Large Animal models for preclinical studies of Heart Failure with preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex condition, characterized by a normal left ventricular ejection fraction
(> 50%) and an abnormal diastolic function. The precise mechanism for the pathophysiology of HFpEF is currently incompletely understood, and the absence of a reliable animal model has hampered the development of new therapies. Indeed, if rodent models have contributed to understanding HFpEF’s mechanisms, large animal models are essential for testing therapies before human trials.

In 2023, Ke Li et al1 described the current understanding of the HFpEF and the methods used to create large animal models of HFpEF.

The pathophysiologic progression of heart failure with preserved ejection fraction
Figure 1. The pathophysiologic progression of heart failure with preserved ejection fraction (hFpEF). Ke Li, Cristiano Cardoso, Angel Moctezuma-Ramirez, Abdelmotagaly Elgalad, Emerson Perin. Evaluation of large animal models for preclinical studies of heart failure with preserved ejection fraction using clinical score systems. Front. Cardiovasc. Med., 2023.

Six different models of HFpEF were reviewed and described:

  1. Aortic banding
  2. Aortic stent
  3. Renal wrap
  4. Renal clamp/embolization
  5. Medication
  6. Combination models (introducing multiple risk factors, such as a high-fat diet, hypertension, and diabetes)

To evaluate the modeling of this complex clinical syndrome in large animal models, Ke Li et al proposed to use clinical scores: HFA-PEFF and H2FPEF. The HFA-PEFF score provides a direct reflection of cardiac factors, such as Left Ventricular diastolic dysfunction, while the H2FPEF score emphasizes extracardiac factors, such as obesity, hypertension and age. Applying these scores to animal models presents unique challenges, and can be achieved using several techniques, including:

  • Echocardiography, to record left ventricular wall thickness, left ventricular end diastolic diameters, left atrial volume index, left ventricular mass index, mitral inflow, tissue Doppler septal and lateral wall mitral velocity, peak tricuspid regurgitation velocity and global longitudinal strain
  • Implantable easyTel + telemetry to continuously monitor blood pressure and ECG.

Amongst the various animal models reviewed, it was noticed that combination models may better reflect the heterogeneity of HFpE and achieved good H2PEF scores. The use of implantable telemetry to continuously record ECG, blood pressure and Left Ventricular pressure was particularly useful in these multifactorial models, and provided valuable hemodynamic data.

Leveraging these clinical scores to assess large animal models of HFpEF has not only pinpointed areas for improvement in future studies but also holds the promise of significant advancements in HFpEF research.


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