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Loop Gain and Sleep Disordered Breathing§ Kingman P. Strohl*, Motoo Yamauchi and Thomas E. Dick Case Western Reserve University, Louis Stokes DVA Medical Center, Cleveland, OH, USA Abstract: There is a close relationship among the types of sleep apnea (central, obstructive, and mixed) in regard to both the pathogenesis and in the clinical management of sleep apnea syndromes. This review will recount the rationale for the use of animal models in understanding intermediate traits, such as the ventilatory responses to hypoxia and reoxygenation, seen with human sleep apnea. One feature of particular interest will be the dynamic responses of the control system, specifically the instability over time that could operate to produce repetitive apneas. The recurrent nature of clinically significant sleep apnea can be understood in terms of feedback control, or “loop gain”. We will discuss findings in a mouse model for recurrent apneas and propose that there exist genetic mechanisms that could determine loop gain in the respiratory control system.
Keywords: Sleep apnea, animal model, hypoxia, respiratory control. INTRODUCTION Sleep Apnea is a common condition, present in 5-9% of the population, and is a medical condition associated with excessive daytime sleepiness [1] and composite risk for cardiovascular morbidity and mortality [2]. The most common form of sleep apnea in adults is called obstructive sleep apnea, for the cause of the cessation of airflow is closure of the naso- and/or oro-pharyngeal airway [3]. Central or nonobstructive apnea, occurs when absent airflow is accompanied by an absence of inspiratory efforts. Components of central and obstructive apneas frequently coexist in a single event, producing a “mixed” apnea [3]; obstructive and central apneas may occur together in the same patient over the same night [4]; and patients with obstructive apneas treated with positive pressure to open the airway often exhibit central apneas [3]. Hence, there is a close relationship between the two patterns of apnea in clinical practice. Pathogenetic factors identified during a clinical examination performed during wakefulness in a patient suspected with sleep apnea are physical traits of obesity including increased neck size, encroachment of the upper airway by soft tissue or by surrounding tissue with high compliance, and a head form that constricts the pharynx and lengthens the naso- and /or oro-pharyngeal air passage [5]. Yet sleep apnea occurs during sleep, and there is consensus that both an obstructive as well as a central apnea start in the context of a reduced central drive [6]. Hence, pathogenesis of sleep apnea stems from both anatomic and functional factors, which alone or in combination predispose the individual to sleep apnea. Moderate-to-severe disease, called sleep apnea syndrome because the sleep-related events are accompanied by wake*Address correspondence to this author at the Case Western Reserve University, Louis Stokes DVA Medical Center, 111j(w) VAMC, 10701 East Boulevard, Cleveland, OH 44107, USA; Tel: 216 231 3399; Fax: 216 231 3475; E-mail:
[email protected] §
A report of a Presentation by Dr. Strohl given at a symposium honoring Neil S. Cherniack, MD. Control of Breathing in Health and Disease, Saturday April 1, 2006. 1573-398X/07 $50.00+.00
time symptoms, occurs in approximately 12 million Americans with the majority (>90%) being under-treated or undiagnosed. While current treatment approaches can have a substantial impact, treatments are either not tolerated or are too intrusive for a significant proportion of patients. For instance, continuous positive airway pressure, while shown to be effective in reducing sleepiness and blood pressure in sleepy patients, is used regularly by 60-80% of patients [7]. Positive airway pressure is not well tolerated by those with mild symptoms, and hence there is an effort to understand functional features of the disease that provide clues to pharmacologic interventions for prevention as well as treatment. A significant proportion (~27%) of recurrent sleep apnea is a heritable trait, and the trait of elevated apnea and hypopneas during sleep is linked to regions of the genome [810]. However, the associations to chromosomal regions are not robust enough to identify a risk pathway, i.e. gene or protein. Thus, sleep apnea, like hypertension and diabetes, is a complex disease in which no one factor is necessary or sufficient to explain the condition in those affected, and no one gene is necessary or sufficient to produce the condition [11]. As a result, genetic research will require large sample sizes coordinated among centers to target regions of the human genome that might produce or protect from sleep apnea. A complementary approach is to utilize animal models to identify heritable traits important in the pathogenesis of the disease and mark regions of the genome that underlie such traits [12]. This review will recount the rationale for the use of animal models to dissect features of respiratory control that are intermediate traits for features seen in human sleep apnea. One feature in particular will be the dynamic responses to the system, specifically those that show instability over time that could operate to produce repetitive apneas. The recurrent nature of clinically significant sleep apnea can be understood in terms of feedback control, or “loop gain”. We will discuss our mouse model for recurrent apneas and propose genetic mechanisms that could determine loop gain in the respiratory control system.
