Creatine Kinase Adenosine Triphosphate and Phosphocreatine Energy Supply in a Single Kindred of Patients With Hypertrophic Cardiomyopathy

      A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 ± 2.3 μmol/g) compared with the controls (9.4 ± 1.2 μmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 ± 0.15 vs 0.38 ± 0.07 s−1, p = 0.035) and the forward CK flux was 44% lower (2.0 ± 1.4 vs 3.6 ± 0.9 μmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Maron B.J.
        Hypertrophic cardiomyopathy: a systematic review.
        JAMA. 2002; 287: 1308-1320
        • 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; 62: 999-1006
        • Spindler M.
        • Saupe K.W.
        • Christe M.E.
        • Sweeney H.L.
        • Seidman C.E.
        • Seidman J.G.
        • Ingwall J.S.
        Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy.
        J Clin Invest. 1998; 101: 1775-1783
        • Rosenzweig A.
        • Watkins H.
        • Hwang D.S.
        • Miri M.
        • McKenna W.
        • Traill T.A.
        • Seidman J.G.
        • Seidman C.E.
        Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes.
        N Engl J Med. 1991; 325: 1753-1760
        • Bottomley P.A.
        • Ouwerkerk R.
        • Lee R.F.
        • Weiss R.G.
        Four-angle saturation transfer (FAST) method for measuring creatine kinase reaction rates in vivo.
        Magn Reson Med. 2002; 47: 850-863
        • Smith C.S.
        • Bottomley P.A.
        • Schulman S.P.
        • Gerstenblith G.
        • Weiss R.G.
        Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium.
        Circulation. 2006; 114: 1151-1158
        • Weiss R.G.
        • Gerstenblith G.
        • Bottomley P.A.
        ATP flux through creatine kinase in the normal, stressed, and failing human heart.
        Proc Natl Acad Sci U S A. 2005; 102: 808-813
        • Gabr R.E.
        • Weiss R.G.
        • Bottomley P.A.
        Correcting reaction rates measured by saturation-transfer magnetic resonance spectroscopy.
        J Magn Reson. 2008; 191: 248-258
        • Bottomley P.A.
        • Atalar E.
        • Weiss R.G.
        Human cardiac high-energy phosphate metabolite concentrations by 1D-resolved NMR spectroscopy.
        Magn Reson Med. 1996; 35: 664-670
        • Bottomley P.A.
        • Hardy C.J.
        • Roemer P.B.
        Phosphate metabolite imaging and concentration measurements in human heart by nuclear magnetic resonance.
        Magn Reson Med. 1990; 14: 425-434
        • Hirsch G.A.
        • Bottomley P.A.
        • Gerstenblith G.
        • Weiss R.G.
        Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts.
        J Am Coll Cardiol. 2012; 59: 802-808
        • Bottomley P.A.
        NMR spectroscopy of the human heart.
        in: Harris R.K. Wasylishen R.E. Encyclopedia of Magnetic Resonance. John Wiley, Chichester2009
        • Gibbs C.
        The cytoplasmic phosphorylation potential: its possible role in the control of myocardial respiration and cardiac contractility.
        J Mol Cell Cardiol. 1985; 17: 727-731
        • Devereux R.B.
        • Alonso D.R.
        • Lutas E.M.
        • Gottlieb G.J.
        • Campo E.
        • Sachs I.
        • Reichek N.
        Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.
        Am J Cardiol. 1986; 57: 450-458
        • Schiller N.B.
        • Shah P.M.
        • Crawford M.
        • DeMaria A.
        • Devereux R.
        • Feigenbaum H.
        • Gutgesell H.
        • Reichek N.
        • Sahn D.
        • Schnittger I.
        • Silverman N.H.
        • Tajik A.J.
        Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.
        J Am Soc Echocardiogr. 1989; 2: 358-367
        • Lang R.M.
        • Bierig M.
        • Devereux R.B.
        • Flachskampf F.A.
        • Foster E.
        • Pellikka P.A.
        • Picard M.H.
        • Roman M.J.
        • Seward J.
        • Shanewise J.S.
        • Solomon S.D.
        • Spencer K.T.
        • Sutton M.S.
