We have shown that systemic and cardiac sympathetic activation is present in heart failure with preserved ejection fraction (HFpEF) patients. Conversely, whereas systemic inflammatory activation was also detected in HFpEF, we did not detect local myocardial release of inflammatory cytokines. Activation of the sympathetic system correlated with both hemodynamic and demographic factors that characteristically cluster together in HFpEF. Together these data suggest that there may be a role for antiadrenergic therapies in certain HFpEF patients. The study does not implicate locally derived cytokines in the myocardial biology of HFpEF, although systemic sources may contribute to the global pathophysiology of HFpEF.