© 2007 Bentham Science Publishers Ltd.
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PROPAGATION OF APNEAS The physiologic features of feedback control are also shown in Fig. 1. The brain and its outputs to the motor nerves and muscles act on a controlled system, consisting of the upper airway, lungs, and chest wall that produce inspiratory and expiratory flow and gas exchange. Gas exchange affects oxygen and carbon dioxide stores in the body, which are sensed by chemoreceptors. Well-characterized organs with chemoreceptor function are located as the carotid body and in the brainstem, but it is apparent that other sensors, such as mechanoreceptors, exist in many places to inform different groups of respiratory neurons in the pons and medulla of pressure, flow, and position. These neuronal pools in turn coordinate the neural outputs to the controlled system. The controller makes breath-to-breath adjustments affecting rate (frequency) and depth (tidal volume) of breathing efforts. The elements of the feedback system are a controller, a controlled system, and sensors. Grodins produced the first schematic model and simulations on how components of feedback control might relate to the control of arterial carbon dioxide levels over time [13, 14]. This new approach to respiratory physiology was based on a systems engineering approach, rather than anatomic connections. However, in a series of papers in 1966, Cherniack, Longobardo, and colleagues addressed this system for the purposes of understanding a clinical problem, periodic breathing, and provided experimental evidence in dog stud-
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ies that, at least in theory, the gain of the controller, the dynamics of gas exchange, and response lags in the vascular compartment of this system can determine a stable breathing pattern or conversely confer risk of an unstable breathing pattern, specifically Cheyne-Stokes respiration or periodic breathing [15-17]. In a more direct way, using a proportional assist ventilator, in 1979 Cherniack et al. demonstrated that manipulation of controller gain produced recurrent central apneas in the anesthetized cat [18]. This experiment validated for the first time the physiologic relevance of feedback control for ventilatory apnea. Thus, the appearance of recurrent central apneas results from a dynamic systems response [19]. Sleep, increased time delay, and increased tendency for the system to over respond (“underdamping”) are all known to promote an unstable breathing pattern though an increased systems response; an engineering term for this is “loop gain” [20]. Mathematical models and studies on humans have focused on how changes in hypoxic sensitivity and CO2 threshold interact to promote recurrent apnea [21-23]. Chemosensitivity, as measured in an open loop system, correlates with recurrent central apneas as Cheyne-Stokes type is more frequently observed in humans with higher peripheral, most likely carotid body, chemosensitivity [24-26]. The studies have used a proportional-assist ventilation to alter and measure system loop gain in humans [27, 28]. There is variability in loop gain among individuals, with
Fig. (1). Panel A illustrates the elements of a feedback control system. Panel B illustrates the physiologic components of the ventilatory control network.
