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. 1999 Nov;82(5):625–629. doi: 10.1136/hrt.82.5.625

Malalignment of the sarcomeric filaments in hypertrophic cardiomyopathy with cardiac myosin heavy chain gene mutation

A Muraishi 1, H Kai 1, K Adachi 1, H Nishi 1, T Imaizumi 1
PMCID: PMC1760777  PMID: 10525522

Abstract

OBJECTIVE—To investigate changes in the alignment of the sarcomeric filaments in hypertrophic cardiomyopathy and the effects of cardiac β myosin heavy chain (β-MHC) mutation on the sarcomeric ultrastructure.
DESIGN—A retrospective analysis.
PATIENTS—Endomyocardial biopsy samples were examined by transmission electron microscopy in seven patients with hypertrophic cardiomyopathy and β-MHC mutation, six with hypertrophic cardiomyopathy but without the mutation, and five controls (with chest pain syndromes).
MAIN OUTCOME MEASURE—Alignment of the sarcomeric filaments and the distance between neighbouring thick myosin filaments.
RESULTS—In controls, cross sections of the sarcomere at the A band showed a highly organised orthohexagonal array with 6 thin actin filaments surrounding one thick myosin filament, whereas in hypertrophic cardiomyopathy the alignment of the sarcomeric filaments was sparse and disrupted. In hypertrophic cardiomyopathy with a mutation, the distance between neighbouring thick myosin filaments was greater than in controls (mean (SD) 45.3 (4.7) v 38.5 (3.5) nm, p < 0.05), and the variance of the distance was greater than in controls (8.0 (0.7) v 4.8 (1.0) nm, p < 0.001) or in patients with hypertrophic cardiomyopathy without a mutation (6.7 (0.6) nm, p < 0.05). In the latter, the variance of the distance was also greater than in the controls (p < 0.01). A significant correlation was found between the grade of the myocyte hypertrophy and the variance of the distance (r = 0.654; p < 0.01).
CONCLUSIONS—The alignment of the sarcomeric filaments is disrupted in hypertrophic cardiomyopathy, particularly when there is β-MHC mutation.


Keywords: hypertrophic cardiomyopathy; β myosin heavy chain; myosin filament; sarcomere

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Figure 1  .

Figure 1  

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Representative electron microphotographs of cross section of the sarcomere at the A band (× 75 000) in a control patient (A) and a patient with hypertrophic cardiomyopathy (B). The bar represents 100 nm.

Figure 2  .

Figure 2  

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(A) The distance (d1, d2, d3, d4,..., dn) between neighbouring thick myosin filaments (arrows) was measured for at least 100 thick filaments in the cross section of the sarcomere at the A band (arrow head, actin thin filament). The average and the standard deviation of the measures (d1, d2, d3, d4,..., dn) were regarded as the thick myosin filament distance and the variance of the thick filament distance in each subject, respectively.(B) Averages of the thick myosin filament distance in patients with hypertrophic cardiomyopathy (HCM) with and without the β myosin heavy chain (β-MHC) mutation and in controls (n = 7, 6, and 5, respectively). (C) Averages of the variance of the thick filament distance in HCM patients with and without the β-MHC mutation and in controls. Error bar denotes 1 SD. *p < 0.05, **p < 0.01, ***p < 0.001 v controls; †p < 0.05 v HCM patients without a β-MHC mutation.

Figure 3  .

