Nearly half of current hospital admissions for heart failure are caused by a type of the disease with no treatment options. Cardiology researchers at UT Southwestern are changing that reality with a fresh approach, detailed in an article recently published in Nature.

There are two types of heart failure. One is called HFrEF, for which we have a number of therapies, including medications, devices, and transplants. The other – HFpEF – has zero options, explained Dr. Joseph Hill, Chief of the Division of Cardiology. HFpEF is the single greatest unmet need in cardiology. Finding a new way to examine it represents a significant advance, as it provides a model necessary to develop and test therapies that could save lives worldwide.

The Centers for Disease Control and Prevention estimates that 5.7 million people have heart failure in the U.S.

One type of the disease – heart failure with preserved ejection fraction (HFpEF) – is a lethal disorder for which there are no effective clinical therapies. The heart muscle becomes too stiff to pump blood efficiently. Most HFpEF patients are obese, have diabetes, and have metabolic syndrome.

A second type is heart failure with reduced ejection fraction (HFrEF), which functions differently. In HFrEF, also known as systolic HF, the heart muscle is not able to contract adequately and, therefore, expels less oxygen-rich blood into the body. Previous heart failure models of HFpEF focused on raising the levels of an enzyme called NO, or nitric oxide synthase.

However, in HFpEF, there is actually too much of the NO enzyme. A strike on this target – with a medical inhibitor, for example – would solve the problem. According to Dr. Hill, who is also Professor of Internal Medicine and Molecular Biology, there are already FDA-approved drugs that inhibit this NO-synthesize enzyme, which could facilitate developing new treatments rapidly.

Dr. Hill’s team looked at current, ineffective models of HFpEF and concluded that none correctly mirrors the realities they see clinically in human patients. They found that combining a high fat diet with a drug that raises blood pressure gave them a “two-hit” model, like a one-two punch to the disease. Next, the team examined results of their model at the cellular level and compared them with human cells. They found that they had replicated the human condition, providing scientists an accurate biological picture that can greatly advance the development of new treatments.

Millions of people worldwide have both obesity and diabetes. The research team believed that these two conditions would lead to HFpEF – a hypothesis they confirmed by duplicating the disease conditions and examining changes at the molecular level.

Heart failure is one of only two forms of cardiovascular disease that is increasing. It’s exploding around the world, said Dr. Hill, who is also Director of the Harry S. Moss Heart Center at UT Southwestern and Editor-in-Chief of Circulation. We dance around the edges of it, treating patients’ diabetes, blood pressure, and other conditions. With this model, we’ll be able to get to the underlying cause so we can get to the root of the problem.

The UT Southwestern researchers are currently taking steps toward moving into human clinical trials based on findings in their preclinical two-hit model. With time, they expect that all heart failure patients will have treatment options.

The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, helped fund the study. Researchers from Johns Hopkins University and the University of Chile also contributed to the study.