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Sep 14, 2012 - Aaron A. Phillips • Shannon S. D. Bredin •. Anita T. Cote ..... Phillips AA, Burr J, Cote AT, Foulds HJ, Charlesworth S, Bredin SS,. Warburton DE ...
Eur J Appl Physiol (2013) 113:785–792 DOI 10.1007/s00421-012-2489-3

ORIGINAL ARTICLE

Aortic distensibility is reduced during intense lower body negative pressure and is related to low frequency power of systolic blood pressure Aaron A. Phillips • Shannon S. D. Bredin • Anita T. Cote • C. Taylor Drury • Darren E. R. Warburton

Received: 3 May 2012 / Accepted: 29 August 2012 / Published online: 14 September 2012 Ó Springer-Verlag 2012

Abstract As sympathetic activity approximately doubles during intense lower body negative pressure (LBNP) of -60 mmHg or greater, we examined the relationship between surrogate markers of sympathetic activation and central arterial distensibility during severe LBNP. Eight participants were exposed to progressive 8-min stages of LBNP of increasing intensity (-20, -40, -60, and -80 mmHg), while recording carotid-femoral pulse wave velocity (cPWV), stroke volume (SV), heart rate, and beatby-beat blood pressure. The spectral power of low frequency oscillations in SBP (SBPLF) was used as a surrogate indicator of sympathetically modulated vasomotor modulation. Total arterial compliance (C) was calculated as C = SV/pulse pressure. Both cPWV and C were compared between baseline, 50 % of the maximally tolerated LBNP stage (LBNP50), and the maximum fully tolerated stage of LBNP (LBNPmax). No change in mean arterial pressure (MAP) occurred over LBNP. An increase in cPWV (6.5 ± 2.2; 7.2 ± 1.4; 9.0 ± 2.5 m/s; P = 0.004) occurred during LBNPmax. Over progressive LBNP, SBPLF increased (8.5 ± 4.6; 9.3 ± 5.8; 16.1 ± 12.9 mmHg2; P = 0.04) and C decreased significantly (18.3 ± 6.8; 14.3 ± 4.1; 11.6 ± Communicated by Massimo Pagani. A. A. Phillips (&)  S. S. D. Bredin  A. T. Cote  C. T. Drury  D. E. R. Warburton Cardiovascular Physiology and Rehabilitation Laboratory, Physical Activity and Chronic Disease Prevention Unit, University of British Columbia, Rm. 205, Unit II Osborne Centre, 6108 Thunderbird Blvd, Vancouver, BC V6T 1Z3, Canada e-mail: [email protected] A. A. Phillips  C. T. Drury  D. E. R. Warburton Faculty of Medicine, Experimental Medicine Program, University of British Columbia, Vancouver, Canada

4.8 ml/mmHg 9 10; P = 0.03). The mean correlation (r) between cPWV and SBPLF was 0.9 ± 0.03 (95 % CI 0.79–0.99). Severe LBNP increased central stiffness and reduced total arterial compliance. It appears that increased sympathetic vasomotor tone during LBNP is associated with reduced aortic distensibility in the absence of changes in MAP. Keywords Hypovolemia  Pulse wave velocity  Compliance  Sympathetic nervous system

Introduction Mean arterial pressure (MAP) exerts an independent influence on central arterial stiffness (Nichols and O’Rourke 2005), however increased sympathetic nervous system (SNS) modulation of vasomotor tone is likely to also play a role (Boutouyrie et al. 1994). From a physiological perspective however, MAP is rarely increased without concomitant increases in SNS activity. Studies have shown increases in aortic stiffness after administration of caffeine (Mahmud and Feely 2001), cold pressor test (Liu et al. 2011), handgrip exercise (Reid and Conway 2006) as well as the Valsalva maneuver (Heffernan et al. 2007). In all of these cases, both MAP and SNS are expected to have increased leading one to question whether the increases in central arterial stiffness were simply due to increases in distending pressure and not a direct influence of increased sympathetic vasomotor tone. The use of lower body negative pressure (LBNP) allows for a unique stimulus whereby sympathetic vasomotor tone is drastically increased (Cooke et al. 2009), while MAP changes minimally, if at all (Cooke et al. 2009; Halliwill et al. 1998; O’Leary et al. 2007). Sympathetic nervous system activity

