Chapter 10 - Cardiorespiratory Coupling: Common Rhythms in Cardiac, Sympathetic, and Respiratory Activities

https://doi.org/10.1016/B978-0-444-63274-6.00010-2Get rights and content

Abstract

Cardiorespiratory coupling is an encompassing term describing more than the well-recognized influences of respiration on heart rate and blood pressure. Our data indicate that cardiorespiratory coupling reflects a reciprocal interaction between autonomic and respiratory control systems, and the cardiovascular system modulates the ventilatory pattern as well. For example, cardioventilatory coupling refers to the influence of heart beats and arterial pulse pressure on respiration and is the tendency for the next inspiration to start at a preferred latency after the last heart beat in expiration. Multiple complementary, well-described mechanisms mediate respiration’s influence on cardiovascular function, whereas mechanisms mediating the cardiovascular system’s influence on respiration may only be through the baroreceptors but are just being identified. Our review will describe a differential effect of conditioning rats with either chronic intermittent or sustained hypoxia on sympathetic nerve activity but also on ventilatory pattern variability. Both intermittent and sustained hypoxia increase sympathetic nerve activity after 2 weeks but affect sympatho-respiratory coupling differentially. Intermittent hypoxia enhances sympatho-respiratory coupling, which is associated with low variability in the ventilatory pattern. In contrast, after constant hypobaric hypoxia, 1-to-1 coupling between bursts of sympathetic and phrenic nerve activity is replaced by 2-to-3 coupling. This change in coupling pattern is associated with increased variability of the ventilatory pattern. After baro-denervating hypobaric hypoxic-conditioned rats, splanchnic sympathetic nerve activity becomes tonic (distinct bursts are absent) with decreases during phrenic nerve bursts and ventilatory pattern becomes regular. Thus, conditioning rats to either intermittent or sustained hypoxia accentuates the reciprocal nature of cardiorespiratory coupling. Finally, identifying a compelling physiologic purpose for cardiorespiratory coupling is the biggest barrier for recognizing its significance. Cardiorespiratory coupling has only a small effect on the efficiency of gas exchange; rather, we propose that cardiorespiratory control system may act as weakly coupled oscillator to maintain rhythms within a bounded variability.

Introduction

Cardiorespiratory coupling (CRC) encompasses various phenomena which result from shared inputs, common rhythms, and complementary functions. In particular, autonomic and respiratory rhythms are expressed in the other’s neural activity, including both pattern generators and motor activity (Dick et al., 2005). This has led us to conceive of reciprocal interaction between the respiratory and autonomic control systems in the function of gas exchange (Fig. 1). In other words, in addition to the well-recognized respiratory influence on autonomic activity, the autonomic system has an influence on respiratory pattern formation. The respiratory influence on autonomic activity is breath to breath, whereas the autonomic influence on respiration can be considered beat to beat (Larsen et al., 2010, Zhu et al., 2013). The effect of a slower rhythm superimposed on a faster one is recognized easily; no doubt this contributed to the early recognition and general acceptance of the influence of respiration on heart rate (HR) and blood pressure (BP). In contrast, the effect of blood pressure on respiration, referred to as cardioventilatory coupling (CVC), is just being recognized. A fundamental deterrent to accepting CRC as being physiologically significant is that it appears to have only a weak role in determining the efficiency of gas exchange. In light of this, we theorize the reciprocal interaction of CRC relates to its physiologic function in pattern formation determining variability of cycles within limits as described for weakly coupled oscillators (Ermentrout and KO, 2009, Ermentrout and Saunders, 2006, Ermentrout et al., 2008, Galan et al., 2010, Galan et al., 2005).

Heartbeat, blood pressure, and ventilation share common frequencies. Billman (2011) wrote a concise history on the observation and quantification of HR and BP and the influence of respiration on these two variables (also see Larsen et al., 2010). Briefly, in 1733 Rev. Stephen Hales reported that respiration modulates HR and BP. This observation was confirmed by Carl Ludwig (1847) who measured the increases in HR and BP during inspiration. The increase in HR during inspiration is referred to as respiratory sinus arrhythmia (RSA) and the increase in BP as Traube–Hering waves. Heart rate and BP are modulated neurally, and both parasympathetic and sympathetic nerves have respiratory-modulated activity patterns. Multiple factors, including mechanical coupling, underlie the increases in HR and BP. Mechanical coupling in the cardiorespiratory system is due to the location of the lungs and heart in the thoracic cavity. Inspiration relies on a decrease in thoracic pleural pressure which draws blood to the heart and increases venous return, which increases HR and cardiac output. However, HR and BP can increase during inspiration in a perfused in situ preparation in which the thorax is wide open and the lungs are removed (Baekey et al., 2008, Baekey et al., 2010, Dick et al., 2009, Julien et al., 2009). Consequently, this review focuses on the neural mechanism (Fig.1).

CVC, a distinct property of CRC was described in the twentieth century by Walter Coleman. He observed animals at the Zoological Gardens in Regent’s Park and reported that the ratio of heart beats to breaths was a whole number (4 and 5:1) in numerous species (Coleman, 1920). More convincingly, a statistical evaluation of the distribution of the time intervals between respiratory phase transitions and the previous or next heart beat identified that the onset of inspiration occurs at a preferred latency after the previous peak in systolic BP (Friedman et al., 2012, Galletly and Larsen, 1999b, Larsen and Galletly, 1999). This interval has the strongest statistical “coupling” compared to the interval between I-onset and the next heart beat and the intervals associated with the inspiratory-to-expiratory phase transition (Friedman et al., 2012). However, CVC is weak and becomes apparent during quiet sleep and anesthesia (Galletly and Larsen, 1997a, Galletly and Larsen, 1997b, Larsen and Galletly, 1999). The proposed mechanism for CVC is that systolic peak BP occurring late in expiration initiates inspiration at a preferred latency and is referred to as the baroreceptor-trigger hypothesis (Galletly and Larsen, 1999a). However, our data indicate that baroreceptor input activates expiratory neurons (Dick and Morris, 2004, Dick et al., 2005), including postinspiratory neurons (Baekey et al., 2010). This would act to delay rather than trigger inspiration. Accordingly, the onset of inspiration would occur at a preferred latency because the magnitude of the delay of inspiratory onset depends on the magnitude and timing of arterial pressure pulse, assuming that equivalent arterial pulse pressures occur at two slightly different latencies in late expiration. The later beat would activate less postinspiratory activity and delay the onset of inspiration less than the earlier one, which could recruit more postinspiratory activity because the neurons producing this activity are less hyperpolarized. Thus, the interval between the systolic arterial pressure peak and the inspiratory onset would be more similar. Either way (triggering or delaying), CVC depends on baroreceptors and carotid sinus sensory activity rather than an interaction between brainstem neural networks that generate cardiac, blood pressure, and respiratory patterns.

The reciprocal nature of autonomic and respiratory rhythms reflects a middle ground in the dichotomy regarding the neural control of homeostasis (Feldman and Ellenberger, 1988). At one end of the dichotomy is the opinion that the cardiovascular and respiratory control systems are two separate but parallel entities with distinct effectors, that is, cardiac and smooth muscles under parasympathetic and sympathetic control and striated musculature under respiratory, somatic motor control. At the other end, the cardiovascular and respiratory systems are controlled by a single neural system controlling gas exchange. While reciprocal nature of the coexpression of arterial pulse and respiratory rhythms indicates, at least, a middle ground of coupled control, the magnitude of coupling depends on various factors, which will be explored in this review.

Heart rate variability (HRV) can be assessed by many tools that examine distributions in the temporal and frequency domains. A common tool to assess HRV is the power spectral density of a continuous data stream of heart beats. Due to the RSA, the power spectral density has a peak at the respiratory frequency, which is referred to as the “high-frequency component of the power spectral density.” The other components are described in detail in the 1996 white paper published by the joint international committee on HRV (1996). One consensus is that autonomic tone, the balance of sympathetic and parasympathetic activities, can be characterized by an analysis of the HRV (Vinik, 2012, Vinik et al., 2011).

While it is beyond the scope of this review to discuss the applicability of the HRV as a biomarker, the high-frequency component of the HRV power spectral density depends on RSA. Even though decreases in HRV have been recognized as a forecasting pathogenesis and morbidity for 50 years Hon and Lee, 1963a, Hon and Lee, 1963b, for example, in predicting a subsequent myocardial infarctions (Buccelletti et al., 2009), we are just beginning to understand the relationship between cardiorespiratory dynamics and disease states that effect brainstem neural networks and control. In this regard, we propose the reciprocal component of cardiorespiratory coupling, CVC, as a biomarker that complements RSA.

The physiologic purpose of cardiorespiratory coupling remains obscure. Teleological reasoning leads to the hypothesis that CRC increases the efficiency of gas exchange by matching pulmonary perfusion to ventilation during inspiration (Hayano et al., 1996). Significant increases in the efficiency of gas exchange were found in a creative experiment in which canine HR was controlled by peripheral vagal nerve stimulation (Hayano et al., 1996). The efficiency of gas exchange was measured during three conditions: (1) replicating RSA, vagal stimulation during expiration, thus causing a relative increase in HR during inspiration; (2) reversing RSA, HR increasing during expiration; or (3) no RSA, HR distributed equally throughout the respiratory cycle. Number of heart beats per respiratory cycle was the same in each condition and the blood gases were maintained. Compared to distributing HR evenly, replicating RSA decreased physiological dead space by 10% and the fraction of intrapulmonary shunt by 51%, whereas reversing RSA increased dead space by 14% and intrapulmonary shunt by 64% (Hayano et al., 1996). However, the physiologic effectiveness appears to be weak (Ben-Tal et al., 2012). Recent optimization modeling studies reported that these effects amounted to just a 3% improvement in gas exchange efficiency (Ben-Tal et al., 2012). Is this 3% improvement relevant; after all, cardiorespiratory uncoupling is not one of the four causes of hypoxemia? But it is well known that mammalian species are intrinsically energy efficient and normally work of breathing is highly efficient for many body habitus reasons (Goldman and Mead, 1973, Goldman et al., 1978, Goldman et al., 1976), consequently to measure an effect of patterning maybe highly significant. A 3% energy conservation from breath to breath may impact highly trained athletes whose CRC is enhanced and severely ill individuals who lose CRC and die of respiratory failure.

Ben-Tal et al. (2012) proposed that RSA acts to minimize cardiac rather than respiratory work. Even though this theory shifts the focus from the work of breathing to that of beating, it still supports the general concept that RSA acts to make gas exchange efficient. However, even in this broader context, Larsen and coworkers have performed series of studies in humans and have not found support for either RSA or CVC enhancing the efficiency of a gas exchange. For example, in one study (Sin et al., 2010), the efficiency of gas exchange was compared between one group of humans with pacemakers which had a stable HR that was independent of the breathing pattern and another group of normal humans. Values of oxygen consumption and carbon dioxide production were obtained at two respiratory frequencies, normal respiratory rate (15 brths/min) and slow, deep breathing (6 brths/min) to accentuate the RSA. In the normal subjects, HR varied by 10% within the respiratory cycle during slow breathing. Even with this magnitude of RSA, gas exchange efficiency was similar in both groups. While the authors concluded that RSA had no effect, the magnitude of the Traube–Hering waves was similar in both groups; whether this was able to compensate for the absence of RSA and optimize the efficiency of gas exchange in the paced group is unknown.

In summary, while it is unlikely that the CRC is a driving force determining the efficiency of gas exchange, it may be one of the few malleable forces. Further, CRC is reduced in illness increasing the work of breathing.

We propose that a purpose of reciprocally coupled interactions between respiration and cardiovascular systems is identified by the theory of coupled oscillators. Mutual coupling increases the variability of the oscillators’ frequencies allowing them to respond and adapt to external perturbations as well as to develop complex patterns of activity (Kuramoto, 1984, Winfree, 2001). These features are essential for the cardiorespiratory system and are generally properties of neural networks (Hoppensteadt and Izhikevich, 1997). For instance, the theory of coupled oscillators predicts that weakly coupled neurons phase-lock their activity in response to sensory stimuli in a stimulus-dependent manner (Galán, 2009 and subject of the next section). Further, in this context and focusing on CRC as a neurally controlled physiologic property, even though the cardiac influence on respiration is weak, it may provide a source for ventilatory pattern variability. Thus, uncoupling will affect the variability of the ventilatory pattern.

