(Circulation. 1997;96:1991-1998.)
© 1997 American Heart Association, Inc.
Articles |
Myocardial Stiffness Is Attributed to Alterations in Cross-Linked Collagen Rather Than Total Collagen or Phenotypes in Spontaneously Hypertensive Rats
From the Laboratory of Cardiovascular Pathophysiology, Departments of Physiology and Nuclear Medicine (G.P.C.), University of the Witwatersrand Medical School, and the Medical University of South Africa (J.T.), Johannesburg.
Background The relative contributions of increases in myocardial collagen, collagen cross-linking, and the ratio of type I to type III collagen to the stiff myocardium in hypertension were determined.
Methods and Results We compared the action of hydralazine (0.07 mmol · kg-1 · d-1) with that of captopril (0.22 mmol · kg-1 · d-1) on the left ventricular end-diastolic (LVED) myocardial stiffness constant, k (g · cm-2) and LV myocardial interstitial characteristics in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) control rats. LVED k (SHR, 27.9±1; WKY, 19.5±1.2; P<.01), myocardial hydroxyproline concentrations (HPRO; µg/mg dry wt) (SHR, 4.19±0.16; WKY, 3.17±0.09; P<.001), and collagen type I/III ratios (SHR, 7.1±0.7; WKY, 2.1±0.2; P<.001) were increased, whereas the percentage of myocardial collagen extracted after cyanogen bromide digestion (an index of cross-linked collagen) was decreased (SHR, 17±3; WKY, 41±4; P<.001) in SHRs compared with WKY controls. Captopril therapy reduced LVED k, myocardial HPRO, collagen type I/III, and augmented collagen solubility (43±4) in SHRs to values similar to those measured in WKY controls. Hydralazine therapy, despite a favorable effect on LVED k in SHRs (20.±1.6, P<.01 compared with untreated SHRs), failed to influence either myocardial HPRO (4.18±0.18) or collagen type I/III (8±1) but did improve collagen solubility (31±2).
Conclusions An association between alterations in LVED k and collagen solubility but not between changes in LVED k and total collagen or phenotype ratios after antihypertensive therapy in SHRs suggests that myocardial stiffness in hypertension is the consequence of an enhanced myocardial collagen cross-linking rather than of an increase in total collagen or type I phenotype concentrations.
Key Words: collagen • hypertension • diastole
This article has been cited by other articles:
 |
|
 |
|
  K. V. Desai, G. A. Laine, R. H. Stewart, C. S. Cox Jr., C. M. Quick, S. J. Allen, and U. M. Fischer Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2428 - H2434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Georges, J.-J. Hui, Z. Gombos, M. E. McCormick, A. Y. Wang, M. Uemura, R. Mick, P. A. Janmey, E. E. Furth, and R. G. Wells Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1147 - G1154. [Abstract] [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]
|
|
|
|
 |
|
 N. Paolocci, B. Tavazzi, R. Biondi, Y. A. Gluzband, A. M. Amorini, C. G. Tocchetti, M. Hejazi, P. M. Caturegli, J. Kajstura, G. Lazzarino, et al. Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 506 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fenning, G. Harrison, R. Rose'meyer, A. Hoey, and L. Brown L-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1408 - H1416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Brown Cardiac extracellular matrix: a dynamic entity Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H973 - H974. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Klotz, R. F. Foronjy, M. L. Dickstein, A. Gu, I. M. Garrelds, A.H. Jan Danser, M. C. Oz, J. D'Armiento, and D. Burkhoff Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness Circulation, July 19, 2005; 112(3): 364 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Lindsey, D. K. Goshorn, C. E. Squires, G. P. Escobar, J. W. Hendrick, J. T. Mingoia, S. E. Sweterlitsch, and F. G. Spinale Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function Cardiovasc Res, May 1, 2005; 66(2): 410 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G.A. Veliotes, A. J. Woodiwiss, D. A.J. Deftereos, D. Gray, O. Osadchii, and G. R. Norton Aldosterone Receptor Blockade Prevents the Transition to Cardiac Pump Dysfunction Induced by {beta}-Adrenoreceptor Activation Hypertension, May 1, 2005; 45(5): 914 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Boerma, J. Wang, J. Wondergem, J. Joseph, X. Qiu, R. H. Kennedy, and M. Hauer-Jensen Influence of Mast Cells on Structural and Functional Manifestations of Radiation-Induced Heart Disease Cancer Res., April 15, 2005; 65(8): 3100 - 3107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gibbs, D. G. A. Veliotes, C. Anamourlis, D. Badenhorst, O. Osadchii, G. R. Norton, and A. J. Woodiwiss Chronic {beta}-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2762 - H2767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. H. Cingolani, X.