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INTEGRATIVE |
1 Penn State Heart and Vascular Institute, General Clinical Research Center, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
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Abstract |
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7 (Post 1), 30 (Post 2) and 50 min (Post 3) after RHA to provide insight into the temporal pattern of responses. Cardiovagal BRS (16.8 ± 1.3, 16.5 ± 1.6, 17.6 ± 2.0 and 17.4 ± 1.5 ms mmHg–1 for Pre, Post 1, Post 2 and Post 3, respectively), HR BRS (–1.1 ± 0.1, –1.1 ± 0.1, –1.3 ± 0.1 and –1.4 ± 0.1 beats min–1 mmHg–1) and sympathetic BRS (–4.5 ± 0.6, –4.4 ± 0.7, –3.7 ± 0.5 and –4.7 ± 1.0 arbitrary units (au) beat–1 mmHg–1) were unchanged by RHA. In contrast, the operating points of the baroreflexes were shifted rightward (to higher levels of BP) and upward (to higher levels of heart rate and MSNA) after RHA (P < 0.05). Time control studies performed in five additional subjects showed no change in any of the measured variables over time. Collectively, these data indicate that short-term exposure to RHA shifts (‘resets’) the baroreflex stimulus–response curve to higher levels of BP without influencing BRS for extended periods of time.
(Received 10 April 2006;
accepted after revision 16 May 2006;
first published online 18 May 2006)
Corresponding author K. D. Monahan: Penn State College of Medicine, Division of Cardiology H047, The Milton S. Hershey Medical Center, 500 University Dr., Hershey, PA 17033-2390, USA. Email: kmonahan{at}psu.edu
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Introduction |
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Previous studies suggest that both basal and reflexive measures of autonomic nervous system function, such as directly recorded muscle sympathetic nerve activity (MSNA) at rest (Carlson et al. 1993) and peripheral chemoreflex sensitivity (Narkiewicz et al. 1999) are elevated in OSA. Moreover, baroreflex control of cardiovagal and sympathetic outflow appears to be impaired in OSA (Carlson et al. 1996; Bonsignore et al. 2002). Treatment of OSA with night-time continuous positive airway pressure increases cardiovagal baroreflex function during sleep and wakefulness (Bonsignore et al. 2002). These data strongly suggest that periods of sleep-disordered breathing, associated with cyclical exposure to asphyxia (hypoxia and hypercapnia), inspiratory resistance, and apnoeas, may be a critical factor underlying changes in autonomic control in OSA. In healthy humans baroreflex function is impaired acutely by increased inspiratory resistance and/or hypoxia and hypercapnia exposure (Cooper et al. 2004). These data support the contention that breathing alterations, which mimic those experienced by OSA patients during sleep, acutely induce baroreflex dysfunction. However, an important limitation of these previous data is that detrimental effects of inspiratory resistance and/or hypoxia and hypercapnia were only assessed during application of the stressors. The fact that baroreflex function is depressed in OSA patients, even in the wakeful hours, suggests that the consequences of stress imposed during sleep persist for extended periods of time after resumption of regular breathing.
Accordingly, in the present study we tested the hypothesis that short-term exposure to intermittent hypoxia and apnoeas impairs cardiac and sympathetic baroreflex function. Moreover, we hypothesized that impairment in baroreflex function persists for an extended period of time after resuming normal breathing. To test these hypotheses, baroreflex function was assessed before and for 1 h after completing a 30 min period of repetitive apnoeas performed during intermittent hypoxia (RHA).
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Methods |
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Nineteen young (18–35 years of age) subjects were studied. All were non-obese (body mass index < 30 kg m–2), normotensive (resting BP < 140/90 mmHg), and non-smokers. Subjects were further screened by medical history and physical examination. The experimental protocol was conducted according to the Declaration of Helsinki and was approved by the Institutional Review Board at the Pennsylvania State University College of Medicine. Written informed consent was obtained from all subjects.
Measurements
Subjects were studied supine after an overnight fast (12 h).
MSNA. Recordings of MSNA were obtained using a tungsten microelectrode inserted in the peroneal nerve. This electrode was adjusted until a site with clear spontaneously occurring MSNA bursts was established using standard criteria (Vallbo et al. 1979). Raw nerve recordings were amplified (20 000–70 000 times), filtered (700–2000 Hz), full-wave rectified, and integrated (0.1 s time constant) to obtain mean voltage neurograms.
Cardiovagal and sympathetic BRS.
Cardiovagal and sympathetic BRS were assessed using the modified Oxford technique (Ebert & Cowley, 1992). Briefly, nitroprusside was injected (50–100 µg) intravenously followed 60 s later by phenylephrine (100–150 µg). Drugs were administered at doses that decreased and increased systolic BP 15 mmHg from baseline levels (Monahan et al. 2004; Monahan & Ray, 2005). For nitroprusside these doses were 50 µg in 5 subjects, 75 µg in 5 subjects, and 100 µg in 4 subjects. For phenylephrine, doses were 100 µg in 2 subjects, 125 µg in 8 subjects, and 150 µg in 4 subjects. Drug doses were the same within a given subject before and after the intervention (see below). Data acquisition began 3 min before nitroprusside infusion and continued for 2 min after phenylephrine infusion. At least 15 min separated consecutive BRS trials. Previously we have established that this interval of time is sufficient to allow for reproducible values of BRS as well as to allow for BP and heart rate (HR) at rest to return to pre-infusion levels (Monahan & Ray, 2005). Cardiovagal BRS was assessed in all subjects. However, due to difficulties in obtaining or maintaining satisfactory MSNA recording sites sympathetic BRS was only measured in 10 experimental and 4 control subjects (see below).
Respiration and oxygen saturation. Partial end-tidal CO2, arterial oxygen saturation (SaO2; earlobe pulse oximetry) and minute ventilation were measured with a respiratory gas monitor (Ohmeda RGM 5200).
Arterial blood pressure and heart rate. Resting BP was determined using a semi-automated device (Welch Allyn). Continuous measurements of BP were made using a Finapres photoplethysmograph (Ohmeda). HR was determined from the ECG.
Experimental protocol
A schematic diagram of the experimental protocol is provided in Fig. 1. Three BRS trials were performed at baseline (Pre) and three trials were performed after the intervention (Post). Post-intervention measures were made 7 (Post 1), 30 (Post 2) and 50 min (Post 3) after completing the intervention to gain insight into possible temporal patterns of changes in physiological function. BP and HR were determined in triplicate before the first baseline (Pre) trial and each trial after the intervention (Post 1, Post 2 and Post 3). The intervention consisted of a 30 min period in which subjects performed repetitive hypoxic apnoeas (RHA) (n
= 14) (Leuenberger et al. 2005). RHA involved subjects performing repetitive voluntary end-expiratory apnoeas (20 s duration) every minute for 30 min (30 total apnoeas) while breathing through a 2-way non-rebreathing facemask. To enhance oxygen desaturation during apnoeas hypoxic gas (10.5% O2) was administered during the period of free breathing. The period of time hypoxic gas was inspired during the 40 s free breathing period was individually adjusted in an attempt to achieve post-apnoeic nadirs in SaO2 in the mid to low 80s (%). At the end of each apnoea subjects were instructed to briefly (1 s) exhale to allow measurement of end-tidal CO2.
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Data analysis
All data were digitally stored on a computer (MacLab 8e, ADInstruments) at a sampling frequency of 400 Hz.
MSNA at rest was quantified as bursts min–1 and as the sum of the area under individual bursts per minute (au min–1). The largest burst at rest was assigned an arbitrary amplitude of 1000 and a portion of the neurogram in which neural silence (i.e. no efferent discharges) occurred was used to set the baseline to zero.
