Heart failure occurs when the heart muscle doesn’t pump blood as well as it should. Blood often backs up and causes fluid to build up in the lungs and in the legs. Unfortunately, heart failure is often identified only when the heart has already deteriorated. Now, researchers at the Hospital for Sick Children (SickKids) have discovered that one of the earliest signs of heart failure is a change in how the heart produces energy. The findings offer a potential way to pre-empt heart failure before the heart begins to deteriorate.

Their study is published in the journal Nature Cardiovascular Research in a paper titled, “KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy.”

“Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear,” wrote the researchers. “Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressing Tbx15, thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of Kdm8 in mouse cardiomyocytes increased H3K36me2 with activation of Tbx15 and repression of target genes in the NAD+ pathway before dilated cardiomyopathy initiated.”

“We were surprised to find that dysregulation of energy production was the earliest sign of heart failure,” said Paul Delgado-Olguín, PhD, a scientist in the Translational Medicine program, and who also led the study. “People associate deficiency in energy production with later stage heart failure, but our findings show this could actually be the cause of heart failure, not a result.”

In a healthy heart, Kdm8 helps to maintain a balanced energy use by repressing TBX15, another protein that decreases energy production.

The research team analyzed a large dataset of gene expressions, in human hearts at a later stage of heart failure and found that KDM8 was less active. This allowed TBX15 to be more highly expressed, leading to changes in metabolism. Researchers also found that TBX15 was expressed at the highest levels in hearts where energy production genes were most strongly suppressed.

“There are many genes that help regulate energy production in our bodies, but we were able to identify changes in specific proteins that occur well before cardiac deterioration,” said Delgado-Olguín.

After identifying a change in energy production as an early sign of heart failure, the research team further explored how metabolic pathways could be modified to prevent the failure.

They observed that the nicotinamide adenine dinucleotide (NAD+) pathway, which regulates energy metabolism, was less active. The team was then able to intervene and prevent heart failure in a mouse model by providing NAD+ injections and boosting energy production.

“This research suggests it may be possible to alter certain metabolic pathways to prevent heart failure before damage to the heart begins,” explained Delgado-Olguín. “Our research sets the stage to identify children and adults that may be at a higher risk of heart failure, and to improve energy balance in their hearts to prevent it.”

“Heart failure is so diverse,” said Delgado-Olguín. “But if we could determine that an individual’s particular heart is not using energy efficiently early on and is at risk of heart failure, we may be able to predict how they respond to treatment targeted to specific metabolic pathways that could prevent cardiac deterioration.”

The research team hopes the latest research from the Delgado-Olguín Lab will lead to new research on early identification and preventative treatment.

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