AHEART June 45/6

Kadambi, Vivek J., Nancy Ball, Evangelia G. Kranias, Richard A. Walsh, and Brian D. Hoit. Modulation of force-frequency relation by phospholamban in genetically engineered mice. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H2245–H2250, 1999.—Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca21 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 (1dP/dtmax), and diastolic function was assessed by both the peak rate (2dP/dtmax) and the time constant (t) of isovolumic LV relaxation, using a high-fidelity LV catheter. Incremental atrial pacing was used to generate heart rate vs. 2dP/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 1dP/dtmax increased in both PLBKO and PLBOE compared with their isogenic controls (both P , 0.05). The HRcrit for LV 1dP/dtmax was significantly higher in PLBKO (427 6 20 beats/min) compared with controls (360 6 18 beats/min), whereas the HRcrit in PLBOE (340 6 30 beats/min) was significantly lower compared with that in isogenic controls (440 6 25 beats/min). The intrinsic heart rates were significantly lower, and the HRcrit and the 6dP/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.