A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy.

Abstract

Regardless of the origin, injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis often progresses to dilated cardiomyopathy (DCM), a major cause of heart failure. In our study, we used a rat model of myosin-induced experimental autoimmune myocarditis (EAM), in which the heart transits from an acute phase (inflammatory myocarditis) to a chronic phase (remodeling and DCM). Our objective was to investigate whether T-3999, a novel phenylpyridazinone, can reduce this progression. Four weeks after myosin injection, T-3999 was administered daily to male Lewis rats in two doses (3 and 10 mg/kg, orally). Four weeks later, treatment was terminated; hemodynamic and echocardiographic measurements were performed; hearts were excised for histopathology and estimation of histamine, mRNA, and protein levels. Mortality rate was reduced by drug treatment. T-3999 reduced % fibrosis and tissue collagen III. Profibrotic markers-transforming growth factor-β(1), tumor necrosis factor-α, and galectin-3--were attenuated by treatment. Mast cell density and degranulation, and tissue histamine concentration were also reduced. This indicates an anti-inflammatory effect of the drug in reducing fibrosis. Hypertrophy was reduced as reflected by reduced myocyte diameter and natriuretic peptide expression. T-3999 treatment increased the sarcoendoplasmic reticulum Ca(2+) ATPase 2 protein level and improved several cardiac function parameters. The reduction of the remodeling process and improvement in myocardial function suggest an effect of T-3999 in attenuating ventricular remodeling in post-myocarditis DCM.

• Authors: Fadia Ali Kamal, Kenichi Watanabe, Meilei Ma, Yuichi Abe, Reyad Elbarbary, Makoto Kodama, Yoshifusa Aizawa
• Journal: Heart and vessels (Heart Vessels) Vol. 26 Issue 1 Pg. 81-90 (Jan 2011) ISSN: 1615-2573 [Electronic] Japan
• PMID: 20922534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiovascular Agents
• Cytokines
• Pyridazines
• Myosins

Topics

• Animals
• Autoimmune Diseases (chemically induced, diagnostic imaging, drug therapy, metabolism, physiopathology)
• Cardiomyopathy, Dilated (diagnostic imaging, etiology, metabolism, physiopathology, prevention & control)
• Cardiovascular Agents (pharmacology)
• Cell Degranulation (drug effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Disease Progression
• Fibrosis
• Hemodynamics (drug effects)
• Histamine Release (drug effects)
• Male
• Mast Cells (drug effects)
• Myocarditis (chemically induced, diagnostic imaging, drug therapy, metabolism, physiopathology)
• Myosins
• Pyridazines (pharmacology)
• Rats
• Rats, Inbred Lew
• Time Factors
• Ultrasonography
• Ventricular Remodeling (drug effects)