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those with an underdamped response to a large breath showing a tendency for cyclic breathing patterns. While at first directed at understanding central apneas and Cheyne-Stokes respiration, Younes et al. [26] argued that cycling of respiratory drive from apnea to hyperpnea is a common feature in all clinically significant sleep apnea. Those with more apneas during the night had higher loop gain measured after the airway obstruction was relieved by positive pressure. Thus, recurrent obstructive and central apnea have as a common feature an elevated loop gain. Thus, while anatomic factors (obesity and head form) are important, it is the overall gain of respiratory adjustments (“loop gain”) which acts and interacts with sleep state and anatomic features to propagate obstructive apneas [29]. A high loop gain promotes recurrent apnea as the response to the initial disturbance is overcompensated, while a low loop gain dampens subsequent oscillations in breathing. Therefore, a genetic approach to understanding periodic breathing could be insightful if one captured some or all of the elements in the respiratory control system that contribute to loop gain and/or offer opportunity to modify loop gain in a predictable manner. TIME DOMAIN RESPONSES TO HYPOXIA AND REOXYGENATION One identifying feature of recurrent apneas is the recurrent hypoxemia resulting from the periods of apnea and the subsequent reoxygenation upon recovery from apneas. While the effects of recurrent hypoxia-reoxygenation can be modeled without apneas, if the issue is the cause of an apnea, the issue becomes how ventilatory control and ventilatory behavior might respond to dynamic changes to oxygenation. The physiologic response to hypoxia has several timedomains and points of potential change [30] During hypoxic exposure there may occur an early peak response followed by a decline in ventilation (so-called “roll-off”); this differs among species and strains. Responses are known to differ among strains of mice and rats, and appear to be determined in large part by only a few regions of the rodent genome [31, 32]. Upon reoxygenation there are two broad classes of divergent responses- one called short-term potentiation where ventilation remains elevated above baseline (pre-hypoxic) values and another called post-hypoxic (frequency or ventilatory) decline where ventilation or frequency can fall below baseline [30]. Short-term potentiation of ventilation evoked by brief hypoxia exposure is thought to promote ventilatory stability [33], and protect against unstable breathing [34]. The absence of short-term potentiation and conversely the presence of post-hypoxic (frequency or ventilatory) decline are reasoned to promote recurrent apneas. Both those with obstructive sleep apnea hypopnea syndrome (OSAHS) [35] and with Cheyne-Stokes respiration [36] often lack shortterm potentiation. In addition, short-term potentiation is lost in some (but not all) patients with post-concussive syndromes and hypoxia provokes periods of apnea in such patients [37]. Thus, restoration of short-term potentiation is identified a potential target for therapy. Hypoxia could produce apnea directly [38] by depression of the respiratory controller [39]. Mechanisms proposed include central accumulation and/or release of inhibitory neu-
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rotransmitters on respiratory neurons [40]. There is an identified role for protein factors, like PDGF and its receptors, in this response [41-43]. Prolonged or episodic hypoxia appears in most animal models to enhance ventilatory instability [33, 44]. In the awake goat [45, 46] and sleeping human [47], subsequent unstable breathing develops if there occurs a fall in CO 2 (hypocapnia), thus implying an interplay among chemoreceptors and integration of the response at a brainstem level. Intermittent hypoxia could evoke changes in the operation of respiratory rhythm generation and evidence suggests a control system that changes over time in response to cycles of hypoxia and reoxygenation [48]. Central neural circuits in some models will determine breathing stability or instability [39, 49-51]. Central neurotransmitters implicated in re-oxygenation responses include serotonin, adenosine, and nitric oxide [52-54]. While the pontine A5 region is interest in orchestrating this response [55], ventilatory responses to hypoxia (and re-oxygenation) involve interconnected neuronal pools in the medulla and pons [56-58]. Responses could involve higher brain centers and not just the pons or medulla [59]. The challenge is to incorporate respiratory pattern generators into the computational models of ventilatory control [60]. A PHENOTYPE-GENOTYPE MODEL FOR PERIODIC BREATHING Animal models of sleep apnea exist in larger mammals (dogs, elephant seals, and some pigs) but rodent models (mice and rats) are more amenable to the study of genetic mechanisms [61]. The key is to pick a trait that may relate to sleep apnea expression or propagation. As