Circulation, Vol 83, 1849-1865, Copyright © 1991 by American Heart Association
KT Weber and CG Brilla
Left ventricular hypertrophy (LVH) is the major risk factor associated with
myocardial failure. An explanation for why a presumptive adaptation such as
LVH would prove pathological has been elusive. Insights into the impairment
in contractility of the hypertrophied myocardium have been sought in the
biochemistry of cardiac myocyte contraction. Equally compelling is a
consideration of abnormalities in myocardial structure that impair organ
contractile function while preserving myocyte contractility. For example,
in the LVH that accompanies hypertension, the extracellular space is
frequently the site of an abnormal accumulation of fibrillar collagen. This
reactive and progressive interstitial and perivascular fibrosis accounts
for abnormal myocardial stiffness and ultimately ventricular dysfunction
and is likely a result of cardiac fibroblast growth and enhanced collagen
synthesis. The disproportionate involvement of this nonmyocyte cell,
however, is not a uniform accompaniment to myocyte hypertrophy and LVH,
suggesting that the growth of myocyte and nonmyocyte cells is independent
of each other. This has now been demonstrated in in vivo studies of
experimental hypertension in which the abnormal fibrous tissue response was
found in the hypertensive, hypertrophied left ventricle as well as in the
normotensive, nonhypertrophied right ventricle. These findings further
suggest that a circulating substance that gained access to the common
coronary circulation of the ventricles was involved. This hypothesis has
been tested in various animal models in which plasma concentrations of
angiotensin II and aldosterone were varied. Based on morphometric and
morphological findings, it can be concluded that arterial hypertension
(i.e., an elevation in coronary perfusion pressure) together with elevated
circulating aldosterone are associated with cardiac fibroblast involvement
and the resultant heterogeneity in tissue structure. Nonmyocyte cells of
the cardiac interstitium represent an important determinant of pathological
LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and
long- term (e.g., mitosis) responses of cardiac fibroblasts require further
investigation and integration of in vitro with in vivo studies. The stage
is set, however, to prevent pathological LVH resulting from myocardial
fibrosis as well as to reverse it.
ARTICLES
Pathological hypertrophy and cardiac interstitium. Fibrosis and renin- angiotensin-aldosterone system
Division of Cardiology, University of Missouri-Columbia, Columbia 65212.
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J E Toblli, G Cao, G DeRosa, and P Forcada Reduced cardiac expression of plasminogen activator inhibitor 1 and transforming growth factor {beta}1 in obese Zucker rats by perindopril Heart, January 1, 2005; 91(1): 80 - 86. [Abstract] [Full Text] [PDF]
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P. Camelliti, T. K. Borg, and P. Kohl Structural and functional characterisation of cardiac fibroblasts Cardiovasc Res, January 1, 2005; 65(1): 40 - 51. [Abstract] [Full Text] [PDF]
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K. Chen, J. L. Mehta, D. Li, L. Joseph, and J. Joseph Transforming Growth Factor {beta} Receptor Endoglin Is Expressed in Cardiac Fibroblasts and Modulates Profibrogenic Actions of Angiotensin II Circ. Res., December 10, 2004; 95(12): 1167 - 1173. [Abstract] [Full Text] [PDF]
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K. Funabiki, K. Onishi, K. Dohi, T. Koji, K. Imanaka-Yoshida, M. Ito, H. Wada, N. Isaka, T. Nobori, and T. Nakano Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2487 - H2492. [Abstract] [Full Text] [PDF]