-P. Yang, Y.-H. Liu, M. Villanueva, N.-E. Rhaleb, and O. A. Carretero Reduction of Cardiac Fibrosis Decreases Systolic Performance Without Affecting Diastolic Function in Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1067 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A Marganski, V. M De Biase, M. L Burgess, and M. Dembo Demonstration of altered fibroblast contractile activity in hypertensive heart disease Cardiovasc Res, December 1, 2003; 60(3): 547 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. McGowan, C. B. Scott, A. Mu, R. J. McCormick, D. P. Thomas, and K. B. Margulies Unloading-induced remodeling in the normal and hypertrophic left ventricle Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2061 - H2068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Herrmann, A. D. McCulloch, and J. H. Omens Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1277 - H1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K.G Koshy, H. K Reddy, and H. H Shukla Collagen cross-linking: new dimension to cardiac remodeling Cardiovasc Res, March 1, 2003; 57(3): 594 - 598. [Full Text] [PDF]
|
|
|
|
|
|
D. Badenhorst, M. Maseko, O. J Tsotetsi, A. Naidoo, R. Brooksbank, G. R Norton, and A. J Woodiwiss Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats Cardiovasc Res, March 1, 2003; 57(3): 632 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Badenhorst, D. Veliotes, M. Maseko, O. J. Tsotetsi, R. Brooksbank, A. Naidoo, A. J. Woodiwiss, and G. R. Norton {beta}-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy Hypertension, March 1, 2003; 41(3): 499 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. H. Cingolani, X.-P. Yang, M. A. Cavasin, and O. A. Carretero Increased Systolic Performance With Diastolic Dysfunction in Adult Spontaneously Hypertensive Rats Hypertension, February 1, 2003; 41(2): 249 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Cingolani, O. R. Rebolledo, E. L. Portiansky, N. G. Perez, and M. C. Camilion de Hurtado Regression of Hypertensive Myocardial Fibrosis by Na+/H+ Exchange Inhibition Hypertension, February 1, 2003; 41(2): 373 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamamoto, T. Masuyama, Y. Sakata, N. Nishikawa, T. Mano, J. Yoshida, T. Miwa, M. Sugawara, Y. Yamaguchi, T. Ookawara, et al. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart Cardiovasc Res, July 1, 2002; 55(1): 76 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Camilion de Hurtado, E. L. Portiansky, N. G. Perez, O. R. Rebolledo, and H. E. Cingolani Regression of cardiomyocyte hypertrophy in SHR following chronic inhibition of the Na+/H+ exchanger Cardiovasc Res, March 1, 2002; 53(4): 862 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. Tsotetsi, A. J. Woodiwiss, M. Netjhardt, D. Qubu, R. Brooksbank, and G. R. Norton Attenuation of Cardiac Failure, Dilatation, Damage, and Detrimental Interstitial Remodeling Without Regression of Hypertrophy in Hypertensive Rats Hypertension, October 1, 2001; 38(4): 846 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Y. Li, Y. Feng, C. F. McTiernan, W. Pei, C. S. Moravec, P. Wang, W. Rosenblum, R. L. Kormos, and A. M. Feldman Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices Circulation, September 4, 2001; 104(10): 1147 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Woodiwiss, O. J. Tsotetsi, S. Sprott, E. J. Lancaster, T. Mela, E. S. Chung, T. E. Meyer, and G. R. Norton Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction Circulation, January 2, 2001; 103(1): 155 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Y. Li, Y. Q. Feng, T. Kadokami, C. F. McTiernan, R. Draviam, S. C. Watkins, and A. M. Feldman Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy PNAS, November 7, 2000; 97(23): 12746 - 12751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Weis, J. L. Emery, K. D. Becker, D. J. McBride Jr, J. H. Omens, and A. D. McCulloch Myocardial Mechanics and Collagen Structure in the Osteogenesis Imperfecta Murine (oim) Circ. Res., October 13, 2000; 87(8): 663 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Thomas, S. D. Zimmerman, T. R. Hansen, D. T. Martin, and R. J. McCormick Collagen gene expression in rat left ventricle: interactive effect of age and exercise training J Appl Physiol, October 1, 2000; 89(4): 1462 - 1468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Y. Li, C. F. McTiernan, and A. M. Feldman Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling Cardiovasc Res, May 1, 2000; 46(2): 214 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Woodiwiss, B. Trifunovic, M. Philippides, and G. R. Norton Effects of an androgenic steroid on exercise-induced cardiac remodeling in rats J Appl Physiol, February 1, 2000; 88(2): 409 - 415. [Abstract] [Full Text] [PDF]
|
|