Flattening the sympathetic-vascular transduction curve

The sympathetic arm of the autonomic nervous system plays a significant role in beat-by-beat regulation of arterial blood pressure (BP) by modulating peripheral vascular tone and has been a fascinating focus of research for decades. Numerous studies have documented the reduction in vascular conductance following reflex increases in muscle sympathetic nerve activity (MSNA) in humans. However, methodological advancements in recent years have provided novel techniques to quantify vascular responses to spontaneous bursts of MSNA (i.e., sympathetic-vascular transduction). In this current issue, Nardone et al. (1) provides an eloquent study that advances our understanding of results obtained from the sympathetic-vascular transduction technique. Nardone et al. (1) evaluated the ongoing issue of baseline MSNA potentially biasing the results of the sympathetic transduction analysis and arrived at a novel statistical approach for normalization. When applying the normalization process within healthy groups of men and women that were comparable in age and sex, yet differing in baseline MSNA and sympathetic transduction, the differences in sympathetic transduction were abolished. The normalization approach is an exciting advancement that may prove to add clarity to the physiological meaning of the data in cases when MSNA is heterogeneous.

The sympathetic-vascular transduction technique involves signal-averaged changes in vascular conductance in a conduit artery following spontaneous bursts of MSNA under normal resting conditions. Signal averaging is a signal processing technique in the time domain meant for enhancing the strength of a small amplitude signal (i.e., reduction in vascular conductance following a spontaneous burst of MSNA) within the noisy data by calculating the mean waveform of multiple repeated waveforms. The signal-averaging approach provides high temporal resolution to the vascular response and is mediated primarily by α₁-adrenergic receptors (2). However, like all research techniques, there are limitations toward the signal-averaging approach. Foremost is the basal level of MSNA, which varies between individuals and may predetermine the pressor response to bursts of MSNA. Indeed, a growing body of evidence suggests that higher sympathetic transduction (i.e., adrenergic sensitivity) may compensate for lower MSNA to maintain blood pressure (BP) in normal adults (3–9). Importantly, the signal averaging approach may lose validity in individuals with high MSNA because the input signal (burst of MSNA) occurs in nearly all cardiac cycles in some cases, whereas the temporal response in the output signal (decrease in vascular conductance) often requires an observation period of 5–8 cardiac cycles following a burst of MSNA. Nardone et al. (1) spearheaded a solution to this ongoing issue with a new index of sympathetic transduction normalized for MSNA.

There are several obstacles that might spring to mind when considering normalized values for sympathetic transduction. One obstacle is that we must assume sympathetic transduction scales proportionately across different levels of MSNA. However, physiology does not always function in a linear fashion. For example, the dose-response relationship between exogenous norepinephrine and vascular conductance is a curve where the vascular response to high concentrations of norepinephrine begins to plateau. Similarly, arterial diameter increases nonlinearly during elevations in BP because the artery is functioning at a higher strain region of the stress-strain curve. Indeed, Nardone et al. (1) provide a clear demonstration of the nonlinear relation between MSNA and sympathetic transduction. Thus, it is evident that individuals with high MSNA are operating on a different region of the “sympathetic transduction curve” compared with individuals with low MSNA.

Nardone et al. (1) used a novel and pragmatic approach of applying a regression between the natural log of MSNA and sympathetic transduction and utilizing the slope of this log-linear regression as a correction exponent for sympathetic transduction. The sympathetic transduction value normalized using the correction exponent was no longer correlated with MSNA. Furthermore, men and women segregated by high and low MSNA showed differing levels of sympathetic transduction, but these differences within groups of men and women were abolished after normalizing sympathetic transduction for MSNA using the correction exponent. This finding is significant because it suggests that the initial difference in sympathetic transduction observed between groups is likely an artifact in the signal-averaging approach resulting from group differences in MSNA.

This significant step of potentially overcoming the confounding influence of baseline MSNA represents another key strength for this technique. Other notable advantages of sympathetic-vascular transduction include spontaneous release of endogenous norepinephrine without intra-arterial infusion of pharmacological agents. Second, when examining the temporal response, the reduction in vascular conductance following bursts of MSNA coincides with the increase in arterial blood pressure (BP) but not the relatively small and brief increase in cardiac output (2, 10, 11). Therefore, the contribution of cardiac output to the isolated pressor response following spontaneous bursts of MSNA is minimal, whereas studies examining the pressor response to reflex increases in sympathetic nerve activity (e.g., cold pressor test, handgrip) must account for elevations in cardiac output. Third, sympathetic-vascular transduction technique can distinguish differences in the vascular response following various MSNA burst patterns and amplitude. Finally, sympathetic-vascular transduction can be determined without a measure of local vascular conductance by simply examining transduction of MSNA to BP, such as in this study by Nardone et al. This assessment is termed “sympathetic transduction” rather than “sympathetic-vascular transduction” because the vascular component is not measured. The major advantage of utilizing transduction of MSNA to BP is that the increase in BP represents the aggregate output from the perspective of overall BP regulation.

It is notable that Nardone et al. (1) specifically utilized diastolic BP as the output value for sympathetic transduction. On the surface, this is understandable because an association between diastolic BP and MSNA has been observed extensively over the past several decades. Sundlöf and Wallin (12) first reported that the occurrence of a MSNA burst was more often correlated with diastolic BP than with systolic BP, pulse pressure, or mean arterial pressure (MAP), and therefore, diastolic BP has been considered the critical input signal for the baroreflex to modulate MSNA. However, when considering sympathetic-vascular transduction, the end-organ response is a decrease in vascular conductance rather than diastolic BP, and the calculation of vascular conductance is determined by MAP. This principle is illustrated by Ohm’s law (total peripheral resistance = MAP/cardiac output). Thus, although there is an interaction between the baroreflex and sympathetic transduction, it is not clear that diastolic BP is more physiologically relevant than MAP. When comparing sympathetic transduction using diastolic BP versus MAP, Nardone et al. (1) noted a significant correlation. However, whether results showed a difference when comparing groups of men and women with high versus low MSNA in the primary analysis is unclear and was not reported. This is important because studies have yet to demonstrate that diastolic BP is more appropriate than MAP or vascular conductance as an output variable for sympathetic transduction. This gap in knowledge further highlights the need for more research behind the technique of sympathetic-vascular transduction.

In summary, Nardone et al. should be highly commended for their contribution. Their work marks a significant milestone, but additional questions loom large. For example, does the correction exponent flatten the curvilinear relation between MSNA and sympathetic transduction when using vascular conductance rather than BP as the output variable? Also, the vasculature is exposed to numerous factors that govern the ability to constrict and relax, and normalizing for interindividual differences in BP (i.e., distending pressure) or arterial diameter are questions that may be on the horizon. Important advancements often generate additional questions, and the current study by Nardone et al. certainly falls within this category.

GRANTS

This paper is supported by the National Heart, Lung, and Blood Institute Grant R01HL159370.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

S.W.H. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.