Pyruvate Dehydrogenase Kinase 4 Underlies the Metabolic Disorder of Cardiomyocytes in Patients With Hypertrophic Cardiomyopathy From Hypertrophy to Heart Failure

Background Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, the role of PDK4 (pyruvate dehydrogenase kinase 4), a key regulator of cardiac glucose and fatty acid oxidation, in HCM‐related heart failure remains unknown. Methods Single‐nucleus RNA sequencing was performed to analyze gene expression in patients with HCM (n=12), categorized into the following groups: normal, reduced, and heart failure. We validated our findings in additional cohorts of patients undergoing septal resection or heart transplantation. Cardiac‐specific Pdk4 knockout mice were crossed with Mybpc3 knockout mice, and PDK4 inhibition was also tested in Mybpc3 knockout mice. Cardiac metabolism was assessed via metabolic flux and Seahorse analysis in vivo and in vitro. Results Single‐nucleus RNA sequencing identified distinct cardiomyocyte clusters, with cardiomyocyte cluster 4 ( PDK4 + cardiomyocytes) significantly associated with impaired cardiac function and highly expressed in the cardiac tissue of patients with HCM heart failure. Elevated PDK4 inhibited pyruvate conversion to acetyl‐coenzyme A, impairing tricarboxylic acid cycle flux and reducing glucose oxidation, as confirmed by metabolic tracking. Both genetic ablation and pharmacological inhibition of PDK4 attenuated heart failure symptoms in Mybpc3 knockout mice. Conclusions Our findings highlight metabolic disturbance, specifically PDK4‐driven suppression of glucose oxidation, as crucial in HCM progression to heart failure. PDK4 represents a promising therapeutic target for preventing or treating heart failure in patients with HCM.