title: Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice.
abstract: BACKGROUND
  Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100).
  
  
  RESULTS
  18-month-old LDLR-/-ApoB100/100 (n = 12), diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion.
  
  
  CONCLUSIONS
  LDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.
authors: Department of Biotechnology and Molecular Medicine at A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors: Suvi E
authors: SE
authors: Heinonen
authors: Mari
authors: M
authors: Merentie
authors: Marja
authors: M
authors: Hedman
authors: Petri I
authors: PI
authors: Mäkinen
authors: Elina
authors: E
authors: Loponen
authors: Ivana
authors: I
authors: Kholová
authors: Fatima
authors: F
authors: Bosch
authors: Markku
authors: M
authors: Laakso
authors: Seppo
authors: S
authors: Ylä-Herttuala
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D053299:Apolipoprotein B-100 / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000209:etiology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006937:Hypercholesterolemia / Q000150:complications / Q000503:physiopathology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D053299:Apolipoprotein B-100; D002316:Cardiotonic Agents; D011973:Receptors, LDL; D004280:Dobutamine; D007335:Insulin-Like Growth Factor II