Optimized murine HFpEF models for translational preclinical studies.

Area of Science:

• Cardiovascular Research
• Animal Models
• Translational Medicine

Background:

• Clinically relevant murine models of heart failure with preserved ejection fraction (HFpEF) are crucial for research.
• Existing "2-hit" (nitrosative stress + metabolic perturbation) and "3-hit" (ageing included) models have limitations regarding mouse substrain and sex.
• Improvements are needed to enhance the translatability of these HFpEF models.

Purpose of the Study:

• To modify and validate existing murine models for HFpEF.
• To improve the "2-hit" model's applicability to C57BL/6J mice.
• To develop an enhanced "4-hit" model for HFpEF that is reproducible across sexes and substrains.

Main Methods:

• Modified the "2-hit" model by increasing L-NAME dosage and protocol duration for C57BL/6N and C57BL/6J mice.
• Developed a "4-hit" model by adding 1% NaCl to deoxycorticosterone pivalate (DOCP) treatment and administering a second DOCP bolus.
• Evaluated HFpEF phenotype induction and maintenance over time in different mouse strains and sexes.

Main Results:

• Successfully induced HFpEF in C57BL/6J mice using an extended "2-hit" L-NAME protocol.
• The enhanced "4-hit" model demonstrated a clear HFpEF phenotype in both male and female C57BL/6N and C57BL/6J mice.
• The HFpEF phenotype was successfully maintained for up to 12 weeks in the "4-hit" model.

Conclusions:

• The modified "2-hit" model is now effective in the C57BL/6J substrain.
• The novel "4-hit" model overcomes aldosterone escape, ensuring sustained HFpEF phenotype.
• These refined models offer enhanced reproducibility across sexes and mouse substrains, advancing HFpEF research.