RESEARCH DIETS

D12492 and L-NAME:
A Reliable Two-Hit Model for HFpEF Research

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Keywords
D12492（60kcal%Fat・高脂肪飼料） L-NAME (Nω-nitro-L-arginine methyl ester) HFpEF 拡張機能障害 心室リモデリング 肺うっ血 心不全 肥満 心血管疾患 高血圧

Heart failure with preserved ejection fraction (HFpEF) remains a major clinical challenge, accounting for more than half of all heart failure cases. Its complex pathophysiology — including diastolic dysfunction, endothelial dysfunction, and metabolic comorbidities — requires robust and translationally relevant preclinical models. The L-NAME + D12492 “two-hit” mouse model has emerged as a leading platform for studying HFpEF in vivo.

The Two-Hit Protocol: L-NAME + D12492 This model induces HFpEF by combining:

• L-NAME (Nω-nitro-L-arginine methyl ester), a nitric oxide synthase inhibitor, traditionally delivered in drinking water (0.5 g/L) to cause hypertension and endothelial dysfunction.
• D12492, a high-fat diet (60% kcal from fat) developed by Research Diets, Inc., used to induce obesity, systemic inflammation, and metabolic syndrome.

Mice are treated for 5 to 15 weeks, depending on the study. This dual-stressor approach mimics multiple comorbid drivers of HFpEF seen in patients.¹

New Option: L-NAME Incorporated in Diet
While the standard protocol uses L-NAME in water, L-NAME can also be incorporated directly into the diet, which offers several practical advantages:

• Diet ID: D16082402, D12492 with 750 mg L-NAME/kg Diet²

Benefits of L-NAME in Diet:

• Simplified Handling: No need to refresh water bottles multiple times per week.
• Improved Consistency: Mice consume food more predictably than water, potentially reducing inter-animal variability in L-NAME intake.
• Early-Stage Adoption: While publications using this specific diet are limited (since it's a recent switch), results from these publictions suggest the phenotype remains similar to the traditional two-hit model.

Key Phenotypic Features of the Model
When applied in susceptible strains (eg. C57BL/6), this model replicates several core HFpEF features:

• Preserved Left Ventricular Ejection Fraction
• Diastolic Dysfunction
• Cardiac Remodeling
• Pulmonary Congestion
• Exercise Intolerance

Strain Matters: Why C57BL/6 Is Superior to FVB/N
Strain selection significantly affects the reliability of the L-NAME + D12492 HFpEF model.
C57BL/6 Mice

• Consistent cardiac, metabolic, and functional HFpEF features
• Robust responses to diet-induced obesity and hypertension
• Reduced exercise tolerance

FVB/N Mice

• Weaker cardiac remodeling, preserved exercise capacity, and milder phenotype^3,4

Summary
The L-NAME + D12492 HFpEF model in C57BL/6 mice remains one of the most translationally relevant platforms for studying HFpEF. Whether L-NAME is delivered through water or directly in diet, the two-hit strategy reliably induces the multifaceted pathophysiology of HFpEF and supports both mechanistic and therapeutic research.

References

• Schiattarella GG, et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature. 2019 Apr;568(7752):351-356. doi: 10.1038/s41586-019-1100-z. Epub 2019 Apr 10. PMID: 30971818; PMCID: PMC6635957.
• Schiattarella GG, et al. Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction. Nat Commun. 2021 Mar 16;12(1):1684. doi: 10.1038/s41467-021-21931-9. PMID: 33727534; PMCID: PMC7966396.
• Li Y, et al. Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype. Am J Physiol Heart Circ Physiol. 2023 Apr 1;324(4):H443-H460. doi: 10.1152/ajpheart.00594.2022. Epub 2023 Feb 10. PMID: 36763506; PMCID: PMC9988529.
• Gao S, et al. Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery. Acta Pharmacol Sin. 2024 Jan;45(1):23-35. doi: 10.1038/s41401-023-01152-0. Epub 2023 Aug 29. PMID: 37644131; PMCID: PMC10770177.

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