title: Progressive induction of left ventricular pressure overload in a large animal model elicits myocardial remodeling and a unique matrix signature.
abstract: OBJECTIVE
  Patients with severe left ventricular pressure overload secondary to aortic stenosis can present with signs and symptoms of heart failure despite normal left ventricular ejection fraction. This process occurs, at least in part, as a result of left ventricular pressure overload-induced extracellular matrix remodeling that promulgates increased left ventricular stiffness and impaired diastolic function. However, the determinants that drive extracellular matrix remodeling in this form of left ventricular pressure overload remain to be fully defined.
  
  
  METHODS
  Left ventricular pressure overload was induced in mature pigs (n = 15) by progressive ascending aortic cuff inflation (once per week for 4 weeks), whereby left ventricular mass, left ventricular ejection fraction, and regional myocardial stiffness (rK(m)) were compared with referent controls (n = 12). Determinants of extracellular matrix remodeling were assessed by measuring levels of mRNA expression for fibrillar collagens, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinase 1 and 4.
  
  
  RESULTS
  With left ventricular pressure overload, left ventricular mass and rK(m) increased by 2- and 3-fold, respectively, compared with control, with no change in left ventricular ejection fraction. Left ventricular myocardial collagen increased approximately 2-fold, which was accompanied by reduced solubility (ie, increased cross-linking) with left ventricular pressure overload, but mRNA expression for fibrillar collagen and matrix metalloproteinases remained relatively unchanged. In contrast, a robust increase in mRNA expression for tissue inhibitors of matrix metalloproteinase-1 and 4 occurred with left ventricular pressure overload.
  
  
  CONCLUSIONS
  In a progressive model of left ventricular pressure overload, which recapitulates the phenotype of aortic stenosis, increased extracellular matrix accumulation and subsequently increased myocardial stiffness were not due to increased fibrillar collagen expression but rather to determinants of post-translational control that included increased collagen stability (thereby resistant to matrix metalloproteinase degradation) and increased endogenous matrix metalloproteinase inhibition. Targeting these extracellular matrix post-translational events with left ventricular pressure overload may hold both diagnostic and therapeutic relevance.
authors: Sisters of Charity Providence Hospitals, Columbia, SC, USA.
authors: William M
authors: WM
authors: Yarbrough
authors: Rupak
authors: R
authors: Mukherjee
authors: Robert E
authors: RE
authors: Stroud
authors: William T
authors: WT
authors: Rivers
authors: J Marshall
authors: JM
authors: Oelsen
authors: Jennifer A
authors: JA
authors: Dixon
authors: Shaina R
authors: SR
authors: Eckhouse
authors: John S
authors: JS
authors: Ikonomidis
authors: Michael R
authors: MR
authors: Zile
authors: Francis G
authors: FG
authors: Spinale
mesh_terms: D000818:Animals; D049628:Body Size; D004195:Disease Models, Animal; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D013552:Swine; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases