Very low frequency blood pressure fluctuations: not only myogenic responsiveness

Abstract

Blood pressure variability: a complex phenomenon The pathophysiological and clinical relevance of blood pressure variability (BPV) is still a matter of lively debate. Although BPV is increasingly recognized as an independent risk factor for target organ damage and cardiovascular events, including stroke in hypertensive patients [1–8], the mechanisms responsible for it are not yet fully elucidated. This is because BPV is a complex phenomenon that includes different components characterized by different frequencies of BP fluctuations [9–12], that is, the so-called high-frequency components (between 0.15 and 0.5 Hz in humans), mainly related to the mechanics of respiration; the low-frequency components (between 0.04 and 0.15 Hz), considered an expression of both sympathetic modulation of peripheral resistance and resonance in the baroreflex loop (see below); and the very low frequency (VLF) components (VLF <0.04 Hz) which include the slowest fluctuations with periods ranging from minutes to hours, as a function of the recording period length. The genesis of VLF components seems to depend on multifold mechanisms, including myogenic tone, thermoregulation, physical activity and sympathetic efferent modulation [9–12]. The BPV complexity in terms of frequency components is accompanied by the concomitant complexity in the responsible mechanisms, including neural and nonneural factors [11,13]. Neural influences may contribute to an increase or a reduction in total BPV by central modulation of cardiac and vascular targets through efferent sympathetic nerves, often triggered by behavioural factors such as exercise, emotion and sleep [11,14–16]. Neural influences originating in the arterial baroreflex loop are also involved and play a complex role in modulating BPV. On the one hand, the arterial baroreflex is actively involved in buffering total BPV, such that baroreflex sensitivity shows an inverse relationship with total BPV. This means that whenever the baroreflex is more effective, BPV tends to be reduced and vice versa [17–19]. On the other hand, arterial baroreflexes may paradoxically exert a promoting role for low-frequency BP oscillations through a resonance phenomenon in the baroreflex loop [20–24]. The role of arterial baroreflexes in modulating very low frequency components has been specifically and deeply investigated by assessing broad band spectral powers of BP and pulse interval [the reciprocal of heart rate (HR)] recorded in controlled conditions and after surgical baroreceptor deafferentation by sinoaortic denervation (SAD) in various animal models [18,25]. SAD was responsible for changes in all the spectral components of systolic BP and pulse interval, thus suggesting the involvement of baroreflex modulation in the genesis of not only the fast but also the slower components of BP and pulse interval variability. In particular, although the baroreflex seems to play a pro-oscillatory role on virtually all the components of pulse interval, the influence of the baroreflex on the spectral components of systolic BP seems to be a much more complex one. In fact, SAD was associated with a significant reduction in the power of spectral components in the low-frequency region, an increase in the power of components in the VLF region and almost no change in the power of high-frequency BP spectral components. These findings indicate that the baroreflex plays a different role in modulating BP fluctuations according to the frequency. It exerts a negligible effect on respiratory components, an expected buffering role in the VLF region and a paradoxical pro-oscillatory role in the low frequency region. In particular, VLF BP fluctuations seem to be the result of opposing interactions between haemodynamic perturbations and the corrective feedback provided by the sympathetic vascular component of the arterial baroreflex. This is demonstrated by the similarity of the effects of SAD [25], chronic chemical sympathectomy [26] and acute neurohumoral blockade combined with noradrenaline infusion on BPV [27]. Worth noting is the fact that these studies have also provided indirect evidence that one major source of slow haemodynamic perturbations is an autoregulatory-like (probably myogenic) response in several regional circulations. It is, thus, likely that in the conscious rat, the relative importance of myogenic and baroreflex responses largely determines the net changes in vascular resistance of regional vascular beds and hence the changes in total peripheral resistances (TPR). Finally, it should be considered that among nonneural mechanisms, apart from myogenic tone, endothelial factors and angiotensin II may also directly affect vasomotor activity and thus BPV [28,29], further increasing the overall complexity of the integrated modulation of this phenomenon. The role of myogenic responsiveness A recent contribution to the assessment of the mechanisms contributing to BPV and its clinical relevance is provided by a work by Stauss et al.[30] published in this issue. Stauss et al. put forward the provocative hypothesis that genetic predisposition to hemorrhagic stroke might be associated with a decreased rather than an increased BPV, and more specifically, with a decrease in its slow (or VLF) component. According to Stauss et al.