Section snippets

Hypoxic Conditioning, Enhancing, and Diminishing CRC

While simultaneously recording sympathetic and respiratory motor activities from adult male Sprague Dawley rats, we noted that respiratory modulation of splanchnic sympathetic nerve activity (sSNA) increases during and after brief (45 s) exposures to hypoxia (8% O2 in the inhaled gas) (Dick et al., 2004). The persistence of enhanced CRC after the stimulus was our first indication of plasticity; in this case, a form of activity dependent, short-term plasticity existed in the sympathetic control

Conclusion

Cardiorespiratory coupling is reciprocal. Both effects, that of respiration on the cardiovascular activity as well as that of the arterial pressure pulse on respiratory activity, can be identified and quantified. However, the role of cardiorespiratory coupling in homeostasis and pathophysiology remains obscure. The plasticity of cardiorespiratory coupling evoked by hypoxia is an intriguing aspect of the cardiorespiratory control system; it draws our attention to limited knowledge about

Acknowledgments

We gratefully acknowledge that this work was supported by NIH HL-080318, NS-069220, and HL-007913 (R. R. D.).

References (63)

  • N.R. Prabhakar et al.

    Mechanisms of sympathetic activation and blood pressure elevation by intermittent hypoxia

    Respir. Physiol. Neurobiol.

    (2010)
  • N.R. Prabhakar et al.

    Intermittent hypoxia augments acute hypoxic sensing via HIF-mediated ROS

    Respir. Physiol. Neurobiol.

    (2010)
  • 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)
  • A.P. Abdala et al.

    Abdominal expiratory activity in the rat brainstem-spinal cord in situ: patterns, origins and implications for respiratory rhythm generation

    J. Physiol.

    (2009)
  • D.M. Baekey et al.

    Pontomedullary transection attenuates central respiratory modulation of sympathetic discharge, heart rate and the baroreceptor reflex in the in situ rat preparation

    Exp. Physiol.

    (2008)
  • A. Ben-Tal et al.

    Evaluating the physiological significance of respiratory sinus arrhythmia: looking beyond ventilation-perfusion efficiency

    J. Physiol.

    (2012)
  • G.E. Billman

    Heart rate variability—a historical perspective

    Front. Physiol.

    (2011)
  • E. Buccelletti et al.

    Heart rate variability and myocardial infarction: systematic literature review and meta-analysis

    Eur. Rev. Med. Pharmacol. Sci.

    (2009)
  • W.M. Coleman

    On the correlation of the rate of heart beat, breathing, bodily movement and sensory stimuli

    J. Physiol.

    (1920)
  • T.E. Dick et al.

    Quantitative analysis of cardiovascular modulation in respiratory neural activity

    J. Physiol.

    (2004)
  • T.E. Dick et al.

    Entrainment pattern between sympathetic and phrenic nerve activities in Sprague-Dawley rat: hypoxia-evoked sympathetic activity during expiration

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2004)
  • T.E. Dick et al.

    Arterial pulse modulated activity is expressed in respiratory neural output

    J. Appl. Physiol.

    (2005)
  • T.E. Dick et al.

    Acute intermittent hypoxia increases both phrenic and sympathetic nerve activities in the rat

    Exp. Physiol.

    (2007)
  • B. Ermentrout et al.

    Phase resetting and coupling of noisy neural oscillators

    J. Comput. Neurosci.

    (2006)
  • B. Ermentrout et al.

    Delays and weakly coupled neuronal oscillators

    Philos. Transact. A Math. Phys. Eng. Sci.

    (2009)
  • J.L. Feldman et al.

    Central coordination of respiratory and cardiovascular control in mammals

    Annu. Rev. Physiol.

    (1988)
  • E.C. Fletcher

    Invited review: physiological consequences of intermittent hypoxia: systemic blood pressure

    J. Appl. Physiol.

    (2001)
  • M.G. Fortuna et al.

    Botzinger expiratory-augmenting neurons and the parafacial respiratory group

    J. Neurosci.

    (2008)
  • L. Friedman et al.

    Cardio-ventilatory coupling in young healthy resting subjects

    J. Appl. Physiol.

    (2012)
  • R.F. Galán

    The phase oscillator approximation in neuroscience: an analytical framework to study coherent activity in neural networks

  • R.F. Galan et al.

    Efficient estimation of phase-resetting curves in real neurons and its significance for neural-network modeling

    Phys. Rev. Lett.

    (2005)
  • Cited by (0)

    View full text