Why the Heart’s Metabolism Fascinates This Scientist

The heart runs an around-the-clock fuel operation, burning almost any nutrient it can get to keep pumping. Understanding this fuel operation is the central focus of scientist Anja Karlstaedt, MD, PhD, and her team. Their work could lead to new treatments for the millions of people with conditions that impair their heart function.

A new study led by Karlstaedt and published in Circulationreports that a specific enzyme plays an important role in keeping the heart beating. The discovery could help scientists create drugs that mimic the enzyme's role and help people with heart failure, a condition in which the heart becomes too weak to pump blood properly.

Karlstaedt, assistant professor of Cardiology in the Smidt Heart Institute at Cedars-Sinai, has spent more than a decade studying heart metabolism-the chemical process that powers the heart. She spoke with theCedars-Sinai Newsroom about her dedication to uncovering treatments for the millions diagnosed with heart failure every year.

How is the heart's metabolism different from the metabolism of other parts of the body?

There are thousands of tiny molecules called metabolites-including amino acids, glucose and fatty acids-that act as an energy source to help cells function properly. The heart is the only organ that can use almost any metabolite.

The heart is also unique because it never stops beating. It's not like other muscles, which can rest. Fueling heart cells requires fine-tuned, organized chemical reactions. The system functions perfectly until something disrupts it, and metabolism is at its center.

What was one of the major discoveries that led to your current work?

My colleagues and I published a study in 2016 in which we discovered that the heart uses unusual fuel-processing routes to adapt to metabolites released by cancer cells. It's like in a city where you have streets and traffic moves along those streets. If a construction site suddenly blocks a street, traffic finds another way around. The heart does the same thing.

We also found that in response to cancer-related metabolic stress, the heart suddenly started using an unusual enzyme called ATP-dependent citrate lyase, or ACL. This enzyme drives the process that creates fatty acids, something we didn't think happened in heart cells. But when we blocked ACL, the heart could not pump well. That told us this enzyme might be much more important for the heart than previously thought.

Could you describe your recent discovery?

We found that when ACL slows down, heart function drops. To make this discovery, we studied heart tissue samples from people with healthy hearts and people with failing hearts. We also observed ACL in the hearts of laboratory mice. When ACL activity decreased, meaning it no longer efficiently produced fatty acids, the heart tried to adapt by taking up more sugar and rewiring parts of its metabolism. But those changes did not fully protect the heart. Instead, the heart had less available energy and did not pump as well.

To dig deeper, we used CardioNet, our computational model of heart metabolism. The model pinpointed another enzyme, IDH1, that compensates for the loss of ACL. When we reduced IDH1 in our model, the heart could pump better. We're now studying whether future heart failure therapies could target IDH1.

What do you hope to accomplish as this work progresses?

Heart failure can look similar from one patient to another, but the underlying metabolic changes may be different. We hope to use our computational model to predict which fuel pathways are disrupted in people with heart failure and which treatments can get the heart working better. We are not there yet, but this study is an important step toward understanding heart failure as a disease of both mechanics and metabolism.

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