This Article Full Text Full Text (PDF) Previous Version of This Article All Versions of this Article: 112/3/364    most recent CIRCULATIONAHA.104.515106v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klotz, S. Articles by Burkhoff, D. Search for Related Content PubMed PubMed Citation Articles by Klotz, S. Articles by Burkhoff, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Structure Biochemistry and metabolism Other myocardial biology Congestive CV surgery: transplantation, ventricular assistance, cardiomyopathy

(Circulation. 2005;112:364-374.)
© 2005 American Heart Association, Inc.

Heart Failure

Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness

Stefan Klotz, MD; Robert F. Foronjy, MD; Marc L. Dickstein, MD; Anguo Gu, MD; Ingrid M. Garrelds, PhD; A.H. Jan Danser, PhD; Mehmet C. Oz, MD; Jeanine D’Armiento, MD, PhD; Daniel Burkhoff, MD, PhD

From the Departments of Medicine (S.K., R.F.F., A.G., J.D., D.B.), Anesthesiology (M.L.D.), and Surgery (M.C.O.), College of Physicians and Surgeons, Columbia University, New York, NY, and Department of Pharmacology (I.M.G, A.H.J.D.), Erasmus Medical Center, Rotterdam, the Netherlands.

Correspondence to Daniel Burkhoff, MD, PhD, Division of Cardiology, Department of Medicine, Columbia University, 177 Ft Washington Ave, MHB5-435, New York, NY 10032. E-mail db59{at}columbia.edu

Received July 24, 2004; de novo received October 18, 2004; revision received February 3, 2005; accepted March 17, 2005.

Background— Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown.

Methods and Results— Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145±33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (P<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (P<0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM.

Conclusions— LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1–to–TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes.

Key Words: cardiomyopathy • collagen • heart-assist devices • heart failure • metalloproteinases

This article has been cited by other articles:

				R. Foronjy, T. Nkyimbeng, A. Wallace, J. Thankachen, Y. Okada, V. Lemaitre, and J. D'Armiento Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1149 - L1157. [Abstract] [Full Text] [PDF]

				Y. Yang, Y. Ma, W. Han, J. Li, Y. Xiang, F. Liu, X. Ma, J. Zhang, Z. Fu, Y.-D. Su, et al. Age-related differences in postinfarct left ventricular rupture and remodeling Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1815 - H1822. [Abstract] [Full Text] [PDF]

				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				L. S. Spruill, A. S. Lowry, R. E. Stroud, C. E. Squires, I. M. Mains, E. C. Flack, C. Beck, J. S. Ikonomidis, A. J. Crumbley, P. J. McDermott, et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1362 - C1373. [Abstract] [Full Text] [PDF]

				S. Maybaum, D. Mancini, S. Xydas, R. C. Starling, K. Aaronson, F. D. Pagani, L. W. Miller, K. Margulies, S. McRee, O.H. Frazier, et al. Cardiac Improvement During Mechanical Circulatory Support: A Prospective Multicenter Study of the LVAD Working Group Circulation, May 15, 2007; 115(19): 2497 - 2505. [Abstract] [Full Text] [PDF]

				A. H. Jan Danser, W. W. Batenburg, and J. H. M. van Esch Prorenin and the (pro)renin receptor--an update Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1288 - 1292. [Full Text] [PDF]

				R. Suzuki, T.-S. Li, A. Mikamo, M. Takahashi, M. Ohshima, M. Kubo, H. Ito, and K. Hamano The reduction of hemodynamic loading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing stem-cell recruitment J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 1051 - 1058. [Abstract] [Full Text] [PDF]

				S. Klotz, A.H. J. Danser, R. F. Foronjy, M. C. Oz, J. Wang, D. Mancini, J. D'Armiento, and D. Burkhoff The Impact of Angiotensin-Converting Enzyme Inhibitor Therapy on the Extracellular Collagen Matrix During Left Ventricular Assist Device Support in Patients With End-Stage Heart Failure J. Am. Coll. Cardiol., March 20, 2007; 49(11): 1166 - 1174. [Abstract] [Full Text] [PDF]

				B. I. Jugdutt and C. Butler Ventricular Unloading, Tissue Angiotensin II, Matrix Modulation, and Function During Left Ventricular Assist Device Support J. Am. Coll. Cardiol., March 20, 2007; 49(11): 1175 - 1177. [Full Text] [PDF]

				D. Vanhoutte, M. W.M. Schellings, M. Gotte, M. Swinnen, V. Herias, M. K. Wild, D. Vestweber, E. Chorianopoulos, V. Cortes, A. Rigotti, et al. Increased Expression of Syndecan-1 Protects Against Cardiac Dilatation and Dysfunction After Myocardial Infarction Circulation, January 30, 2007; 115(4): 475 - 482. [Abstract] [Full Text] [PDF]

				D. G. Renlund and A. G. Kfoury When the Failing, End-Stage Heart Is Not End-Stage N. Engl. J. Med., November 2, 2006; 355(18): 1922 - 1925. [Full Text] [PDF]

				G. L. Brower, J. D. Gardner, M. F. Forman, D. B. Murray, T. Voloshenyuk, S. P. Levick, and J. S. Janicki The relationship between myocardial extracellular matrix remodeling and ventricular function. Eur. J. Cardiothorac. Surg., October 1, 2006; 30(4): 604 - 610. [Abstract] [Full Text] [PDF]