In Failing Hearts, Cardiomyocytes Alter Metabolism

While the heart cells normally burn fatty acids, when things go wrong ketones become the preferred fuel source.

By | June 1, 2016

CHANGE-UP: Healthy cardiomyocytes (left panel) mainly use fatty acids as their energy source. But in a mouse model of heart failure and in failing human hearts (right panel), cardiomyocytes depend more on ketones for energy. 
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The paper
G. Aubert et al., “The failing heart relies on ketone bodies as a fuel,” Circulation, 133:698-705, 2016.

As organs go, the heart is an energy hog. To keep it fueled, mitochondria within cardiomyocytes (heart muscle cells) constantly churn out ATP as a product of the citric acid cycle. In the heart, most of the cycle’s substrates come from the metabolism of fatty acids, but the organ can also make use of other compounds such as lactate or ketones.

When Daniel Kelly of Sanford Burnham Prebys Medical Discovery Institute in Orlando, Florida, learned that some rare genetic disorders both cause dysfunction of the heart muscle and simultaneously disrupt fatty acid oxidation and increase ketone metabolism, he wondered if ketones might play a role in heart failure. “It was kind of a genetic proof of concept that these fuel changes might really be important, rather than just innocent bystanders,” he says.

During starvation, the liver makes extra ketones, allowing the brain to switch to ketones for fuel when glucose is low. To find out whether a similar process occurs early in heart failure, Kelly’s team mimicked two common causes of human heart failure—heart attack and hypertension caused by aorta constriction—in mice, and performed proteomic analyses four weeks later.

They observed lowered levels of proteins that process fatty acids for energy and increased levels of a ketone-metabolizing enzyme called βOHB dehydrogenase 1 (BDH1). They also found elevated levels of three ketone metabolites, and when the team perfused excised hearts with a radioactively labeled version of the ketone βOHB, hypertrophied hearts ate up more of the ketone to produce substrates for the citric acid cycle than healthy hearts did.

Kenneth Margulies and colleagues at the University of Pennsylvania saw similar metabolic changes in failing human hearts sampled during surgery or removed during cardiac transplantation (Circulation, 133:706-16, 2016). Margulies’s team observed that the expression of the genes for BDH1 and other ketone-metabolizing enzymes ramped up in failing heart tissue. Although failing hearts and healthy controls (from organ donors) displayed no differences in the abundance of proteins involved in fatty acid oxidation, failing ones had lower levels of fatty acid intermediates called acylcarnitines, suggesting the hearts were not using their normal fuel source.

Both mice and humans with heart failure had increased concentrations of ketones in their serum, hinting that ketone production in the liver was increased. “This was really fascinating because that means there is a liver-heart connection,” Kelly says. To find out if that’s the case, he plans to study mice lacking an enzyme required for ketone production in the liver.

These mice will also be useful in discerning whether the switch to ketones is a good thing. “We don’t know if it’s adaptation or maladaptation,” says Heinrich Taegtmeyer, a cardiologist at the University of Texas Health Science Center in Houston. Figuring that out could potentially inform ways to protect hearts in bad situations.

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