title: Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload.
abstract: Patients with aortic stenosis develop various degrees of myocardial hypertrophy and heart failure (HF) despite comparable transvalvular gradients. An important element in the transition from compensated hypertrophy to HF is dilatation of the left ventricle (LV). The molecular pathology associated with LV dilatation and development of HF is not known. Thus, we examined potential differences in the regulation of myocardial extracellular matrix (ECM) constituents in mice with hypertrophy only (ABnonHF) and with HF (ABHF) as response to comparable pressure overload. The ascending aorta was banded, or left loose in sham-operated mice. Increased lung weight and left atrial diameter indicating pulmonary congestion were used to identify ABHF mice. Cardiac function and geometry were evaluated by echocardiography. Despite comparable pressure gradients and cardiac output, ABHF had reduced fractional shortening (23%), reduced systolic (28%) and diastolic (32%) tissue velocity and increased LV internal dimension in diastole (10%) and systole (17%) (LVIDd/s) compared to ABnonHF (p≤0.05). Microarray analyses identified 120 differently regulated genes related to ECM in ABHF compared to ABnonHF (p≤0.05). Interestingly, in ABHF, we found a 24% (p≤0.05) reduction of the LV collagen VIII protein levels despite increased levels of LV total collagen by 23% (p≤0.05). LV collagen VIII correlated negatively with LVIDd (R=0.55, p=0.03) and LVIDs (R=0.72, p=0.002). As this protein may function as a "sealant" binding collagen fibrils together, reduction of collagen VIII could potentially contribute to LV dilatation and development of HF.
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål and University of Oslo, Kirkeveien 166, 0407 Oslo, Norway.
authors.forename: Biljana
authors.initials: B
authors.lastname: Skrbic
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bjørnstad
authors.forename: Henriette S
authors.initials: HS
authors.lastname: Marstein
authors.forename: Cathrine R
authors.initials: CR
authors.lastname: Carlson
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.forename: Sigrid
authors.initials: S
authors.lastname: Bjørnstad
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Theis
authors.initials: T
authors.lastname: Tønnessen
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011312:Pressure; D020257:Ventricular Remodeling