A, Toldo S. A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II. Am J Physiol Heart Circ Physiol 309: H771-H778, 2015. First published July 17, 2015; doi:10.1152/ajpheart.00282.2015.-Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ϳ50% 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 (AT II) 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 AT II (0.2 mg·kg Ϫ1 ·day Ϫ1 ) or volume-matched vehicle (N ϭ 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. AT II 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 AT II recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.heart failure with preserved ejection fraction; diastolic dysfunction; animal model; angiotensin II; end-diastolic pressure; isovolumetric relaxation time
NEW & NOTEWORTHY
Chronic infusion of low-dose angiotensin II in the mouse induces diastolic dysfunction and HFpEF in the absence of pressure overload, LV systolic dysfunction, LV dilatation or hypertrophy, and metabolic abnormalities. This model may be considered a novel tool for mechanistic preclinical studies in HFpEF with translational potential.HEART FAILURE (HF) WITH PRESERVED ejection fraction (HFpEF) is a clinical syndrome of symptoms of HF, such as breathlessness and exercise intolerance, associated with impaired left ventricular (LV) diastolic function in the presence of a normal LV ejection fraction (LVEF Ͼ 50%) (2). HFpEF carries significant morbidity and mortality burdens, and the prevalence of the disease has increased over the past 30 yr (2, 17). To date, the mechanisms underlying diastolic dysfunction and the progression of HFpEF are poorly understood. The path...