In this engaging episode, Dr. Olguín delves deep into the intricate connection between cardiac metabolism and heart failure, focusing on the crucial role of the enzyme lysine demethylase 8 (Kdm8). Dr. Olguín's groundbreaking research suggests that Kdm8 ensures the smooth functioning of the mitochondrial gene network by suppressing the gene Tbx15, thereby preventing dilated cardiomyopathy, a condition that can lead to lethal heart failure. Through their work on mice, the research team found that a lack of Kdm8 increases a certain type of protein modification which activates Tbx15, subsequently leading to a drop in target genes within the NAD+ pathway before the onset of dilated cardiomyopathy. Furthermore, the team discovered that NAD+ supplementation could prevent dilated cardiomyopathy in Kdm8-deficient mice. Remarkably, KDM8 was found to be downregulated in human hearts afflicted by dilated cardiomyopathy. Higher TBX15 expression was found in a subgroup of these hearts, which were also strongly marked by the downregulation of genes encoding mitochondrial proteins. This in-depth discussion with Dr. Olguín not only reveals how KDM8 regulates TBX15 to maintain cardiac metabolism but also opens up a wider conversation on how the epigenetic dysregulation of metabolic gene networks might initiate deterioration of the myocardium, potentially underlying the heterogeneity of dilated cardiomyopathy. This episode is a must-listen for anyone interested in cutting-edge research on heart disease and the complex interplay between genetics, epigenetics, and metabolism.

Ahmed, A., et al. KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy. Nat Cardiovasc Res 2, 174–191 (2023). https://doi.org/10.1038/s44161-023-00214-0