Improving heart failure with reduced ejection fraction (HFpEF) treatment using a mathematical model of physiology

Improving heart failure with reduced ejection fraction (HFpEF) treatment using a mathematical model of physiology

For 47 years, the University of Mississippi Medical Center Physiology Department has been developing computer simulations of integrative physiology for research purposes. The current model, HumMod, is comprised of 14 organ systems, and includes the nervous system, endocrine system (hormones and glands that secrete them), circulatory physiology (the heart, blood volume, and blood vessels), and the kidneys. I have created tools that generate and analyze large sets of computer-generated (virtual) patients. With these techniques HumMod has been used for hypothesis generation and for understanding underlying physiological mechanisms that are not able to be determined in either whole animal or human experiments. This proposed work will use these tools and this mathematical model of human physiology to develop a realistic virtual population for studying heart failure and its treatment. Heart failure (HF) is a complicated disease, and HF patients can have largely different ejection fractions. Ejection fraction refers to how well your heart pumps blood. It is the amount of blood pumped out of your heart's lower chambers (ventricles) to the body's organs each time it contracts. Some people with a normal ejection fraction (50-70% of blood pumped out) also have HF. This is known as HF with preserved ejection fraction (HFpEF).Published data from my laboratory show that the model is robust and can realistically simulate HFpEF, kidney disease, and multiple types of treatments including the drug that was investigated in the PARAGON-HF trial: the angiotensin/neprilysin inhibitor (ARNI). ARNI is a medicine resulting from the combination of two drugs (sacubitril and valsartan), which are a class of drugs that are used to treat hypertension (high blood pressure). With the PARAGON-HF trial individual patient data, I will be able to train a race-specific virtual population model (namely white and black populations) and virtually investigate heart and kidney mechanisms for the benefits seen with ARNI. The aim of the study is to artificially increase the Black population sample in the PARAGON-HF trial to determine the efficacy of ARNI on this underrepresented subgroup in the trial (only 2% of the population), who are subject to a higher than average disease burden. Indeed, Black Americans experience higher rates of hypertension, kidney disease, ventricle diastolic dysfunction, and disproportionate HFpEF burden, hospitalization, and death as compared to whites. Black Americans are consistently underrepresented in clinical trials. While the response to ARNI has not been shown to be different in black HF patients with low ejection fraction as compared to whites (CHAMP-HF and PIONEER-HF trials), it's impact in black HFpEF/CKD patients is unclear.

[{ "PostingID": 21065, "Title": "NOVARTIS-CLCZ696D2301", "Description": "Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF)" }]