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Blood pressure oscillations
The existence of respiratory fluctuations in ABP has long been identified with the first records tracing back to Stephen Hales in 1733. Later, in 1760 Albrect von Haller was the first to note rhythmic fluctuations also occurring in heart rate (fc). However, neither Hales nor Haller made assumptions regarding a link between respiratory activity and cardiovascular fluctuations (Leake, 1962). The first accounts of respiratory-related oscillations in ABP came in the mid-1800s with Traube (and later Hering) observing slow oscillations at around seven cycles per minute when artificial respiration was interrupted in vagotomised dogs and cats. These oscillations ceased after two or three minutes of respiratory arrest, which led both Traube and Hering to postulate that they were linked to a strong respiratory centre discharge modulating the rhythmic activity of a vasomotor centre (Killip, 1962). Just a few years later, in 1876, Mayer described ABP oscillations in spontaneously breathing rabbits that were slower than breathing frequency (fR), but that matched those described previously by Traube and Hering. In 1882, Fredericq reviewed the work of Mayer, Hering and Traube and concluded that the oscillations described by Traube and Hering occurred at respiratory frequency, while Mayer’s waves were slower than the respiratory rhythm (Larsen, Tzeng, Sin et al., 2010).
The respiratory variations in ABP were explored in further detail in a seminal paper by Dornhorst, Howard and Leathart (1952b). In a series of small experiments in human volunteers, published in a single paper, Dornhorst and colleagues demonstrated that the amplitude of ABP oscillations increased with decreasing fR, while the phase relation between respiration and ABP was also altered by a change in fR. Furthermore, the respiratory-driven variation in ABP seemed to be enhanced in the upright posture (compared to supine), while apnoea elicited regular ABP waves at a rate of around six cycles per minute, confirming the previous accounts of Mayer. Another important observation by Dornhorst and colleagues was that the respiratory modulation of LVSV was induced by respiratory driven fluctuations in intrathoracic pressure, which influenced right atrial filling, and that passive inflation of the lungs resulted in a 180° phase inversion between respiration and LVSV. Moreover, the relationship between respiration and LVSV also seemed to show a frequency dependent phase pattern, which the authors attributed to pulmonary transit time, i.e. the time required for blood to transit between the right and left sides of the heart. Nonetheless, the most important finding was perhaps the identification of a synchronisation between respiratory driven variations in LVSV and those observed in peripheral resistance, when breathing at around 6 breaths·min-1 (0.1 Hz). It was suggested that at this fR, the oscillations of LVSV and peripheral resistance were timed in such a way that they reinforced each other, thus creating a resonance effect (see also paragraphs dedicated to coherence and entrainment in section 2-4.5).
Earlier, in 1951, two different studies by Arthur Guyton reported vasomotor oscillations is anaesthetised, hypovolemic dogs that underwent progressive denervation; they concluded that so-called Mayer waves were sympathetically mediated (Guyton, Batson, Smith et al., 1951, Guyton and Harris, 1951). These findings were expanded by Preiss and Polosa (1974), who identified a synchrony between sympathetic preganglionic nerve activity patterns and the occurrence of the Mayer waves, in anaesthetised or otherwise decerebrated cats. One subsequent study from the same group, supported the existence of temporal associations between respiratory rhythm, sympathetic outflow and ABP oscillations (Preiss, Kirchner and Polosa, 1975).
The body of evidence that rose from these (and other) studies in animals gave support to the theory that fluctuations occurring at the respiratory frequency must involve the presence of a central mechanism modulating sympathetic cardiovascular activity, and synchronised with breathing. The slower Mayer waves, were suggested to stem directly from sympathetically mediated vascular resistance oscillations (Cohen and Taylor, 2002).
Heart rate oscillations
The study of heart rate (fc) and heart rate variability (HRV) received less attention initially than that of ABP. However, a series of relevant accounts regarding the existence of oscillation in fc and the driving mechanisms, were made throughout the 19th century. Around 1845, Ernst and Eduard Weber showed that fc was depressed by vagus nerve activity, while Albert Bezold demonstrated in 1867 that other nerves (sympathetic efferents) innervating the heart had cardioacceleratory properties (Hurst, Fye and Zimmer, 2005). Herman Stannius (1852) established that heart rhythmicity and automaticity originated in the sino-atrial node, while Czermak’s (1866) report of cardiac deceleration is response to increased pressure applied to the carotid sinus preceded Heinrich Hering’s 1924 description of the cardiac baroreceptor reflex (Leake, 1962, Fleming, 1997, Fye, 2000, Larsen et al., 2010).
