Review
Respiratory sinus arrhythmia in conscious humans during spontaneous respiration

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Abstract

Respiratory sinus arrhythmia (RSA) is the beat-to-beat fluctuation in heart rate at the frequency of the respiratory cycle. While it is common to study RSA under conditions of controlled breathing, where respiratory frequency, and sometimes tidal volume and inspiratory:expiratory ratio are controlled, the effect of controlled breathing on RSA is not clear. While not all studies exploring the effects of controlled breathing on RSA magnitude are consistent, some of the best-designed studies addressing this question did find a significant effect. In addition to respiratory timing influencing heartbeats, there is evidence that cardiac timing also influences respiratory timing, termed cardioventilatory coupling. Thus, the timing interactions between the cardiac and respiratory systems are complex, and bi-directional. Controlled breathing eliminates one aspect of this relationship, and studies designed to understand cardiorespiratory physiology conducted under these conditions need to be interpreted with an understanding that they may not represent normal physiology.

Introduction

Some of the earliest medical texts (Chinese and Egyptian) that we have access to note the importance of the pulse as a prognostic indicator, but do not comment on pulse irregularity (Acierno, 1994). In 1582 Galileo used the regularity of his own pulse to time the swinging of pendulums, an experiment that suggests that he had no notion of beat-to-beat heart rate variability. Stephen Hales is generally credited as being the first to describe phasic fluctuations in blood pressure in his Statistical Haemastatiks, published in 1733 and in 1760 Albrect von Haller was the first to note that there were also rhythmic fluctuations of heart rate. It is significant however that neither Hales nor Haller linked these cardiovascular fluctuations to respiratory activity (Koepchen, 1984, Leake, 1962).

Poiseuille (1799–1869) in 1828, using his invention, the hemodynamometer, to measure arterial blood pressure, showing that the fluctuations in pressure described by Hales were related to respiratory activity. Carl Ludwig (1816–1895), in 1847, also described the relationship between in arterial pressure and respiration, but also demonstrated that heart rate fluctuations were related to respiratory activity. Thus Ludwig is generally credited with the first description of respiratory sinus arrhythmia (RSA). He suggested that the mechanism of the arterial pressure fluctuation was the mechanical effect of changes in intrathoracic pressure, associated with respiration, on blood vessels. His was the first proposed explanation for RSA (Koepchen, 1984, Leake, 1962). However it was soon demonstrated by Donders (1852) and Einbrodt (1860), that the changes in intrathoracic pressure associated with breathing were not large enough to account for the observed changes in arterial blood pressure and the involvement of a neural reflex arc was therefore proposed (Koepchen, 1984, Leake, 1962).

Following Ludwig's work there was considerable interest in the study of blood pressure variability throughout the rest of the 19th and into the 20th Century. Traube in 1865 performed experiments in paralysed, vagotomised dogs in which slow waves (with a period of around 9 s) were observed in arterial pressure. E. Hering, repeated these experiments 4 years later again in paralysed vagotomised dogs and, in addition, managed to temporarily exclude the heart without disruption of the blood pressure waves, thereby demonstrating that the waves were not of cardiac origin. Hering termed these oscillations in blood pressure “Traube waves” and viewed them as being synchronous with a central respiratory rhythm (Koepchen, 1984, Leake, 1962).

In 1876 Mayer described blood pressure waves in spontaneously breathing rabbits that were slower than the respiratory rhythm, but at about the frequency described by Traube and Hering, and called these “Hering waves”. Fredericq in 1882 studied the work of Traube, Hering and Mayer, and concluded that Traube–Hering waves occurred at the respiratory frequency, and that Mayer waves were slower than the respiratory frequency. Since this time there has been considerable confusion over both the origins and nomenclature of these arterial pressure waves and their interaction with cardiac and respiratory rhythmicity. In 1984 Koepchen reviewed the extensive, primarily German, literature on the subject and agreed with Fredericq's classification, although he noted that all blood pressure waves were influenced by respiratory activity (Koepchen, 1984).

While this work on blood pressure fluctuations was progressing there was relatively little interest in heart rate variability. However a number of key discoveries regarding neural control of cardiac timing were made. The Weber brothers Ernst (1795–1878) and Eduard (1806–1871) demonstrated that the vagus nerve depressed heart rate, and shortly after this Albert Bezold (1836–1868) demonstrated that there were also accelerator nerves that innervated the heart. Herman Stannius (1808–1883) analysed the automaticity and rhythmicity of different sections of the heart and demonstrated that the heartbeat originated at the sinus node. Johann Czermak (1828–1873) demonstrated that the heart rate slowed when pressure was applied to the carotid sinus and this lead to the description of the baroreceptor reflex by HE Hering in 1924 (Acierno, 1994, Leake, 1962).

