Effects of calcium, inorganic phosphate, and pH on isometric force in single skinned cardiomyocytes from donor and...

Area of Science:

• Cardiovascular Physiology
• Cardiac Muscle Mechanics
• Heart Failure Pathophysiology

Background:

• Ischemia causes increased intracellular calcium, inorganic phosphate (P(i)), and decreased pH.
• Altered contractile protein composition in heart failure may change myocardial response to these ions and pH.

Purpose of the Study:

• Investigate the effects of Ca(2+), P(i), and pH on force development in donor and failing human hearts.
• Determine if altered contractile protein composition in heart failure modifies the myocardial response.

Main Methods:

• Studied isometric force in mechanically isolated Triton-skinned single myocytes from human left ventricular myocardium.
• Assessed force changes in response to varying concentrations of P(i), pH, and Ca(2+).
• Measured myosin light chain 2 phosphorylation levels.

Main Results:

• Force declined with increased P(i) and increased with pH, independent of donor vs. failing status.
• Force potentiation occurred with P(i) incubation, greater at submaximal [Ca(2+)].
• Ca(2+) sensitivity of force increased in end-stage failing myocardium, inversely correlated with myosin light chain 2 phosphorylation.

Conclusions:

• Contractile protein alterations in end-stage heart failure affect Ca(2+) responsiveness but not cross-bridge force generation or P(i)/pH dependence.
• Increased Ca(2+) responsiveness in end-stage failure may mitigate force reduction from pH and P(i) changes at submaximal [Ca(2+)].