Collagen Crosslinking in the Heart: Relationship to Development and Function

The hydroxypyridinium (HP) crosslink is the predominant non-reducible collagen crosslink in heart. HP concentration in left ventricle (LV) increases progressively throughout life, and this increase is thought to reflect the slower turnover of collagenous proteins seen with aging, allowing mature extracellular matrix (ECM) collagen to crosslink more heavily. There are also species differences with higher levels of crosslinking found in the hearts of larger mammals including humans, compared to smaller mammals such as the rat. Marked deviations from normal in the concentration of this crosslink are implicated in a variety of left ventricular hypertrophies and altered ventricular function. Interestingly these deviations may be bi-directional in nature, ranging from an apparent lack of the crosslink in a mouse cardiomyopathy model, to a doubling in HP concentration in viable myocardium post-infarction. This review outlines the major pathway involved in the formation of myocardial collagen crosslinks. Possible mechanisms by which rate of crosslink formation and deposition are regulated will be discussed, and functional implications of altered crosslinking patterns addressed.