        • Stewart W.J.
        Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
        J Am Soc Echocardiogr. 2005; 18: 1440-1463
        • Dalen H.
        • Thorstensen A.
        • Aase S.A.
        • Ingul C.B.
        • Torp H.
        • Vatten L.J.
        • Stoylen A.
        Segmental and global longitudinal strain and strain rate based on echocardiography of 1266 healthy individuals: the HUNT study in Norway.
        Eur J Echocardiogr. 2010; 11: 176-183
        • Nagueh S.F.
        • Appleton C.P.
        • Gillebert T.C.
        • Marino P.N.
        • Oh J.K.
        • Smiseth O.A.
        • Waggoner A.D.
        • Flachskampf F.A.
        • Pellikka P.A.
        • Evangelisa A.
        Recommendations for the evaluation of left ventricular diastolic function by echocardiography.
        Eur J Echocardiogr. 2009; 10: 165-193
        • Jung W.I.
        • Sieverding L.
        • Breuer J.
        • Hoess T.
        • Widmaier S.
        • Schmidt O.
        • Bunse M.
        • van Erckelens F.
        • Apitz J.
        • Lutz O.
        • Dietze G.J.
        31P NMR spectroscopy detects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy.
        Circulation. 1998; 97: 2536-2542
        • Cuda G.
        • Fananapazir L.
        • Epstein N.D.
        • Sellers J.R.
        The in vitro motility activity of beta-cardiac myosin depends on the nature of the beta-myosin heavy chain gene mutation in hypertrophic cardiomyopathy.
        J Muscle Res Cell Motil. 1997; 18: 275-283
        • 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; 269: 1603-1605
        • Ingwall J.S.
        • Weiss R.G.
        Is the failing heart energy starved? On using chemical energy to support cardiac function.
        Circ Res. 2004; 95: 135-145
        • Ingwall J.S.
        • Kramer M.F.
        • Fifer M.A.
        • Lorell B.H.
        • Shemin R.
        • Grossman W.
        • Allen P.D.
        The creatine kinase system in normal and diseased human myocardium.
        N Engl J Med. 1985; 313: 1050-1054
        • Wallimann T.
        • Dolder M.
        • Schlattner U.
        • Eder M.
        • Hornemann T.
        • O'Gorman E.
        • Ruck A.
        • Brdiczka D.
        Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology.
        Biofactors. 1998; 8: 229-234
        • Abraham M.R.
        • Selivanov V.A.
        • Hodgson D.M.
        • Pucar D.
        • Zingman L.V.
        • Wieringa B.
        • Dzeja P.P.
        • Alekseev A.E.
        • Terzic A.
        Coupling of cell energetics with membrane metabolic sensing. Integrative signaling through creatine kinase phosphotransfer disrupted by M-CK gene knock-out.
        J Biol Chem. 2002; 277: 24427-24434
        • Wallimann T.
        • Wyss M.
        • Brdiczka D.
        • Nicolay K.
        • Eppenberger H.M.
        Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the “phosphocreatine circuit” for cellular energy homeostasis.
        Biochem J. 1992; 281: 21-40
        • Ingwall J.S.
        Energy metabolism in heart failure and remodelling.
        Cardiovasc Res. 2009; 81: 412-419
        • Tian R.
        • Christe M.E.
        • Spindler M.
        • Hopkins J.C.
        • Halow J.M.
        • Camacho S.A.
        • Ingwall J.S.
        Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart.
        J Clin Invest. 1997; 99: 745-751
        • Okada M.
        • Mitsunami K.
        • Inubushi T.
        • Kinoshita M.
        Influence of aging or left ventricular hypertrophy on the human heart: contents of phosphorus metabolites measured by 31P MRS.
        Magn Reson Med. 1998; 39: 772-782
        • Jung W.I.
        • Hoess T.
        • Bunse M.
        • Widmaier S.
        • Sieverding L.
        • Breuer J.
        • Apitz J.
        • Schmidt O.
        • van Erckelens F.
        • Dietze G.J.
        • Lutz O.
        Differences in cardiac energetics between patients with familial and nonfamilial hypertrophic cardiomyopathy.
        Circulation. 2000; 101: E121