A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction

Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1407-18. doi: 10.1152/ajpheart.00542.2015. Epub 2015 Sep 4.


Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

Keywords: heart failure with preserved ejection fraction; hypertensive heart disease; oxidative stress; pressure-volume analysis; titin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / etiology
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology*
  • Connectin / metabolism
  • Desoxycorticosterone Acetate / toxicity
  • Diet, Western
  • Dilatation, Pathologic / etiology
  • Dilatation, Pathologic / physiopathology
  • Disease Models, Animal
  • Female
  • Heart Atria / physiopathology
  • Heart Failure / etiology
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / physiopathology*
  • Hyperlipidemias / chemically induced
  • Hyperlipidemias / complications
  • Hypertension / chemically induced
  • Hypertension / complications*
  • Hypertrophy / etiology
  • Hypertrophy / pathology
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / pathology
  • Hypertrophy, Left Ventricular / physiopathology*
  • Mineralocorticoids / toxicity
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Nitric Oxide Synthase / metabolism
  • Phosphorylation
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Stroke Volume*
  • Superoxides / metabolism
  • Swine


  • Connectin
  • Mineralocorticoids
  • Protein Isoforms
  • Superoxides
  • Desoxycorticosterone Acetate
  • Nitric Oxide Synthase
  • Proto-Oncogene Proteins c-akt