Frequency dependent force generation correlates with sarcoplasmic calcium ATPase activity in human myocardium

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Congestive heart failure (CHF) is characterized by impaired cardiac contractility.
• Both reduced sarcoplasmic Ca(2+)-ATPase (SERCA2) function and a negative force-frequency relationship (FFR) are observed in CHF.
• The interplay between SERCA2 activity and FFR in human heart failure requires further investigation.

Purpose of the Study:

• To investigate the relationship between frequency potentiation, sarcoplasmic Ca(2+)-ATPase activity, and SERCA2 protein expression in human myocardium.
• To determine if impaired SERCA2 function contributes to the negative FFR in heart failure.

Main Methods:

• Human left ventricular papillary muscle strips from failing and nonfailing hearts were electrically stimulated to assess frequency potentiation.
• Sarcoplasmic Ca(2+)-ATPase activity (Vmax) and protein expression of SERCA2, phospholamban, and calsequestrin were measured.
• Correlations between force-frequency changes, Ca(2+)-ATPase activity, and SERCA2 protein levels were analyzed.

Main Results:

• Failing myocardium exhibited a negative FFR, while nonfailing myocardium showed positive FFR.
• Maximal Ca(2+)-ATPase activity (Vmax) was significantly reduced in failing myocardium compared to nonfailing.
• SERCA2, phospholamban, and calsequestrin protein expressions remained unchanged in failing hearts.
• Maximal Ca(2+)-ATPase activity strongly correlated with the frequency-dependent change in force of contraction.

Conclusions:

• The decreased function of sarcoplasmic Ca(2+)-ATPase activity, not its expression, is a key factor in the negative force-frequency relationship in human heart failure.
• Reduced SERCA2 enzyme function contributes significantly to impaired contractility in heart failure.