Cardiac-specific overexpression of calsequestrin results in left ventricular hypertrophy, depressed force-frequency relation and pulsus alternans in vivo

Cardiac-specific overexpression of calsequestrin has been shown to result in significant decreases in contractile parameters and intracellular Ca2+ transients in vitro. Therefore, the purpose of the present study was to determine the effects of calsequestrin overexpression on basal cardiac function and the force-frequency relation in vivo, Calsequestrin overexpression mice (CSQ-OE. n = 20) and their isogenic controls (WT) were studied with an integrative approach using transthoracic echocardiography. stress-shortening relations, and invasive hemodynamics in intact closed-chest mice, hi-mode echocardiography indicated that calsequestrin overexpression resulted in concentric hypertrophy (+52 %) and an increase in LV ejection phase indices. However, mean end-systolic stress-shortening coordinates revealed that at matched end-systolic wall-stress, fractional shortening was depressed in CSQ-OE mice, This was confirmed by depressed indices of LV isovolumic contraction and relaxation in CSQ-OE v WT mice, Furthermore, overexpression of calsequestrin resulted in a downward and leftward shift of the biphasic force-frequency relation; thus, the critical heart (HRcrit) was significantly lower in calsequestrin-overexpression mice (264 +/- 15 bpm) than in wild-type controls (365 +/- 21 bpm). Surprisingly, calsequestrin overexpression was associated with the induction of pulsus alternans in every animal (at an average heart rate of 428 +/- 26 bpm), whereas none of the wild-type controls displayed this phenomenon. We conclude that: (i) although increased levels of calsequestrin result in decreased myocardial contractility and a depressed force-frequency relation, LV wall stress is reduced and chamber function is normal, and (ii) an increase in SR Ca2+ storage capacity induces pulsus alternans in the intact anesthetized mouse. (C) 2000 Academic Press.