Skip to main content
SpringerLink
Log in

Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

β-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (αMHC403) has been extensively used to study various mechanistic aspects of HCM. There is general skepticism whether mouse and human disease features are similar. Herein we compare morphologic and functional characteristics, and disease evolution, in a transgenic mouse and a single family with a MHC mutation. Ten male αMHC403 transgenic mice (at t-5 weeks, −12 weeks, and −24 weeks) and 10 HCM patients from the same family with a β-myosin heavy chain mutation were enrolled. Morphometric, conventional echocardiographic, tissue Doppler and strain analytic characteristics of transgenic mice and HCM patients were assessed. Ten male transgenic mice (αMHC403) were examined at ages −5 weeks, −12 weeks, and −24 weeks. In the transgenic mice, aging was associated with a significant increase in septal (0.59±0.06 vs. 0.64±0.05 vs. 0.69±0.11 mm, P<0.01) and anterior wall thickness (0.58±0.1 vs. 0.62±0.07 vs. 0.80±0.16 mm, P<0.001), which was coincident with a significant decrease in circumferential strain (−22%±4% vs. −20%±3% vs. −19%±3%, P=0.03), global longitudinal strain (−19%±3% vs. −17%±2% vs. −16%±3%, P=0.001) and E/A ratio (1.9±0.3 vs. 1.7±0.3 vs. 1.4±0.3, P=0.01). The HCM patients were classified into 1st generation (n=6; mean age 53±6 years), and 2nd generation (n=4; mean age 32±8 years). Septal thickness (2.2±0.9 vs. 1.4±0.1 cm, P<0.05), left atrial (LA) volume (62±16 vs. 41±5 mL, P=0.03), E/A ratio (0.77±0.21 vs. 1.1±0.1, P=0.01), E/e’ ratio (25±10 vs. 12±2, P=0.03), global left ventricular (LV) strain (−14%±3% vs. −20%±3%, P=0.01) and global LV early diastolic strain rate (0.76±0.17 s−1 vs. 1.3±0.2 s-1, P=0.01) were significantly worse in the older generation. In β-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The αMHC403 transgenic mouse model closely recapitulates human disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Seidman CE, Seidman JG. Molecular genetic studies of familial hypertrophic cardiomyopathy. Basic Res Cardiol, 1998,93(Suppl 3):13–16

    Article  PubMed  CAS  Google Scholar 

  2. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA, 2002,287(10):1308–1320

    Article  PubMed  Google Scholar 

  3. Hernandez OM, Housmans PR, Potter JD. Invited review: pathophysiology of cardiac muscle contraction and relaxation as a result of alterations in thin filament regulation. J Appl Physiol, 2001,90(3):1125–1136

    PubMed  CAS  Google Scholar 

  4. Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol, 2001,33(4):655–670

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Morimoto S. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res, 2008,77(4):659–666

    Article  PubMed  CAS  Google Scholar 

  6. Tsoutsman T, Bagnall RD, Semsarian C. Impact of multiple gene mutations in determining the severity of cardiomyopathy and heart failure. Clin Exp Pharmacol Physiol, 2008,35(11):1349–1357

    Article  PubMed  CAS  Google Scholar 

  7. Redwood CS, Moolman-Smook JC, Watkins H. Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy. Cardiovasc Res, 1999,44(1):20–36

    Article  PubMed  CAS  Google Scholar 

  8. Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med, 1995,332(16): 1058–1064

    Article  PubMed  CAS  Google Scholar 

  9. Watkins H, Rosenzweig A, Hwang DS, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med, 1992,326(17):1108–1114

    Article  PubMed  CAS  Google Scholar 

  10. Geisterfer-Lowrance AA, Christe M, Conner DA, et al. A mouse model of familial hypertrophic cardiomyopathy. Science, 1996,272(5262):731–734

    Article  PubMed  CAS  Google Scholar 

  11. Georgakopoulos D, Christe ME, Giewat M, et al. The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an alpha-cardiac myosin heavy chain missense mutation. Nat Med, 1999,5(3):327–330

    Article  PubMed  CAS  Google Scholar 

  12. McConnell BK, Fatkin D, Semsarian C, et al. Comparison of two murine models of familial hypertrophic cardiomyopathy. Circ Res, 2001,88(4):383–389

    Article  PubMed  CAS  Google Scholar 

  13. Vikstrom KL, Factor SM, Leinwand LA. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy. Mol Med, 1996,2(5):556–567

    PubMed  CAS  PubMed Central  Google Scholar 

  14. de Simone G, Wallerson DC, Volpe M, et al. Echocardiographic measurement of left ventricular mass and volume in normotensive and hypertensive rats. Necropsy validation. Am J Hypertens, 1990,3(9):688–696

    Article  Google Scholar 

  15. Nishimura RA, Appleton CP, Redfield MM. Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: a simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol, 1996,28(5):1226–1233

    Article  PubMed  CAS  Google Scholar 

  16. Bauer M, Cheng S, Jain M, et al. Echocardiographic speckle-tracking based strain imaging for rapid cardiovascular phenotyping in mice. Circ Res, 2011,108(8):908–916