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R. Kawakami, Y. Saito, I. Kishimoto, M. Harada, K. Kuwahara, N. Takahashi, Y. Nakagawa, M. Nakanishi, K. Tanimoto, S. Usami, et al. Overexpression of Brain Natriuretic Peptide Facilitates Neutrophil Infiltration and Cardiac Matrix Metalloproteinase-9 Expression After Acute Myocardial Infarction Circulation, November 23, 2004; 110(21): 3306 - 3312. [Abstract] [Full Text] [PDF]
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K. Chen, J. Chen, D. Li, X. Zhang, and J. L. Mehta Angiotensin II Regulation of Collagen Type I Expression in Cardiac Fibroblasts: Modulation by PPAR-{gamma} Ligand Pioglitazone Hypertension, November 1, 2004; 44(5): 655 - 661. [Abstract] [Full Text] [PDF]
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J. M. McCurley, S. U. Hanlon, S.-k. Wei, E. F. Wedam, M. Michalski, and M. C. Haigney Furosemide and the progression of left ventricular dysfunction in experimental heart failure J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1301 - 1307. [Abstract] [Full Text] [PDF]
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S. Rosenkranz TGF-{beta}1 and angiotensin networking in cardiac remodeling Cardiovasc Res, August 15, 2004; 63(3): 423 - 432. [Abstract] [Full Text] [PDF]
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P. M. Mottram, B. Haluska, R. Leano, D. Cowley, M. Stowasser, and T. H. Marwick Effect of Aldosterone Antagonism on Myocardial Dysfunction in Hypertensive Patients With Diastolic Heart Failure Circulation, August 3, 2004; 110(5): 558 - 565. [Abstract] [Full Text] [PDF]
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Z. Y. Fang, J. B. Prins, and T. H. Marwick Diabetic Cardiomyopathy: Evidence, Mechanisms, and Therapeutic Implications Endocr. Rev., August 1, 2004; 25(4): 543 - 567. [Abstract] [Full Text] [PDF]
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R. Nakamura, J. Kato, K. Kitamura, H. Onitsuka, T. Imamura, Y. Cao, K. Marutsuka, Y. Asada, K. Kangawa, and T. Eto Adrenomedullin Administration Immediately After Myocardial Infarction Ameliorates Progression of Heart Failure in Rats Circulation, July 27, 2004; 110(4): 426 - 431. [Abstract] [Full Text] [PDF]
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 J. E. Larkin, B. C. Frank, R. M. Gaspard, I. Duka, H. Gavras, and J. Quackenbush Cardiac transcriptional response to acute and chronic angiotensin II treatments Physiol Genomics, July 8, 2004; 18(2): 152 - 166. [Abstract] [Full Text] [PDF]
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 L. Elsherif, Y. Jiang, J. T. Saari, and Y. J. Kang Dietary Copper Restriction-Induced Changes in Myocardial Gene Expression and the Effect of Copper Repletion Experimental Biology and Medicine, July 1, 2004; 229(7): 616 - 622. [Abstract] [Full Text] [PDF]
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G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]
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M. Wong, L. Staszewsky, R. Latini, S. Barlera, R. Glazer, N. Aknay, A. Hester, I. Anand, and J. N. Cohn Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure: Valsartan heart failure trial (Val-HeFT) echocardiographic data J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2022 - 2027. [Abstract] [Full Text] [PDF]
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Y. Matsui, N. Jia, H. Okamoto, S. Kon, H. Onozuka, M. Akino, L. Liu, J. Morimoto, S. R. Rittling, D. Denhardt, et al. Role of Osteopontin in Cardiac Fibrosis and Remodeling in Angiotensin II-Induced Cardiac Hypertrophy Hypertension, June 1, 2004; 43(6): 1195 - 1201. [Abstract] [Full Text] [PDF]
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 T. Tokudome, T. Horio, M. Fukunaga, H. Okumura, J. Hino, K. Mori, F. Yoshihara, S.-I. Suga, Y. Kawano, M. Kohno, et al. Ventricular Nonmyocytes Inhibit Doxorubicin-Induced Myocyte Apoptosis: Involvement of Endogenous Endothelin-1 as a Paracrine Factor Endocrinology, May 1, 2004; 145(5): 2458 - 2466. [Abstract] [Full Text] [PDF]
