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INVITED EDITORIAL
Department of Biomedical Engineering
S. Maugeri Foundation, IRCCS
Scientific Institute of Montescano
Montescano (PV), Italy
e-mail: gdpinna{at}fsm.it
BY GOVERNING THE AUTONOMIC OUTFLOW to the heart and blood vessels, arterial baroreceptors play a central role in controlling short-term blood pressure responses to the hemodynamic perturbations continuously occurring in daily life. Abnormalities in baroreflex function are thought to play an important pathogenic role in the setting of cardiovascular disease, by reducing the restraining influence on the sympathetic nervous system and the excitatory influence on the vagal outflow to the heart. Although several effector mechanisms are under baroreflex control, the baroreceptor-heart rate reflex has received the greatest attention so far, likely due to the ease of measurement of baroreflex sensitivity (BRS), i.e., the magnitude of the reflex change in interbeat interval (IBI) per unit change in arterial pressure (AP). Experimental and clinical evidence suggests that a depressed BRS is associated with an increased risk for life-threatening arrhythmias and cardiac mortality (7).
Although BRS has classically been measured by using vasoactive drugs (e.g., phenylephrine), considerable efforts have been devoted to the development of alternative methods based on the analysis of spontaneous oscillations of AP and IBI (3). These techniques are inherently simpler, noninvasive, and less costly. Moreover, they do not interfere with the transduction properties of baroreceptors and do not simultaneously activate other reflexes, mainly excitatory via afferent sympathetic fibers, that may exert a confounding effect in the measurement process. Among these noninvasive methods, the measurement of the average transfer function modulus (gain function) between AP and IBI in the low-frequency (LF, 0.04–0.15 Hz) band is of particular interest, as it allows one to precisely define the components of the dynamics of the baroreflex involved in the measurement and to minimize the disturbing influence of respiration (by using paced breathing). The mathematical background and computational criteria of the transfer function method (TF-BRS) are well established (4, 6), as well as its relationship with the phenylephrine method (6). Recent studies have demonstrated its capability to detect the change in baroreflex function following structural cardiovascular disease (6) and its clinical and prognostic relevance (5). The precise relationship between TF-BRS and its physiological counterpart, however, is still not fully understood.
The input signals for the measurement of TF-BRS are the slow, nonrespiratory AP oscillations commonly known as Mayer waves, which in humans are located in the center of the LF band. Although the matter is still debated, a large body of experimental data from human and animal studies, as well as the use of mathematical modeling, support the notion that Mayer waves represent mainly, although not exclusively, the effect of a resonance phenomenon in the closed-loop negative-feedback baroreflex control of vasomotor tone (1, 2). Resonance, however, is a by-product of the normal operation of the baroreflex, the price to pay to guarantee effective buffering of hemodynamic perturbations at other frequencies (1). It thus appears that TF-BRS, resonance, and AP buffering are strictly related to each other and that the understanding of this relationship is crucial for a proper interpretation of TF-BRS measurements.
In this issue of the Journal of Applied Physiology, van de Vooren and colleagues (10) elegantly explore this link using a simplified version of a previously validated hybrid model of blood pressure control. Using computer simulations with different combinations of gains in the three baroreflex limbs controlling heart rate and total vascular resistance, the authors determined which limb is the main determinant of blood pressure-buffering capacity and examined the relationship between buffering capacity and resonance. They also assessed the relative contribution of cardiac sympathetic and vagal feedback gains to the magnitude of TF-BRS and investigated whether TF-BRS is related to AP-buffering capacity. Both physiological and pathological conditions (heart failure) were considered. The study focuses on different dynamic conditions of autonomic control in the supine position rather than on different hemodynamic states (e.g., standing vs. supine) and explores a frequency range between 0.05 and 0.3 Hz. This allowed them to greatly simplify the model by removing the effect of venous return and contractility on stroke volume.
The model shows a resonance at the typical frequency of Mayer waves (
0.1 Hz) and AP buffering at lower frequencies. Buffering capacity appears to be mostly dependent on sympathetic peripheral resistance control and is strongly, albeit nonlinearly, related to AP resonance. There is no inherent problem in measuring BRS by the transfer function around the Mayer frequency, except a slight negative bias at high levels of cardiac sympathetic gain. TF-BRS appears to depend almost exclusively on the vagal feedback gain to the heart and the relationship is linear; therefore, LF oscillations of IBI mainly represent vagal transmission of blood pressure oscillations via the baroreflex. As concerns the crucial relationship between TF-BRS and AP buffering, the study (10) shows that they are almost uncorrelated. Hence, the measurement of BRS does not provide information on the capability of the baroreflex to dampen AP oscillations, unless coupled vagal and sympathetic feedback gains are assumed.
The study (10) significantly contributes to our understanding of some important aspects of cardiovascular autonomic control and provides valuable information for the physiological interpretation of a largely used, simple, and clinically useful index of BRS. Moreover, it provides interesting insights on the role and interplay of the three baroreflex limbs in determining beat-to-beat cardiovascular variability, integrating the present debate on this subject (2). In this respect, the results of the study provide support to the notion that cardiovascular variability in the LF band largely reflect the integrity of the baroreflex control of peripheral resistance (responsible for the generation of Mayer waves) and of the baroreflex control of heart rate (responsible for translating blood pressure oscillations into modulation of autonomic outflow to the sinus node) (8). Furthermore, the study highlights the importance of vagal activity for the generation of heart rate variability.
It should be stressed, however, that the conclusions drawn from the study critically depend on the appropriateness of the model used in the simulations. In this regard, it has to be kept in mind that besides the already-mentioned simplifications in model structure, inaccuracies in the chosen values of model parameters describing the dynamics of the various components of the baroreflex loops cannot be excluded. This, however, is a problem common to all mathematical models of blood pressure control.
Being measured in a closed-loop condition, TF-BRS would also reflect the mechanical feedforward of IBI changes on AP. In the van de Vooren et al. study (10), model parameters potentially affecting the feedforward gain (e.g., arterial compliance) were not changed in the simulations, and hence their effect was not explored. Therefore, the study leaves open the question of whether the feedforward mechanism significantly affects TF-BRS. Yet, the model suggests that fluctuations in IBI contribute negligibly to the variability of AP, and the direction of such effect, in agreement with previous experimental studies (9), is toward increasing rather than dampening AP changes.
REFERENCES
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