As is the case with ABP, two clearly distinct rhythms have been identified in fc. The first has a cycle duration of approximately 10 s (0.1 Hz), i.e. like the previously described Mayer waves in ABP. This rhythm has been attributed to various mechanisms, but most recently has been assumed to reflect an integrated response to baroreflex-mediated fluctuations in sympathetic outflow to the vasculature and in parasympathetic and sympathetic cardiac activity, in response to ABP oscillations (De Boer, Karemaker and Strackee, 1987, Di Rienzo, Parati, Radaelli et al., 2009).
A second oscillation of fc occurs at the respiratory frequency (fR) and is thought to represent both mechanically-driven central blood volume changes, and autonomic neural fluctuations that are synchronised with breathing (Cohen and Taylor, 2002). These respiratory-synchronous swings in fc are termed respiratory sinus arrhythmia (RSA) and though they have received considerable research interest over the last decades, the exact mechanisms underpinning the origin(s) and amplitude of RSA remain elusive (see section 2-4.3 for a description of current theories relating to the mechanisms and function of RSA).
In 1936, Anrep, Pascual and Rössler, conducted a series of elegant experiments in dogs, seeking to clarify the mechanism underlying RSA (Anrep, Pascual and Rossler, 1936a, b). This was the first serious attempt to test systematically the existing theories of the time. There were, and remain, three ‘schools of thought’ in relation to the origin(s) of RSA:
- lung-originated reflex mechanism, (initially proposed by Edwald and Heinrich Hering);
- central interaction between cardiac and respiratory control centres (defended by Traube, Fredericq and Heymans);
- based on Francis Bainbridge’s work, changes in atrial filling and ABP occurring with changes in intrathoracic pressure.
Anrep et al.’s (1936a, b) experiments provided a unifying perspective, suggesting that RSA was due to a combination of factors, more specifically: 1) a direct inhibitory influence of central respiratory neurones upon cardiac vagal activity; and, 2) a reflex cardiac response to mechanical inflation of the lung.
The mechanisms responsible for RSA in human beings were explored in detail in a later series of studies conducted by Freyschuss and Melcher (1976a, b, c), who attributed RSA to: 1) a reflex response from cardio-pulmonary receptors to variations in venous return with breathing, and; 2) pulmonary stretch reflexes. Studies over the 40 years since the work of Freyschuss and Melcher have elucidated many of the factors that influence the magnitude of RSA (see section 2-4.3).
Oscillations occurring at 0.1Hz – Mayer waves
The current, prevalent theory suggests that Mayer waves are the result of resonances in the baroreflex control loop, occurring at 0.1 Hz in human beings (Julien, 2006). Within this conceptual framework, it has been argued that the existence of fixed time delays in the vascular baroreflex control loop lead to the production of resonant, self-sustained oscillations in ABP. The amplitude of Mayer waves is thus determined both by the sensitivity of the sympathetic branch of the baroreceptor reflex, and the strength of the triggering perturbations (De Boer et al., 1987, Julien, 2006).
Finally, some researchers have proposed an additive role of reflex (neurogenic) and myogenic processes, by which rhythmic oscillations in blood vessels are generated by pacemaker cells in the vascular smooth muscle contracting in response to variations in intravascular pressure, thereby contributing to the generation and amplitude of Mayer waves (Johnson, 1991, Stefanovska and Bracic, 1999a, b, Stefanovska, Bracic and Kvernmo, 1999).
Oscillations occurring at the respiratory frequency – Traube-Hering waves
The respiration-coupled blood pressure oscillations are partly explained by mechanical effects of respiration and, most likely, also by the vagally induced RSA (Eckberg and Sleight, 1992, Karemaker, 1999). Recent evidence also supports the notion that the respiratory fluctuations in ABP are, at least partly, the consequence of respiratory mediated changes in sympathetic outflow to the periphery; thereby suggesting central respiratory-sympathetic coupling as a putative mechanism for the Traube-Hering waves (Simms, Paton, Pickering et al., 2009, Towie, Hart and Pickering, 2012, Shantsila, McIntyre, Lip et al., 2015).
