ESC Heart Fail. 2026 Mar 11:xvag072. doi: 10.1093/eschf/xvag072. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: The most clinically representative murine models of HFpEF include a "2-hit" model combining nitrosative stress with metabolic perturbation and a "3-hit" model that also includes ageing. Both models have important limitations with regard to sub-strain and sex.
METHODS: The 2-hit model protocol was modified to reproduce HFpEF in both C57BL/6N and 6J mice by increasing L-NAME doses (0.5 g/L to 1.75 g/L) and protocol lengths (7 weeks to 13 weeks). For the 3-hit model, in addition to deoxycorticosterone pivalate [DOCP], we added 1% NaCl drinking water to enhance and prolong the effect of DOCP ("4-hit"). To maintain the phenotype, a second bolus of DOCP was administered after 8 weeks.
RESULTS: HFpEF was successfully induced in C57BL/6J mice when exposed to a 13-week 2-hit L-NAME protocol with gradually increasing dosage from 1.0 g/L to 1.75 g/L. For the 4-hit mice, a clear HFpEF phenotype was observed in C57BL/6N and 6J mice in both male and females, and maintained for up to 12 weeks.
CONCLUSIONS: These modifications ensure the 2-hit model is induced in J substrain of C57BL/6 mice. The 4-hit model prevents aldosterone escape and enhances reproducibility across sexes and substrains.
PMID:41812219 | DOI:10.1093/eschf/xvag072