It takes two to tango: the coherence of cardiac output and sympathetic nerve activity
Year: 2007
Type: article
Abstract: One of the current challenges in human physiology is integrating the accepted qualitative components of blood pressure control into a coherent model that is in agreement with empirical data. For this purpose, this Journal Club article discusses a provocative empirical study that was recently published in The Journal of Physiology by Fu et al. (2006). On a beat-to-beat basis, mean arterial blood pressure (MAP) is the product of cardiac output (CO) and total peripheral resistance (TPR) (MAP = CO × TPR). The short-term control of blood pressure is regulated by the arterial baroreflex system that influences blood pressure via the parasympathetic (i.e. the vagus nerve) and sympathetic nervous system. In general, during rest the parasympathetic system regulates heart rate, and thereby CO, and the sympathetic system causes arteriolar vasoconstriction which regulates peripheral resistance. (Under resting conditions the influence of the sympathetic system on CO by augmenting cardiac contractility is thought to be minor; Rowell, 1993.) Sympathetic outflow to skeletal muscle vasculature (i.e. muscle sympathetic nerve activity, MSNA) can be directly assessed using microneurography. MSNA comes in surges (‘bursts’) that are synchronous to the cardiac cycle. Multi-unit recordings of sympathetic neurones in a peripheral nerve bundle yields MSNA, which can be expressed as burst frequency (bursts per minute) or burst incidence (bursts per 100 beats). Since burst frequency and burst incidence do not differentiate among burst amplitudes, ‘total activity’ (arbitrary units per minute) may give additional information (Halliwill et al. 1996). In resting subjects, MSNA correlates well with sympathetic vasoconstrictor traffic to other tissues, including the heart and kidney. This evidence, along with the observation of a significant correlation (r= 0.61) between MSNA and TPR in supine subjects (Charkoudian et al. 2005), suggests that MSNA at rest is a reliable index of ‘net’ sympathetic vasoconstrictor activity to the whole body. Among normotensive individuals there is a wide variability of MSNA at baseline. Resting MSNA is quite reproducible in individual subjects, but can vary as much as 7- to 10-fold among normotensive individuals with similar blood pressures (Charkoudian et al. 2005, 2006). As a result, MSNA has little or no (Charkoudian et al. 2005, 2006) relationship with resting blood pressure among healthy subjects. Recently Charkoudian et al. (2005) showed that among normotensive individuals during supine rest there is an inverse relation between CO and MSNA at baseline, such that individuals with a high CO exhibit a low resting MSNA and vice versa. Against this background, Fu et al. (2006) set out to assess the arterial baroreflex control of MSNA during prolonged orthostatic stress. They studied how MSNA, CO, left ventricular stroke volume (SV) and TPR are modulated during sustained upright posture and hypothesized that baroreflex control over MSNA would subside during prolonged orthostatic stress. After 30 min of supine rest, 20 healthy subjects were subjected to 45 min of 60 deg head up tilt on a tilt table with a saddle. MSNA (expressed as burst frequency, burst incidence and total activity), arterial blood pressure (Finapres, Ohmeda, USA) and heart rate (from electrocardiogram) were continuously measured. CO was measured using an acetylene rebreathing technique, during supine rest, and at the 5th, 10th, 20th, 30th and 40th minute of head up tilt. During the study seven subjects developed presyncope, leaving 13 subjects whose data are included in the paper. Compared to the supine position, diastolic blood pressure increased during all stages of orthostatic stress (mean from ∼65 to ∼78 mmHg). Systolic blood pressure did not change significantly. MSNA increased from ∼18 to ∼36 bursts min−1 after 5 min of tilt (data derived from the authors Figure 2). During the 45 min of tilt there was a further increase to ∼43 bursts min−1 at the final stage. Baroreflex control of MSNA was assessed using the slope of the linear correlation between total MSNA activity and diastolic blood pressure while supine and during early (2nd–5th minute), middle (17th–20th minute) and late stages of tilting (42nd–45th minute). Sympathetic baroreflex sensitivity increased in the first stage of head up tilt (from ∼−300 to ∼−700 a.u. beat−1 mmHg−1), but did not change further during tilt. Stroke volume (SV) was calculated from CO and the heart rate was measured during the rebreathing. TPR was calculated as MAP × CO−1. Both SV and CO decreased progressively during head up tilt (103 to 75 to 55 ml; 7.74 to 6.31 to 4.91 l min−1), whereas TPR increased (873 to 1247 to 1541 dyn s cm−5). Using linear regression analysis for each subject the authors assessed the relation between MSNA and SV (combining supine rest and stages of orthostatic stress). The same was done for MSNA and TPR. Within subjects MSNA (both burst frequency and total activity) was inversely related to SV (mean r= 0.88). TPR within subjects was positively related to MSNA (mean r= 0.82 for burst incidence, mean r= 0.75 for total activity). Among subjects both relations (i.e. ΔMSNA ×ΔSV−1 and ΔTPR ×ΔMSNA−1) varied (by a factor of ∼2–5, derived from the authors' Figures 3 and 5). The paper by Fu et al. (2006) contributes