Oscillations occurring at the Mayer wave frequency
One increasingly popular theory states that these 0.1Hz frequency oscillations reflect a resonant behaviour of the baroreflex control loop, determined by inherent, fixed delays in the sympathetic control loop (De Boer et al., 1987). This would suggest that 0.1Hz oscillations in fc are the direct consequence of the ABP fluctuations at the same frequency. However, this only seems to be observed consistently in situations where vascular sympathetic outflow is high (e.g. head-up tilt, or standing). Typically, under other conditions, low-frequency ABP and fc oscillations show wide inconsistencies in coherence (i.e. spectral correlation) (Taylor and Eckberg, 1996, Hamner, Morin, Rudolph et al., 2001, Cohen and Taylor, 2002).
Respiratory sinus arrhythmia
The physiology underlying the interrelationship of breathing and heart rate variability (HRV) has been known for many years. Its best known manifestation is the phenomenon of respiratory sinus arrhythmia (RSA), which is the broadly accepted term describing the oscillations of the RR interval of the ECG occurring at a frequency similar to respiration. This phenomenon has been suggested to have an important teleological function, either by, 1) improving the efficiency of gas exchange by matching the alveolar ventilation with pulmonary perfusion throughout the respiratory cycle (Yasuma & Hayano, 2004), 2) reducing workload of the heart while maintaining normal levels of blood gases (Ben-Tal et al., 2012), 3) counteracting respiratory variations in LVSV, Q̇ and ABP (Toska and Eriksen 1993; Elstad et al. 2001; Elstad, 2012; Elstad et al. 2015). Notwithstanding the existence of these theories, the precise underlying mechanisms and function of RSA, if any, remain unclear.
Currently there are four mechanisms proposed as potential generators of RSA:
- Reflex inhibition of the cardioinhibitory center by the slowly adapting stretch receptors (SASR) in the lungs;
- Central irradiation of inhibitory impulses from the respiratory centers to the cardioinhibitory center;
- Increased filling of the right atrium during inspiration, which activates mechanoreceptors at the junction of the great veins with the right atrium, increasing sympathetic activity to the sinus node (Bainbridge refex); and
- a change in sensitivity of the arterial baroreflex occurring in phase with the respiration.
The following section describes the evidence supporting each of the four theories:
RSA as a manifestation of vagal afferent input from lung mechanoreceptors
The first hypothesis arises from some of the first studies conducted on RSA, in the late 1930s. Anrep and colleagues (Anrep et al., 1936a, b) concluded that the mechanisms responsible for RSA included a reflex inhibition arising from the activation of mechanoreceptors in the lungs.
More than two decades later, de Burgh Daly and Scott (1958) described the cardiovascular responses to stimulation of the carotid arterial chemoreceptors in anaesthetized dogs, and showed that the primary response of bradycardia was not seen when breathing increased in response to the stimulation, but was seen when ventilation was controlled. They attributed the overriding of this primary reflex response to the activation of the lungs’ mechanoreceptors, more particularly SASRs. The SASRs are vagal afferents believed to lie in the airway smooth muscle (Schelegle and Green, 2001, West and Luks, 2016). According to Adrian’s classic paper (Adrian, 1933), the SASRs are primarily responsive to changes in lung volume, are inhibited by deflation and tend to adapt slowly to sustained inflation (hence the nomenclature). The stimulation of these receptors triggers cardio-acceleration; the so-called Hering-Breuer reflex. Importantly, the stimulation of SARs promotes slowing of breathing frequency (fR) by extending expiratory time, but unlike other mammals, which show a reflex response at resting lung volumes (Widdicombe, 1961b), respiratory pattern in human beings is not altered unless VT exceeds 1 L (Iber, Simon, Skatrud et al., 1995). However, more recent evidence shows that afferent vagal feedback from SASR does modulate breathing in healthy adults, particularly when the perception of chest wall movements is suppressed (BuSha, Judd, Manning et al., 2001, BuSha, Stella, Manning et al., 2002).
The involvement of SASRs in RSA was supported by the research of Haymet and McCloskey (1975), reporting inhibition of both baroreceptor and chemoreceptor effects on fc during inspiration. Furthermore, Gandevia and colleagues (Gandevia, McCloskey and Potter, 1978) reported that, in dogs, this inhibition is abolished by denervation of the lungs. These authors also reported that the level of inhibition was dependent upon the rate of lung inflation and that this inhibition only occurred during the inspiratory phase of breathing.
Important to the context of this thesis, the reflex increase in fc with lung expansion has direct implications for the acute chronotropic response to SDB, as studies in both lung denervated dogs and human beings showed almost complete abolishen of RSA in the absence of afferent feedback from the lungs, thereby lending support to an obligatory contribution from lung vagal feedback to the generation of RSA (Anrep et al., 1936a, Taha et al., 1995). Furthermore, both the rate of change of lung volume (Davis, Fowler and Lambert, 1956) and increasingly negative intrapleural pressures (Widdicombe, 1961a, Davenport, Frazier and Zechman, 1981) are known to increase the afferent discharge from the SASRs. Collectively, these data supported the hypothesis that excitation of lung SASRs underpinned RSA.
