Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice

• Published in: Cardiovascular research Vol. 82; no. 1; pp. 84 - 92
• Main Authors: Abraham, Theodore P., Jones, Michelle, Kazmierczak, Katarzyna, Liang, Hsin-Yueh, Pinheiro, Aurelio C., Wagg, Cory S., Lopaschuk, Gary D., Szczesna-Cordary, Danuta
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2009
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Calcium - metabolism; Cardiac function; Cardiology. Vascular system; Cardiomyopathy, Hypertrophic, Familial - diagnostic imaging; Cardiomyopathy, Hypertrophic, Familial - genetics; Cardiomyopathy, Hypertrophic, Familial - metabolism; Cardiomyopathy, Hypertrophic, Familial - physiopathology; Cardiovascular system; Disease Models, Animal; Echocardiography; Echocardiography, Doppler, Pulsed; Genotype; Heart; Hemodynamics - genetics; Humans; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Myocardial Contraction - genetics; Myocarditis. Cardiomyopathies; Myocardium - enzymology; Myocardium - metabolism; Myofibrillar ATPase; Myofibrils - metabolism; Myosin Light Chains - genetics; Myosin Light Chains - metabolism; Myosin regulatory light chain (RLC); Original; Phenotype; Phosphorylation; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Ultrasonic investigative techniques; Ventricular Dysfunction, Left - diagnostic imaging; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - physiopathology; Myosin regulatory light chain (RLC); Echocardiography; Myofibrillar ATPase; Cardiac function; Cardiac performance; Cardiovascular disease; Light peptide chain; Myocardial disease; Phlebology; Heart disease; Myosin; Cardiology; Sonography; Enzyme; Family study; Rodentia; Adenosinetriphosphatase; Vertebrata; Mammalia; Mouse; Dysfunction; Animal; Hypertrophic cardiomyopathy; Hydrolases; Models; Circulatory system
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvp016

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 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. Methods and 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 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. Conclusion 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.