title: A self-perpetuating vicious cycle of tissue damage in human hibernating myocardium.
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. 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-beta1 evident by a 5-fold increase of fibroblasts and macrophages exhibiting a TGF-beta1 content 3-fold larger than in control, and a > 3-fold increase in TGF-beta1 mRNAby rt-PCR. The number of angiotensin converting enzyme (ACE) containing structures was increased (n/mrm2: 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 (microm: 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 microm. 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.
authors.affiliation: Department of Cardiology, University of Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Elsässer
authors.forename: E
authors.initials: E
authors.lastname: Decker
authors.forename: S
authors.initials: S
authors.lastname: Kostin
authors.forename: S
authors.initials: S
authors.lastname: Hein
authors.forename: W
authors.initials: W
authors.lastname: Skwara
authors.forename: K D
authors.initials: KD
authors.lastname: Müller
authors.forename: S
authors.initials: S
authors.lastname: Greiber
authors.forename: W
authors.initials: W
authors.lastname: Schaper
authors.forename: W P
authors.initials: WP
authors.lastname: Klövekorn
authors.forename: J
authors.initials: J
authors.lastname: Schaper
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015415:Biomarkers; D017252:CD3 Complex / Q000032:analysis; D018031:Connexin 43 / Q000032:analysis; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D017682:Myocardial Stunning / Q000000981:diagnostic imaging / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D015635:Radionuclide Ventriculography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013794:Thallium Radioisotopes; D016212:Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1; D014463:Ultrasonography; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D017252:CD3 Complex; D018031:Connexin 43; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013794:Thallium Radioisotopes; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C508960:TGFB1 protein, human; C496314:NOS3 protein, human