Inhibition of collagen cross-linking: effects on fibrillar collagen and left ventricular diastolic function. Kato, Satoshi, Francis G. Spinale, Ryuhei Tanaka, Wendy Johnson, George Cooper, Iv, Michael R. Zile. Gazes Cardiac Research Institute, Cardiology Division of the Department of Medicine, Medical University of South Carolina, the Ralph H. Johnson Department of Veterans Affairs Medical Center, and the Cardiothoracic Surgery Division of the Department of Surgery, Charleston, South Carolina.
APStracts 2:0147H, 1995.
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 physiologic effects of a reduction in fibrillar collagen content and cross-linking in the intact left ventricle. Collagen cross-linking was inhibited by treating 5 normal adult pigs with b-aminoproprionitrile (BAPN, 10 g/day, p.o.) for 6 weeks; 5 normal untreated pigs served as controls. Left ventricular volume, mass, and function were determined by simultaneous echocardiography and catheterization. Chamber stiffness, defined by pressure versus volume data and myocardial stiffness, defined by stress versus 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 (362 mg/gDW in control to 27 2 mg/gDW 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). Thus, BAPN inhibited collagen cross-linking, decreased total collagen and disrupted collagen distribution and integrity. These changes in the fibrillar collagen network resulted in a reduction in chamber and myocardial stiffness. These findings provide evidence to suggest that the fibrillar collagen matrix is a primary determinant of LV diastolic stiffness in the normal heart. 

Received 12 December 1994; accepted in final form 15 March 1995.
APS Manuscript Number H1083-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 19 April 1995.