Na(+)-H(+) exchanger inhibitor prevents early death in hereditary cardiomyopathy

Area of Science:

• Cardiology
• Molecular Biology
• Pharmacology

Background:

• Hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH) exhibit intracellular Na(+) and Ca(2+) overloads, elevated NHE-1 levels, necrosis, hypertrophy, heart failure, and early death.
• The role of NHE-1 in the pathogenesis of hereditary cardiomyopathy requires further investigation.

Purpose of the Study:

• To investigate the effects of lifelong preventive or curative treatments with an NHE-1 inhibitor (EMD 87580) or an ACE inhibitor (cilazapril) on cardiac parameters and survival in HCMH.
• To elucidate the involvement of NHE-1 and ion overloads in the progression of hereditary cardiomyopathy.

Main Methods:

• HCMH were subjected to lifelong preventive treatment (310 days from 30 days old) or curative treatment (85 days from 275 days old) with EMD 87580 or cilazapril.
• Cardiac parameters including necrosis, hypertrophy, heart-to-body mass ratio, intracellular Na(+) and Ca(2+) levels, and NHE-1 protein levels were assessed.
• Creatine kinase levels and survival rates were monitored.

Main Results:

• Lifelong preventive treatment with EMD 87580 significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, reduced heart-to-body mass ratio, and prevented Na(+) and Ca(2+) overloads and increased NHE-1 levels.
• Preventive EMD 87580 treatment decreased creatine kinase levels and significantly prevented early death in HCMH.
• Curative EMD 87580 treatment also prevented hypertrophy and early death, while cilazapril showed no significant beneficial effects.

Conclusions:

• Elevated NHE-1 levels and subsequent Na(+) and Ca(2+) overloads are implicated in the pathological process of heart failure and early death in HCMH.
• NHE-1 inhibition with EMD 87580 demonstrates significant promise for preventing early mortality in hereditary cardiomyopathy.