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol, 1986,57(6):450–458

    Article  PubMed  CAS  Google Scholar 

  18. Pavlopoulos H, Nihoyannopoulos P. Strain and strain rate deformation parameters: from tissue Doppler to 2D speckle tracking. Int J Cardiovasc Imaging, 2008,24(5):479–491

    Article  PubMed  Google Scholar 

  19. Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol, 2006,98(5):699–704

    Article  PubMed  Google Scholar 

  20. Korinek J, Wang J, Sengupta PP, et al. Two-dimensional strain-a Doppler-independent ultrasound method for quantitation of regional deformation: validation in vitro and in vivo. J Am Soc Echocardiogr, 2005,18(12):1247–1253

    Article  PubMed  Google Scholar 

  21. Langeland S, D’Hooge J, Wouters PF, et al. Experimental validation of a new ultrasound method for the simultaneous assessment of radial and longitudinal myocardial deformation independent of insonation angle. Circulation, 2005,112(14):2157–2162

    Article  PubMed  Google Scholar 

  22. Leitman M, Lysyansky P, Sidenko S, et al. Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr, 2004,17(10):1021–1029

    Article  PubMed  Google Scholar 

  23. Serri K, Reant P, Lafitte M, et al. Global and regional myocardial function quantification by two-dimensional strain: application in hypertrophic cardiomyopathy. J Am Coll Cardiol, 2006,47(6):1175–1181

    Article  PubMed  Google Scholar 

  24. Wang Q, Moncman CL, Winkelmann DA. Mutations in the motor domain modulate myosin activity and myofibril organization. J Cell Sci, 2003,116(Pt 20):4227–4238

    Article  PubMed  CAS  Google Scholar 

  25. Kim SJ, Iizuka K, Kelly RA, et al. An alpha-cardiac myosin heavy chain gene mutation impairs contraction and relaxation function of cardiac myocytes. Am J Physiol, 1999,276(5 Pt 2):H1780–1787

    PubMed  CAS  Google Scholar 

  26. Tyska MJ, Hayes E, Giewat M, et al. Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res, 2000,86(7):737–744

    Article  PubMed  CAS  Google Scholar 

  27. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell, 2001,104(4):557–567

    Article  PubMed  CAS  Google Scholar 

  28. Ferrans VJ, Morrow AG, Roberts WC. Myocardial ultrastructure in idiopathic hypertrophic subaortic stenosis. A study of operatively excised left ventricular outflow tract muscle in 14 patients. Circulation, 1972,45(4):769–792

    CAS  Google Scholar 

  29. Spindler M, Saupe KW, Christe ME, et al. Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Clin Invest, 1998,101(8):1775–1783

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Semsarian C, Ahmad I, Giewat M, et al. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest, 2002,109(8):1013–1020

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Louie EK, Edwards LC, 3rd. Hypertrophic cardiomyopathy. Prog Cardiovasc Dis, 1994,36(4):275–308

    Article  PubMed  CAS  Google Scholar 

  32. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol, 2003,42(9):1687–1713

    Article  PubMed  Google Scholar 

  33. Pinamonti B, Di Lenarda A, Nucifora G, et al. Incremental prognostic value of restrictive filling pattern in hypertrophic cardiomyopathy: a Doppler echocardiographic study. Eur J Echocardiogr, 2008,9(4):466–471

    PubMed  Google Scholar 

  34. Factor SM, Butany J, Sole MJ, et al. Pathologic fibrosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol, 1991,17(6):1343–1351

    Article  PubMed  CAS  Google Scholar 

  35. Shah PM. Hypertrophic cardiomyopathy and diastolic dysfunction. J Am Coll Cardiol, 2003,42(2):286–297

    Article  PubMed  Google Scholar 

  36. Gwathmey JK, Warren SE, Briggs GM, et al. Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J Clin Invest, 1991,87(3):1023–1031

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Cannon RO, 3rd, Schenke WH, Maron BJ, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol, 1987,10(1):53–62

    Article  PubMed  Google Scholar 

  38. Betocchi S, Hess OM, Losi MA, et al. Regional left ventricular mechanics in hypertrophic cardiomyopathy. Circulation, 1993,88(5 Pt 1):2206–2214

    Article  PubMed  CAS  Google Scholar 

  39. Rajiv C, Vinereanu D, Fraser AG. Tissue Doppler imaging for the evaluation of patients with hypertrophic cardiomyopathy. Curr Opin Cardiol, 2004,19(5):430–436

    Article  PubMed  Google Scholar 

  40. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation, 2003,107(19):2446–2452

    Article  PubMed  Google Scholar 

  41. Bellavia D, Pellikka PA, Abraham TP, et al. Evidence of impaired left ventricular systolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler echocardiography. Am J Cardiol, 2008,101(7):1039–1045

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA

    Hong-chang Luo  (罗鸿昌), Iraklis Pozios, Styliani Vakrou, Lars Sorensen, Roselle M. Abraham & Theodore Abraham

  2. Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Hong-chang Luo  (罗鸿昌)

Authors
  1. Hong-chang Luo  (罗鸿昌)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iraklis Pozios
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Styliani Vakrou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lars Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roselle M. Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Theodore Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodore Abraham.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, Hc., Pozios, I., Vakrou, S. et al. Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 34, 634–639 (2014). https://doi.org/10.1007/s11596-014-1329-6

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-014-1329-6

Key words

Search

Navigation