Cardiac Sympathetic Nerve Activity Is Not Elevated in Ovine Hypertensive HFpEF.

Abstract

BACKGROUND The sympathetic nervous system is a crucial mediator of cardiovascular variables during exercise. However, its role in heart failure with preserved ejection fraction (HFpEF), where exercise intolerance is a cardinal feature, is poorly understood. Currently, there is scant and no clear evidence of heightened cardiac sympathetic nerve activity (CSNA) in HFpEF, which might explain why β-blockers lack convincing prognostic benefit in this syndrome. Accordingly, we utilized gold standard direct recordings to test the hypothesis that resting levels of CSNA are not elevated in HFpEF. We also tested whether β-blockers in HFpEF cause further impairments in the hemodynamic determinants of exercise capacity. METHODS Experiments were conducted in a conscious large animal (ovine) model of hypertensive HFpEF that exhibits similarly impaired exercise hemodynamics as patients with HFpEF. Direct recordings of CSNA were made in this model and compared with non-HFpEF sheep. In addition, hemodynamic responses to graded treadmill exercise testing were compared before and after β-blocker administration. RESULTS Gold standard direct recordings of resting CSNA were not elevated in HFpEF sheep. Inhibition of this activity using a β-blocker further impaired exercise hemodynamics (cardiac output, heart rate and pulmonary capillary wedge pressure) in HFpEF sheep. In addition, non-HFpEF and HFpEF sheep exhibited differential exercise hemodynamic responses to β-blockers. CONCLUSIONS Our data demonstrates that CSNA is not elevated in an ovine model of hypertensive HFpEF and suggests that favorable exercise hemodynamics in HFpEF are reliant upon β-adrenergic activation. Our findings provide a mechanistic rationale for why β-blockers should be avoided in patients with HFpEF.