a result, others and we have directed our attention to common mouse strains in which there are significant intra-strain differences in the ventilatory response to hypoxia [62, 63]. There is success in regard to this approach in identifying the physical location of gene regions associated with ventilatory responsiveness to hypoxia [64]. It turns out that inheritance influences a significant proportion of ventilatory rate and rhythm and the response to hypoxia and hypercapnia [64, 65], a concept directly supported by studies in knock-out animals [66, 67]. In the study of naturally occurring variations, an interplay of a few major genes appear to influence the level of ventilation on hypoxia [31], and the finding of differences in the pattern of breathing among strains in wakefulness, slow wave sleep, and active sleep [68] implies that genetic background strongly affects features of breathing rate and ventilatory behavior despite broad changes in state. In the course of looking at differences in rat strains to hypoxia and hypercapnia we noticed differences in the response to re-oxygenation [53]. In this study post-hypoxic decline occurred in a strain (the Brown Norway) that already had a reduced response compared to other strains [69]. We confirmed that differences in the ventilatory response to reoxygenation occurred in the presence of similar hypoxic ventilatory responses in the mouse [63]. This is shown in Fig. 2 (top panel). In this instance the breathing pattern after 5 minutes of hypoxia in the B6 shows an immediate (20-50 seconds) slowing of respiratory rate and minute ventilation below the baseline values, while the A/J after experiencing the same hypoxic stress shows an elevated frequency and
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Fig. (2). The top panel compares the ventilatory behavior before and upon re-oxygenation after hypoxia (in this instance 5 minutes of 10% oxygen) in the B6 and A/J mouse. The bottom panels show longer time tracings indicating the pattern of breathing over time upon reoxygenation in the B6 or A/J mouse. The B6 pattern resembles periodic breathing.
ventilation. The former response is called post-hypoxic frequency decline, while the latter is termed short-term potentiation. During the studies in the awake state, however, we observed ventilatory instability repeatedly in the B6 animals that resembled recurrent central apneas similar to CheyneStokes pattern (Fig. 2, bottom panel). In the published report of this phenomenon, Han et al. [70] concluded that in this model the occurrence of unstable breathing occurred after hypoxia with or without added carbon dioxide, and of levels of the re-oxygenation gases. A subsequent study reported persistence of strain differences in post-hypoxic frequency responses with anesthesia [71]. This difference in patterning was confirmed by spatial statistical analysis. From these studies, we have concluded that strainspecific differences in respiratory pattern and the tendancy for variability are robust genetic traits. We believe that the neural substrate for these differences, at least partially, exists within subcortical structures generating the breathing pattern. NITRIC OXIDE SYNTHASE MODULATION OF THIS PHENOTYPE Kline et al. reported that in genetic models mice with a downregulated neural nitric oxide synthase (NOS-1 knockout mice) respiratory frequency decreased when the animals were exposed to 100% oxygen compared to wild type mice [72, 73]. As we had observed post-hypoxic frequency de-
cline after application of a non-specific NOS inhibitor in the Sprague Dawley rat strain [53, 74], we tested whether we could alter post-hypoxic behavior in the B6 and/or A/J mice, using administration of a rather selective nNOS blocker (7nitroindazole or 7-NI, 60 mg/kg) [75]. Both strains of A/J and B6 mice exhibited post-hypoxic frequency decline, i.e. the absence of short-term potentiation with 7-NI. B6 mice continued to exhibit both post-hypoxic frequency decline and periodic breathing with longer cycles and apnea length. In contrast, A/J mice did not show any tendency toward periodic breathing with 7-NI. Therefore, a drug (7-NI) was a tool which further differentiated the traits between the A/J and B6 strains, and one could uncoupled the findings of post-hypoxic frequency and ventilatory decline from the occurrence of periodic breathing. Hence, as we altered the genetic set point of the subject (animal), findings suggest that there are natural variations in the mouse genome that determine the ventilatory responses and that the neural nitric oxide synthase pathway effects differ depending upon genetic background. TOWARDS A GENETIC DISSECTION OF PERIODIC BREATHING To test the inheritance properties of this phenotype, one can study strains derived from B6 animals. There is a panel of strains in which third generation animals from an A/J and B6 cross were brother-sister mated for 20 or more generations to create recombinant in-bred strains [76]. This mixes the two genomes and fixes the alleles on each chromosome.