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has been shown to drastically increase at pressures above 60 % of the highest LBNP tolerable (Cooke et al. 2009) and double at -60 mmHg (Goswami et al. 2008). Three prior studies have examined central arterial stiffness during LBNP however all employed relatively low levels of orthostatic stress (less than -50 mmHg) (Alessandri et al. 2010; Lydakis et al. 2008; Sonesson et al. 1997). These studies did not show an increase in central artery stiffness, however it is possible that the LBNP stimulus in prior studies may not have been great enough to augment central arterial stiffness. In light of the fact that these results are cited in support of the idea that sympathetic activation does not influence central arterial stiffness (Failla et al. 1999; Kosch et al. 2002; Sugawara et al. 2007), a more careful consideration of the relationship between SNS and central arterial stiffness is warranted using intense LBNP where sympathetic vasomotor tone is likely to be markedly increased. Accordingly, we aimed to measure central arterial stiffness using pulse wave velocity (PWV) between the carotid and femoral artery, which is considered the gold standard for evaluating central arterial stiffness (Laurent et al. 2006), during moderate and severe LBNP. Also, we evaluated total arterial compliance (C) by the ratio of stroke volume (SV) to pulse pressure (PP), which has been shown to be an acceptable surrogate for the Windkesselmodel based estimates (Chemla et al. 1998; Randall et al. 1986). These indicators of arterial stiffness were used to examine the influence of LBNP on arterial stiffness without changes in MAP. This information has the potential to aid in the understanding of the relationship between sympathetic vasomotor tone, regional arterial stiffness and orthostatic tolerance. As the central aorta has long-been shown to be innervated by the post-synaptic sympathetic neurons, we expect that central PWV will increase during severe LBNP (Tebbs 1898).

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76 ± 11 kg) with a body mass index of 23 ? 2 kg/m2. All participants were instructed to abstain from caffeine, exercise, and alcohol for 24 h prior to testing. Our required sample size was determined a priori based on a conservatively anticipated 10 % change in carotid-femoral PWV (cPWV) (Mahmud and Feely 2001). According to the literature, this sample would provide strong enough power to test our hypothesis (Liang et al. 1998). Experimental protocol The experimental protocol involved one testing day. All participants were tested between 12:00 and 15:00 h. Upon entering the laboratory, measurements of stature, body mass, and seated blood pressure were made prior to instrumentation, which was directly followed by a supine rest period and a progressive LBNP protocol. After 15 min of baseline data at ambient barometric pressure, 8-min stages of progressive LBNP occurred. Lower body pressure stages of -20, -40, -60 and -80 mmHg were applied. The negative pressure was terminated if any of the following symptoms were observed: (1) a sudden drop in heart rate or blood pressure, (2) a sustained drop in systolic blood pressure below 90 mmHg, and/or (3) at the participant request. Qualitative symptoms of nausea, excessive sweating, tunnel vision, light headedness, and/or dizziness were also used to identify pre-syncope. This technique has been used to simulate orthostasis in a variety of situations and populations as a means to study cardiovascular response to gravitational challenge, central hypovolemia and haemorrhage (Goswami et al. 2008). Ambient temperature in the laboratory was 21–22 °C. Participants wore a neoprene skirt and were positioned supine in the pressure chamber, straddling a bicycle seat, and sealed below the waist to the iliac crest. Each stage of LBNP consisted of an initial 3 min in order to reach haemodynamic equilibrium followed by 5 min where ‘‘steady-state’’ haemodynamic measures were recorded.

Materials and methods Haemodynamic measures Ethical approval All participants provided written informed consent in accord with the Clinical Research Ethics Board at the University of British Columbia, which approved this study. This study conformed to the standards set by the latest revision of the Declaration of Helsinki. Participants Eight male individuals who were non-smokers and had no history of cardiovascular disease participated in this study (age: 24 ± 4 years, height: 179 ± 8 cm, weight:

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Before collecting baseline data, participants rested for 5 min in a supine position while being instrumented with an automated brachial blood pressure cuff (BpTRU-BPM100, Coquitlam, BC. Canada), an electrocardiogram (ECG), impedance cardiography (HIC-3000, Bio-Impedance Technology, Inc.), and finger photoplethysmography on the middle finger of the left hand (Finometer MIDI, FMS, Amsterdam, Netherlands). For all stages, brachial blood pressure was recorded after 3 min and again 1 min later. The two blood pressure recordings were averaged to provide blood pressure at each stage. Stroke volume (SV) and heart rate (HR) were recorded every minute from the

