A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

作者：Regan Jessica A; Mauro Adolfo Gabriele; Carbone Salvatore; Marchetti Carlo; Gill Rabia; Mezzaroma Eleonora; Raleigh Juan Valle; Salloum Fadi N; Van Tassell Benjamin W; Abbate Antonio; Toldo Stefano^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2015, 309(5): H771-H778.

DOI：10.1152/ajpheart.00282.2015

• heart failure with preserved ejection fraction
• diastolic dysfunction
• animal model
• angiotensin II
• end-diastolic pressure
• isovolumetric relaxation time

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents similar to 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 (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(-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. AT(II) infusion had no effects on systemic arterial blood pressure. AT(II) 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.

• 出版日期2015-9-1