CLINICAL RESEARCH: HEART FAILURE
Identification of a Potential Cardiac Antifibrotic Mechanism of Torasemide in Patients With Chronic Heart Failure
Begoña López, PhD*,
Arantxa González, PhD*,
Javier Beaumont, PhD*,
Ramón Querejeta, MD, PhD ,
Mariano Larman, MD and
Javier Díez, MD, PhD*, ,*
* Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
Division of Cardiology, Donostia University Hospital, San Sebastián, Spain
Division of Hemodynamics, Guipuzcoa Polyclinics, San Sebastián, Spain
Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain.
Manuscript received February 20, 2007;
revised manuscript received April 25, 2007,
accepted April 30, 2007.
* Reprint requests and correspondence: Dr. Javier Díez, Área de Ciencias Cardiovasculares, CIMA, Avenida Pío XII 55, 31008 Pamplona, Spain. (Email: jadimar{at}unav.es).
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.
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Abbreviations and Acronyms
| | CVF = collagen volume fraction | | HF = heart failure | | MMP = matrix metalloproteinase | | mRNA = messenger ribonucleic acid | | PCP = procollagen type I carboxy-terminal proteinase | | PCPE = procollagen type I carboxy-terminal proteinase enhancer | | PICP = carboxy-terminal propeptide of procollagen type I | | TIMP = tissue inhibitor of matrix metalloproteinase |
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