RSA resulting from a central generator
The findings of some of the aforementioned studies also provided support for the hypothesis of a central inhibitory impulse underpinning the generation of RSA (point 2 above). Studies conducted in dogs demonstrated the existence of an inhibitory effect of inspiration upon baro- and chemo-receptor reflex effects upon fc, leading to a bradycardia during the expiratory phase of breathing (Davidson, Goldner and McCloskey, 1976), which occurred even when ventilation was temporarily stopped and the baro- and chemo-receptor stimuli were delivered in the inspiratory phase of the neural respiratory cycle (Gandevia et al., 1978).
Studies in human beings confirmed the modulation of vagal responsiveness to arterial baroreceptor stimulation (Eckberg and Orshan, 1977, Eckberg et al., 1980), while the observation of the maintained fc rhythms within the typical respiratory band, even during apnoea and concomitant absence of respiratory movements, has provided yet more evidence to support a role for central irradiation of inhibitory impulses from the respiratory center in the generation of RSA (Hirsch and Bishop, 1981, Kollai and Mizsei, 1990). The influence of the respiratory control centre is not limited to its effect upon cardio-vagal motoneurons, it also modulates the activity of sympathetic motoneurons. It appears that vagal cardio-motoneurons are inhibited during the inspiratory phase, but are mildly activated during expiration (Gilbey, Jordan, Richter et al., 1984, Richter and Spyer, 1990).
On the other hand, sympathetic neurons exhibit great inter-species variability in their pattern of discharge, which may account the variety of confounding findings across the literature (Eckberg, Nerhed and Wallin, 1985, Richter and Spyer, 1990). That said, sympathetic outflow demonstrates a systematic pattern of respiratory modulation, in that excitation in one phase of respiration, is accompanied by inhibition in the opposite respiratory phase (Richter and Spyer, 1990). In human beings, inhibition of the sympathetic motoneuron discharge seems to occur mostly during inspiration, whilst increased sympathetic activity is observed particularly in late-expiration (Eckberg et al., 1985, Seals, Suwarno, Joyner et al., 1993, St. Croix, Satoh, Morgan et al., 1999).
These, and other obervations, gave way to the well-known ‘respiratory gate’ theory proposed by Dwain Eckberg(Eckberg, 2003), which expanded on the ‘respiratory gating’ concept introduced by Lopes and Palmer, almost 30 years earlier (Lopes and Palmer, 1976). The technological breakthroughs occuring during the three decades between Lopes and Palmer’s provocative work and Eckberg’s review, allowed a deeper comprehension of the interrelation between autonomic cardiovascular and respiratory control. According to Eckberg, these shed light on the ‘respiratory gate’ concept. Eckberg’s theory postulates that the respiratory modulation of fc can be best described as a ‘gate’ consisting of inspiratory interneurons (probably located winthin the nucleus tractus solitarius; a brainstem structure that receives and relays vagal afferent feedback from the cardiovascular system and other structures in central nervous system), which control the passage of impulses into the nucleus ambiguous (Lopes and Palmer, 1976, Eckberg, 2003).
The first of Eckberg’s new concepts was that evidence of respiratory activity could be found imprinted upon human autonomic signals. It is known that as breathing rate decreases the RR intervals fluctuations (RSA) increase, as does the total spectral power (Hirsch and Bishop, 1981, Eckberg, 1983, Saul, Berger, Chen et al., 1989, Song and Lehrer, 2003). Simultaneously, important but smaller fluctuations have also been detected in ABP and SNA (Badra, Cooke, Hoag et al., 2001). Together with previously reported evidence regarding the responsiveness of vagal motoneurons to baroreceptor stimulation (Eckberg and Orshan, 1977, Eckberg et al., 1980), these findings led Eckberg to define the ‘respiratory gate’ as a sinusoidally variying, constantly open gate (Eckberg, 2003) that regulates both vagal and sympathetic motoneuron responsiveness to external inputs, particularly of baroreflex origin (Eckberg et al., 1985, Eckberg, 2003, Rothlisberger, Badra, Hoag et al., 2003).
