Inhibition of collagen cross-linking: effects on fibrillar collagen and ventricular diastolic function

Abstract

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)

An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

“…Because the filling pressures observed pre-and posttreatment were not different, this result is consistent with decreased stiffness: A given pressure will distend a less stiff myocardium more than a stiff one. An analogous increase in EDV has been observed previously during pharmacologic inhibition of collagen cross-links by another agent in a rodent model (11). The significant rise of stroke volume observed in the basal state and a further increase during dextran infusion (Fig.…”

“…The latter was normalized for the EDV, because the slope of dP͞dV versus P has been found to be sensitive to variations in cardiac muscle volume (10). With a progressive increase in volumes calculated, myocardial stiffness would be expected to increase as a preloaddependent phenomenon (9,11). Myocardial stiffness was calculated from E ϭ k⅐stress.…”

Gene Expression Analysis of Murine and Human Osteoarthritis Synovium Reveals Elevation of Transforming Growth Factor β–Responsive Genes in Osteoarthritis‐Related Fibrosis

“…Moreover, in Yorkshire pigs, inhibition of LOX with ␤-aminopropionitrile reduced chamber and myocardial stiffness by inhibiting collagen crosslinking compared to that in normal untreated pigs (41). Therefore, blocking of LOX may be considered a potential therapeutic target for interference with OA-related fibrosis.…”

Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

“…It is known that excessive myocardial fibrosis and abnormalities in the ECM result in a significant decrease in myocardial compliance, and thus impairment of diastolic function. 29 It is important to note that diastolic dysfunction is a significant component of ischemic heart failure that is very difficult to manage and treat clinically. Therefore, the improvements in diastolic function conferred by TIMP-1 overexpression are therapeutically very significant findings.…”