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

Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca2+ pump acti vity and myocardial contractility. To determine whether and to what extent phospholamban modulates the force-frequency relation and ventricular relaxa tion in vivo, we studied transgenic mice overexpressing phospholamban (PLBO E), gene-targeted mice without phospholamban (PLBKO), and isogenic wild-typ e controls. Contractility was assessed by the peak rate of left ventricular (LV) isovolumic contraction (+ dP/dt(max)), and diastolic function was ass essed by both the peak rate (- dP/dt(max)) and the time constant (tau) of i sovolumic LV relaxation, using a high-fidelity LV catheter. Incremental atr ial pacing was used to generate heart rate vs. -dP/dt(max) (force-frequency ) relations. Biphasic force-frequency relations were produced in all animal s, and the critical heart rate (HRcrit) was taken as the heart rate at whic h dP/dt(max) was maximal. The average LV +dP/dt(max) increased in both PLBK O and PLBOE compared with their isogenic controls (both P < 0.05). The HRcr it for LV +dP/dt(max), 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 si gnificantly lower, and the HRcrit, and the +/-dP/dt(max) at HRcrit were sig nificantly greater in FVB/N than in SvJ control mice. We conclude that 1) t he level of phospholamban is a critical negative determinant of the force-f requency relation and myocardial contractility in vivo, and 2) contractile parameters may differ significantly between strains of normal mice.