Abstract
Recently, we proposed the hypothesis that a vicious cycle exists in human hibernating myocardium (HM) between the progression of myocyte degeneration and the development of fibrosis [1]. We now investigated the pathomechanism of this cycle in more detail and established a correlation between the severity of the morphological changes and the degree of postoperative functional recovery of HM.
HM was diagnosed by dobutamine echocardiography, thallium-201 scintigraphy and radionuclide ventriculography. Functional recovery was present at 3 months after coronary bypass surgery but remained unchanged at 15 months. Forty patients were subdivided into 2 groups: A with complete and B with incomplete recovery. Biopsies taken during surgery and studied by electron microscopy, immunocytochemistry, rt-PCR, and morphometry revealed myocyte degeneration and inflammatory and fibrinogenic changes in a widened interstitial space. We report here for the first time an upregulation of TGF-β1 evident by a 5-fold increase of fibroblasts and macrophages exhibiting a TGF-β1 content 3-fold larger than in control, and a > 3-fold increase in TGF-β1 mRNA by rt-PCR. The number of angiotensin converting enzyme (ACE) containing structures was increased (n/mm2: control - 11.4, A - 17.6, B - 19.2, control vs. A and B, p < 0.05). Fibrosis was more severe in group B than A or control (%: C - 10.1; A - 21.2; B - 40.6; p < 0.05). Capillary density was significantly reduced (n/mm2: C - 1152; A - 782; B - 579, p < 0.05) and intercapillary distance was widened (μm: C - 29.5, A - 36.1, B - 43.3, p < 0.05). The number of CD 3 (n/mm2: C - 5.0; A - 9.6; B - 9.4, ns) and CD 68 positive cells (n/mm2: C - 37.2; A - 80.7; B - 55.0, C vs. A p < 0.05) was elevated in HM as compared to control indicating an inflammatory reaction. Cut-off points for functional recovery are fibrosis > 32%, capillary density < 660/mm2 and intercapillary distance > 39.0 μm.
In HM a self-perpetuating vicious cycle of tissue alterations leads to progressive replacement fibrosis and continuous intracellular degeneration which should be interrupted by early revascularization.
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References
Elsässer A, Schlepper M, Zimmermann R, Klövekorn WP, Schaper J: The extracellular matrix in hibernating myocardium–a significant factor causing structural defects and cardiac dysfunction. Mol Cell Biochem 186: 147-158, 1998
Rahimtoola SH: The hibernating myocardium. Am Heart J 117: 211-221, 1989
Rahimtoola SH: The hibernating myocardium in ischaemia and congestive heart failure. Eur Heart J 14: 212-220, 1993
Vanoverschelde JL, Wijns W, Borgers M, Heyndrickx G, Depré C, Flameng W, Melin JA: Chronic myocardial hibernation in humans. From bedside to bench. Circulation 95: 1961-1971, 1997
Camici PG, Wijns W, Borgers M, deSilva R, Ferrari R, Knuuti J, Lammertsma AA, Liedtke AJ, Paternostro G, Vatner SF: Pathophysiological mechanisms of chronic reversible left ventricular dysfunction due to coronary artery disease (hibernating myocardium). Circulation 96: 3205-3214, 1997
Wijns WW, Vatner SF, Camici PG: Hibernating myocardium. N Engl J Med 339: 173-181, 1998
Elsässer A, Schlepper M, Klövekorn W-P, Cai WJ, Zimmermann R, Müller K-D, Strasser R, Kostin S, Gagel C, Münkel B, Schaper W, Schaper J: Hibernating myocardium–an incomplete adaptation to ischemia. Circulation 96: 2920-2931, 1997
Standke R, Hör G, Maul FD: Fully automated sectorial equilibrium radionuclide ventriculography. Proposal of a method for routine use: exercise and follow-up. Eur J Nucl Med 8: 77-83, 1983
Honig CR, Gayeski TE: Capillary reserve and tissue oxygen transport in normal and hypertrophied hearts. Perspect Cardiovasc Res 8: 249-260, 1983
Kostin S, Hein S, Bauer EP, Schaper J: Spatiotemporal development and distribution of intercellular junctions in adult rat cardiomyocytes in culture. Circ Res 85: 154-167, 1999
Chomczynski P, Sacchi N: Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156-159, 1987
Brand T, Schneider MD: The TGF-β superfamily in myocardium: Ligands, receptors, transduction, and function. J Moll Cell Cardiol 27: 5-18, 1995
Weber KT: Cardiac interstitium in health and disease: The fibrillar collagen network. J Am Coll Cardiol 13: 1637-1652, 1989
Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI: Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 62: 757-765, 1988
Sun Y, Weber KT: Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart. J Moll Cell Cardiol 28: 851-858, 1996
Weber KT: Extracellular matrix remodeling in heart failure. Circulation 96: 4065-4082, 1997
Moncada S, Higgs EA: Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J 9: 1319-1330, 1995
Maes A, Flameng W, Nuyts J, Borgers M, Shivalkar B, Ausma J, Bormans G, Schiepers C, Deroo M, Mortelmans L: Histological alterations in chronically hypoperfused myocardium-correlation with PET findings. Circulation 90: 735-745, 1994
Dakik HA, Howell JF, Lawrie GM, Espada R, Weilbaecher DG, He ZX, Mahmarian JJ, Verani MS: Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgery: Correlation with histopathology and postoperative improvement in cardiac function. Circulation 96: 2892-2898, 1997
Depre C, Vanoverschelde JL, Melin JA, Borgers M, Bol A, Dion R, Wijns W: Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Physiol 268: 1265-1275, 1995
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Elsässer, A., Decker, E., Kostin, S. et al. A self-perpetuating vicious cycle of tissue damage in human hibernating myocardium. Mol Cell Biochem 213, 17–28 (2000). https://doi.org/10.1023/A:1007182617215
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DOI: https://doi.org/10.1023/A:1007182617215