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R. S. Vasan, J. C. Evans, E. J. Benjamin, D. Levy, M. G. Larson, J. Sundstrom, J. M. Murabito, F. Sam, W. S. Colucci, and P. W. F. Wilson Relations of Serum Aldosterone to Cardiac Structure: Gender-Related Differences in the Framingham Heart Study Hypertension, May 1, 2004; 43(5): 957 - 962. [Abstract] [Full Text] [PDF]
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 D. S.H. Bell Heart Failure: A Serious and Common Comorbidity of Diabetes Clin. Diabetes, April 1, 2004; 22(2): 61 - 65. [Abstract] [Full Text] [PDF]
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Y. Li, I. Kishimoto, Y. Saito, M. Harada, K. Kuwahara, T. Izumi, I. Hamanaka, N. Takahashi, R. Kawakami, K. Tanimoto, et al. Androgen Contributes to Gender-Related Cardiac Hypertrophy and Fibrosis in Mice Lacking the Gene Encoding Guanylyl Cyclase-A Endocrinology, February 1, 2004; 145(2): 951 - 958. [Abstract] [Full Text] [PDF]
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M. P. Ocaranza, G. Diaz-Araya, J. E. Carreno, D. Munoz, J. P. Riveros, J. E. Jalil, and S. Lavandero Polymorphism in gene coding for ACE determines different development of myocardial fibrosis in rats Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H498 - H506. [Abstract] [Full Text] [PDF]
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K. Tokuda, H. Kai, F. Kuwahara, H. Yasukawa, N. Tahara, H. Kudo, K. Takemiya, M. Koga, T. Yamamoto, and T. Imaizumi Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis Hypertension, February 1, 2004; 43(2): 499 - 503. [Abstract] [Full Text] [PDF]
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 N. K. Hollenberg Treatment of the Patient With Diabetes Mellitus and Risk of Nephropathy: What Do We Know, and What Do We Need to Learn? Arch Intern Med, January 26, 2004; 164(2): 125 - 130. [Full Text] [PDF]
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 C. Salih, K. P. McCarthy, and S. Y. Ho The fibrous matrix of ventricular myocardium in hypoplastic left heart syndrome: a quantitative and qualitative analysis Ann. Thorac. Surg., January 1, 2004; 77(1): 36 - 40. [Abstract] [Full Text] [PDF]
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H. S. Hahn, Y. Marreez, A. Odley, A. Sterbling, M. G. Yussman, K. C. Hilty, I. Bodi, S. B. Liggett, A. Schwartz, and G. W. Dorn II Protein Kinase C{alpha} Negatively Regulates Systolic and Diastolic Function in Pathological Hypertrophy Circ. Res., November 28, 2003; 93(11): 1111 - 1119. [Abstract] [Full Text] [PDF]
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S. L. Liu, S. Schmuck, J. Z. Chorazcyzewski, R. Gros, and R. D. Feldman Aldosterone Regulates Vascular Reactivity: Short-Term Effects Mediated by Phosphatidylinositol 3-Kinase-Dependent Nitric Oxide Synthase Activation Circulation, November 11, 2003; 108(19): 2400 - 2406. [Abstract] [Full Text] [PDF]
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B. Pitt, N. Reichek, R. Willenbrock, F. Zannad, R. A. Phillips, B. Roniker, J. Kleiman, S. Krause, D. Burns, and G. H. Williams Effects of Eplerenone, Enalapril, and Eplerenone/Enalapril in Patients With Essential Hypertension and Left Ventricular Hypertrophy: The 4E-Left Ventricular Hypertrophy Study Circulation, October 14, 2003; 108(15): 1831 - 1838. [Abstract] [Full Text] [PDF]
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G. Bledsoe, L. Chao, and J. Chao Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1479 - H1488. [Abstract] [Full Text] [PDF]
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M. Domanski, J. Norman, B. Pitt, M. Haigney, S. Hanlon, and E. Peyster Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD) J. Am. Coll. Cardiol., August 20, 2003; 42(4): 705 - 708. [Abstract] [Full Text] [PDF]
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