title: A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II.
abstract: Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg(-1)·day(-1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Regan
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Adolfo Gabriele
authors.initials: AG
authors.lastname: Mauro
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Carbone
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Rabia
authors.initials: R
authors.lastname: Gill
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Juan
authors.initials: J
authors.lastname: Valle Raleigh
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, Virginia; and stoldo2@vcu.edu.
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0002-1588-4019
authors.initials: S
authors.lastname: Toldo
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D055104:Infusions, Subcutaneous; D008297:Male; D051379:Mice; D013318:Stroke Volume
chemical_list: D000804:Angiotensin II
keywords: angiotensin II; animal model; diastolic dysfunction; end-diastolic pressure; heart failure with preserved ejection fraction; isovolumetric relaxation time