Heart Failure Model Could Boost Drug Research

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Patients suffering from heart failure with preserved ejection fraction have few therapeutic options.

Dr. Lina Shehadeh and collaborating researchers."
Lina Shehadeh, Ph.D. (fourth from left), and collaborating researchers.

Researchers at the University of Miami Miller School of Medicine have developed a mouse model that replicates heart failure with preserved ejection fraction (HFpEF), which has very limited treatment options. Ejection fraction measures how much blood the heart’s left ventricle pumps with each beat. The authors believe this new model will boost HFpEF research and expand therapeutic options for patients. The study was published on September 3 in the Journal of the American Heart Association.

“Heart failure is the number one killer in the world, causing more deaths than cancer,” said professor and scientist Lina Shehadeh, Ph.D., senior author on the study. “Half of heart failure patients have reduced ejection fraction, while the other half have preserved ejection fraction. Heart failure with reduced ejection fraction has an entire panel of drugs, but its counterpart has virtually no therapies, and this has been a major dilemma in the field.”

HFpEF has few treatments in part because the available models have been inadequate, never fully capturing the condition’s complexity. HFpEF can differ substantially between patients, who may also suffer from obesity, diabetes, hypertension, chronic kidney disease, and other co-morbidities.

The Miller School team created a model with hyperlipidemia (increased fat in the blood), but without obesity, diabetes, kidney disease or hypertension, which replicates a specific HFpEF patient subtype: increased lipids in the heart and high risk of sudden death.

Reverse Engineering a Model
xanthelasma
Xanthelasma develops among hyperlipidemic patients.

The researchers used data from human patients to reverse engineer the model. First, the team increased LDL receptor levels in the heart, mimicking a trait they found in HFpEF patients. Also, they blocked an enzyme called lipoprotein lipase, which breaks down triglycerides. Other researchers have demonstrated reduced lipoprotein lipase expression in HFpEF patients’ hearts.

“This gave us a mouse with increased LDL cholesterol in the heart, not just in the blood,” said Dr. Shehadeh, whose lab focuses on cardiovascular disease and cardiac regeneration as well as rare kidney disease and Duchenne muscular dystrophy. “This made a huge difference, giving the mouse similar HFpEF traits to what we see in patients, such as diastolic dysfunction, which is caused by increased heart stiffness, fibrosis, arrhythmia, exercise intolerance, and sudden death. Most interestingly, the mouse has fat patches around the eyes (xanthelasma) as seen in hyperlipidemic patients.”

Lina Shehadeh, Ph.D.
Lina Shehadeh, Ph.D.

The study united an all-star team of University of Miami researchers, including Joshua Hare, M.D., who directs the Miller School’s Interdisciplinary Stem Cell Institute, and Jeffrey Goldberger, M.D., chief of the cardiovascular division. In addition, first author Monique Williams, M.D., has been funded with a coveted NIH Diversity Supplement Award.

The new model is the first step in a long-term effort to develop HFpEF treatments. Now that UM scientists have developed it, researchers everywhere will have a new tool to investigate more effective therapies.

“We are presenting the field with this model,” said Dr. Shehadeh, who expressed her gratitude to the NIH and the Miami Heart Research Institute for continuous funding of her lab. “We are hopeful it will help break through this therapeutic bottleneck. Now, we can test different drugs and hopefully find ones that work for these patients.”

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