Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model

•Early cardiac mitochondrial dysfunction is mediated by transcriptional down-regulation of the mitochondrial proteome.•Comprehensive metabolic remodeling is conserved throughout HFpEF progression and includes increased amino acid and lipid species, indicative of impaired oxidative metabolism.•Transcriptional and metabolic remodeling of skeletal muscle suggests cardiac signaling as a mediator of peripheral tissue maladaptation.•Unbiased systems-level analysis provides new mechanisms underlying HFpEF development.