Identification of a Potential Cardiac Antifibrotic Mechanism of Torasemide in Patients With Chronic Heart Failure

Identification of a Potential Cardiac Antifibrotic Mechanism of Torasemide in Patients With Chronic Heart Failure

Begoña López, Arantxa González, Javier Beaumont, Ramón Querejeta, Mariano Larman, Javier Díez

We investigated whether torasemide inhibits procollagen type I carboxy-terminal protease (PCP), the enzyme responsible for the extracellular generation of collagen type I, in patients with chronic heart failure. The PCP activation diminished in torasemide-treated but not in furosemide-treated patients. The PCP inhibition was associated with reduction of myocardial collagen in torasemide-treated patients. These findings suggest that the ability of torasemide to decrease myocardial fibrosis in heart failure is related to the inhibition of myocardial PCP.

Objectives

This study sought to investigate whether torasemide inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules (i.e., procollagen type I carboxy-terminal proteinase [PCP]).

Background

Torasemide has been reported to reduce myocardial fibrosis in patients with chronic heart failure (HF).

Methods

Chronic HF patients received either 10 to 20 mg/day oral torasemide (n = 11) or 20 to 40 mg/day oral furosemide (n = 11) in addition to their standard HF therapy. At baseline and after 8 months from randomization, right septal endomyocardial biopsies were obtained to analyze the expression of PCP by Western blot and the deposition of collagen fibers (collagen volume fraction [CVF]) with an automated image analysis system. The carboxy-terminal propeptide of procollagen type I (PICP) released as a result of the action of PCP on procollagen type I was measured in serum by radioimmunoassay.

Results

The ratio of PCP active form to PCP zymogen, an index of PCP activation, decreased (p < 0.05) in torasemide-treated patients and remained unchanged in furosemide-treated patients. A reduction (p < 0.01) in both CVF and PICP was observed in torasemide-treated but not in furosemide-treated patients. Changes in PCP activation were positively correlated (p < 0.001) with changes in CVF and changes in PICP in patients receiving torasemide.

Conclusions

These findings suggest the hypothesis that the ability of torasemide to reduce myocardial fibrosis in chronic HF patients is related to a decreased PCP activation. Further studies are required to ascertain whether PCP may represent a new target for antifibrotic strategies in chronic HF.