Lean ZSF1 rats in basic research on heart failure with preserved ejection fraction

Aims: ZSF1 obese rats harbouring two mutant leptin receptor alleles (Lepr^cp and Lepr^fa) develop metabolic syndrome and heart failure with preserved ejection fraction (HFpEF), making them a widely used animal model in cardiometabolic research. Studies using ZSF1 rats have contributed significantly to the elucidation of pathophysiological mechanisms underlying HFpEF and therapeutic strategies against this multi-organ syndrome. In contrast, hybrid, lean ZSF1 rats (L-ZSF1) do not develop HFpEF and generally serve as controls, disregarding the possibility that the presence of one mutant Lepr allele might affect left ventricular ejection fraction (LVEF), diastolic dysfunction and other relevant HFpEF parameters, such as N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and cardiac inflammation, which could increase during disease manifestation.

Methods and results: We collected specimens and echocardiography data of male and female L-ZSF1 rats (n = 165; ZSF1-Lepr^faLepr^cp/Crl) at the age of 6-32 weeks from four independent research groups and performed genotyping as well as the genotype-phenotype analyses. The genotype distribution within L-ZSF1 was in line with the Hardy-Weinberg equilibrium. Genotypes were not associated with CD68 counts (n = 52, P = 0.886), E/e' ratio (n = 125, P > 0.250) and NT-proBNP (n = 126, P = 0.874). LVEF significantly decreased from 25 weeks of age (P = 0.021) but was independent of the genotype (P = 0.768 at <25 weeks of age and P = 0.069 at ≥25 weeks of age, n = 128).

Conclusions: In conclusion, validation of the genotype distribution in L-ZSF1 rats revealed no associations between the genotype and HFpEF-relevant measures, namely, NT-proBNP, CD68 count, LVEF or E/e'.