Background: Metabolic comorbidities are frequent in patients with heart failure with preserved ejection fraction (HFpEF). We recently demonstrated that chronotropic incompetence and exercise intolerance are associated with intrinsic sinoatrial (SAN) dysfunction in animal models of HFpEF. However, there are no studies investigating whether metabolic dysfunction in HFpEF can lead to mitochondrial dysfunction in the SAN. Hypothesis: Our recent findings uncovering SAN pacemaker dysfunction in HFpEF upon metabolic stress led us to test the hypothesis that mitochondrial dysfunction may underlie this condition. Methods: Male C57Bl6 mice fed high fat diet (HFD) plus nitric oxide inhibitor (L-NAME) or regular chow served as HFpEF and control, respectively. Optical mapping, transcriptomics, targeted quantitative proteomics of mitochondrial proteins, mitochondrial respiration and reactive oxygen species (ROS) assays were conducted using explanted mouse SAN tissue or isolated pacemaker cells. Results: SAN from HFpEF-verified animals after 20 weeks of HFD+LNAME exhibited prolonged SAN recovery time after pacing (100%; P<0.05). RNA sequencing revealed augmentation of gene clusters related to metabolism (i.e. ucp and pdk4 ) and extracellular matrix expansion (i.e. col, postn and Cilp1 ). Targeted proteomics validated SAN RNA-sequencing findings, showing upregulation of proteins related to ROS scavenging, fatty acid transport and TCA/OXPHOS (i.e. SOD, CPT2 and DHSA/B). Depressed maximal mitochondrial respiration was seen in isolated mitochondria from SAN of HFpEF animals compared to controls (-42%; P<0.05). This was supported by increased generation of mitochondrial ROS in single pacemaker cells from HFpEF SAN (70%; P<0.05). Acute mitochondrial dysfunction induced by a mitochondrial uncoupler (FCCP) elicited a pronounced prolongation of SAN recovery time in HFpEF compared to controls (165%; P<0.05). Conclusion: Our results indicate that mitochondrial function is depressed in SAN from HFpEF animals, and is associated with SAN pacemaker dysfunction. Further studies are required to test cause-and-effect and to evaluate potential therapeutic strategies targeting mitochondrial pathways for HFpEF associated abnormalities of sinus rhythm.

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