Systems Pharmacology Model of Heart Failure with Preserved Ejection Fraction
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality in the US. An excessive burden of comorbidities characterizes the clinical profile of this patient population. These comorbidities are typically more numerous and heterogeneous than that which is observed amongst individuals who are diagnosed with heart failure with reduced ejection fraction (HFrEF). In HFpEF, cardiac dysfunction is thought to arise from the systemic inflammatory conditions brought upon by these comorbidities. This may explain why existing cardio-centric therapies have been unable to benefit the HFpEF population. Herein, we have embraced the multi-factorial nature of HFpEF and employed a systems pharmacology approach that transcends conventional target-based discovery. The integration of multiple HFpEF RNA sequencing datasets across different species was processed and analyzed through a drug repurposing pipeline. Glucocorticoid agonists were predicted to reverse these HFpEF signatures. We then utilized a recently developed chrono-pharmacologic scheduling protocol to administer prednisone in a two-hit mouse model of HFpEF. This was observed to significantly improve diastolic function following HFpEF treatment, as well as cardiomyocyte hypertrophy and vascular rarefication. Cardiomyocytes were then isolated from HFpEF mice treated with either vehicle or prednisone. These results indicated that prednisone treatment directly benefited contractile parameters in isolated cardiomyocytes. In summary, we have used an innovative drug-discovery approach that is particularly well suited to identifying compounds capable of targeting complex polygenic diseases such as HFpEF. Next, we demonstrated the utility of this approach byperforming in vivo and in vitro studies, highlighting the use of intermittent prednisone as a potentially beneficial strategy in treating HFpEF.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2024
- Accession Number
- AD1227024
Entities
People
- Sang G. Ong
Organizations
- University of Illinois at Chicago