Relation of functional and morphological changes in mitochondria to myocardial contractile and relaxation reserves in asymptomatic to mildly symptomatic patients with hypertrophic cardiomyopathy

AIMS To examine the relation between mitochondrial dysfunction and myocardial contractile and relaxation reserves in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS Thirty HCM patients (LVEF >or=60%) underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial (99m)Tc-sestamibi scintigraphy at rest to calculate washout rate. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The HCM patients were divided into two groups-group A: normal force-frequency relation and a pressure half-time (T(1/2)) of <30 ms (n = 15); group B: abnormal force-frequency relation or T(1/2) of >or=30 ms (n = 15). The (99m)Tc-sestamibi washout rate was significantly correlated with T(1/2) for all patients (r = 0.74, P < 0.01) and was also significantly greater in group B (29.2 +/- 6.3%) than in group A (19.3 +/- 3.1%). The abundance of mRNAs for mitochondrial electron transport-related enzymes was significantly higher in group A than in group B. Mitochondria showed a greater variation in size and were more disorganized in group B than in group A. CONCLUSION Mitochondria showed functional impairment and morphological disorganization in the left ventricle of HCM patients without baseline systolic dysfunction. These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.

[1]  M. Horie,et al.  A novel clinical indicator using Tc-99m sestamibi for evaluating cardiac mitochondrial function in patients with cardiomyopathies , 2007, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[2]  K. Okumura,et al.  Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Matrix Metalloproteinase 2–Deficient Mice , 2007, Circulation research.

[3]  Stefan Neubauer,et al.  The failing heart--an engine out of fuel. , 2007, The New England journal of medicine.

[4]  Yidong Bai,et al.  Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex , 2006, Journal of bioenergetics and biomembranes.

[5]  Richard B Devereux,et al.  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 Cardio , 2005, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[6]  H. Watkins,et al.  Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion. , 2003, Trends in genetics : TIG.

[7]  L. Leinwand,et al.  Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy. , 2003, American journal of physiology. Heart and circulatory physiology.

[8]  Gino A Cortopassi,et al.  High-throughput measurement of mitochondrial membrane potential in a neural cell line using a fluorescence plate reader. , 2002, Biochemical and biophysical research communications.

[9]  T. Takano,et al.  Assessment of myocardial washout of Tc-99m-sestamibi in patients with chronic heart failure: Comparison with normal control , 2002, Annals of nuclear medicine.

[10]  J. Marín-García,et al.  Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. , 2001, Cardiovascular research.

[11]  H. Izawa,et al.  Reduced Myocardial Sarcoplasmic Reticulum Ca2+-ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy , 2001, Circulation.

[12]  Y. Nakaya,et al.  Impaired retention of technetium-99m tetrofosmin in hypertrophic cardiomyopathy. , 2001, The American journal of cardiology.

[13]  P. Elliott,et al.  Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. , 2000, Journal of the American College of Cardiology.

[14]  B. Lorell,et al.  Contractile Reserve and Intracellular Calcium Regulation in Mouse Myocytes From Normal and Hypertrophied Failing Hearts , 2000, Circulation research.

[15]  R. Schwinger,et al.  SERCA2a activity correlates with the force-frequency relationship in human myocardium. , 2000, American journal of physiology. Heart and circulatory physiology.

[16]  R. Kapsa,et al.  Mitochondrial respiratory chain activity in idiopathic dilated cardiomyopathy. , 2000, Journal of cardiac failure.

[17]  T. Hewett,et al.  Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. , 1999, The Journal of clinical investigation.

[18]  D. Bers,et al.  Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. , 1999, Circulation research.

[19]  D. Wallace.  Mitochondrial diseases in man and mouse. , 1999, Science.

[20]  G. Comi,et al.  Coexistence of mitochondrial DNA and β myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure , 1998, Heart.

[21]  E. Arbustini,et al.  Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy. , 1998, The American journal of pathology.

[22]  T. Araki,et al.  Technetium-99m-tetrofosmin, technetium-99m-MIBI and thallium-201 uptake in rat myocardial cells. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  Y. Yoo,et al.  Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal. , 1998, Biochemistry.

[24]  W. Williams,et al.  Hypertrophic cardiomyopathy. Clinical spectrum and treatment. , 1995, Circulation.

[25]  D. Kass,et al.  Diminished Contractile Response to Increased Heart Rate in Intact Human Left Ventricular Hypertrophy Systolic Versus Diastolic Determinants , 1993, Circulation.

[26]  A. Friedl,et al.  Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. , 1991, Circulation.

[27]  J. Kronauge,et al.  Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence. , 1990, Circulation.

[28]  J. Kronauge,et al.  Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium(I) in cultured mouse fibroblasts. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[29]  B. Maron,et al.  Relation between extent of left ventricular hypertrophy and occurrence of sudden cardiac death in hypertrophic cardiomyopathy. , 1990, Journal of the American College of Cardiology.

[30]  M. Feldman,et al.  Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. , 1988, The Journal of clinical investigation.

[31]  W. Williams,et al.  Hypertrophic cardiomyopathy. The importance of the site and the extent of hypertrophy. A review. , 1985, Progress in cardiovascular diseases.

[32]  W. G. Wood,et al.  Mitochondria and sarcoplasmic reticulum function in cardiac hypertrophy and failure. , 1973, The American journal of physiology.

[33]  W. Henry,et al.  Asymmetric Septal Hypertrophy: Echocardiographic Identification of the Pathognomonic Anatomic Abnormality of IHSS , 1973, Circulation.

[34]  大島 覚.  Cardiac sympathetic dysfunction correlates with abnormal myocardial contractile reserve in dilated cardiomyopathy patients , 2008 .

[35]  R. Walsh,et al.  Modulation of force-frequency relation by phospholamban in genetically engineered mice , 1999 .

[36]  稲垣 将文.  Impaired force-frequency relations in patients with hypertensive left ventricular hypertrophy a possible physiological marker of the transition from physiological to pathological hypertrophy , 1999 .

[37]  L. B. Chen,et al.  Mitochondrial membrane potential in living cells. , 1988, Annual review of cell biology.