According to Eckberg and colleagues (Eckberg, 2003, Rothlisberger et al., 2003), not only does respiration gate muscle sympathetic nerve activity, it also determines the timing of spontaneous baroreflex sequences through a cascade of events:
- the respiratory gate opens and sympathetic bursts appear;
- the sympathetic bursts increase ABP, triggering baroreflex RR interval prolongations;
- the increase of ABP silences sympathetic motoneurones, ABP falls, leading to RR interval shortening.
Importantly, the Rothlisberger et al. (2003) study suggested that respiration did not affect the BRS, as BRS was similar during spontaneous breathing and apnoea.
The magnitude of respiratory gating of neural outflow depends critically on the level of stimulation. This is supported by evidence showing abolition of respiratory modulation of vagal motoneurone response with intense baroreceptor stimulation (Eckberg and Orshan, 1977), or pharmacologically elevated ABP, leading to diminished RSA (Goldberger, Ahmed, Parker et al., 1994). Similar findings arose from experiments exploring graded passive upright tilt and its effects on SNA; they observed that significant inspiratory-expiratory differences of sympathetic outflow in the supine position and lower tilt angles disappear when moving to an upright posture (Cooke, Hoag, Crossman et al., 1999).
I think you may need a short senentce or two here summarising this section.
RSA resulting from atrial stimulation
A third putative mechanism for the generation of RSA suggests it is underpinned by the stimulation of mechanoreceptors located mainly in the junctions of the great veins with the right atrium. A more in-depth characterisation of these atrial baroreceptors has been previously provided in section 2-2.2. The first evidence of the existence of such afferents came from the studies of Francis Bainbridge, who demonstrated that the infusion of saline or blood into the jugular vein of the anesthetised dog produced tachycardia (Bainbridge, 1915), with similar cardiac acceleration being produced by increased venous return accompanying inspiration, in anesthetised cats and dogs (Bainbridge, 1920); this phenomenon was later to become known as the Bainbridge reflex.
The Bainbridge reflex was studied throughout the 20th century, with subsequent researchers confirming its existence and clarifying its anatomical and physiological features, mostly in dogs (Coleridge et al., 1957, Ledsome and Linden, 1964, 1967, Horwitz and Bishop, 1972, Vatner, Boettcher, Heyndrickx et al., 1975). Later studies demonstrated a species-dependency of the Brainbridge reflex, suggesting a much attenuated magnitude of response in human beings than had been previously observed in dogs (Boettcher, Zimpfer and Vatner, 1982). A more dominant arterial baroreceptor mechanism and lower baseline vagal tone in human beings, thus precluding substantial vagal-withdrawal-mediated increases in fc, are the likely factors behind the less potent response observed in human beings (Boettcher et al., 1982). Interestingly, in supine, conscious human beings, undergoing graded increases in central blood volume (within physiological range), the baroreflex vagal-mediated decrease in fc was dominant during the initial increases in blood volume, but was suppressed when central blood volume was increased further. This was consistent with the existence of a mild Bainbridge reflex in human beings, and suggested a potential role in controlling short-term fluctuations of fc, and thus RSA (Barbieri, Triedman and Saul, 2002).
Despite the supporting evidence of the existence of cardiac modulation in response to changes in central blood volume, and potentially by respiratory-driven changes in venous return, it is still unclear if the dominant mechanism underpinning change in fc is of reflex origin (Bainbridge reflex) or, mainly myogenic. Studies in heart transplanted individuals (with no vagal innervation of the heart) demonstrated the existence of respiratory modulation of fc (RSA), likely linked to a direct mechanical stretch of atrial walls, induced by respiratory variations in venous return (Bernardi et al., 1989, Taha et al., 1995).
RSA resulting from baroreflex mechanisms
The fourth and final mechanism proposed to underlie the generation of RSA is related to the arterial baroreflex. The deformation of mechanosensitive baroreceptors provides afferent neural information to the medullary centres, via the vagus nerve, resulting in increases or decreases in the outflow of efferent sympathetic nerve traffic to the peripheral vasculature and heart, as well as efferent vagal traffic to the heart. A more detailed description of the mechanisms of action has been provided previously in section 2-2.1.
The idea that RSA could be mainly determined by respiratory driven alterations in ABP, transiently affecting fc by stimulation of the aortic arch and carotid baroreceptors, was first suggested by Schwheitzer in 1937, and later supported by a 1961 paper from Koepchen and colleagues (cit by de Burgh Daly, 1986) . These early studies, performed in isolated and perfused carotid sinuses. garnered little support, primarily because they failed to explain why during slow breathing, tachycardia could occur in the presence of an increase in ABP (de Burgh Daly, 1986). However, the discovery of a within-breath variation in the responsiveness of cardiac vagal motoneurones to incoming baroreceptor afferent traffic (Haymet and McCloskey, 1975, Eckberg and Orshan, 1977, Eckberg et al., 1980) shed new light on the matter, and re-ignited interest in the role of the baroreflex in the generation and amplitude of RSA.
