Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure.
The aim of this study was to investigate whether torasemide modifies collagen cross-linking in the failing human heart. We analyzed the degree of cross-linking and the expression of the enzyme lysyl oxidase, which regulates cross-linking, in the myocardium of patients with chronic heart failure at baseline and after 8 months of treatment with either torasemide or furosemide in addition to their standard heart failure therapy. Whereas lysyl oxidase protein expression was very scarce in normal hearts, it was highly expressed in failing hearts. Cross-linking was increased (P<0.001) in heart failure patients compared with normal hearts. These 2 parameters decreased (P=0.021 and P=0.034) in torasemide-treated patients and remained unchanged in furosemide-treated patients. In addition, more (P=0.009) patients showed normalization of left ventricular chamber stiffness in the torasemide subgroup than in the furosemide subgroup after treatment. Lysyl oxidase expression correlated with cross-linking (r=0.661; P<0.001), and cross-linking correlated with left ventricular chamber stiffness (r=0.452; P=0.002) in all patients. These findings show for the first time that lysyl oxidase overexpression is associated with enhanced collagen cross-linking in the failing human heart. In addition, we report that the ability of torasemide to correct both lysyl oxidase overexpression and enhanced collagen cross-linking results in normalization of left ventricular chamber stiffness in patients with heart failure. Lysyl oxidase may thus represent a target for reduction of stiff collagen and improvement of left ventricular mechanical properties in heart failure patients.
López
Begoña
B
Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
Querejeta
Ramón
R
González
Arantxa
A
Beaumont
Javier
J
Larman
Mariano
M
Díez
Javier
J
D000368:Aged; D003094:Collagen / Q000378:metabolism*; D004232:Diuretics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005665:Furosemide / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D011446:Prospective Studies; D008249:Protein-Lysine 6-Oxidase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D000077786:Torsemide; D014463:Ultrasonography; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
D004232:Diuretics; D013449:Sulfonamides; D005665:Furosemide; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D000077786:Torsemide