UCLA researchers from the Department of Medicine have discovered a novel therapeutic target to treat heart failure with preserved ejection fraction (HFpEF), which afflicts approximately half of all patients with heart failure.
BACKGROUND: Heart failure is one of the leading causes of death and disease with over 500,000 cases diagnosed each year in the United States and over 60 million worldwide. Heart failure with preserved ejection fraction (HFpEF) refers to the condition of which the heart pumps less blood out to the body than is needed, also termed diastolic dysfunction. HFpEF makes up approximately half of heart failure cases. Notably, the pathogenesis of HFpEF is distinct from heart failure with reduced ejection fraction (HFrEF). Current therapeutic strategies for heart failure are effective for HFrEF but not for HFpEF. To date there are no effective treatments for HFpEF and limited knowledge exists regarding the molecular pathways regulating heart dysfunction in HFpEF. Accordingly, novel scientific research and related therapeutic strategies specifically targeting the underlying mechanisms of HFpEF are of great interest to clinicians as new therapies could improve health outcomes of a multitude of patients.
INNOVATION: Researchers at UCLA conducted a bioinformatics study of over 100 different strains of mice to understand the crosstalk between the liver and heart. They identified a liver-derived protein coagulator as a critical regulator of heart gene expression and diastolic dysfunction, a key trait of HFpEF. Work from the Lusis group demonstrates that overexpression of this factor in HFpEF mouse models decreased the diastolic function phenotype and reduced inflammation through the BMP-Smad1/5 signaling pathway without altering blood coagulation. Conversely, genetic knockout mouse models of this factor sensitize the mice to heart failure attributed to diastolic dysfunction. Increasing the activity and expression of this liver-derived coagulation factor is an effective and specific approach to improve heart function, chronic inflammation, and metabolic disorders associated with mice model of HFpEF.
POTENTIAL APPLICATIONS:
- Therapy for heart failure with preserved ejection fraction (HFpEF)
- Early preventative treatment
- Administration following heart events or surgery
ADVANTAGES:
- Increased specificity and therapeutic efficacy towards diastolic dysfunction caused by HFpEF
- Reduction of inflammation and secondary metabolic dysfunction derived from HFpEF
- Works through a separate mechanism than current standard-of-care treatments
DEVELOPMENT-TO-DATE: Proof of concept shown in disease mice models and relevant patents have been filed.
Related Papers (from the inventors only): Cao Y, Lusis AJ. Coagulation factor with potential for the treatment of heart failure. Clin Transl Med. 2022 Dec;12(12):e1144. doi: 10.1002/ctm2.1144. PMID: 36513961; PMCID: PMC9747747.
Keywords: Heart failure, heart failure with preserved ejection fraction (HFpEF), cardiovascular disease, liver, FXI, metabolic disease