Heart failure -- a challenge to our current concepts of excitation-contraction coupling

Area of Science:

• Cardiology
• Molecular Biology
• Physiology

Background:

• Novel therapeutic strategies for congestive heart failure (CHF) are limited by incomplete understanding of cardiac excitation-contraction (EC) coupling.
• Cardiac hypertrophy and failure involve complex phenotypes, necessitating accurate myocardial function assessment in experimental models.

Purpose of the Study:

• To review current knowledge and identify key molecular mechanisms underlying EC coupling defects in normal and failing hearts.
• To explore potential therapeutic targets for CHF by elucidating the causes of impaired myocardial contractility.

Main Methods:

• Review of invasive and non-invasive techniques for quantifying myocardial function in experimental models (e.g., rats, mice).
• Discussion of in vitro contractility and EC coupling studies in relation to in vivo myocardial function.
• Critical evaluation of limitations associated with techniques like whole-cell patch clamp.

Main Results:

• Myocardial failure is characterized by reduced fractional shortening and contraction velocity.
• Two primary factors contribute to heart failure: reduced sarcoplasmic reticulum (SR) Ca(2+) load (linked to phospholamban phosphorylation) and a defect in SR Ca(2+) release trigger.
• The Ca(2+) release defect may be exacerbated by reduced SR Ca(2+) reuptake capacity and is not solely due to altered Ca(2+)-induced Ca(2+) release (CICR) gain.

Conclusions:

• Understanding the molecular basis of EC coupling is crucial for developing novel CHF therapies.
• Defects in SR Ca(2+) handling, specifically reduced Ca(2+) load and impaired release mechanisms, are central to myocardial failure.
• Further research into the identified molecular defects offers promising avenues for future therapeutic interventions in CHF.