Discovered important component of cardiac force-frequency relationship

Objective: To investigate the role of SERCA (sarcoplasmic reticulum Ca²⁺ ATPase) and phospholamban in regulating the cardiac force-frequency relationship

Background: The cardiac force-frequency relationship (enhanced cardiac contractility at higher rates of stimulation) has been recognized for over a century as one of the most fundamental mechanisms in cardiac muscle physiology, yet its mechanisms have eluded thorough understanding. SERCA and phospholamban together are perhaps the most powerful regulators of cardiac contractility, but their role in the cardiac force-frequency relationship had not been systematically investigated.

Methods: SERCA and phospholamban were overexpressed in adult rabbit ventricular myocytes by an adenoviral approach. Time course and magnitude of cell shortening were measured as a function of stimulation frequency. In addition, the force-frequency relationship was evaluated in papillary muscles from wild-type mice, SERCA transgenic mice, and phospholamban knock-out mice.

Results: The force-frequency relationship is positively related to the ratio of phospholamban to SERCA (Am. J. Physiol. 276: H779-H785, 1999. - ABSTRACT). In particular, using papillary muscles from phospholamban knock-out mice allowed us to directly identify phospholamban as a major determinant of the cardiac force-frequency relationship (Am. J. Physiol., 278: H249-H255, 2000. - ABSTRACT)