important information to the ongoing efforts to unify the accepted qualitative mechanisms of short-term (efferent) blood pressure regulation with the empirical data that show widely varying stroke volume, heart rate, cardiac output and MSNA among normotensive subjects. The inverse relation between stroke volume and MSNA, as earlier described among supine subjects, is now shown to also be present within subjects, and to persist during orthostatic stress. Although the authors did not include a similar regression between MSNA and CO, the data provided showing a declining CO while MSNA increases would be in agreement with an inverse CO–MSNA relation. In contrast to previous studies, which only related MSNA as burst incidence or burst frequency to TPR (Charkoudian et al. 2005), the regression of total MSNA to TPR provides a potentially more ‘physiological’ approach, since arterioles respond to single neurones firing rather than to the integrated variable ‘burst’. However, this can only be reliably done within a given subject, since intersubject variability in the proximity of the electrode to the nerve can also contribute to differences in burst size. The authors make a linear regression of MSNA and TPR, including both supine and head-up-tilt data. However, one could argue that such variation in gravitational stresses could introduce potential confounds into data interpretation. Orthostatic stress (i.e. tilt) increases the hydrostatic pressure column that stresses the arteriolar vasculature (Rowell, 1993) and is likely to affect the extent to which sympathetic traffic leads to vasoconstriction. This would mean that (within a subject) MSNA while supine has a different relation to TPR than while upright (Intra-individual changes in the relation between MSNA and vasoconstriction caused by experimental procedures have been documented before (Halliwill et al., 1996).). Another factor that is not taken into account in the design of the study is the interindividual variability of the intrinsic vascular adrenergic responsiveness. A previous study showed that this may vary by up to a factor of 2–3 among healthy subjects in an isolated vascular bed (Charkoudian et al. 2006). This may explain some of the interindividual variation in the MSNA–TPR relationships in the current paper. Together, the orthostatic load and the adrenergic responsiveness (the ‘combined vascular responsiveness’) determine the effect of a given amount of MSNA on TPR. The increased MSNA outflow from a given change in diastolic blood pressure during orthostatic stress would be in agreement with a lower combined vascular responsiveness. Irrespective of these potential limitations, an off-set on TPR is evident from the linear regressions made by the authors' (∼400–700 dyn s cm−5, derived from the authors Figure 3). This is likely to represent the non-sympathetically mediated portion of TPR determined by the mechanical properties of the conduit vessels and the relaxed arterioles (TPRoffset). In summary the novelty of the study by Fu et al. (2006) lies in documenting a sustained relation between MSNA and stroke volume, as well as a relation between total peripheral resistance and MSNA during prolonged orthostatic stress. A limitation to the study is that it does not consider variations in vascular transduction of MSNA depending on adrenergic responsiveness and changes in posture as discussed above. Furthermore, the paper would have gained further prominence if it had tried to bring together MSNA and cardiac output as independent contributors to mean arterial pressure. This could for example be done by a multiple linear regression analysis (see Appendix). Herein lies an apparent challenge for future research. Based on the considerations above, one could speculate that using a multiple linear regression approach could produce a model similar to the one below in which mean arterial blood pressure in steady state is given as: MAP = (CO) × (TPRoffset+ ((‘combined vascular responsiveness’× MSNA)). Combined vascular responsiveness is suggested as a composite factor consisting of vascular adrenergic responsiveness (Halliwill et al. 1996; Charkoudian et al. 2005) and gravitational loading of the arteriolar bed from a hydrostatic column (Rowell, 1993). In Fig. 1 this function is plotted at two different levels of combined vascular responsiveness. This approach may be able to relate more than two cardiovascular parameters (e.g. MSNA and CO; CO and MAP) and thereby explain more of the interindividual and intraindividual variations. Mean arterial pressure (MAP) as a function of cardiac output (CO) and Total MSNA Not having the complete data set from the discussed paper available, this surface plot takes as a hypothetical value for TPRoffset 3 mmHg l−1 min−1. For reasons of clarity data are plotted over a wider than physiological MAP range (i.e. starting at 0 mmHg). The two planes represent two different levels of ‘combined vascular responsiveness’ (0.8 arbitrary units (a.u.) upper plane; and 0.2 a.u. lower plane). We thank Christiane Hesse and Nisha Charkoudian for commenting on an earlier version of the manuscript. C.T.P.K. is supported by the Fulbright Program and the Netherlands Heart Foundation (no. 2004T007). This support is gratefully acknowledged.
Source: The Journal of Physiology
Authors: C. T. Paul Krediet, Maile L. Ceridon
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1994136236