Great advances resulted from the mathematical modelling work of De Boer et al. (1987), and later TenVoorde, Faes, Janssen et al. (1995), in which they advocated that ABP was altered mechanically by the act of breathing, with an immediate response from fc (within the same heart beat), determined by a fast-acting cardiac vagal baroreflex loop.
This hypothesis gained support from studies using neck suction to stimulate the carotid baroreceptors in conjunction with paced breathing (Piepoli, Sleight, Leuzzi et al., 1997, Keyl, Dambacher, Schneider et al., 2000). Piepoli and colleagues reported that RSA could be either mimicked or supressed through the stimulation of arterial baroreceptors with neck suction. When delivering continuous sinusoidal neck suction at the frequency of respiration during apnoea, they managed to reproduce oscillations in ABP, thus supporting the idea of a mechanical origin of respiratory oscillations in ABP. In the same study, similar stimulation of a non-baroreflex area (thigh) had no measureable effect on RSA, confirming the carotid baroreceptors as the source of the resulting RSA. The contribution of a baroreflex mechanism to the generation and amplitude of RSA was also demonstrated by the attenuation of RSA when carotid stimulation was delivered at a phase of the respiratory cycle that would counteract the normal phase relation between respiration and ABP (Piepoli et al., 1997). This was further supported by Keyl et al.’s data (2000), demonstrating that neck suction at 0.2Hz produced a similar time lag between systolic blood pressure (SBP) change and RR interval alteration to that observed with paced breathing at 0.25Hz.
What does determine respiratory sinus arrhythmia?
All things considered, it seems that there is unlikely to be a single, unifying mechanism controlling the generation and magnitude of RSA. In a highly interesting point/counterpoint paper in the Journal of Applied Physiology, both Dwain Eckberg and John Karemaker (with some important input to the discussion being provided from other expert members of the scientific community) defended their differing views regarding the main determinant(s) of RSA (Eckberg, 2009a, b, Julien, Parkes, Tzeng et al., 2009, Karemaker, 2009a, b, c). Eckberg strongly advocated that central gating was sufficient to explain respiratory frequency RR interval fluctuations and that the latency between blood pressure changes and parallel RR interval changes, as defined by cross-spectral phase, was too short for meaningful baroreflex responses to be mounted. Contrarily, Karemaker championed the important role of the baroreflex in the generation and in the magnitude of RSA, and argued that if all RSA is due to central modulation alone, similar-sized oscillations would be expected in both systolic (SBP) and diastolic blood pressures (DBP). Karemaker went on to argue that while a large respiratory variability in SBP exists, DBP varies very little, thus arguing for a very quick cardiovagal-baroreceptor loop, in line what he and others had previously demonstrated with mathematical models (De Boer et al., 1987). In the end, both acknowledged the existence of an undefined blend of baroreflex mechanism and central gating in the generation of respiratory frequency RR interval fluctuations, with Karemaker also pointing out the importance of other reflex input mechanisms. These included those resulting from the effects of respiration upon venous return and the resulting pressure changes inside the heart chambers, which are known to have a modulating effect upon autonomic outflow (Karemaker, 2009c). Nonetheless, apart from the intricacy of the underlying physiology here discussed, and some concessions with regards to the existence of multiple mechanisms underpinning RSA, the fact remains that no one has yet managed to provide unequivocal evidence in support of a unifying model, if in fact one exists, underpinning respiratory-related fluctuations in RR interval.
Historically, ever since it has been possible to obtain direct recordings of sympathetic nerve activity (SNA), evidence of respiratory modulation has been reported (Okada and Fox, 1967, Hagbarth and Vallbo, 1968, Preiss et al., 1975, Gerber and Polosa, 1978, Eckberg et al., 1985). Despite the evidence that sympathetic outflow is not uniform across the different vascular beds, it is accepted that cardiac, splanchnic, renal and muscle sympathetic nerve activity (MSNA) are strongly influenced by baroreceptor and chemoreceptor stimulation (Hart, Head, Carter et al., 2017). Thus, the measurement of MSNA provides a convenient indicator of sympathetic vasoconstrictor outflow to these vascular beds (Wallin, Esler, Dorward et al., 1992, Wallin, Thompson, Jennings et al., 1996). Also, important for the foregoing discussion, MSNA shows highly inter-individual variability, but very low intra-individual variability (Fagius and Wallin, 1993).
Respiratory modulation of MSNA
In healthy individuals, vagally mediated lung stretch reflex is the primary mechanism through which MSNA is modulated by respiration (Seals, Suwarno and Dempsey, 1990, Seals et al., 1993), with the degree of lung inflation affecting the magnitude of the respiratory modulation. This however, the latter is not observed in lung denervated individuals, which despite showing modulation of MSNA at the respiratory frequency, did not demonstrate a potentiation of this effect at elevated tidal volumes (Seals et al., 1993)
A contribution of baroreceptor afferent stimulation by respiratory induced changes in ABP has also been advocated as a contributor to the fluctuations in MSNA, within the respiratory frequency band (St. Croix et al., 1999). During spontaneous breathing, MSNA usually reaches a nadir in late inspiration and peaks during expiration (Dempsey, Sheel, St Croix et al., 2002). However, the modulatory influence of respiration upon MSNA seems to be attenuated in some disease conditions, including hypertension (Fisher, Reynolds, Farquhar et al., 2010, Fisher, McIntyre, Farquhar et al., 2011), and to a lesser extent in chronic heart failure (Goso, Asanoi, Ishise et al., 2001). Furthermore, while older people tend to have generally higher MSNA than their younger counterparts, the pattern of respiratory inhibition of MSNA does not show substantial age-related modifications (Shantsila, McIntyre, et al., 2015). As mentioned earlier in section 2-4.2, the respiratory modulation of MSNA likely represents a causative relationship, with the presence and amplitude of ABP fluctuations occurring in parallel with respiration.
Fluctuations in MSNA occurring at 0.1Hz
Reported oscillations in SNA at a frequency close to that of the so-called Mayer waves in blood pressure has led to the assumption that MSNA oscillations driven by a central oscillator could be responsible for the ABP Mayer waves (Julien, 2006). Studies in animal models have demonstrated that fluctuations in SNA persist even when ABP oscillations are abolished, and are thus independent of baroreflex control (Preiss and Polosa, 1974, Grasso, Rizzi, Schena et al., 1995). Further evidence of a possible link between a central modulator of SNA and Mayer waves has been shown in vagotomised, baroreflex-denervated, anesthetised cats, where oscillations in both medullary neurons and cardiac SNA was detected at the Mayer wave frequency (Montano, Gnecchi-Ruscone, Porta et al., 1996, Montano, Cogliati, da Silva et al., 2000).
There is some support for a centrally originated rhythm in SNA that is independent of baroreflex afferent signals, but only under strict experimental conditions. Data from human beings, under physiological conditions, where the arterial baroreflex is the dominant ABP regulatory mechanism, shows a necessary modulation of ABP Mayer waves by reflex mechanisms (Julien, 2006). This can be demonstrated clearly by sino-aortic deafferentation, where the complete removal of baroreflex afferent input abolishes Mayer waves despite the presence of oscillations in vasomotor outflow (Di Rienzo, Parati, Castiglioni et al., 1991, Julien, Zhang, Cerutti et al., 1995, Mancia, Parati, Castiglioni et al., 1999). Thus, sinusoidal baroreflex stimulation occurring at 0.1Hz, as a consequence of resonances in the baroreflex control loop triggering an ABP rhythm, could be the main driver of 0.1Hz fluctuations in SNA (Malpas, Leonard, Guild et al., 2001).
Importantly the magnitude of SNA outflow to each vascular bed will be determined by said organ’s baroreceptor sensitivity, and will be delivered with a fixed time delay in relation to the previous ABP perturbation. The combination of the delays from the different vascular beds, including the skeletal muscle vasculature, kidney, gut and lungs, imply that the response of vascular resistance following the change in ABP could amplify said oscillations, instead of buffering them, thereby contributing to the 0.1 Hz fluctuations in ABP by a mechanism other than a central oscillator (Malpas et al., 2001).
The previous points in this section have highlighted the presence of rhythmicity in cardiovascular signals occurring at the respiratory frequency (fR), but also at lower frequencies, which in humans, tend do occur with a periodicity circa 10s (0.1 Hz).
