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 i n significant decreases in contractile parameters and intracellular Ca2+ tr ansients in vitro. Therefore, the purpose of the present study was to deter mine 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 int egrative approach using transthoracic echocardiography. stress-shortening r elations, and invasive hemodynamics in intact closed-chest mice, hi-mode ec hocardiography indicated that calsequestrin overexpression resulted in conc entric hypertrophy (+52 %) and an increase in LV ejection phase indices. Ho wever, mean end-systolic stress-shortening coordinates revealed that at mat ched end-systolic wall-stress, fractional shortening was depressed in CSQ-O E mice, This was confirmed by depressed indices of LV isovolumic contractio n and relaxation in CSQ-OE v WT mice, Furthermore, overexpression of calseq uestrin resulted in a downward and leftward shift of the biphasic force-fre quency relation; thus, the critical heart (HRcrit) was significantly lower in calsequestrin-overexpression mice (264 +/- 15 bpm) than in wild-type con trols (365 +/- 21 bpm). Surprisingly, calsequestrin overexpression was asso ciated with the induction of pulsus alternans in every animal (at an averag e heart rate of 428 +/- 26 bpm), whereas none of the wild-type controls dis played 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 al ternans in the intact anesthetized mouse. (C) 2000 Academic Press.