Directly recorded cardiac sympathetic nerve activity is not elevated and β-blockers further impair exercise capacity in ovine heart failure with preserved ejection fraction

The sympathetic nervous system coordinates changes in cardiovascular variables during exercise. However, its role in heart failure with preserved ejection fraction (HFpEF), in which exercise intolerance is a cardinal feature, is poorly understood. In patients with HFpEF, there is no clear evidence that cardiac sympathetic nerve activity (CSNA) is elevated. Nonetheless, this has not deterred the prescription of β-blockers in HFpEF despite the lack of a convincing prognostic benefit with their use in this syndrome. Therefore, the supposition that sympathetic hyperactivity to the heart is present in HFpEF has never been directly assessed. Accordingly, this study tested the hypothesis that resting levels of CSNA are normal in HFpEF. Consequently, we also tested whether β-blockers in HFpEF cause further impairments in exercise capacity. Gold standard direct recordings of resting CSNA were made in conscious HFpEF and non-HFpEF ewes. Hemodynamic determinants of exercise capacity, such as cardiac output (CO) and pulmonary capillary wedge pressure (PCWP), along with coronary blood flow (CoBF), were then measured in sheep during graded treadmill exercise testing with and without a β-blocker (intravenous propranolol). Compared to non-HFpEF sheep, HFpEF sheep had higher resting mean arterial pressure (113±21.3 vs 78.9±9.0 mmHg, P < 0.0001, unpaired t test) but similar resting heart rate and cardiac output. Additionally, HFpEF sheep exhibited diastolic dysfunction (lateral E/e’ = 4.25±0.77 vs 3.63±0.54, P = 0.028, unpaired t test; left ventricular end-diastolic pressure = 13±5 vs 0.5±1 mmHg, P = 2.1x10 -6 , unpaired t test) without overt systolic impairment (left ventricular ejection fraction = 62±8 vs 63±8%, P = 0.67, unpaired t test). Resting CSNA burst frequency and incidence were not different between HFpEF and non-HFpEF sheep. During exercise, HFpEF sheep had impaired CO and elevated PCWP responses. Propranolol did not alter resting hemodynamics in HFpEF sheep but further attenuated the exercise CO (peak Δ: 4.08±1.27 vs 4.86±1.55 L/min, P = 0.007, ANOVA interaction effect) and augmented the exercise PCWP (peak: 17.9±1.82 vs 16.4±3.16 mmHg, P = 0.044, ANOVA interaction effect) responses. Additionally, while the exercise CoBF response was similar between HFpEF and non-HFpEF sheep, only HFpEF sheep had impaired exercise CoBF and coronary vascular conductance responses with propranolol. Our results demonstrate that in HFpEF, directly recorded resting levels of CSNA are not elevated and β-blockers further impair multiple hemodynamic determinants of exercise capacity. Therefore, we suggest that in the absence of a compelling indication, β-blockers should be avoided (or deprescribed) in patients with HFpEF. This study was supported by the Heart Foundation of New Zealand and the Health Research Council of New Zealand. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.