[30], such a decrease is mostly mediated by a decreased myogenic responsiveness observed in the cerebral vasculature as well as in the whole arterial system of stroke-prone spontaneously hypertensive rats (SHRs). The suggestion is intriguing, but a few critical considerations need to be made in relation to this work. First of all, it is important to note that the bulk of BPV is concentrated at very low frequencies in both humans (VLF band starts at <0.04–0.05 Hz) [31] and rats (the corresponding frequencies being <0.15 Hz) [23]. Thus, overall BPV (when estimated from global indices such as the standard deviation of beat-to-beat BP values) is roughly equivalent to its VLF component, especially in the case of long-lasting recordings. The question is then which mechanism might link stroke with a decrease in the amplitude of VLF fluctuations in BP. In the brain, myogenic constriction of proximal arteries prevents BP surges from being transmitted to the downstream vasculature and is, thereby, an important physiological mechanism of protection against hemorrhagic stroke. Stroke-prone SHRs exhibit an impaired cerebrovascular myogenic responsiveness prior to stroke, which might facilitate the initiation of haemorrhage [32]. The hypothesis tested by Stauss et al.[30] is that the decreased myogenic responsiveness observed in the cerebral vasculature of stroke-prone SHRs is part of a generalized impairment of myogenic responses in the whole circulation, which, in turn, is reflected in a decreased VLF component of BPV. The myogenic response is the primary mechanism of pressure autoregulation of blood flow in regional circulations. The myogenic response and BP tend to form a vicious circle because any change in BP will be amplified by a parallel change in regional vascular resistances. Following this reasoning, Cowley et al.[33] stated that autoregulation ‘…would have devastating effects on arterial pressure control if (it) predominated in all regions of the systemic circulation…’. In other words, the myogenic response, if unopposed, would dramatically increase BPV. Reciprocally, a generalized impairment of myogenic responsiveness would result in a reduced BPV. Considering the kinetics of the myogenic response [34], this effect would be restricted to VLF fluctuations in BP. In their study, Stauss et al.[30] report that stroke-prone SHRs have a decreased VLF component of BPV compared with stroke-resistant SHRs. They demonstrate that nifedipine, which blocks the myogenic response, decreases the VLF fluctuations of BP in both stroke-prone and stroke-resistant SHRs, even after partial restoration of BP with an arginine vasopressin (AVP) infusion. This effect is not observed with sodium nitroprusside combined with AVP infusion. Finally, it is shown that in conscious dogs, nifedipine decreases the gain of the transfer function relating TPR to BP, which is also taken to indicate that the myogenic response contributes to VLF BPV. The approach followed by Stauss et al.[30], however, has some limitations. One of them is that dihydropyridine L-type calcium channel blockers not only block the myogenic response but also strongly interfere with the action of most endogenous vasoconstrictors. Therefore, any direct neurohumoral contribution to BPV, including that of sympathetic influences, was probably attenuated after nifedipine administration. In this respect, it is remarkable that the reduction of BPV after nifedipine administration was not restricted to the VLF band but was also observed in the low frequency band, where it is established that myogenic responses are not effective, and sympathetic effects predominate [24]. The experiment with sodium nitroprusside was important to control the effects of lowering the BP level, but giving nitric oxide is not equivalent to blocking L-type calcium channels in terms of vascular reactivity to endogenous vasoconstrictors. Another limitation of the study by Stauss et al.[30] relates to the use they make of the transfer function relating BP (input signal) and TPR (output signal) in conscious dogs. The properties of this transfer function (gain and phase functions) were supposedly supporting the statement that the myogenic response directly has an impact on BPV in the VLF range. However, the use of the cross-spectral transfer function between the mean arterial pressure (MAP) and TPR signals is simply invalid here. First, the cross-spectral transfer function is a noncausal correlation technique that does not have directionality. When this technique is used in an open loop condition, the results are clear, but in a closed loop condition, as in the present study, the results are open to interpretation. In this case, we absolutely know that TPR affects MAP, as the authors acknowledge, but the whole point of this article is to develop a technique to somehow demonstrate that MAP may affect TPR through a myogenic positive feedback mechanism. The phase of 0° with no change with frequency in the VLF range is highly consistent with TPR affecting MAP (and not vice versa), which can be expected to happen almost instantly as there is a direct link between TPR and MAP. There are autoregressive techniques that can be used to measure transfer relations during closed-loop operation [35] by building causality into the formulation, but the cross-spectral method cannot be used for the same purpose. The other option would have been to perform open-loop experiments. Indeed, to properly interpret the BP–TPR transfer function, the baroreflex system would need to be opened, either mechanically (by using the Moissejeff's procedure) or pharmacologically (by blocking the autonomic nervous system). In the open-loop configuration, myogenic responses are left unopposed and the BP–TPR phase decreases linearly with a slope proportional to the fixed time delay inherent in the response. As previously mentioned, in conscious rats, an effect common to SAD and chronic sympathectomy with guanethidine is a marked enhancement of VLF fluctuations in BP [36,37]. Taken together, these simple observations strongly suggest that the sympathetic component of the baroreceptor reflex plays an important role in limiting VLF fluctuations of BP. Surprisingly, the renal sympathetic nerve activity (RSNA) of normal rats is, however, only weakly related to BP in the VLF band as indicated by the low coherence values computed between the two variables [23,36]. This lack of coupling points either to nonlinearities in the relation or to the interference of noise sources affecting either variable. Obviously, applying coherence analysis to BP time series containing both neurally mediated and nonneurally mediated BP variations would inevitably result in low BP–RSNA coherence values. Similarly, coherence values would remain low if RSNA time series were containing both baroreflex-mediated and nonbaroreflex-mediated RSNA variations. Interestingly, the SAD procedure did not noticeably alter the amplitude of VLF fluctuations of RSNA, which demonstrates that central nervous structures can generate slow fluctuations of RSNA in the absence of baroreflex influences. On the other hand, coherence between BP and RSNA in the VLF band was not increased after SAD, thus indicating that BP tends to vary independent of RSNA after baroreceptor denervation [23,36]. In an attempt to identify the nonneural mechanisms contributing to VLF fluctuations in BP, haemodynamic studies have been performed on conscious rats after acute ganglionic blockade [27]. To allow for any BP fall due to vasodilator influences, the basal mean level of vascular tone was restored with a continuous infusion of noradrenaline. In this areflexic preparation, BP was highly unstable, and this lability was secondary to slow fluctuations (mainly increases) of systemic vascular conductance (the reciprocal of TPR). Interestingly, the BP changes were usually initiated by sharp decreases in stroke volume and cardiac output so that the conductance changes lagged behind the BP changes by about 1 s, and then amplified and prolonged the BP variations. The latter sequence of events was demonstrated by computing the phase function between BP (input signal) and systemic vascular conductance (output signal). Phase decreased linearly as a function of frequency in the 0–0.2 Hz frequency range, indicating the presence of a 1-s fixed-time delay between BP and conductance [27]. This haemodynamic pattern is strongly suggestive of predominant autoregulatory behaviour, possibly involving a myogenic response in regional vascular beds. The measurement of muscular and mesenteric blood flows in areflexic rats confirmed that autoregulatory-like (presumably myogenic) responses are a major source of BPV in the absence of a neural control of the circulation [27]. In sympathectomized rats, another source of haemodynamic perturbations has been identified in the skeletal muscle circulation where abrupt vasodilatations invariably occur at the onset of body movements and initiate a fall in BP [26]. As mentioned above, these experimental data led some investigators to formulate the hypothesis that VLF fluctuations in BP largely result from the continuous interplay between haemodynamic perturbations (especially the myogenic response) and the corrective action provided by the sympathetic limb of the baroreceptor reflex (Fig. 1) [38]. By using BP and RSNA time series collected in conscious SAD rats and parameters of the transfer function relating RSNA to BP, it was examined whether BP and RSNA variabilities actually observed in baroreceptor-intact rats could be predicted [23]. By progressively increasing the baroreflex gain, it was possible to compute virtual BP and RSNA power spectra that increasingly deviated from their progenitor spectra. In particular, BP spectral power decreased in the VLF range (as a result of baroreflex buffering of haemodynamic perturbations) and increased in the low-frequency band (as a result of increasing instability at the resonance frequency of the loop, i.e. at the frequency of the so-called Mayer waves).Fig. 1Therefore, the finding of a decreased VLF power in BP spectra can be interpreted as resulting either from a decreased influence of haemodynamic perturbations (including the myogenic response) or from an increased effectiveness of the sympathetic baroreflex (or, of course, from any combination of both). Luft et al.[39] have indeed reported that splanchnic sympathetic nerve activity is more reactive to BP changes in conscious stroke-prone SHRs than in WKY rats. In conclusion, whereas the study by Stauss et al.[30] indicates that the myogenic response may contribute to BP variability in addition to neural factors, it does not seem to provide a final demonstration that this mechanism is the main determinant of VLF BP fluctuations and, thus, that the latter might provide an indicator of the risk of hemorrhagic stroke, at least in the experimental animal. Such a stimulating issue would, thus, need to be further addressed through a more adequate methodological approach.