The alignment of the different rhythms when breathing at a frequency close to 0.1Hz (6 breaths.min-1) is thought to produce synchronisation, entrainment (of respiration, ABP and fc) and resonance (likely from the baroreflex control of ABP and fc, leading to amplification of the oscillations in these physiological variables). This phenomenon is sometimes referred to as ‘coherent breathing’ (McCraty and Tomasino, 2004, Elliot and Edmonson, 2006) and normally results in smooth, sinusoid patterns in vascular and cardiac rhythms, which translates into a very high-amplitude peak in the low frequency (LF; 0.04-0.15 Hz) band of the HRV and BPV power spectrum (McCraty and Tomasino, 2004).
The mechanism behind this amplification of the cardiovascular rhythmicity is believed to be linked to the resonance characteristics in the vascular baroreflex control loop. Resonances are typical of some physical systems, more specifically those that comprise fixed delays (Grodins, 1963, cited by Lehrer, 2013). These result in very high amplitude oscillations at a specific frequency (resonant frequency) when a stimulus is applied with the same or similar frequency. Furthermore, existing oscillations at other frequencies are completely suppressed in the presence of resonant fluctuations (Lehrer, 2013).
While ABP and fc oscillations are irregular and small during spontaneous breathing, these become much larger and regular when breathing at the resonant frequency, or close to it. Although the mechanism proposed by Lehrer, Vaschillo and others to explain the effects of breathing at resonant frequencies is likely an over-simplification (Lehrer, Vaschillo and Vaschillo, 2000, Vaschillo et al., 2002), the existence of a slow breathing frequency, which amplifies cardiovascular oscillations, is undeniable, and might be of clinical relevance. According to Vaschillo and colleagues (2002), resonant breathing is characterised by:
- Respiration and fc with a 0º phase relation (completely in phase);
- ABP and fc with a 180º phase relation (completely in anti-phase)
The authors associated the aforementioned phase relations to a ~5 s delay within the cardiac baroreflex loop. They also argued that this interpretation was strenghtened further by evidence that the ABP resonant frequency lay at even lower frequencies, corresponding to the time delay of the vascular baroreflex loop (Vaschillo et al., 2002) and argued that the mechanical effect of breathing triggers a decrease in fc that reduces blood flow and therefore ABP, thus promoting a stimulus for fc to increase. Despite being physiologically plausible, it has been previously demonstrated that RSA only significantly contributes to the amplitude of ABP variations when sympathetic tone is suppressed (Saul, Berger, Albrecht et al., 1991).
Postural changes impact autonomic activity and can therefore change the contribution of RSA to ABP fluctuations, particularly when considering variations in systolic blood pressure (SBP) in the supine position (Elstad, Toska, Chon et al., 2001). Therefore, any causality between RSA and ABP must be interpreted with care. Furthermore, others have reported a quicker time course of the action (2 s of time delay followed by 2s of time constant for the maximal response to be attained) of the sympathetic baroreflex control of the vasculature (TenVoorde et al., 1995, van de Vooren, Gademan, Swenne et al., 2007) than the 5 s delay proposed by Vaschillo. Thus, it is likely that Vaschillo’s explanation is deficient by virtue of being unable to explain how and if other mechanisms producing rhythmic oscillations in fc, ABP and SNA (described earlier in this section) contribute to, or buffer, the amplitude of the observed resonant behaviour.
The advent of new mathematical methods has permitted the study of cardiac, respiratory and vascular fluctuations in the frequency domain and to better understand the phase relationships between the different rhythms. In addition, the widespread use of methods like the neck pressure/section chamber and the application of lower body positive/negative pressure or tilt techniques have permitted selective manipulation of inputs to cardiovascular receptors and/or to gradually change autonomic tone, in human beings. Furthermore, the development of minimally invasive ways of assessing MSNA, and the reliable non-invasive measurement of beat-to-beat ABP, LVSV and Q̇, has permitted in vivo studies in human beings, which were only previously possible in animal models. Taken together, the research using these techniques has furthered the understanding of cardiovascular rhythms and their interaction with breathing, but overall, the exact underlying mechanisms remain somewhat elusive. Figure 2-9 represents one of the many attempts in the literature to provide an integrated picture of the existing oscillations affecting ABP fluctuations.
Circles reflect local oscillators in the central nervous system or in smooth muscle system (myogenic mechanisms) Arrows represent feedback systems that oscillate under certain conditions. ARAS – Ascending reticular activating system (series of nuclei in the brainstem of which the reticular formation is the most relevant); III – Baroreceptor circuit; IV – Chemoreceptor circuit; V – Brain ischemic circuit. From Koepchen (1991).
 Structure in the brainstem that is responsible for vagal efferent traffic to the heart.
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