Loop Gain and Sleep Disordered Breathing
Differences in expression of post-hypoxic recurrent apneas in some but not all A/J-B6 recombinant inbred strains reflect the inheritance of alleles that affect ventilatory stability. Another methodology for the mapping of complex traits in mice utilizes chromosome substitution strains (CSSs) as an alternative mapping resource [77]. Dr. Nadeau and colleagues have generated a panel of mice in which each A/J chromosome has been individually introduced onto the B6 background in a homozygous fashion, effectively replacing the B6 chromosome. Breeding informed by rapid genotyping will result in the creation of CSSs representing the 19 autosomes, two sex chromosomes and the mitochondria. The A/J and B6 CSSs were constructed because the two strains differ in a number of physiological traits, the genome sequence for each strain is largely completed, and complete bacterial artificial chromosome (BAC) libraries exist for each strain (bacpac.chori.org). We have preliminary data from panel of 12 CCSs. We found, as we did with 7-NI challenge, an independence of the trait of recurrent apneas from the post-hypoxic short-term potentiation and post-hypoxic frequency decline. In Fig. 3, we show some examples from this survey. As we have previously shown the A/J shows short term-potentiation and in contrast, the B6 animal shows post-hypoxic frequency decline (PHFD) of -20%. In CSS b6a1 (n =10), b6a11 (n =6), ba14 (n =6), and b6a16 (n=5), either the b6 PHFD is attenuated or the A/J STP phenotype partially reappears despite the presence of only one A/J chromosome. Fig. 3 indicates that several chromosomes and perhaps multiple alleles can influence this response to reoxygenation. Thus, genetic differ-
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ences that produce post-hypoxic frequency decline or short term potentiation are not closely linked to the pattern of recurrent apneas or non-apneic oscillations or to the hypoxic response. Fig. 3 also presents the variance among these four chromosomal substitution strains in response to 7-NI using a protocol previously described [70]. After 7-NI the A/J strain shows post-hypoxic frequency decline, as does the B6, and a tendency for this to happen occurs in b6a14; however, CSS strains b6a1 and b6a16 do not. Unexpectedly, CSS b6a16, which had exhibited some post-hypoxic frequency decline at baseline, now exhibits a tendency for short-term potentiation after 7-NI. How 7-NI transforms not only recurrent apnea but also post-hypoxic frequency is at present unknown. In this survey, the b6a1 strain was the least consistent in regard to the appearance of periodic breathing before as well as after 7-NI administration, indicating that Chromosome 1 might be the initial focus for defining further the genetic regions of interest that produce recurrent apneas. Reversal of the B6 recurrent apnea phenotype by substitution of a A/J chromosome was independent of frequency, minute ventilation, and the ventilatory response to hypoxia at 1 and 5 minutes of exposure (data not shown), consistent with our published observations in recombinant inbred strains [63, 70]. A PROPOSAL The concepts we use to understand this model of recurrent apneas in the B6 strain are built upon the ideas of Cherniack and Longobardo, and the ideas of loop gain. It was
Fig. (3). We illustrate preliminary data from a survey of chromosomal substitution strains to illustrate the variation in post-hypoxic behavior according to genetic background, and drug administration. The vertical axis represents the change between post-hypoxic frequency and baseline with short-term potentiation (STP) as positive values and post-hypoxic frequency decline (PHFD) as negative values. The first 2 bars represent mean values of pre- and post-hypoxic frequency for A/J and B6 mice. The other 4 pairs of bars are chromosomal substitution strains for A/J 1, 11, 14, and 16 on a B6 background. The gray bars represent values (mean and SD) before 7-NI; and the open bars, values after 7-NI.
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Lynn, who in a paper looking at oxygen saturation profiles, commented on the parallels between respiratory events and cardiac arrhythmias [78]. In both abnormal states there are cycles of events, often occurring once a preset condition or set of conditions is present, both anatomically and functionally, to set the stage for recurrent events. In sleep apnea there occurs a cycle from apnea to recovery to re-entry into apnea, airway closing and airway opening can occur at specific points in the cycle, depending upon airway collapsibility and relative activation of upper airway and chest wall muscles.
of the "athlete's heart", that is, eccentric, physiologic hypertrophy, slower heart rates, and increased exercise endurance; both strains have a resting normal ejection fraction for the mouse [80]. The gain of the ventilatory response to hypoxia and hypercapnia, moreover, is similar between the strains [63]. Thus we suggest that the differences between the A/J and B6 mouse strains are at the level of the respiratory controller. These data on the modification of apnea length by a drug that inhibits neural nitric oxide synthase are consistent with this idea.
This concept is shown in Fig. 4. An apnea (or hypopnea) is broken by a combination of arousal mechanisms, respiratory drive mechanisms, and in the case of obstructive apneas, by establishing a patent upper airway, an event which may be delayed due to the mechanical features of reopening a closed airway. Recovery from an apnea occurs and will be maintained according to the properties of the central pattern generator over time. If there is an overshoot or if there is the presence of post-hypoxic decline there is a fall in respiratory drive, and re-entry into an apnea. Even if the apnea is purely central, it often happens that the upper airway closes or nearly closes [79].
Therefore, our current working hypothesis is that “loop gain” may be an emergent property within the central nervous system. Specifically the brainstem- pons and medulla. While we at present have no direct evidence, we, as did Longobardo et al. [60], suggest that properties of gain and phase lag might arise from the interconnections of inhibitory and excitatory circuits in the pons and medulla. Models of this system, supported by in vitro studies of the isolated brainstem preparation, suggest that by varying the thresholds among these neuronal groups can influence the stability of the model outputs for respiratory frequency [81-83].
As outlined in Fig. 1, one would need to consider where the difference between A/J and B6 might exist. We have measured lung and chest wall mechanics and while we cannot exclude its influence completely, we feel it is unlikely that the elements of the controlled system differentiate the two strains. Blood pressure at rest is similar among strains but relative to A/J, B6 mice have a phenotype characteristic
Thus our model is that naturally occurring variations in genes influence one or more properties in pathways to or within the respiratory controller to produce a stable or unstable pattern. One or more proteins could be involved in determining neuronal set-points and/or neurotransmitter release or effects. Identification of sub-chromosomal regions that sensitize (desensitize) ventilatory responses would implicate one or more specific gene-messenger RNA-protein effector
Fig. (4). Panel A illustrates an example of post-hypoxic periodic breathing in the C57BL/6J (B6) mouse, indicating periods of apnea and hyperpnea. Panel B is based on the concept developed by Linn (Lynn, 1997) and based upon the oximetry record, but adapted for thinking about the recurrent apnea seen in the B6 model of recurrent central apnea and about the relation of central events to the onset and recovery from an obstructive apnea.
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pathways that act to produce a high “loop gain” in the B6 and a low “loop gain” in the A/J mouse strain. The similarity (synteny) among the mammalian genomes will permit informed studies of candidate genes in human and might produce insight into pharmacological therapy for sleep apnea [84]. ACKNOWLEDGEMENTS VA Research Service (KPS), NS052452 (KPS), Fuji Respironics (MY), and HL-25830 (TED). REFERENCES [1] [2]
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Revised: December 11, 2006
Accepted: December 14, 2006