Cardiovagal BRS was quantified as the slope of the linear portion of the R-R interval–systolic BP relation (over 2 mmHg pressure ranges or ‘bins’) from the nadir to peak systolic BP response during each BRS trial (Ebert & Cowley, 1992; Rudas et al. 1999). Additionally, a measure of HR BRS was obtained from the HR–systolic BP relation. Points clearly falling in either the threshold or saturation region were removed from the analysis (Halliwill & Minson, 2002). Both measures were made to avoid any potential concerns that may be present if resting HR changes. The operating point of the cardiac arm of the baroreflex in relation to brachial systolic BP, HR and R-R interval was determined as the mean values of these variables measured before each BRS trial (Fig. 5).
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To determine if baroreflex resetting (shift in the stimulus–response relation) occurred (Pre to Post) we calculated predicted HR, R-R interval and MSNA levels relative to an arbitrary pressure from the respective stimulus–response relation (Fig. 5). The arbitrary pressure used was the resting systolic (for HR and R-R interval) and diastolic BP (for MSNA) determined in the baseline period (Pre).
Cardiovagal BRS trials with linear correlation coefficients (r-value) > 0.70 (Smyth et al. 1969; Rudas et al. 1999) during the Pre measures were averaged (up to 3) and a single value is reported. Individual trials after the intervention (Post 1, Post 2 and Post 3) were compared on a trial-to-trial basis to baseline levels (Pre) to gain insight into possible temporal patterns of change. The same process occurred for sympathetic BRS except that the criterion for retaining a sympathetic BRS value was an r value > 0.50 (Carlson et al. 1996; Rudas et al. 1999). An investigator blinded to the experimental condition performed all analyses.
Statistical analysis
Differences in baseline subject characteristics were determined by t test. Responses to the intervention were determined using a linear mixed effects model (one-way repeated measures ANOVA). When significant main effects were identified, specific contrasts were then made using Dunnett's post hoc tests. Corrections for multiple comparisons were made. Statistical significance was established at P < 0.05.
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Results |
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Subject characteristics are presented in Table 1.
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Repetitive apnoeas performed during intermittent hypoxia induced cyclical changes in SaO2 from immediately before apnoea to shortly after the end of apnoea (98.0 ± 0.2 to 83.0 ± 1.0%; P < 0.05) (Fig. 2). Additionally, apnoeas increased end-tidal CO2 from immediately before apnoea to the peak increase after the end of apnoea (35.0 ± 0.4 to 41.0 ± 0.4 mmHg; P < 0.05) (Fig. 2). Minute ventilations did not differ in the 5 min period before (7.3 ± 0.4 l min–1) and after (7.3 ± 0.3 l min–1) RHA.
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Systolic, diastolic and mean BP increased from baseline (Pre) levels after RHA. These increases persisted throughout the Post period (1 h) (Fig. 3). Similarly MSNA measured at rest increased from baseline (Pre) levels after RHA. These increases persisted throughout the Post period (Fig. 3). HR was unchanged from baseline (Pre) levels after RHA (Fig. 3).
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The effects of RHA on indices of BRS are presented in Fig. 4. Cardiovagal BRS was unchanged from baseline (Pre) levels after RHA (16.8 ± 1.3, 16.5 ± 1.6, 17.6 ± 2.0 and 17.4 ± 1.5 ms mmHg–1 for Pre, Post 1, Post 2, and Post 3, respectively; P = 0.92). Similar responses were noted for both HR BRS (–1.1 ± 0.1, –1.1 ± 0.1, –1.3 ± 0.1 and –1.4 ± 0.1 beats min–1 mmHg–1; P = 0.34) as well as sympathetic BRS (–4.5 ± 0.6, –4.4 ± 0.7, –3.7 ± 0.5 and –4.7 ± 1.0 au beat–1 mmHg–1; P = 0.20). In contrast the stimulus–response relations for all measures of baroreflex function were shifted rightward and upward (HR and sympathetic BRS) to higher levels of BP by RHA suggesting that RHA reset the baroreflexes. These shifts are visually apparent in the group-averaged stimulus–response relations (Fig. 5). To quantify the magnitude of resetting that occurred we calculated HR, R-R interval and MSNA levels at identical levels of systolic (HR and R-R interval) and diastolic (MSNA) BP Pre and Post. The BP level was the systolic or diastolic BP measured at baseline (Pre). These analyses indicated that HR (64 ± 4, 75 ± 5, 79 ± 5* and 78 ± 4* beats min–1 for Pre, Post 1, Post 2 and Post 3, respectively; *P < 0.05 compared to Pre) and MSNA (1783 ± 378, 2701 ± 544, 4470 ± 810* and 4153 ± 1025* au min–1) increased (main effect P < 0.05) and R-R interval (959 ± 61, 848 ± 56, 763 ± 42* and 784 ± 59* ms) decreased (main effect P < 0.05) at a given pressure after RHA.
