title: Histological changes in a model of chronic heart failure induced by multiple sequential coronary microembolization in sheep.
abstract: OBJECTIVE
  Valuable models of chronic heart failure to perform histological studies are scarce. The authors aimed at investigating histological changes of the heart, lung, liver and kidneys in a stable and reproducible animal model of chronic heart failure in sheep.
  
  
  METHODS
  In 8 sheep (N.=8, 77+/-2 kg) chronic heart failure was induced by multiple sequential microembolization through bolus injection of polysterol microspheres (90 microm, N=25 000) into the left main coronary artery. Microembolization (ME) was repeated up to three times in two to three week intervals until animals started to develop stable signs of heart failure. Therefore, clinical and hemodynamic parameters were measured (Troponin T, heart and respiratory rate, cardiac output) after each embolization. Clinical examination was carried out by a veterinarian. All animals were followed for 3 months after first microembolization and then euthanized for histological examination. Histological data of the heart, lung, liver and the kidneys were analyzed in hematoxylin-eosin (HE) stains (10x, 25x, 100x) at baseline (control group) and at 3 months after first ME. Additionally preparations of heart tissue were stained with Picro-Sirius-Red (PSR) for planimetric quantification. A score from 0 to 4 according to Rassler et al. (2005) was used to assess the degree of lung injury.
  
  
  RESULTS
  All animals developed histological signs of heart failure as indicated by island-like, patchy fibrosis of the heart. Planimetric quantification (PSR stain) of the heart revealed a significant increase of the total amount of fibrosis from 8+/-2% (base) to 21+/-4% (3 months) (P<0.05), which was distributed homogeneously throughout the left ventricle (20+/-3% left ventricular [LV] anterior wall, 21+/-4% LV posterior wall, 20+/-4% septum). Histologic analysis of the lung demonstrated a moderate degree of interstitial edema and pronounced peribronchial processes of inflammation with beginning proliferation of fibrotic tissue. Liver tissue showed histological changes in terms of pericentral adiposis as sign of hypoxia in course of lacking perfusion. Signs of liver congestion could be detected histological in form of central-venous accumulation of erythrocytes and dissolution of liver tissue in proximity of the central veins. Kidney preparations illustrated loss of endothelial function and vascular occlusions, caused by microspheres, with decline of renal parenchyma particularly of the tubules.
  
  
  CONCLUSIONS
  Multiple sequential intracoronary microembolization can effectively induce myocardial dysfunction with histological signs of chronic ischemic cardiomyopathy and pathological changes of lung, liver and kidney, which can directly be coursed by chronic heart failure. Thus, the present model may be suitable in experimental work on heart failure and LV assist devices, e.g. for studying the impact of mechanical unloading, mechanisms of recovery and reverse remodeling.
authors.affiliation: Department of Thoracic, Cardiac and Vascular Surgery, University Hospital of Goettingen, Goettingen, Germany. schmitto@med.uni-goettingen.de
authors.forename: J D
authors.initials: JD
authors.lastname: Schmitto
authors.forename: P
authors.initials: P
authors.lastname: Ortmann
authors.forename: P
authors.initials: P
authors.lastname: Ortomann
authors.forename: T
authors.initials: T
authors.lastname: Vorkamp
authors.forename: F
authors.initials: F
authors.lastname: Heidrich
authors.forename: P
authors.initials: P
authors.lastname: Kolat
authors.forename: A F
authors.initials: AF
authors.lastname: Popov
authors.forename: H
authors.initials: H
authors.lastname: Doerge
authors.forename: M
authors.initials: M
authors.lastname: Grossmann
authors.forename: R
authors.initials: R
authors.lastname: Seipelt
authors.forename: G
authors.initials: G
authors.lastname: Ramadori
authors.forename: A F
authors.initials: AF
authors.lastname: Schöndube
authors.forename: A
authors.initials: A
authors.lastname: Schöndube
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003324:Coronary Artery Disease / Q000150:complications* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004617:Embolism / Q000150:complications* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D007269:Injections, Intra-Arterial; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008863:Microspheres; D009206:Myocardium / Q000473:pathology*; D011137:Polystyrenes / Q000008:administration & dosage; D015203:Reproducibility of Results; D012756:Sheep
chemical_list: D011137:Polystyrenes