For decades, cardiovascular physiology has been built on the assumption that arterial barorecep-tors adjust heart rate (HR) to maintain a defined blood pressure set point. We challenge this paradigm fundamentally. Blood pressure and heart rate both change substantially in response to physiological stress and neither returns reliably to a fixed baseline value. This raises the question of whether a higher-order variable, one that remains stable while blood pressure and heart rate reset freely might better represent a truly defended, “set-point” quantity. We hypothesized that instantaneous baroreceptor gain (IBS), expressed as the change in R-R interval per unit change in systolic blood pressure (SBP), has a coefficient of variation (IBS CV) that is invariant across different physiological challenges. If IBS CV is fixed, then ΔHR and ΔSBP must vary proportionally, maintaining a stable gain relationship even as each changes in magnitude. This constraint suggests that blood pressure and heart rate are adjustable outputs that reset freely in response to physiological demand, rather than defended targets in their own right. An invariant IBS CV guarantees that the baroreflex arc behaves consistently and predictably across the full range of physiological states: the brain can rely on a stable gain relationship between blood pressure and heart rate, enabling reliable closed-loop cardiovascular control without having to recalibrate the relationship under every new condition.

To test this hypothesis, we had healthy adult volunteers undergo either the cold pressor test or passive orthostatic challenge. Heart rate (HR), systolic blood pressure (SBP), IBS (the regression coefficient of R-R intervals on their respective systolic blood pressures), and the coefficients of variation (CV, i.e. standard deviation ÷ mean value) of each were measured at baseline and during each stress perturbation. During orthostatic challenge, HR rose significantly while SBP fell significantly. Classically, this HR rise is attributed to baroreflex compensation for falling pressure. However, the critical observation is that SBP was not restored to baseline. Instead, it remained substantially reduced while HR stayed persistently elevated and HR CV increased significantly. A system primarily defending a blood pressure set point should augment baroreflex gain and suppress pressure variability; instead mean IBS showed no significant change, SBP CV amplified more than threefold, and IBS CV was unchanged. During the cold pressor test, both HR and SBP rose simultaneously, which is inconsistent with a pressure-defending system that would have suppressed HR in response to the large rise in SBP. IBS CV was also stable across this perturbation while SBP CV amplified dramatically. These findings challenge the classical baroreceptor set-point model and suggest that IBS CV, not blood pressure, is the primary regulated cardiovascular variable.

The authors have declared no competing interest.

This was not a clinical trial. We used human subjects, therefore it was deemed clinical research rather than basic science or laboratory animals.

This work was supported by the Henry M. Jackson Foundation for Military Medicine under Grant No. HU0001-23-2-0125. No one received any third party payment for this work.

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Study was approved by the Wayne State University Institutional Review Board, FWA #0002460, IRB00000325 for M1- Medical adult.

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