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39 ± 3 compared to 44 ± 3 mmHg for Pre and Post, respectively; P < 0.05). This difference appears to be the result of a greater decrease in BP after nitroprusside (14 ± 1 compared to 21 ± 2 mmHg; P < 0.05) rather than a greater increase in BP after phenylephrine infusion (26 ± 3 compared to 24 ± 3 mmHg; P
= 0.35). In contrast the rate of change in BP from the nadir to peak change in BP during the BRS trials was identical Pre and Post (0.66 ± 0.06 compared to 0.66 ± 0.09 mmHg s–1; P
= 0.96). Time control studies
Haemodynamics, MSNA and BRS (cardiovagal, HR and sympathetic) were stable over the duration of the study in control subjects (Table 2).
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Discussion |
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The RHA protocol used in the present study provides a complex and variable stimulus to subjects, which acutely mimics the breathing patterns that occur during sleep in patients with OSA. These stimuli variably include periods of asphyxia, hyperpnoea, hypopnoea, and apnoea. Previous studies in healthy humans have used a similar RHA protocol to acutely study changes in cardiovascular/autonomic function in humans. These studies have reported that RHA increases MSNA (Cutler et al. 2004b; Leuenberger et al. 2005), BP (Leuenberger et al. 2005) and chemoreflex sensitivity (Cutler et al. 2004a) at rest for extended periods of time (up to 2 h) after RHA. These data establish that RHA is a powerful model to: (1) acutely induce changes in autonomic/cardiovascular function, (2) acutely study the effects of altered breathing on autonomic control in humans, and (3) gain insight into the temporal pattern of changes in physiological function by obtaining multiple measurements after resumption of regular breathing.
Our finding of no change in cardiovagal or sympathetic BRS, but a rightward and upward shift in the operating point of the baroreflexes (for HR and MSNA) after RHA is similar to those effects observed during acute continuous systemic hypoxia. Specifically, it has been reported that cardiovagal and sympathetic BRS are unaltered by short-term (18 min) continuous systemic hypoxia, but that the baroreflexes are reset to operate around a higher baseline level of BP (Halliwill & Minson, 2002; Halliwill et al. 2003). Thus, for a given level of BP both HR and MSNA are elevated by hypoxia. In the present study in addition to exposing individuals to systemic hypoxia (intermittently), repetitive apnoeas (30 in total) were performed. This protocol unlike continuous systemic hypoxia induces cyclical changes in arterial blood oxygenation (cycling saturation/desaturation). Thus, RHA (30 min) may be a more physiologically stressful stimulus than a shorter period of continuous systemic hypoxia (achieving similar decreases in SaO2). This factor may help explain how RHA induced prolonged periods of baroreflex resetting that persisted beyond the period of RHA. However, we cannot exclude the possibility that hypoxia exposure alone does not elicit prolonged periods of baroreflex resetting as Halliwill et al. did not make any measurements after removal of the hypoxic stimulus (Halliwill & Minson, 2002; Halliwill et al. 2003). However, as MSNA may remain elevated for extended periods of time after continuous systemic hypoxia exposure (20 min) (Morgan et al. 1995; Tamisier et al. 2004) we cannot rule out that the resetting persisted.