Figure 3  

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Correlation between the grade of cardiomyocyte hypertrophy and the thick myosin filament distance (A), and the variance of the thick filament distance (B). Controls, triangles; patients with hypertrophic cardiomyopathy and a β myosin heavy chain (β-MHC) mutation, filled circles; patients with hypertrophic cardiomyopathy without a β-MHC mutation, empty circles.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bonne G., Carrier L., Richard P., Hainque B., Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ Res. 1998 Sep 21;83(6):580–593. doi: 10.1161/01.res.83.6.580. [DOI] [PubMed] [Google Scholar]
  2. Cuda G., Fananapazir L., Zhu W. S., Sellers J. R., Epstein N. D. Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. J Clin Invest. 1993 Jun;91(6):2861–2865. doi: 10.1172/JCI116530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Geisterfer-Lowrance A. A., Kass S., Tanigawa G., Vosberg H. P., McKenna W., Seidman C. E., Seidman J. G. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990 Sep 7;62(5):999–1006. doi: 10.1016/0092-8674(90)90274-i. [DOI] [PubMed] [Google Scholar]
  4. Harada H., Kimura A., Nishi H., Sasazuki T., Toshima H. A missense mutation of cardiac beta-myosin heavy chain gene linked to familial hypertrophic cardiomyopathy in affected Japanese families. Biochem Biophys Res Commun. 1993 Jul 30;194(2):791–798. doi: 10.1006/bbrc.1993.1891. [DOI] [PubMed] [Google Scholar]
  5. Kai H., Muraishi A., Sugiu Y., Nishi H., Seki Y., Kuwahara F., Kimura A., Kato H., Imaizumi T. Expression of proto-oncogenes and gene mutation of sarcomeric proteins in patients with hypertrophic cardiomyopathy. Circ Res. 1998 Sep 21;83(6):594–601. doi: 10.1161/01.res.83.6.594. [DOI] [PubMed] [Google Scholar]
  6. Louie E. K., Edwards L. C., 3rd Hypertrophic cardiomyopathy. Prog Cardiovasc Dis. 1994 Jan-Feb;36(4):275–308. doi: 10.1016/s0033-0620(05)80036-2. [DOI] [PubMed] [Google Scholar]
  7. Marian A. J., Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation. 1995 Sep 1;92(5):1336–1347. doi: 10.1161/01.cir.92.5.1336. [DOI] [PubMed] [Google Scholar]
  8. Marian A. J., Yu Q. T., Mann D. L., Graham F. L., Roberts R. Expression of a mutation causing hypertrophic cardiomyopathy disrupts sarcomere assembly in adult feline cardiac myocytes. Circ Res. 1995 Jul;77(1):98–106. doi: 10.1161/01.res.77.1.98. [DOI] [PubMed] [Google Scholar]
  9. Maron B. J., Epstein S. E. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am J Cardiol. 1979 Jun;43(6):1242–1244. doi: 10.1016/0002-9149(79)90160-7. [DOI] [PubMed] [Google Scholar]
  10. Maron B. J. Hypertrophic cardiomyopathy. Curr Probl Cardiol. 1993 Nov;18(11):639–704. doi: 10.1016/0146-2806(93)90025-w. [DOI] [PubMed] [Google Scholar]
  11. Nishi H., Kimura A., Harada H., Adachi K., Koga Y., Sasazuki T., Toshima H. Possible gene dose effect of a mutant cardiac beta-myosin heavy chain gene on the clinical expression of familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 1994 Apr 15;200(1):549–556. doi: 10.1006/bbrc.1994.1483. [DOI] [PubMed] [Google Scholar]
  12. Nishi H., Kimura A., Harada H., Koga Y., Adachi K., Matsuyama K., Koyanagi T., Yasunaga S., Imaizumi T., Toshima H. A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy. Circulation. 1995 Jun 15;91(12):2911–2915. doi: 10.1161/01.cir.91.12.2911. [DOI] [PubMed] [Google Scholar]
  13. Nishi H., Kimura A., Harada H., Toshima H., Sasazuki T. Novel missense mutation in cardiac beta myosin heavy chain gene found in a Japanese patient with hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 1992 Oct 15;188(1):379–387. doi: 10.1016/0006-291x(92)92396-f. [DOI] [PubMed] [Google Scholar]
  14. Schwartz K., Carrier L., Guicheney P., Komajda M. Molecular basis of familial cardiomyopathies. Circulation. 1995 Jan 15;91(2):532–540. doi: 10.1161/01.cir.91.2.532. [DOI] [PubMed] [Google Scholar]
  15. Seki Y., Kai H., Kai M., Muraishi A., Adachi K., Imaizumi T. Myocardial DNA strand breaks are detected in biopsy tissues from patients with dilated cardiomyopathy. Clin Cardiol. 1998 Aug;21(8):591–596. doi: 10.1002/clc.4960210811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sweeney H. L., Straceski A. J., Leinwand L. A., Tikunov B. A., Faust L. Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem. 1994 Jan 21;269(3):1603–1605. [PubMed] [Google Scholar]
  17. Thierfelder L., Watkins H., MacRae C., Lamas R., McKenna W., Vosberg H. P., Seidman J. G., Seidman C. E. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701–712. doi: 10.1016/0092-8674(94)90054-x. [DOI] [PubMed] [Google Scholar]

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