Modulation of force-frequency relation by phospholamban in genetically engineered mice.

Abstract

Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca2+ pump activity and myocardial contractility. To determine whether and to what extent phospholamban modulates the force-frequency relation and ventricular relaxation in vivo, we studied transgenic mice overexpressing phospholamban (PLBOE), gene-targeted mice without phospholamban (PLBKO), and isogenic wild-type controls. Contractility was assessed by the peak rate of left ventricular (LV) isovolumic contraction (+dP/dtmax), and diastolic function was assessed by both the peak rate (-dP/dtmax) and the time constant (tau) of isovolumic LV relaxation, using a high-fidelity LV catheter. Incremental atrial pacing was used to generate heart rate vs. -dP/dtmax (force-frequency) relations. Biphasic force-frequency relations were produced in all animals, and the critical heart rate (HRcrit) was taken as the heart rate at which dP/dtmax was maximal. The average LV +dP/dtmax increased in both PLBKO and PLBOE compared with their isogenic controls (both P < 0.05). The HRcrit for LV +dP/dtmax was significantly higher in PLBKO (427 +/- 20 beats/min) compared with controls (360 +/- 18 beats/min), whereas the HRcrit in PLBOE (340 +/- 30 beats/min) was significantly lower compared with that in isogenic controls (440 +/- 25 beats/min). The intrinsic heart rates were significantly lower, and the HRcrit and the +/-dP/dtmax at HRcrit were significantly greater in FVB/N than in SvJ control mice. We conclude that 1) the level of phospholamban is a critical negative determinant of the force-frequency relation and myocardial contractility in vivo, and 2) contractile parameters may differ significantly between strains of normal mice.