title: Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice.
abstract: OBJECTIVE
  Several mutations in the ventricular myosin regulatory light chain (RLC) were identified to cause familial hypertrophic cardiomyopathy (FHC). Based on our previous cellular findings showing delayed calcium transients in electrically stimulated intact papillary muscle fibres from transgenic Tg-R58Q and Tg-N47K mice and, in addition, prolonged force transients in Tg-R58Q fibres, we hypothesized that the malignant FHC phenotype associated with the R58Q mutation is most likely related to diastolic dysfunction.
  
  
  RESULTS
  Cardiac morphology and in vivo haemodynamics by echocardiography as well as cardiac function in isolated perfused working hearts were assessed in transgenic (Tg) mutant mice. The ATPase-pCa relationship was determined in myofibrils isolated from Tg mouse hearts. In addition, the effect of both mutations on RLC phosphorylation was examined in rapidly frozen ventricular samples from Tg mice. Significantly, decreased cardiac function was observed in isolated perfused working hearts from both Tg-R58Q and Tg-N47K mice. However, echocardiographic examination showed significant alterations in diastolic transmitral velocities and deceleration time only in Tg-R58Q myocardium. Likewise, changes in Ca(2+) sensitivity, cooperativity, and an elevated level of ATPase activity at low [Ca(2+)] were only observed in myofibrils from Tg-R58Q mice. In addition, the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles.
  
  
  CONCLUSIONS
  Our results suggest that the N47K and R58Q mutations may act through similar mechanisms, leading to compensatory hypertrophy of the functionally compromised myocardium, but the malignant R58Q phenotype is most likely associated with more severe alterations in cardiac performance manifested as impaired relaxation and global diastolic dysfunction. At the molecular level, we suggest that by reducing the phosphorylation of RLC, the R58Q mutation decreases the kinetics of myosin cross-bridges, leading to an increased myofilament calcium sensitivity and to overall changes in intracellular Ca(2+) homeostasis.
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Abraham
authors.forename: Michelle
authors.initials: M
authors.lastname: Jones
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kazmierczak
authors.forename: Hsin-Yueh
authors.initials: HY
authors.lastname: Liang
authors.forename: Aurelio C
authors.initials: AC
authors.lastname: Pinheiro
authors.forename: Cory S
authors.initials: CS
authors.lastname: Wagg
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Danuta
authors.initials: D
authors.lastname: Szczesna-Cordary
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D018619:Echocardiography, Doppler, Pulsed; D005838:Genotype; D006439:Hemodynamics / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D018994:Myosin Light Chains; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium