HFpEF Rodent Models

Two-Hit HFpEF Rodent Model for Preclinical Efficacy Studies

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiometabolic syndrome characterized by impaired diastolic function, exercise intolerance, ventricular remodeling, and preserved left ventricular ejection fraction.

Its clinical prevalence continues to increase, yet effective therapies remain limited.

At IPST, the Two-Hit HFpEF model is used to evaluate therapeutic candidates in a translational setting that reproduces several key features of human disease, including metabolic stress, cardiac remodeling, impaired relaxation, fibrosis, and reduced functional capacity.

This model is particularly valuable for programs targeting diastolic dysfunction, cardiometabolic disease, fibrosis, inflammation, or exercise intolerance.

Two-Hit HFpEF Model — Methodology

Species: mice or rats
Induction approach: high-fat diet combined with L-NAME in drinking water
Typical in-life phase: approximately 12 weeks
Typical total study duration: approximately 15 weeks
Disease features induced: metabolic stress, diastolic dysfunction, ventricular remodeling, fibrosis, and reduced exercise capacity
Study flexibility: treatment initiation can be adapted for prevention, early intervention, or reversal study designs depending on the therapeutic objective

This model is designed to reproduce multiple contributing drivers of HFpEF rather than a single isolated insult. As a result, it provides a useful platform for assessing compounds intended to improve diastolic performance, reduce fibrosis, modulate inflammation, improve metabolic status, or restore functional capacity.

Study design can be tailored to the sponsor’s mechanism of action and desired endpoints.

HFpEF - Readouts & Application

Readouts:

Echocardiography: ventricular structure and function, including diastolic indices
Invasive hemodynamics / PV loops: assessment of cardiac performance and diastolic dysfunction
Histology: H&E, Picrosirius Red, and other stains as appropriate
Cardiac remodeling: hypertrophy, fibrosis, and tissue architecture changes
Exercise tolerance / functional capacity: treadmill or related performance endpoints
Biomarkers: circulating or tissue-based markers can be incorporated depending on study objectives

Application:

The Two-Hit HFpEF model is intended for the preclinical evaluation of drug candidates targeting diastolic dysfunction and associated cardiometabolic disease. It reproduces several important features of human HFpEF, including preserved ejection fraction, impaired ventricular relaxation, fibrosis, and reduced exercise tolerance.

The model is well suited for assessing the efficacy of agents aimed at improving cardiac function, limiting remodeling, reducing fibrosis or inflammation, and enhancing overall functional status.

At IPST, functional, hemodynamic, biochemical, and histological endpoints can be integrated into a study design aligned with the sponsor’s therapeutic hypothesis.