Heart failure is frequently detected only after the heart has already weakened. This is due in large part to the fact that the aetiology of heart failure is unclear in around 70% of cases. Researchers at The Hospital for Sick Children (SickKids) have discovered that one of the early indicators of heart failure is a shift in how the heart creates energy, with the results potentially giving a technique to prevent heart failure before it occurs.
The study, led by Dr. Paul Delgado-Olguin, a Scientist in the Translational Medicine programme, and funded by the Ted Rogers Centre for Heart Research, may also assist to understand the wide range of causes of heart failure.
“We were surprised to find that dysregulation of energy production was the earliest sign of heart failure,” says Delgado-Olguin. “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.”
Changes in energy production indicate cardiac disease
A protein called lysine demethylase 8 (Kdm8) helps to maintain a balanced energy consumption, often known as metabolism, in a healthy heart by inhibiting TBX15, another enzyme that reduces energy generation. The study team evaluated a big dataset on gene expression, the process by which DNA is translated to proteins, in human hearts at a later stage of heart failure and discovered that KDM8 was less active.
This increased the expression of TBX15, resulting in metabolic alterations. Researchers also discovered that TBX15 was most abundant in hearts where energy production genes were most substantially inhibited. “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,” says Delgado-Olguin.
Following the discovery of the shift in energy production as an early warning of heart failure, the study team dug further to see how metabolic pathways may be altered to avoid the failure. They discovered that the nicotinamide adenine dinucleotide (NAD+) pathway, which governs energy metabolism, was less active as a result. The researchers were subsequently able to intervene and avert heart failure in a mouse model by injecting NAD+ and increasing energy production.
“This research suggests it may be possible to alter certain metabolic pathways to prevent heart failure before damage to the heart begins,” says Delgado-Olguin. “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.”
Precision medicine might aid in the prediction and prevention of heart failure.
This research contributes to the future of Precision Child Health at SickKids, an effort to provide tailored treatment for every child, according to the study team.
“Heart failure is so diverse,” says Delgado-Olguin. “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.”
While worldwide research on NAD+ therapy in late-stage heart failure is ongoing, the Delgado-Olguin Lab expects that this current study may spur new research on early detection and preventative treatment.