Cardiovascular Research Advance Access first published online on January 15, 2009
This version [Accepted Manuscript] published online on January 19, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp016
Diastolic Dysfunction in Familial Hypertrophic Cardiomyopathy Transgenic Model Mice
1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami FL 33136
2 Division of Cardiology, Johns Hopkins University, Baltimore MD
3 Cardiovascular Research Group, University of Alberta, Edmonton T6G 2S2, Canada
* Correspondence: Dr. Danuta Szczesna-Cordary University of Miami Miller School of Medicine 1600 NW 10th Ave Miami, FL 33136 Phone: (305) 243-2908 FAX: (305) 243-4555 E-mail: dszczesna{at}med.miami.edu
Aims: 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 fibers from transgenic Tg-R58Q and Tg-N47K mice and, in addition, prolonged force transients in Tg-R58Q fibers, we hypothesized that the malignant FHC phenotype associated with the R58Q mutation is most likely related to diastolic dysfunction.
Methods: Cardiac morphology and in vivo hemodynamics by echocardiography as well as cardiac function in isolated perfused working hearts were assessed in transgenic mutant mice. The ATPase-pCa relationship was determined in myofibrils isolated from transgenic (Tg) mouse hearts. In addition, the effect of both mutations on RLC phosphorylation was examined in rapidly frozen ventricular samples from Tg mice.
Results: 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 Ca2+ sensitivity, cooperativity and an elevated level of ATPase activity at low [Ca2+] 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 Ca2+ homeostasis.
KEYWORDS Cardiac function; chocardiography; myofibrillar ATPase; myosin regulatory light chain (RLC)
Time for primary review: 29 days
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