Cardiac Dysfunction in Hypertrophic Cardiomyopathy Mutant Tropomyosin Mice Is Transgene-Dependent, Hypertrophy-Independent, and Improved by β-Blockade
- 9 August 2002
- journal article
- research article
- Published by Wolters Kluwer Health in Circulation Research
- Vol. 91 (3), 255-262
- https://doi.org/10.1161/01.res.0000027530.58419.82
Abstract
Familial hypertrophic cardiomyopathy (FHC) has been linked to mutations in proteins of the cardiac contractile apparatus, including α-tropomyosin (Tm). Mice expressing αTm in the heart were developed to determine the effects of FHC mutant Tm on cardiac structure and function from single cardiac myocytes to whole organ function in vivo. Expression of E180G mutant Tm did not produce cardiac hypertrophy or detectable changes in cardiac muscle morphology. However, E180G mutant Tm expression increased the Ca2+ sensitivity of force production in single cardiac myocytes in a transgene expression–dependent manner. Contractile dysfunction in single myocytes manifested organ level dysfunction, as conductance-micromanometry showed E180G Tm mice had significantly slowed relaxation (diastolic dysfunction) under physiological conditions. The diastolic dysfunction in E180G Tm mice was no longer evident during β-blockade because propranolol eliminated the effect of E180G Tm to slow myocardial relaxation. Cellular and organ level dysfunction were evident in E180G Tm mice in the absence of significant cardiac structural abnormalities normally associated with FHC. These findings therefore suggest that diastolic dysfunction in FHC may be a direct consequence of FHC mutant protein expression. In addition, because diastolic dysfunction in E180G Tm mice is dependent on inotropic status, cardiovascular stress may play an important role in FHC pathogenesis.Keywords
This publication has 18 references indexed in Scilit:
- The Genetic Basis for CardiomyopathyCell, 2001
- Transgenic expression of green fluorescence protein can cause dilated cardiomyopathyNature Medicine, 2000
- Animal models of hypertrophic cardiomyopathyCurrent Opinion in Cardiology, 2000
- Comparison of intravenous and pulmonary artery injections of hypertonic saline for the assessment of conductance catheter parallel conductanceCardiovascular Research, 2000
- Remodeling the Cardiac Sarcomere Using TransgenesisAnnual Review of Physiology, 2000
- Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice.JCI Insight, 1998
- Clinical Features of Hypertrophic Cardiomyopathy Caused by Mutation of a “Hot Spot” in the Alpha-Tropomyosin GeneJournal of the American College of Cardiology, 1997
- Chapter 15 Adenovirus—Mediated Myofilament Gene Transfer into Adult Cardiac MyocytesMethods in Cell Biology, 1997
- Skeletal troponin C reduces contractile sensitivity to acidosis in cardiac myocytes from transgenic mice.Proceedings of the National Academy of Sciences, 1993
- Differential sensitivity to isoprenaline of troponin I and phospholamban phosphorylation in isolated rat heartsBiochemical Journal, 1990