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Journal of Cardiovascular Translational Research

Erschienen in:

01.12.2009

Experimental Therapies in Hypertrophic Cardiomyopathy

verfasst von: Ali J. Marian

Erschienen in: Journal of Cardiovascular Translational Research | Ausgabe 4/2009

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Abstract

The quintessential clinical diagnostic phenotype of human hypertrophic cardiomyopathy (HCM) is primary cardiac hypertrophy. Cardiac hypertrophy is also a major determinant of mortality and morbidity including the risk of sudden cardiac death (SCD) in patients with HCM. Reversal and attenuation of cardiac hypertrophy and its accompanying fibrosis is expected to improve morbidity as well as decrease the risk of SCD in patients with HCM.The conventionally used pharmacological agents in treatment of patients with HCM have not been shown to reverse or attenuate established cardiac hypertrophy and fibrosis. An effective treatment of HCM has to target the molecular mechanisms that are involved in the pathogenesis of the phenotype. Mechanistic studies suggest that cardiac hypertrophy in HCM is secondary to activation of various hypertrophic signaling molecules and, hence, is potentially reversible. The hypothesis is supported by the results of genetic and pharmacological interventions in animal models. The results have shown potential beneficial effects of angiotensin II receptor blocker losartan, mineralocorticoid receptor blocker spironolactone, 3-hydroxy-3-methyglutaryl-coenzyme A reductase inhibitors simvastatin and atorvastatin, and most recently, N-acetylcysteine (NAC) on reversal or prevention of hypertrophy and fibrosis in HCM. The most promising results have been obtained with NAC, which through multiple thiol-responsive mechanisms completely reversed established cardiac hypertrophy and fibrosis in three independent studies. Pilot studies with losartan and statins in humans have established the feasibility of such studies. The results in animal models have firmly established the reversibility of established cardiac hypertrophy and fibrosis in HCM and have set the stage for advancing the findings in the animal models to human patients with HCM through conducting large-scale efficacy studies.

Arad, M., Maron, B. J., Gorham, J. M., Johnson, W. H., Jr., Saul, J. P., Perez-Atayde, A. R., et al. (2005). Glycogen storage diseases presenting as hypertrophic cardiomyopathy. New England Journal of Medicine, 352, 362–372.PubMedCrossRef

Araujo, A. Q., Arteaga, E., Ianni, B. M., Buck, P. C., Rabello, R., & Mady, C. (2005). Effect of Losartan on left ventricular diastolic function in patients with nonobstructive hypertrophic cardiomyopathy. American Journal of Cardiology, 96, 1563–1567.PubMedCrossRef

Bauersachs, J., Stork, S., Kung, M., Waller, C., Fidler, F., Hoyer, C., et al. (2007). HMG CoA reductase inhibition and left ventricular mass in hypertrophic cardiomyopathy: a randomized placebo-controlled pilot study. European Journal of Clinical Investigation, 37, 852–859.PubMedCrossRef

Benjamin, E. J., & Levy, D. (1999). Why is left ventricular hypertrophy so predictive of morbidity and mortality? American Journal of the Medical Sciences, 317, 168–175.PubMedCrossRef

Bentley, D. R., Balasubramanian, S., Swerdlow, H. P., Smith, G. P., Milton, J., Brown, C. G., et al. (2008). Accurate whole human genome sequencing using reversible terminator chemistry. Nature, 456, 53–59.PubMedCrossRef

Blanchard, E., Seidman, C., Seidman, J. G., LeWinter, M., & Maughan, D. (1999). Altered crossbridge kinetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. Circulation Research, 84, 475–483.PubMed

Boltwood, C. M., Jr., Chien, W., & Ports, T. (2004). Ventricular tachycardia complicating alcohol septal ablation. New England Journal of Medicine, 351, 1914–1915.PubMedCrossRef

Chen, M. S., Xu, F. P., Wang, Y. Z., Zhang, G. P., Yi, Q., Zhang, H. Q., et al. (2004). Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis. Journal of Molecular and Cellular Cardiology, 37, 889–896.PubMedCrossRef

Chimenti, C., Pieroni, M., Morgante, E., Antuzzi, D., Russo, A., Russo, M. A., et al. (2004). Prevalence of fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation, 110, 1047–1053.PubMedCrossRef

10.

De Windt, L. J., Lim, H. W., Haq, S., Force, T., & Molkentin, J. D. (2000). Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart. Cross-talk between cardiac hypertrophic signaling pathways. Journal of Biological Chemistry, 275, 13571–13579.PubMedCrossRef

11.

Delbosc, S., Cristol, J. P., Descomps, B., Mimran, A., & Jover, B. (2002). Simvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension, 40, 142–147.PubMedCrossRef

12.

Demedts, M., Behr, J., Buhl, R., Costabel, U., Dekhuijzen, R., Jansen, H. M., et al. (2005). High-Dose acetylcysteine in idiopathic pulmonary fibrosis. New England Journal of Medicine, 353, 2229–2242.PubMedCrossRef

13.

Ding, B., Price, R. L., Borg, T. K., Weinberg, E. O., Halloran, P. F., & Lorell, B. H. (1999). Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin. Circulation Research, 84, 729–734.PubMed

14.

Elliott, P. M., Gimeno, B., Jr., Mahon, N. G., Poloniecki, J. D., & McKenna, W. J. (2001). Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet, 357, 420–424.PubMedCrossRef

15.

Fatkin, D., McConnell, B. K., Mudd, J. O., Semsarian, C., Moskowitz, I. G., Schoen, F. J., et al. (2000). An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 106, 1351–1359.PubMedCrossRef

16.

Flores-Ramirez, R., Lakkis, N. M., Middleton, K. J., Killip, D., Spencer, W. H., 3rd, & Nagueh, S. F. (2001). Echocardiographic insights into the mechanisms of relief of left ventricular outflow tract obstruction after nonsurgical septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy. Journal of the American College of Cardiology, 37, 208–214.PubMedCrossRef

17.

Fujita, H., Sugiura, S., Momomura, S., Omata, M., Sugi, H., & Sutoh, K. (1997). Characterization of mutant myosins of Dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. Molecular force level of mutant myosins may have a prognostic implication. Journal of Clinical Investigation, 99, 1010–1015.PubMedCrossRef

18.

Gaasch, W. H., & Zile, M. R. (2004). Left ventricular diastolic dysfunction and diastolic heart failure. Annual Review of Medicine, 55(373–94), 373–394.PubMedCrossRef

19.

Georgakopoulos, D., Christe, M. E., Giewat, M., Seidman, C. M., Seidman, J. G., & Kass, D. A. (1999). The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an alpha-cardiac myosin heavy chain missense mutation [see comments]. Natural Medicines, 5, 327–330.CrossRef

20.

Haider, A. W., Larson, M. G., Benjamin, E. J., & Levy, D. (1998). Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. Journal of the American College of Cardiology, 32, 1454–1459.PubMedCrossRef

21.

Haim, T. E., Dowell, C., Diamanti, T., Scheuer, J., & Tardiff, J. C. (2007). Independent FHC-related cardiac troponin T mutations exhibit specific alterations in myocellular contractility and calcium kinetics. Journal of Molecular and Cellular Cardiology, 42, 1098–1110.PubMedCrossRef

22.

Harada, K., & Potter, J. D. (2004). Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca2+ sensitivity of cardiac muscle contraction. Journal of Biological Chemistry, 279, 14488–14495.PubMedCrossRef

23.

Harada, K., Takahashi-Yanaga, F., Minakami, R., Morimoto, S., & Ohtsuki, I. (2000). Functional consequences of the deletion mutation deltaGlu160 in human cardiac troponin T. Journal of Biochemistry, 127, 263–268.PubMed

24.

Hernandez, O. M., Szczesna-Cordary, D., Knollmann, B. C., Miller, T., Bell, M., Zhao, J., et al. (2005). F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers. Journal of Biological Chemistry, 280, 37183–37194.PubMedCrossRef

25.

Ho, C. Y., Sweitzer, N. K., McDonough, B., Maron, B. J., Casey, S. A., Seidman, J. G., et al. (2002). Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation, 105, 2992–2997.PubMedCrossRef

26.

Hori, Y., Ueda, M., Nakayama, T., Saegusa, N., Uehara, M., Lee, K., et al. (2007). Occurrence of de novo sustained monomorphic ventricular tachycardia induced after percutaneous transluminal alcohol septal myocardial ablation for hypertrophic obstructive cardiomyopathy. International Journal of Cardiology, 119, 403–407.PubMedCrossRef

27.

Hoshikawa, Y., Ono, S., Suzuki, S., Tanita, T., Chida, M., Song, C., et al. (2001). Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. Journal of Applied Physiology, 90, 1299–1306.PubMed

28.

Indolfi, C., Di Lorenzo, E., Perrino, C., Stingone, A. M., Curcio, A., Torella, D., et al. (2002). Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation, 106, 2118–2124.PubMedCrossRef

29.

Kim, J. I., Ju, Y. S., Park, H., Kim, S., Lee, S., Yi, J. H., et al. (2009). A highly annotated whole-genome sequence of a Korean individual. Nature, 460, 1011–1015.PubMed

30.

Kitaoka, H., Kubo, T., Okawa, M., Hitomi, N., Furuno, T., & Doi, Y. L. (2006). Left ventricular remodeling of hypertrophic cardiomyopathy: longitudinal observation in rural community. Circulation, 70, 1543–1549.CrossRef

31.

Knoll, R., Hoshijima, M., Hoffman, H. M., Person, V., Lorenzen-Schmidt, I., Bang, M. L., et al. (2002). The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell, 111, 943–955.PubMedCrossRef

32.

Kopp, J., Seyhan, H., Muller, B., Lanczak, J., Pausch, E., Gressner, A. M., et al. (2006). N-acetyl-L-cysteine abrogates fibrogenic properties of fibroblasts isolated from Dupuytren’s disease by blunting TGF-beta signalling. Journal of Cellular and Molecular Medicine, 10, 157–165.PubMedCrossRef

33.

Krumholz, H. M., Larson, M., & Levy, D. (1995). Prognosis of left ventricular geometric patterns in the Framingham Heart Study. Journal of the American College of Cardiology, 25, 879–884.PubMedCrossRef

34.

Levy, D., Garrison, R. J., Savage, D. D., Kannel, W. B., & Castelli, W. P. (1990). Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. New England Journal of Medicine, 322, 1561–1566.PubMedCrossRef

35.

Levy, S., Sutton, G., Ng, P. C., Feuk, L., Halpern, A. L., Walenz, B. P., et al. (2007). The diploid genome sequence of an individual human. PLoS Biology, 5, e254.PubMedCrossRef

36.

Liao, J. K., & Laufs, U. (2005). Pleiotropic effects of statins. Annual Review of Pharmacology and Toxicology, 45, 89–118.PubMedCrossRef

37.

Lim, D. S., Lutucuta, S., Bachireddy, P., Youker, K., Evans, A., Entman, M., et al. (2001). Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation, 103, 789–791.PubMed

38.

Lim, H. W., De Windt, L. J., Mante, J., Kimball, T. R., Witt, S. A., Sussman, M. A., et al. (2000). Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition. Journal of Molecular and Cellular Cardiology, 32, 697–709.PubMedCrossRef

39.

Liu, D. D., Kao, S. J., & Chen, H. I. (2008). N-acetylcysteine attenuates acute lung injury induced by fat embolism. Critical Care Medicine, 36, 565–571.PubMedCrossRef

40.

Liu, R. M., Liu, Y., Forman, H. J., Olman, M., & Tarpey, M. M. (2004). Glutathione regulates transforming growth factor-{beta}-stimulated collagen production in fibroblasts. American Journal of Physiology. Lung Cellular and Molecular Physiology, 286, L121–L128.PubMedCrossRef

41.

Lombardi, R., Bell, A., Senthil, V., Sidhu, J., Noseda, M., Roberts, R., et al. (2008). Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies. Cardiovascular Research, 79, 109–117.PubMedCrossRef

42.

Lombardi, R., Rodriguez, G., Chen, S. N., Ripplinger, C. M., Li, W., Chen, J., et al. (2009). Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation, 119, 1398–1407.PubMedCrossRef

43.

Lowey, S., Lesko, L. M., Rovner, A. S., Hodges, A. R., White, S. L., Low, R. B., et al. (2008). Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone. Journal of Biological Chemistry, 283, 20579–20589.PubMedCrossRef

44.

Luo, J. D., Zhang, W. W., Zhang, G. P., Guan, J. X., & Chen, X. (1999). Simvastatin inhibits cardiac hypertrophy and angiotensin-converting enzyme activity in rats with aortic stenosis. Clinical and Experimental Pharmacology and Physiology, 26, 903–908.PubMedCrossRef

45.

Lutucuta, S., Tsybouleva, N., Ishiyama, M., Defreitas, G., Wei, L., Carabello, B., et al. (2004). Induction and reversal of cardiac phenotype of human hypertrophic cardiomyopathy mutation cardiac troponin T-Q92 in switch on-switch off bigenic mice. Journal of the American College of Cardiology, 44, 2221–2230.PubMedCrossRef

46.

Marian, A. J. (2000). Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet, 355, 58–60.PubMedCrossRef

47.

Marian, A. J. (2007). Hypertrophic cardiomyopathy. In C. C. Liew & V. Dzau (Eds.), Cardiovascular genetics and genomics for the gardiologist (pp. 30–54). Hoboken, NJ:Wiley-Blackwell.CrossRef

48.

Marian, A. J. (2008). Clinical implications of the “personal” genome. Current Atherosclerosis Reports, 10, 361–363.PubMedCrossRef

49.

Marian, A. J. (2008). Genetic determinants of cardiac hypertrophy. Current Opinion in Cardiology, 23, 199–205.PubMedCrossRef

50.

Marian, A. J. (2008). Hypertrophic Cardiomyopathy. In R. E. Rackel & E. T. Bope (Eds.), Conn’s current therapy (pp. 333–335). Philadelphia: Saunders-Elsevier.

51.

Marian, A. J., Senthil, V., Chen, S. N., & Lombardi, R. (2006). Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. Journal of the American College of Cardiology, 47, 827–834.PubMedCrossRef

52.

Maron, B. J. (2002). Hypertrophic cardiomyopathy: a systematic review. Journal of the American Medical Association, 287, 1308–1320.PubMedCrossRef

53.

Maron, B. J., Dearani, J. A., Ommen, S. R., Maron, M. S., Schaff, H. V., Gersh, B. J., et al. (2004). The case for surgery in obstructive hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 44, 2044–2053.PubMedCrossRef

54.

Maron, B. J., Doerer, J. J., Haas, T. S., Tierney, D. M., & Mueller, F. O. (2009). Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation, 119, 1085–1092.PubMedCrossRef

55.

Maron, B. J., Shen, W. K., Link, M. S., Epstein, A. E., Almquist, A. K., Daubert, J. P., et al. (2000). Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. New England Journal of Medicine, 342, 365–373.PubMedCrossRef

56.

Maron, B. J., Spirito, P., Shen, W. K., Haas, T. S., Formisano, F., Link, M. S., et al. (2007). Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. Journal of the American Medical Association, 298, 405–412.PubMedCrossRef

57.

Maron, M. S., Olivotto, I., Zenovich, A. G., Link, M. S., Pandian, N. G., Kuvin, J. T., et al. (2006). Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation, 114, 2232–2239.PubMedCrossRef

58.

Matsumura, Y., Elliott, P. M., Virdee, M. S., Sorajja, P., Doi, Y., & McKenna, W. J. (2002). Left ventricular diastolic function assessed using Doppler tissue imaging in patients with hypertrophic cardiomyopathy: relation to symptoms and exercise capacity. Heart, 87, 247–251.PubMedCrossRef

59.

McGregor, J. B., Rahman, A., Rosanio, S., Ware, D., Birnbaum, Y., & Saeed, M. (2004). Monomorphic ventricular tachycardia: a late complication of percutaneous alcohol septal ablation for hypertrophic cardiomyopathy. American Journal of the Medical Sciences, 328, 185–188.PubMedCrossRef

60.

McLeod, C. J., Ommen, S. R., Ackerman, M. J., Weivoda, P. L., Shen, W. K., Dearani, J. A., et al. (2007). Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. European Heart Journal, 28, 2583–2588.PubMedCrossRef

61.

McMahon, C. J., Nagueh, S. F., Pignatelli, R. H., Denfield, S. W., Dreyer, W. J., Price, J. F., et al. (2004). Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation, 109, 1756–1762.PubMedCrossRef

62.

McTaggart, D. R. (2004). Diltiazem reverses tissue Doppler velocity abnormalities in pre-clinical hypertrophic cardiomyopathy. Heart, Lung & Circulation, 13, 39–40.CrossRef

63.

Montgomery, D. E., Tardiff, J. C., & Chandra, M. (2001). Cardiac troponin T mutations: correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice. Journal of Physiology, 536, 583–592.PubMedCrossRef

64.

Morimoto, S., Lu, Q. W., Harada, K., Takahashi-Yanaga, F., Minakami, R., Ohta, M., et al. (2002). Ca(2+)-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 99, 913–918.PubMedCrossRef

65.

Morimoto, S., Nakaura, H., Yanaga, F., & Ohtsuki, I. (1999). Functional consequences of a carboxyl terminal missense mutation Arg278Cys in human cardiac troponin T. Biochemical and Biophysical Research Communications, 261, 79–82.PubMedCrossRef

66.

Morita, H., Seidman, J., & Seidman, C. E. (2005). Genetic causes of human heart failure. Journal of Clinical Investigation, 115, 518–526.PubMed

67.

Moriyama, T., Kawada, N., Nagatoya, K., Takeji, M., Horio, M., Ando, A., et al. (2001). Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. Kidney International, 59, 2095–2103.PubMed

68.

Nagueh, S. F., Bachinski, L. L., Meyer, D., Hill, R., Zoghbi, W. A., Tam, J. W., et al. (2001). Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation, 104, 128–130.PubMed

69.

Nagueh, S. F., Chen, S., Patel, R., Tsybouleva, N., Lutucuta, S., Kopelen, H. A., et al. (2004). Evolution of expression of cardiac phenotypes over a 4-year period in the beta-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 36, 663–673.PubMedCrossRef

70.

Nagueh, S. F., Kopelen, H. A., Lim, D. S., Zoghbi, W. A., Quinones, M. A., Roberts, R., et al. (2000). Tissue Doppler imaging consistently detects myocardial contraction and relaxation abnormalities, irrespective of cardiac hypertrophy, in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation, 102, 1346–1350.PubMed

71.

Nagueh, S. F., Lakkis, N. M., Middleton, K. J., Spencer, W. H., III, Zoghbi, W. A., & Quinones, M. A. (1999). Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation, 99, 254–261.PubMed

72.

Nakaura, H., Morimoto, S., Yanaga, F., Nakata, M., Nishi, H., Imaizumi, T., et al. (1999). Functional changes in troponin T by a splice donor site mutation that causes hypertrophic cardiomyopathy. American Journal of Physiology, 277, C225–C232.PubMed

73.

Nakaura, H., Yanaga, F., Ohtsuki, I., & Morimoto, S. (1999). Effects of missense mutations Phe110Ile and Glu244Asp in human cardiac troponin T on force generation in skinned cardiac muscle fibers. Journal of Biochemistry (Tokyo), 126, 457–460.

74.

Niimura, H., Bachinski, L. L., Sangwatanaroj, S., Watkins, H., Chudley, A. E., McKenna, W., et al. (1998). Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. New England Journal of Medicine, 338, 1248–1257.PubMedCrossRef

75.

Niimura, H., Patton, K. K., McKenna, W. J., Soults, J., Maron, B. J., Seidman, J. G., et al. (2002). Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation, 105, 446–451.PubMedCrossRef

76.

Oi, S., Haneda, T., Osaki, J., Kashiwagi, Y., Nakamura, Y., Kawabe, J., et al. (1999). Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. European Journal of Pharmacology, 376, 139–148.PubMedCrossRef

77.

Olivotto, I., Gistri, R., Petrone, P., Pedemonte, E., Vargiu, D., & Cecchi, F. (2003). Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 41, 315–321.PubMedCrossRef

78.

Ommen, S. R., Maron, B. J., Olivotto, I., Maron, M. S., Cecchi, F., Betocchi, S., et al. (2005). Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 46, 470–476.PubMedCrossRef

79.

Ommen, S. R., Shah, P. M., & Tajik, A. J. (2008). Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: past, present and future. Heart, 94, 1276–1281.PubMedCrossRef

80.

Osio, A., Tan, L., Chen, S. N., Lombardi, R., Nagueh, S. F., Shete, S., et al. (2007). Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circulation Research, 100, 766–768.PubMedCrossRef

81.

Ostman-Smith, I., Wettrell, G., & Riesenfeld, T. (1999). A cohort study of childhood hypertrophic cardiomyopathy: improved survival following high-dose beta-adrenoceptor antagonist treatment. Journal of the American College of Cardiology, 34, 1813–1822.PubMedCrossRef

82.

Patel, R., Nagueh, S. F., Tsybouleva, N., Abdellatif, M., Lutucuta, S., Kopelen, H. A., et al. (2001). Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation, 104, 317–324.PubMedCrossRef

83.

Ripplinger, C. M., Li, W., Hadley, J., Chen, J., Rothenberg, F., Lombardi, R., et al. (2007). Enhanced transmural fiber rotation and connexin 43 heterogeneity are associated with an increased upper limit of vulnerability in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation Research, 101, 1049–1057.PubMedCrossRef

84.

Rust, E. M., Albayya, F. P., & Metzger, J. M. (1999). Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins. Journal of Clinical Investigation, 103, 1459–1467.PubMedCrossRef

85.

Sarikas, A., Carrier, L., Schenke, C., Doll, D., Flavigny, J., Lindenberg, K. S., et al. (2005). Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants. Cardiovascular Research, 66, 33–44.PubMedCrossRef

86.

Sata, M., & Ikebe, M. (1996). Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome. Journal of Clinical Investigation, 98, 2866–2873.PubMedCrossRef

87.

Schiffmann, R., Murray, G. J., Treco, D., Daniel, P., Sellos-Moura, M., Myers, M., et al. (2000). Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proceedings of the National Academy of Sciences of the United States of America, 97, 365–370.PubMedCrossRef

88.

Seggewiss, H. (2001). Current status of alcohol septal ablation for patients with hypertrophic cardiomyopathy. Current Cardiology Reports, 3, 160–166.PubMedCrossRef

89.

Seggewiss, H., Gleichmann, U., Faber, L., Fassbender, D., Schmidt, H. K., & Strick, S. (1998). Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: acute results and 3-month follow-up in 25 patients. Journal of the American College of Cardiology, 31, 252–258.PubMedCrossRef

90.

Semsarian, C., Ahmad, I., Giewat, M., Georgakopoulos, D., Schmitt, J. P., McConnell, B. K., et al. (2002). The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. Journal of Clinical Investigation, 109, 1013–1020.PubMed

91.

Senthil, V., Chen, S. N., Tsybouleva, N., Halder, T., Nagueh, S. F., Willerson, J. T., et al. (2005). Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation Research, 97, 285–292.PubMedCrossRef

92.

Sherrid, M. V., Barac, I., McKenna, W. J., Elliott, P. M., Dickie, S., Chojnowska, L., et al. (2005). Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 45, 1251–1258.PubMedCrossRef

93.

Sirenko, S. G., Potter, J. D., & Knollmann, B. C. (2006). Differential effect of troponin T mutations on the inotropic responsiveness of mouse hearts—role of myofilament Ca2+ sensitivity increase. Journal of Physiology (Online), 575, 201–213.CrossRef

94.

Solaro, R. J., Varghese, J., Marian, A. J., & Chandra, M. (2002). Molecular mechanisms of cardiac myofilament activation: modulation by pH and a troponin T mutant R92Q. Basic Research in Cardiology, 97(Suppl 1), I102–I110.PubMed

95.

Sorajja, P., Valeti, U., Nishimura, R. A., Ommen, S. R., Rihal, C. S., Gersh, B. J., et al. (2008). Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation, 118, 131–139.PubMedCrossRef

96.

Spirito, P., Bellone, P., Harris, K. M., Bernabo, P., Bruzzi, P., & Maron, B. J. (2000). Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. New England Journal of Medicine, 342, 1778–1785.PubMedCrossRef

97.

Sussman, M. A., Lim, H. W., Gude, N., Taigen, T., Olson, E. N., Robbins, J., et al. (1998). Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science, 281, 1690–1693.PubMedCrossRef

98.

Sweeney, H. L., Feng, H. S., Yang, Z., & Watkins, H. (1998). Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function. Proceedings of the National Academy of Sciences of the United States of America, 95, 14406–14410.PubMedCrossRef

99.

Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G., & Potter, J. D. (2000). Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. Journal of Biological Chemistry, 275, 624–630.PubMedCrossRef

100.

Taigen, T., De Windt, L. J., Lim, H. W., & Molkentin, J. D. (2000). Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 97, 1196–1201.PubMedCrossRef

101.

Takeda, Y., Yoneda, T., Demura, M., Usukura, M., & Mabuchi, H. (2002). Calcineurin inhibition attenuates mineralocorticoid-induced cardiac hypertrophy. Circulation, 105, 677–679.PubMedCrossRef

102.

Takemoto, M., Node, K., Nakagami, H., Liao, Y., Grimm, M., Takemoto, Y., et al. (2001). Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. Journal of Clinical Investigation, 108, 1429–1437.PubMed

103.

Takimoto, E., & Kass, D. A. (2007). Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension, 49, 241–248.PubMedCrossRef

104.

Talreja, D. R., Nishimura, R. A., Edwards, W. D., Valeti, U. S., Ommen, S. R., Tajik, A. J., et al. (2004). Alcohol septal ablation versus surgical septal myectomy: comparison of effects on atrioventricular conduction tissue. Journal of the American College of Cardiology, 44, 2329–2332.PubMedCrossRef

105.

Tam, S. K., Gu, W., Mahdavi, V., & Nadal-Ginard, B. (1995). Cardiac myocyte terminal differentiation. Potential for cardiac regeneration. Annals of the New York Academy of Sciences, 752(72–9), 72–79.PubMedCrossRef

106.

Tanigawa, G., Jarcho, J. A., Kass, S., Solomon, S. D., Vosberg, H. P., Seidman, J. G., et al. (1990). A molecular basis for familial hypertrophic cardiomyopathy: an alpha/beta cardiac myosin heavy chain hybrid gene. Cell, 62, 991–998.PubMedCrossRef

107.

Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., et al. (1998). A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 101, 2800–2811.PubMedCrossRef

108.

Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., et al. (1999). Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. Journal of Clinical Investigation, 104, 469–481.PubMedCrossRef

109.

Tirouvanziam, R., Conrad, C. K., Bottiglieri, T., Herzenberg, L. A., Moss, R. B., & Herzenberg, L. A. (2006). High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proceedings of the National Academy of Sciences of the United States of America, 103, 4628–4633.PubMedCrossRef

110.

Tobacman, L. S., Lin, D., Butters, C., Landis, C., Back, N., Pavlov, D., et al. (1999). Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy. Journal of Biological Chemistry, 274, 28363–28370.PubMedCrossRef

111.

Tsybouleva, N., Zhang, L., Chen, S., Patel, R., Lutucuta, S., Nemoto, S., et al. (2004). Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation, 109, 1284–1291.PubMedCrossRef

112.

Wang, J., Wang, W., Li, R., Li, Y., Tian, G., Goodman, L., et al. (2008). The diploid genome sequence of an Asian individual. Nature, 456, 60–65.PubMedCrossRef

113.

Wheeler, D. A., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., et al. (2008). The complete genome of an individual by massively parallel DNA sequencing. Nature, 452, 872–876.PubMedCrossRef

114.

Wilcox, W. R., Banikazemi, M., Guffon, N., Waldek, S., Lee, P., Linthorst, G. E., et al. (2004). Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. American Journal of Human Genetics, 75, 65–74.PubMedCrossRef

115.

Woo, A., Williams, W. G., Choi, R., Wigle, E. D., Rozenblyum, E., Fedwick, K., et al. (2005). Clinical and echocardiographic determinants of long-term survival after surgical myectomy in obstructive hypertrophic cardiomyopathy. Circulation, 111, 2033–2041.PubMedCrossRef

116.

Xia, Z., Kuo, K. H., Nagareddy, P. R., Wang, F., Guo, Z., Guo, T., et al. (2007). N-acetylcysteine attenuates PKCbeta2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats. Cardiovascular Research, 73, 770–782.PubMedCrossRef

117.

Yamazaki, T., Suzuki, J., Shimamoto, R., Tsuji, T., Ohmoto-Sekine, Y., Ohtomo, K., et al. (2007). A new therapeutic strategy for hypertrophic nonobstructive cardiomyopathy in humans. A randomized and prospective study with an Angiotensin II receptor blocker. International Heart Journal, 48, 715–724.PubMedCrossRef

118.

Yanaga, F., Morimoto, S., & Ohtsuki, I. (1999). Ca2+ sensitization and potentiation of the maximum level of myofibrillar ATPase activity caused by mutations of troponin T found in familial hypertrophic cardiomyopathy. Journal of Biological Chemistry, 274, 8806–8812.PubMedCrossRef

119.

Zafarullah, M., Li, W. Q., Sylvester, J., & Ahmad, M. (2003). Molecular mechanisms of N-acetylcysteine actions. Cellular and Molecular Life Sciences, 60, 6–20.PubMedCrossRef

120.

Zile, M. R., Baicu, C. F., & Gaasch, W. H. (2004). Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. New England Journal of Medicine, 350, 1953–1959.PubMedCrossRef

121.

Zile, M. R., & Brutsaert, D. L. (2002). New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation, 105, 1387–1393.PubMedCrossRef

Titel: Experimental Therapies in Hypertrophic Cardiomyopathy
verfasst von: Ali J. Marian
Publikationsdatum: 01.12.2009
Verlag: Springer US
Erschienen in: Journal of Cardiovascular Translational Research / Ausgabe 4/2009
Print ISSN: 1937-5387
Elektronische ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-009-9132-7

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