Abstract 4368026: Comprehensive echocardiographic analysis of optimized rodent models of heart failure with preserved ejection fraction identifies superior LV filling pressure surrogates

Abstract

Background: In drug development, rodent models that faithfully recapitulate human disease are critical for evaluating the therapeutic effects and confirming the mechanisms of action of novel targets. For heart failure with preserved ejection fraction (HFpEF), ZSF1 obese rats and high-fat diet (HFD)+L-NAME-treated C57BL/6N mice are two widely-used preclinical rodent models. Both exhibit impaired diastolic function with normal ejection fraction, but the HFpEF phenotype in HFD+L–NAME mice tends to be relatively mild. While E/e' is clinically established as a surrogate for LV filling pressure, there is limited assessment of LV filling pressure surrogates including E/e' in rodent models. Hypothesis: Modifying treatment protocol promotes the development of a more robust HFpEF phenotype in rodent models. Furthermore, employing a combination of multiple readouts enhances the prediction of disease status in these preclinical models. Methods: We increased L-NAME dose and increased duration of HFD+L-NAME model induction to 20-40 weeks in male 12 week old C57BL/6N mice. In female ZSF1 obese rats, we performed longitudinal assessment from 16-40 weeks of age. Multiple readouts were collected in HFD+L–NAME mice alongside age-matched healthy controls, as well as female ZSF1 obese rats with ZSF1 lean controls to confirm their HFpEF phenotype and comorbidities including echocardiography (conventional, LV and LA strain analysis, LV HDF using Vevo Strain 2.0), treadmill testing, organ masses, and invasive hemodynamics (Millar PV catheter). Results: Increasing the dose of L-NAME in drinking water to 1g/L and the treatment period of both HFD and L-NAME to >20 weeks enhanced HFpEF phenotype characterized by obesity, hypertension, LV hypertrophy, elevated E/e’ and LVEDP, impaired LV strain and HDF, impaired LA strain, and reduced exercise capacity. Similarly, female ZSF1 obese rats developed a robust HFpEF phenotype marked by obesity, hypertension, LV hypertrophy, elevated E/e’ and LVEDP, impaired LA strain, and reduced exercise capacity. Using linear regression, we identified echocardiographic predictors of elevated LVEDP in both models that outperform E/e’ including LV HDF strength, LA reservoir strain, LVMI, and IVRT. Conclusions: Increased L-NAME dose and prolonged model induction with HFD+L-NAME produce a robust HFpEF phenotype. Additionally, strain analysis is a more reliable predictor of elevated LV filling pressure than E/e’ in HFpEF preclinical rodent models.