In 1936 Anrep et al. described a series of elegant experiments in dogs in which they sought to elucidate the mechanisms underlying RSA (Anrep et al., 1936). In the introduction to their paper the controversial nature of this question was outlined. One argument (held by E Hering and HE Hering) was that RSA was caused by a reflex originating in the lungs. Another group (including Traube, Fredericq and Heymans) maintained that RSA was due to central interactions between cardiac and respiratory control, while a third group (including Bainbridge and Hilton) argued that RSA was due to changes in blood pressure occurring with inspiratory changes in intrathoracic pressure. Anrep et al.’s experiments suggested however that respiratory sinus arrhythmia was due to a combination of three factors; (1) the direct influence of central respiratory neurones on cardiac neurones, (2) an indirect effect on heart rate of changes in blood pressure and (3) a reflex cardiac response to mechanical inflation of the lung.

Studies over the 75 years since the work of Anrep et al. have elucidated many of the factors which influence the magnitude of RSA. They have demonstrated that RSA is present from birth, increases up to the early adulthood and then decreases in magnitude with age (Hrushesky et al., 1984). RSA magnitude is greater at lower respiratory frequencies, and with higher tidal volumes (Hirsch and Bishop, 1981). RSA increases in amplitude during non-rapid eye movement sleep (Jurysta et al., 2006). Diminished RSA is associated with adverse clinical outcomes in a range of patient groups, including acute myocardial infarction (Fei et al., 1996a) and heart failure (Fei et al., 1996b), and is a risk factor for sudden infant death syndrome (Schechtman et al., 1992). Despite these advances in our understanding of the relevance of RSA, debate over the mechanisms of RSA continues (Cohen and Taylor, 2002, Eckberg, 2009, Karemaker, 2009a).

Part of the difficulty in elucidating the mechanism/s of RSA is that fluctuations in heart period in response to respiratory activity are related to the respiratory frequency (Angleone and Coulter, 1964), tidal volume (Hirsch and Bishop, 1981) and inspiratory:expiratory (I:E) ratio (Strauss-Blasche et al., 2000). Any role of baroreceptor feedback in the genesis of RSA is further linked to changes in preload, after load and stroke volume that occur with changing intrathoracic pressure (Toska and Eriksen, 1993), and reflex changes in sympathetic and parasympathetic outflow. Central interactions between respiratory and cardiovascular neurones are also influenced by a host of other interactions. There are fluctuations in heart rate, blood pressure and respiratory activity at other frequencies.

Temporal variations in respiratory period, tidal volume, and I:E ratio are all observed during spontaneous breathing (Bruce, 1996). Both the periodic and nonperiodic variability observed are due to feedback mechanisms (Bruce, 1996) in much the same way that beat-to-beat heart rate fluctuations reflect different feedback mechanisms in cardiovascular control (Cohen and Taylor, 2002). However, respiratory variability has received far less attention than heart rate variability (HRV). The central respiratory network receives, and is conditioned by, feedback from a large range of sources including lung and upper airway stretch receptors, peripheral and central chemoreceptors and critically, cardiovascular receptors (Bruce, 1996). The spontaneous control of breathing is also obviously subject to short-term voluntary control that allows all of these feedback mechanisms to be overridden by cortical inputs.

One of our recent interests has been the study of the effect of cardiac timing on subsequent respiratory activity. We have referred to this as cardioventilatory coupling (Galletly and Larsen, 2001, Tzeng et al., 2003, Tzeng et al., 2007b). While there are interpretations of this phenomenon that differ from our own (Hoyer et al., 1997, Hoyer et al., 2001), we believe that we have produced strong evidence that the cardiac activity of baroreceptor afferents is capable of prematurely triggering inspiratory onset (Tzeng et al., 2007b) resulting in a temporal alignment of inspiration to a preceding heart beat. This evidence includes the persistence of coupling under conditions where heart rate is controlled by pacing (Tzeng et al., 2007b) or pseudorandom in atrial fibrillation (Larsen et al., 1999), and the significant decrease in coupling observed following baroreceptor denervation in the rat (Tzeng et al., 2007b). We have demonstrated that cardiac timing can be a significant determinant of respiratory variability (Galletly and Larsen, 1999), altering tidal volume, I:E ratio and breath-to-breath respiratory frequency (Larsen et al., 2003). Cardioventilatory coupling is most apparent in the resting state, sleep and under conditions of low cognitive and physical load.

While RSA is the modulation of heart rate by respiratory activity, cardioventilatory coupling is a triggering of respiration by cardiac activity. Thus the relationship between heart rate and respiration is bi-directional, and very complex.

Attempts to uncouple these interrelationships in human experimental subjects have relied on (a) on pharmacological intervention (Pagani et al., 1986), (b) physical interventions such as altering body position (Hayano et al., 1994), (c) electrically stimulating the heart (Taylor and Eckberg, 1996) and (d) the voluntary control of respiratory activity (Hirsch and Bishop, 1981). While these interventions are potentially powerful tools for probing the mechanisms of RSA, results achieved using these tools may be influenced in ways that are not fully understood. With respect to controlled respiratory activity, the key question that remains unresolved is what does this do to RSA? Since controlled respiration removes the possible influence of cardiac activity on respiratory timing, we have disrupted the normal bi-directional system of which RSA is only a component outward manifestation.