Previous studies in humans have examined the possible influences that inspiratory resistance, hypoxia, hypercapnia and apnoea acutely exert on baroreflex function. Recently, Cooper and colleagues reported that inspiratory resistance decreased the gain of baroreflex control of vascular resistance and that hypoxia exposure shifted the stimulus–response curve rightward suggesting resetting (Cooper et al. 2004). When both physiological stressors were applied simultaneously, baroreflex gain was reduced and the stimulus–response curve was displaced rightward to higher pressures. These data strongly suggest that increased inspiratory resistance and hypoxia alter baroreflex function (impaired BRS as well as resetting the carotid baroreflex). The effects of apnoea on baroreflex function are less clear. A single apnoea has been shown not to alter baroreflex control of MSNA during application of neck suction (Muenter Swift et al. 2003). However, after completion of the apnoea there was a very transient (< 1 min) impairment in baroreflex control of sympathoexcitation during neck pressure. Collectively, our present findings importantly extend these prior findings by showing that changes in baroreflex function that occur during stressors designed to mimic OSA can induce persistent changes in baroreflex function that extend beyond the exposure to the stressors (intermittent hypoxia, hypercapnia and apnoea).
Most studies that have assessed baroreflex function in humans with OSA have concluded that baroreflex dysfunction occurs. Specifically, cardiovagal BRS has been shown in most (Carlson et al. 1996; Bonsignore et al. 2002), but not all studies (Narkiewicz et al. 1998) to be depressed in OSA. Additionally, baroreflex control of MSNA (i.e. sympathetic BRS) during decreases in BP are blunted in OSA (Carlson et al. 1996; Narkiewicz et al. 1998). Our present study does not support a role for short-term periods of altered breathing (repetitive apnoeas performed during intermittent hypoxia exposure) promoting decreases in cardiovagal or sympathetic BRS. However, our data do suggest that the operating points of both the cardiovagal and sympathetic baroreflex are reset to higher levels of BP, HR and MSNA. The resetting of the baroreflex to higher levels of BP is a characteristic feature of hypertension (McCubbin et al. 1956). It is unknown how long this resetting persisted in our study as we only acquired measurements for 1 h after RHA. However, it is possible that even short-term shifts to higher levels of BP may be of physiological relevance. Over time these repetitive exposures to acute hypertension may predispose even normotensive OSA patients to the development of hypertension. This suggestion is supported by data suggesting that OSA may precede the development of chronic hypertension (Peppard et al. 2000).
Several limitations are associated with the present study. First, our RHA intervention exposed individuals to only 30 apnoeas performed during intermittent hypoxia. Thus, the level of stress exerted on our subjects during RHA was probably less than that exerted on an OSA patient during an entire nights sleep. Therefore, we cannot exclude the possibility that longer periods of RHA would depress BRS. Second, in our experience the modified Oxford technique does not allow full characterization of the baroreflex stimulus–response curve. This has been reported by others (Halliwill & Minson, 2002). Thus, we cannot determine with certainty if the set point of the baroreflex stimulus–response curve was altered, although our data relating to changes in the operating point pressure, MSNA and HR do suggest that this is the case. This is an inherent limitation in the methods available to assess integrated baroreflex responses in intact humans safely. Lastly, measurements were made in healthy young adults. It is possible that different effects would be observed in other populations.
In conclusion, these data suggest that short-term (30 min) exposure to repetitive apnoeas (single 20 s apnoea every minute) performed during intermittent hypoxia does not impair cardiovagal or sympathetic BRS in healthy young humans, but does appear to reset the baroreflexes to operate around a new higher level of BP at rest. This resetting is evident by a rightward (to higher BP) and upward shift (for HR and MSNA) in the stimulus–response curve. Thus both HR and MSNA are increased at a given level of BP after RHA.
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, Post 1; 
, Post 2; and 
, Post 3) and error bars. Note the similar responses, as evidenced by the slope of the respective regressions that were observed before (Pre) and after (Post 1, Post 2, and Post 3) the 30 min period of RHA for each expression of BRS (see also 
), and MSNA, increased after RHA (*
P < 0.05).