Sympathetic activation and the force-frequency relationship in heart failure with reduced ejection fraction

Straw, S.; Gupta, A.; Bretheron, B.; Cole, C. A.; Brown, O. I.; Kamalathasan, S.; Drozd, M.; Lowry, J. E.; Corrigan, J.; Paton, M. F.; Burgess, R.; Kearney, M. T.; Cubbon, R. M.; Witte, K. K.; Gierula, J.

doi:10.64898/2026.08.24.746885

bioRxiv · 10.64898/2026.08.24.746885

Sympathetic activation and the force-frequency relationship in heart failure with reduced ejection fraction

Straw, S.·Gupta, A.·Bretheron, B.·Cole, C. A.·Brown, O. I.·Kamalathasan, S.·Drozd, M.·Lowry, J. E.·Corrigan, J.·Paton, M. F.·Burgess, R.·Kearney, M. T.·Cubbon, R. M.·Witte, K. K.·Gierula, J.

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Abstract

Background Limited heart rate rise contributes to reduced exercise tolerance for people who have heart failure with reduced ejection fraction (HFrEF), yet rate-adaptive pacing does not improve functional capacity due to an attenuated force-frequency relationship (FFR). How the FFR relates to total peripheral resistance and sympathetic tone in HFrEF is unknown. Methods In a prospective, observational study, participants with HFrEF and controls underwent an incremental pacing protocol, during which heart rate was increased from 50 to 140 beats per minute. At each heart rate increment LV contractility was measured by echocardiography to determine the FFR, as well as continuous beat-to-beat measurement of systolic and diastolic blood pressures with a plethysmography device to determine cardiac output, total peripheral resistance and blood pressure variability (BPV). A microneurography study was then conducted to measure muscle sympathetic nerve activity (MSNA) during incremental pacing. Results A total of 157 participants with HFrEF and 55 controls (mean age 71.1{+/-}1.4 years, 172 (81.1%) male) underwent the pacing protocol. We observed single units in seven of 11 participants who participated in the microneurography study. In both groups, LV contractility and cardiac output increased until the peak of the FFR, after which these declined. We observed a reduction in total peripheral resistance, blood pressure variability, MSNA frequency and incidence coinciding with the peak of the FFR, beyond which these increased. Whilst these relationships were present in both groups, they were more evident in participants with HFrEF. Conclusions For people with HFrEF there is a bidirectional relationship between heart rate and sympathetic activation, with a nadir of sympathetic tone occurring at the peak of the FFR. Both excessively low and high heart rates are accompanied by greater sympathetic activation. Taken together, these data suggest that optimal heart rate targets for HFrEF are likely to be individual.

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Straw, S., Gupta, A., Bretheron, B., Cole, C. A., Brown, O. I., Kamalathasan, S., Drozd, M., Lowry, J. E., Corrigan, J., Paton, M. F., Burgess, R., Kearney, M. T., Cubbon, R. M., Witte, K. K., Gierula, J.. 2026-09-01. Sympathetic activation and the force-frequency relationship in heart failure with reduced ejection fraction. https://doi.org/10.64898/2026.08.24.746885

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