title: Cardiac-specific overexpression of calsequestrin results in left ventricular hypertrophy, depressed force-frequency relation and pulsus alternans in vivo.
abstract: Cardiac-specific overexpression of calsequestrin has been shown to result in significant decreases in contractile parameters and intracellular Ca(2+)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. M-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 (HR(crit)) 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 Ca(2+)storage capacity induces pulsus alternans in the intact anesthetized mouse.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati Medical Center, 231 Bethesda Avenue, ML 0575 Cincinnati, OH, 45267-0542, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Schmidt
authors.forename: V J
authors.initials: VJ
authors.lastname: Kadambi
authors.forename: N
authors.initials: N
authors.lastname: Ball
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: R A
authors.initials: RA
authors.lastname: Walsh
authors.forename: E G
authors.initials: EG
authors.lastname: Kranias
authors.forename: B D
authors.initials: BD
authors.lastname: Hoit
mesh_terms: D000818:Animals; D002155:Calsequestrin / Q000502:physiology*; D004452:Echocardiography; D015870:Gene Expression; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction
chemical_list: D002155:Calsequestrin