Collagen Cross-Linking Is Associated With Cardiac Remodeling in Hypertrophic Obstructive Cardiomyopathy

Background Collagen cross-linking is covalent bonds among collagen fibers from catalysis of lysyl oxidase (LOX) and advanced glycation end products (AGEs). We aimed to evaluate the formation of enzymatic and nonenzymatic collagen cross-linking and its clinical significance in patients with hypertrophic obstructive cardiomyopathy. Methods and Results Forty-four patients with hypertrophic obstructive cardiomyopathy who underwent surgical myectomy were consecutively enrolled. Cardiovascular magnetic resonance parameters of left atrial/left ventricular function were measured, including peak filling rate (PFR) and early peak emptying rate (PER-E). Total collagen was the sum of soluble and insoluble collagen, which were assessed by collagen assay. The myocardial LOX and AGEs expression were measured by molecular and biochemical methods. Compared with patients without atrial fibrillation, insoluble collagen (P=0.018), insoluble collagen fraction (P=0.017), and AGEs (P=0.039) were higher in patients with atrial fibrillation, whereas LOX expression was similar (P=0.494). The insoluble collagen fraction was correlated with PFR index (PFR normalized by left ventricular filling volume) (r=-0.44, P=0.005), left atrial diameters (r=0.36, P=0.021) and PER-E index (PER-E normalized by left ventricular filling volume) (r=-0.49, P=0.001).Myocardial LOX was positively correlated with total collagen (r=0.37, P=0.025) and insoluble collagen fraction (r=0.53, P < 0.001), but inversely correlated with PFR index (r=-0.43, P=0.006) and PER-E index (r=-0.35, P=0.027). In multiple regression analysis, myocardial LOX was independently associated with PFR, while insoluble collagen fraction showed independent correlation with PER-E after adjustment for clinical confounders. Conclusions Collagen cross-linking plays an important role on heart remodeling in hypertrophic obstructive cardiomyopathy. Myocardial LOX expression is independently correlated with left ventricular stiffness, while accumulation of AGEs cross-links might be associated with the occurrence of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy.