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

Abstract

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⁻¹vs. 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.

Keywords

familial hypertrophic cardiomyopathy / transgenic mice / age-related

References

[1] SeidmanCE, SeidmanJG. Molecular genetic studies of familial hypertrophic cardiomyopathy. Basic Res Cardiol, 1998, 93(Suppl3): 13-16

[2] MaronBJ. Hypertrophic cardiomyopathy: a systematic review. JAMA, 2002, 287(10): 1308-1320

[3] HernandezOM, HousmansPR, PotterJD. 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

[4] MarianAJ, RobertsR. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol, 2001, 33(4): 655-670

[5] MorimotoS. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res, 2008, 77(4): 659-666

[6] TsoutsmanT, BagnallRD, SemsarianC. Impact of multiple gene mutations in determining the severity of cardiomyopathy and heart failure. Clin Exp Pharmacol Physiol, 2008, 35(11): 1349-1357

[7] RedwoodCS, Moolman-SmookJC, WatkinsH. Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy. Cardiovasc Res, 1999, 44(1): 20-36

[8] WatkinsH, McKennaWJ, ThierfelderL, 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

[9] WatkinsH, RosenzweigA, HwangDS, et al.. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med, 1992, 326(17): 1108-1114

[10] Geisterfer-LowranceAA, ChristeM, ConnerDA, et al.. A mouse model of familial hypertrophic cardiomyopathy. Science, 1996, 272(5262): 731-734

[11] GeorgakopoulosD, ChristeME, GiewatM, 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

[12] McConnellBK, FatkinD, SemsarianC, et al.. Comparison of two murine models of familial hypertrophic cardiomyopathy. Circ Res, 2001, 88(4): 383-389

[13] VikstromKL, FactorSM, LeinwandLA. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy. Mol Med, 1996, 2(5): 556-567

[14] de SimoneG, WallersonDC, VolpeM, 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

[15] NishimuraRA, AppletonCP, RedfieldMM. 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

[16] BauerM, ChengS, JainM, et al.. Echocardiographic speckle-tracking based strain imaging for rapid cardiovascular phenotyping in mice. Circ Res, 2011, 108(8): 908-916

[17] DevereuxRB, AlonsoDR, LutasEM, et al.. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol, 1986, 57(6): 450-458

[18] PavlopoulosH, NihoyannopoulosP. Strain and strain rate deformation parameters: from tissue Doppler to 2D speckle tracking. Int J Cardiovasc Imaging, 2008, 24(5): 479-491

[19] PiratB, McCullochML, ZoghbiWA. 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

[20] KorinekJ, WangJ, SenguptaPP, 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

[21] LangelandS, D’HoogeJ, WoutersPF, 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

[22] LeitmanM, LysyanskyP, SidenkoS, 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

[23] SerriK, ReantP, LafitteM, 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

[24] WangQ, MoncmanCL, WinkelmannDA. Mutations in the motor domain modulate myosin activity and myofibril organization. J Cell Sci, 2003, 116(Pt20): 4227-4238

[25] KimSJ, IizukaK, KellyRA, et al.. An alpha-cardiac myosin heavy chain gene mutation impairs contraction and relaxation function of cardiac myocytes. Am J Physiol, 1999, 276(5Pt2): H1780-1787

[26] TyskaMJ, HayesE, GiewatM, 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

[27] SeidmanJG, SeidmanC. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell, 2001, 104(4): 557-567

[28] FerransVJ, MorrowAG, RobertsWC. 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

[29] SpindlerM, SaupeKW, ChristeME, et al.. Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Clin Invest, 1998, 101(8): 1775-1783

[30] SemsarianC, AhmadI, GiewatM, et al.. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest, 2002, 109(8): 1013-1020

[31] LouieEK, EdwardsLC3rd. Hypertrophic cardiomyopathy. Prog Cardiovasc Dis, 1994, 36(4): 275-308

[32] MaronBJ, McKennaWJ, DanielsonGK, 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

[33] PinamontiB, Di LenardaA, NuciforaG, et al.. Incremental prognostic value of restrictive filling pattern in hypertrophic cardiomyopathy: a Doppler echocardiographic study. Eur J Echocardiogr, 2008, 9(4): 466-471

[34] FactorSM, ButanyJ, SoleMJ, 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

[35] ShahPM. Hypertrophic cardiomyopathy and diastolic dysfunction. J Am Coll Cardiol, 2003, 42(2): 286-297

[36] GwathmeyJK, WarrenSE, BriggsGM, et al.. Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J Clin Invest, 1991, 87(3): 1023-1031

[37] CannonRO3rd, SchenkeWH, MaronBJ, 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

[38] BetocchiS, HessOM, LosiMA, et al.. Regional left ventricular mechanics in hypertrophic cardiomyopathy. Circulation, 1993, 88(5Pt1): 2206-2214

[39] RajivC, VinereanuD, FraserAG. Tissue Doppler imaging for the evaluation of patients with hypertrophic cardiomyopathy. Curr Opin Cardiol, 2004, 19(5): 430-436

[40] KoyamaJ, Ray-SequinPA, FalkRH. 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

[41] BellaviaD, PellikkaPA, AbrahamTP, 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