title: Left ventricular eccentric remodeling and matrix loss are mediated by bradykinin and precede cardiomyocyte elongation in rats with volume overload.
abstract: OBJECTIVE
  We hypothesized that left ventricular (LV) remodeling and matrix loss in volume overload (VO) are mediated by bradykinin (BK) and exacerbated by chronic angiotensin-converting enzyme (ACE) inhibition.
  
  
  BACKGROUND
  Chronic ACE inhibition increases anti-fibrotic BK and does not attenuate LV remodeling in pure VO. The relative contribution of changes in extracellular matrix versus cardiomyocyte elongation in acute and chronic LV chamber remodeling during VO is unknown.
  
  
  METHODS
  Echocardiography, LV collagen content, and isolated cardiomyocytes were studied in rats after aortocaval fistula (ACF) of 12 h, 2 and 5 days, and 4, 8, and 15 weeks. We also studied ACF rats after BK2 receptor (BK2R) blockade (2 days) or ACE inhibition (4 weeks).
  
  
  RESULTS
  At 2 days after ACF, LV end-diastolic dimension (LVEDD)/wall thickness was increased, and LV interstitial collagen was decreased by 50% without cardiomyocyte elongation. The BK2R blockade prevented collagen loss and normalized LVEDD/wall thickness. From 4 to 15 weeks after ACF, interstitial collagen decreased by 30% and left ventricular end-systolic (LVES) dimension increased despite normal LVES pressure and isolated cardiomyocyte function. The ACE inhibition did not decrease LVEDD/wall thickness, further decreased LV interstitial collagen, and did not improve LV fractional shortening despite decreased LVES pressure.
  
  
  CONCLUSIONS
  Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without cardiomyocyte elongation. Acute BK2R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.
authors.affiliation: Department of Physiology, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama 35294-2180, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Ryan
authors.forename: Emily C
authors.initials: EC
authors.lastname: Rothstein
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Aban
authors.forename: Jose A
authors.initials: JA
authors.lastname: Tallaj
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lucchesi
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use; D003094:Collagen / Q000187:drug effects; D003971:Diastole; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology*; D009929:Organ Size; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C065679:icatibant; D003094:Collagen; D017257:Ramipril; D001920:Bradykinin