Exploring therapeutic strategies in heart failure with preserved ejection fraction
Exploring therapeutic strategies in heart failure with preserved ejection fraction
In this thesis of Horly Li we used a multi-hit mouse model to explore novel therapeutic strategies for heart failure with preserved ejection fraction (HFpEF). These novel strategies focused on modulation of key metabolic and inflammatory pathways.
Our first target of interest was nicotinamide N-methyltransferase (NNMT), a key enzyme in the nicotinamide pathway that has been proven to contribute to HFpEF pathogenesis. We demonstrated that NNMT inhibition had cardioprotective effects that resulted in structural and functional improvements. These effects are comparable to SGLT2 inhibitors, which represent the current standard of care. Despite similar outcomes, we found that these drugs act via different mechanisms. We also investigated the effect of MCC950, a NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor. We observed that MCC950 resulted in cardiac improvements, reinforcing the therapeutic promise of inflammatory pathway targeting in HFpEF.
Although males and females experience similar cardiovascular risk factors during life, heart failure (HF) present in a sex-specific manner. Underlying pathophysiological mechanisms remain to be elucidated. We therefore investigated HF development in male and female mice using our multifactorial HF model. We observed that males developed HF with a more reduced ejection fraction with patchy fibrosis, whereas females developed a HFpEF-like phenotype with diffuse, interstitial fibrosis. Targeting these different fibrotic responses with the traditional HF drug Eplerenone resulted in cardiac improvement in males, but not in females. Use of the non-traditional anti-fibrotic and anti-inflammatory agent Mesalazine improved cardiac function and structure in males and females, underscoring the necessity of developing sex-specific therapeutic strategies for HF.
Overall, this work provides extensive preclinical evidence supporting metabolic and inflammatory targeting in HFpEF and emphasizes the importance of sex-specific treatment approaches. These findings encourage further translational research and interdisciplinary efforts toward personalized strategies for at-risk patients.