.01 in BAPN, P < 0.05) and myocardial stiffness (10.4 +/- 0.5 in control to 6.6 +/- 0.5 in BAPN, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Kato
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S
Gazes Cardiac Research Institute, Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.
Spinale
F G
FG
Tanaka
R
R
Johnson
W
W
Cooper
G
G
Zile
M R
MR
D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D003094:Collagen / Q000502:physiology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003971:Diastole; D004548:Elasticity; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009210:Myofibrils / Q000378:metabolism*; D013552:Swine; D014018:Tissue Distribution; D016277:Ventricular Function, Left / Q000187:drug effects
D003432:Cross-Linking Reagents; D000629:Aminopropionitrile; D003094:Collagen