Section snippets

Theoretical concerns

Angleone and Coulter (1964) argued that earlier work on characterisation of RSA was inadequate, as it limited the exploration to one respiratory frequency and one tidal volume, and that systematic exploration of a range of frequencies and tidal volumes was required to fully understand RSA. Since that time controlled ventilation, either at a fixed frequency (Pagani et al., 1986), with stepwise changes in frequency (Cooke et al., 1998), or with pseudorandom fluctuations in frequency (Berger et

Mechanisms of RSA

Anrep et al. (1936) sought to resolve the debate regarding the mechanisms responsible for RSA in a series of elaborate and invasive studies of RSA in the dog. They argued that RSA was due to a mechanical component due to changes in intrathoracic pressure, a central component due to influence of central respiratory neurones on cardiac outflow and a reflex effect of blood pressure on heart beat timing.

Bernardi et al. (1989) were the first to demonstrate that RSA was still present in heart

Physiological significance of RSA

While there has been intense interest in the mechanism(s) and determinants of RSA over the last 100 years, aside from the argument that RSA acts to buffer blood pressure fluctuations, there has been relatively little focus on the physiological significance of RSA. In their elegant study, Hayano et al. (1996) demonstrated in dogs that the cardiac acceleration during inspiration led to a clustering of heart beats. The increase in heart beats during inspiration led to an increase in pulmonary

Conclusions

There remains considerable interest in the mechanisms responsible for RSA, and the physiological consequences of these respiratory fluctuations in heart beats remains to be understood. One of the most widely used tools to probe RSA is controlled breathing. The attractiveness of this tool is that it removes the need to correct for breath-to-breath variability in respiratory activity, and allows a range of respiratory frequencies and tidal volumes to be explored in a controlled fashion. However

Acknowledgements

YC Tzeng was supported by a grant from the New Zealand Heart Foundation (Grant No. 1284), and PYW Sin by a University of Otago Postgraduate Scholarship.

References (65)

  • Y.-C. Tzeng et al.

    Paradoxical respiratory sinus arrhythmia in the anesthetized rat

    Auton. Neurosci.

    (2005)
  • L.C. Acierno

    The History of Cardiology

    (1994)
  • A. Angleone et al.

    Respiratory sinus arrhythemia: a frequency dependent phenomenon

    J. Appl. Physiol.

    (1964)
  • G.V. Anrep et al.

    Respiratory variations of the heart rate. I. The reflex mechanism of the respiratory arrhythmia

    Proc. Roy. Soc. London. Ser. B

    (1936)
  • L.J. Badra et al.

    Respiratory modulation of human autonomic rhythms

    Am. J. Physiol. Heart Circ. Physiol.

    (2001)
  • R.D. Berger et al.

    Assessment of autonomic response by broad-band respiration

    IEEE Trans. Biomed. Eng.

    (1989)
  • L. Bernardi et al.

    Respiratory sinus arrhythmia in the denervated human heart

    J. Appl. Physiol.

    (1989)
  • L. Bernardi et al.

    Clinical assessment of respiratory sinus arrhythmia by computerized analysis of RR interval and respiration

    G Ital. Cardiol.

    (1992)
  • E.N. Bruce

    Temporal variations in the pattern of breathing

    J. Appl. Physiol.

    (1996)
  • A.J. Camm et al.

    Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology

    Eur. Heart J.

    (1996)
  • M.A. Cohen et al.

    Short-term cardiovascular oscillations in man: measuring and modelling the physiologies

    J. Physiol. (Lond.)

    (2002)
  • W.H. Cooke et al.

    Controlled breathing protocols probe human autonomic cardiovascular rhythms

    Am. J. Physiol.

    (1998)
  • D. Cysarz et al.

    Cardiorespiratory synchronization during Zen meditation

    Eur. J. Appl. Physiol.

    (2005)
  • T.E. Dick et al.

    Quantitative analysis of cardiovascular modulation in respiratory neural activity

    J. Physiol. (Lond.)

    (2004)
  • D.L. Eckberg

    Human sinus arrhythmia as an index of vagal cardiac outflow

    J. Appl. Physiol.

    (1983)
  • D.L. Eckberg

    The human respiratory gate

    J. Physiol. (Lond.)

    (2003)
  • D.L. Eckberg

    Point:counterpoint: respiratory sinus arrhythmia is due to a central mechanism vs. respiratory sinus arrhythmia is due to the baroreflex mechanism

    J. Appl. Physiol.

    (2009)
  • M. Elstad et al.

    Respiratory sinus arrhythmia: opposite effects on systolic and mean arterial pressure in supine humans

    J. Physiol. (Lond.)

    (2001)
  • L. Fei et al.

    Decreased heart rate variability in patients with congestive heart failure and chronotropic incompetence

    Pacing Clin. Electrophysiol.

    (1996)
  • N.D. Giardino et al.

    Respiratory sinus arrhythmia is associated with efficiency of pulmonary gas exchange in healthy humans

    Am. J. Physiol. Heart Circ. Physiol.

    (2003)
  • O. Gilad et al.

    Phase-averaged characterization of respiratory sinus arrhythmia pattern

    Am. J. Physiol. Heart Circ. Physiol.

    (2005)
  • J. Hayano et al.

    Effects of respiratory interval on vagal modulation of heart rate

    Am. J. Physiol.

    (1994)
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