Developing an integrated in vivo model of HFpEF in female rats: metabolic stress, cardiac dysfunction and altered excitation-contraction coupling

Background Heart failure with preserved ejection fraction (HFpEF) represents over 50% of HF cases, predominantly affecting women with comorbidities such as ageing, hypertension, obesity, and left ventricular diastolic dysfunction. This multifactorial aetiology includes pathophysiological complexities that make HFpEF a therapeutic challenge. The aims of the current study were to (i) develop a rat model combining the chronic hypertension and metabolic imbalance observed in HFpEF (ii) evaluate in vivo structural cardiac modifications and (iii) identify the subcellular processes underlying this pathophysiology.

Methods Female Wistar Han ex-breeder rats were fed a 60% high-fat diet for 12 weeks, with 0.576mg/kg/day Ang II infused via surgically implanted minipumps, for 4 weeks. During the study, body weight, echocardiographic parameters and blood biochemistry were monitored regularly. After the study period, lipid distribution was quantified. Additionally, cardiac tissue was harvested to assess fibrotic remodelling and protein expression changes.

Results HFpEF rats exhibited variable increases in body weight gain (Ctrl:5.25±1.06%; HFpEF:11.3±3.0%; N Ctrl =4, N HFpEF =8; p=0.091) with more visceral fat deposits, and reduced circulatory triglycerides. Hypertrophy was observed in kidneys and hearts, and elevated fractional shortening (Ctrl:52.2±1.4%; HFpEF:59.0±2%; N Ctrl =6, N HFpEF =7; p=0.018). Myocardial interstitial fibrosis with collagen deposition was also increased in HFpEF (Ctrl:11.9±0.4% HFpEF:50.1±3.3% N Ctrl =3, N HFpEF =4; p=0.001). Biochemical analysis revealed dysregulation of calcium-handling proteins including LTCC, p-RyR2, PLB and NCX.

Conclusion This novel HFpEF model offers a robust platform to investigate HFpEF mechanisms. This demonstrates clear structural and functional alterations, including myocardial hypertrophy, fibrosis and dysregulated calcium cycling expression, which may explain the diastolic dysfunction observed in HFpEF. Future studies will address disease progression, therapeutic interventions, and compensatory mechanisms.