Circulation. 2003;108:929-932
Published online before print August 18, 2003, doi: 10.1161/01.CIR.0000088782.99568.CA
Published online before print August 18, 2003, doi: 10.1161/01.CIR.0000088782.99568.CA
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;108:929.)
© 2003 American Heart Association, Inc.
Brief Rapid Communications |
Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart
From the Division of Cardiology, Department of Medicine (D.S., C.L., M.L., R.T., D.D., G.T., D.A.K.), Johns Hopkins University, Baltimore, Md; and the National Heart, Lung and Blood Institute/Laboratory of Cardiac Energetics (O.F., E.M.), National Institutes of Health, Bethesda, Md.
Correspondence to David A. Kass, Halsted 500, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass{at}jhmi.edu
Received January 27, 2003; de novo received May 27, 2003; revision received July 14, 2003; accepted July 18, 2003.
Background— Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility.
Methods and Results— Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial–paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression.
Conclusions— LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.
Key Words: heart failure • pacing • molecular biology • sarcoplasmic reticulum
This article has been cited by other articles:
 |
|
 |
|
  M. Miura, Y. Wakayama, H. Endoh, M. Nakano, Y. Sugai, M. Hirose, H. E. ter Keurs, and H. Shimokawa Spatial non-uniformity of excitation-contraction coupling can enhance arrhythmogenic-delayed afterdepolarizations in rat cardiac muscle Cardiovasc Res, July 3, 2008; (2008) cvn162v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Auricchio and F. W. Prinzen Update on the pathophysiological basics of cardiac resynchronization therapy Europace, July 1, 2008; 10(7): 797 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Sweeney and F. W. Prinzen Ventricular Pump Function and Pacing: Physiological and Clinical Integration Circ Arrhythmia Electrophysiol, June 1, 2008; 1(2): 127 - 139. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chakir, S. K. Daya, R. S. Tunin, R. H. Helm, M. J. Byrne, V. L. Dimaano, A. C. Lardo, T. P. Abraham, G. F. Tomaselli, and D. A. Kass Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization Circulation, March 18, 2008; 117(11): 1369 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Vanderheyden, W. Mullens, L. Delrue, M. Goethals, B. de Bruyne, W. Wijns, P. Geelen, S. Verstreken, F. Wellens, and J. Bartunek Myocardial Gene Expression in Heart Failure Patients Treated With Cardiac Resynchronization Therapy: Responders Versus Nonresponders J. Am. Coll. Cardiol., January 15, 2008; 51(2): 129 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Leclercq Upgrading from right ventricular pacing to biventricular pacing in pacemaker patients with chronic heart failure Heart, January 1, 2008; 94(1): 102 - 107. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Byrne, R. H. Helm, S. Daya, N. F. Osman, H. R. Halperin, R. D. Berger, D. A. Kass, and A. C. Lardo Diminished Left Ventricular Dyssynchrony and Impact of Resynchronization in Failing Hearts With Right Versus Left Bundle Branch Block J. Am. Coll. Cardiol., October 9, 2007; 50(15): 1484 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Europace, October 1, 2007; 9(10): 959 - 998. [Full Text] [PDF]
|
|
|
|
 |
|
 Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Eur. Heart J., September 2, 2007; 28(18): 2256 - 2295. [Full Text] [PDF]
|
|
|
|
|
|
K. Vernooy, R. N.M. Cornelussen, X. A.A.M. Verbeek, W. Y.R. Vanagt, A. van Hunnik, M. Kuiper, T. Arts, H. J.G.M. Crijns, and F. W. Prinzen Cardiac resynchronization therapy cures dyssynchronopathy in canine left bundle-branch block hearts Eur. Heart J., September 1, 2007; 28(17): 2148 - 2155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Akar, R. D. Nass, S. Hahn, E. Cingolani, M. Shah, G. G. Hesketh, D. DiSilvestre, R. S. Tunin, D. A. Kass, and G. F. Tomaselli Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1223 - H1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Stellbrink It's the metabolism, stupid! Why electrophysiologists should be interested in biomarkers of heart failure Eur. Heart J., July 1, 2007; 28(13): 1541 - 1542. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Helm, M. Byrne, P. A. Helm, S. K. Daya, N. F. Osman, R. Tunin, H. R. Halperin, R. D. Berger, D. A. Kass, and A. C. Lardo Three-Dimensional Mapping of Optimal Left Ventricular Pacing Site for Cardiac Resynchronization Circulation, February 27, 2007; 115(8): 953 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Saxon, M. R. Bristow, J. Boehmer, S. Krueger, D. A. Kass, T. De Marco, P. Carson, L. DiCarlo, A. M. Feldman, E. Galle, et al. Predictors of Sudden Cardiac Death and Appropriate Shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial Circulation, December 19, 2006; 114(25): 2766 - 2772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. C. Bilchick, S. K. Saha, E. Mikolajczyk, L. Cope, W. J. Ferguson, W. Yu, S. Girouard, and D. A. Kass Differential regional gene expression from cardiac dyssynchrony induced by chronic right ventricular free wall pacing in the mouse Physiol Genomics, September 14, 2006; 26(2): 109 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kuramochi, X. Guo, D. B. Sawyer, and C. C. Lim Rapid electrical stimulation induces early activation of kinase signal transduction pathways and apoptosis in adult rat ventricular myocytes Exp Physiol, July 1, 2006; 91(4): 773 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Donal, C. Leclercq, C. Linde, and J.-C. Daubert Effects of cardiac resynchronization therapy on disease progression in chronic heart failure Eur. Heart J., May 1, 2006; 27(9): 1018 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Lindner, J. Sorensen, J. Vogt, E. Fricke, D. Baller, D. Horstkotte, and W. Burchert Cardiac Efficiency and Oxygen Consumption Measured with 11C-Acetate PET After Long-Term Cardiac Resynchronization Therapy J. Nucl. Med., March 1, 2006; 47(3): 378 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Wiegerinck, A. O. Verkerk, C. N. Belterman, T. A.B. van Veen, A. Baartscheer, T. Opthof, R. Wilders, J. M.T. de Bakker, and R. Coronel Larger Cell Size in Rabbits With Heart Failure Increases Myocardial Conduction Velocity and QRS Duration Circulation, February 14, 2006; 113(6): 806 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O. Sweeney and F. W. Prinzen A New Paradigm for Physiologic Ventricular Pacing J. Am. Coll. Cardiol., January 17, 2006; 47(2): 282 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Rosen and I. S. Cohen Cardiac memory ... new insights into molecular mechanisms J. Physiol., January 15, 2006; 570(2): 209 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Smiseth and E. W. Remme Regional Left Ventricular Electric and Mechanical Activation and Relaxation J. Am. Coll. Cardiol., January 3, 2006; 47(1): 173 - 174. [Full Text] [PDF]
|
|
|
|
|
|
C. D'Ascia, A. Cittadini, M. G. Monti, G. Riccio, and L. Sacca Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-{alpha} expression, and apoptotic death in failing human myocardium Eur. Heart J., January 2, 2006; 27(2): 201 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dilaveris, A. Pantazis, G. Giannopoulos, A. Synetos, J. Gialafos, and C. Stefanadis Upgrade to biventricular pacing in patients with pacing-induced heart failure: can resynchronization do the trick? Europace, January 1, 2006; 8(5): 352 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Fallavollita, B. J. Riegel, G. Suzuki, U. Valeti, and J. M. Canty Jr. Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2688 - H2696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Patberg, M. N. Obreztchikova, S. F. Giardina, A. J. Symes, A. N. Plotnikov, J. Qu, P. Chandra, D. McKinnon, S. R. Liou, A. V. Rybin, et al. The cAMP response element binding protein modulates expression of the transient outward current: Implications for cardiac memory Cardiovasc Res, November 1, 2005; 68(2): 259 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Desideri, L. Cortigiani, A. I. Christen, S. Coscarelli, D. Gregori, P. Zanco, R. Komorovsky, and J. J. Bax The Extent of Perfusion-F18-Fluorodeoxyglucose Positron Emission Tomography Mismatch Determines Mortality in Medically Treated Patients With Chronic Ischemic Left Ventricular Dysfunction J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1264 - 1269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ando, R. G. Katare, Y. Kakinuma, D. Zhang, F. Yamasaki, K. Muramoto, and T. Sato Efferent Vagal Nerve Stimulation Protects Heart Against Ischemia-Induced Arrhythmias by Preserving Connexin43 Protein Circulation, July 12, 2005; 112(2): 164 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Spragg, F. G. Akar, R. H. Helm, R. S. Tunin, G. F. Tomaselli, and D. A. Kass Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts Cardiovasc Res, July 1, 2005; 67(1): 77 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Stellbrink Heart rate, regularity, and synchronicity in heart failure: a tale of three brothers Eur. Heart J., April 1, 2005; 26(7): 637 - 638. [Full Text] [PDF]
|
|
|
|
|
|
N. Preumont, J.-L. Jansens, G. Berkenboom, P. van de Borne, E. Stoupel, and S. Goldman Effects of right ventricular pacing on regional myocardial glucose metabolism Europace, January 1, 2005; 7(6): 584 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Danik, F. Liu, J. Zhang, H. J. Suk, G. E. Morley, G. I. Fishman, and D. E. Gutstein Modulation of Cardiac Gap Junction Expression and Arrhythmic Susceptibility Circ. Res., November 12, 2004; 95(10): 1035 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E.J. Teunissen, H. J. Jongsma, and M. F.A. Bierhuizen Regulation of myocardial connexins during hypertrophic remodelling Eur. Heart J., November 2, 2004; 25(22): 1979 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nahlawi, M. Waligora, S. M. Spies, R. O. Bonow, A. H. Kadish, and J. J. Goldberger Left ventricular function during and after right ventricular pacing J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1883 - 1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Moss The heart does not have Alzheimer's disease: Electrical and mechanical cardiac memory after ventricular pacing J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1889 - 1890. [Full Text] [PDF]
|
|
|
|
|
|
F. G. Akar, D. D. Spragg, R. S. Tunin, D. A. Kass, and G. F. Tomaselli Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy Circ. Res., October 1, 2004; 95(7): 717 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Peschar, K. Vernooy, R. N Cornelussen, X. A.A.M Verbeek, R. S Reneman, M. A Vos, and F. W Prinzen Structural, electrical and mechanical remodeling of the canine heart in AV-block and LBBB Eur. Heart J. Suppl., August 1, 2004; 6(suppl_D): D61 - D65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Auricchio and C M Yu Beyond the measurement of QRS complex toward mechanical dyssynchrony: cardiac resynchronisation therapy in heart failure patients with a normal QRS duration Heart, May 1, 2004; 90(5): 479 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Leclercq and J. M. Hare Ventricular Resynchronization: Current State of the Art Circulation, January 27, 2004; 109(3): 296 - 299. [Full Text] [PDF]
|
|
|
|
|
|
A. Auricchio and W. T. Abraham Cardiac Resynchronization Therapy: Current State of the Art: Cost Versus Benefit Circulation, January 27, 2004; 109(3): 300 - 307. [Full Text] [PDF]
|
|