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impedance cardiography after steady state was reached and averaged for each stage. Cardiac output (Q) was calculated as Q (L/min) = SV 9 HR. Mean arterial pressure (MAP) was calculated as MAP (mmHg) = (2 9 DBP ? SBP)/3. In order to calculate total peripheral resistance (TPR; mmHg/L/min), MAP was divided by Q (Livingstone et al. 2010). Heart rate as well as beat-by-beat changes in R–R interval and blood pressure were recorded. The Finometer signal was corrected to the average of the two brachial pressures recorded over each LBNP stage. Spontaneous blood pressure variability (BPV) was calculated using blood pressure from continuous collection of 5-min duration. Commercially available software (Nevrokard BRS 5.7.0. Nevrokard, Izola, Slovenia) was used to calculate BPV according to previously described limits (Cote et al. 2012). Briefly, for BPV, fast Fourier transform analyses of blood pressure were employed to spectral density of blood pressure. The power of low frequency oscillations of systolic blood pressure (SBPLF) was represented by the area under the systolic blood pressure low frequency power spectrum (LF: 0.04–0.14). Total arterial compliance Total systemic arterial compliance was calculated at rest and for each stage according to the formula C (ml/ mmHg 9 10) = SV/PP 9 10 where SV and PP are averaged over the final 5 min of the stage (Chemla et al. 1998). Aortic pulse wave velocity A single investigator collected blood pressure waveforms (Infrared Plethysmograph; ML1020PPG, ADInstruments, Colorado Springs, CO) over a minimum of 30 consecutive cardiac cycles from each LBNP stage, which were chosen based on visual interpretation of the clearest waveform signals. Infrared plethysmography provides accurate estimates of pulse wave arrival time (Loukogeorgakis et al. 2002). The cardiac cycles were averaged to calculate the foot-to-foot pulse transit time between the left carotid artery and left femoral artery (two-sites). The shortest distances between the sites of pulse contour collection were measured to the nearest 0.5 cm using a standard measuring tape. The segmental distances were divided by the corresponding pulse transit time in order to calculate PWV between the carotid artery and femoral artery. The same investigator (AP) recorded and analyzed all arterial pressure wave forms and segment distances. While analyzing cPWV files, the investigator was blinded to the subject ID as well as LBNP stage. We have used this technique and described it in detail elsewhere (Phillips 2010; Phillips et al. 2012b). Within our laboratory, using these techniques

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and a ‘‘plethysmograph to plethysmograph’’ signal, we have documented a high cPWV repeatability (coefficient of variation = 5.5 %). As the femoral probe was located within the LBNP chamber, special care was taken to stabilize the femoral probe. Also, close visual interpretation was made prior to each collection to ensure a stable and accurate pulse contour. A researcher (AP) adjusted the probe, if necessary, at the beginning of each stage. We did not multiply our cPWV measures by 0.8, as our purpose was not to compare to normative data but within group comparisons (Van Bortel et al. 2002). Data analysis In the interest of standardizing for tolerance between participants, we compared baseline to 50 % of the last fully completed LBNP stage before pre-syncope occurred (LBNP50) and the last fully completed stage (LBNPmax). This is a more relevant study design for comparing orthostatic responses between participants as individual tolerance varies greatly (Cote et al. 2012; O’Leary et al. 2007). The level of LBNP used for LBNP50 was decided upon according to the following criteria aimed at finding a midpoint for orthostatic tolerance. Firstly, those with LBNPmax of -80 mmHg had LBNP50 at the -40 mmHg stage. For those with LBNPmax at -60 mmHg however, the -40 stage was chosen as LBNP50 if they presented with pre-syncopal symptoms at the latter part of -60 mmHg. On the other hand, if pre-syncopal symptoms occurred in the earlier half of the -60 mmHg stage, the -20 mmHg was used for LBNP50. Changes in cardiovascular, aortic stiffness and autonomic variables over time (Baseline, LBNP50, LBNPmax) were evaluated using repeated measures analysis of variance. Main effects between stage differences were tested using Bonferroni confidence interval adjustment. For each individual, the correlation coefficient (r) was calculated for the relationship between MAP and SBPLF with cPWV and C. These coefficients were then averaged across all participants and a 95 % confidence interval was constructed. Because HR does not influence foot-to-foot PWV, as measured in this study, we did not relate cPWV to our measures of HR (Hayward et al. 2002). The level of significance was set a priori at P \ 0.05. Data are presented as mean ± standard error unless otherwise reported. Data analysis was performed using SPSS 16.0.

Results During LBNP, 1 participant experienced pre-syncope at -60 mmHg while 3 others experienced pre-syncope at -80 mmHg. The remaining participants did not experience signs or symptoms of pre-syncope. Therefore, LBNPmax

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Table 1 Mean ± standard deviation of various parameters during moderate and severe lower body negative pressure (n = 8) Variable

Baseline

LBNP50

LBNPmax

P value

SBP (mmHg)

117 ± 15

113 ± 18

105 ± 24

0.09

DBP (mmHg)

66 ± 9

69 ± 9

69 ± 16

0.56

MAP (mmHg)

83 ± 11

84 ± 11

85 ± 23

0.89  

HR (beats/min)

58 ± 4

65 ± 7*

86 ± 19

SV (mL)

94 ± 31

62 ± 21*

40 ± 19 

Q (L/min)

5.4 ± 1.7

3.8 ± 1.0*

3.2 ± 1.2*

\0.001

TPR (mmHg/L/min)

17 ± 5

22 ± 5*

28 ± 9 

\0.001

C (mL/mmHg 9 10)

18 ± 6

14 ± 4

12 ± 5

0.01

0.002 0.001

The P value represents influence of time (LBNP) SBP systolic blood pressure, DBP diastolic blood pressure, MAP mean arterial pressure, HR heart rate, SV stroke volume, Q cardiac output, TPR total peripheral resistance, C total arterial compliance * Denotes significantly different from baseline (P \ 0.05)   Denotes significantly different from baseline and LBNP50 (P \ 0.05)

was -40 mmHg for 1 participant, -60 mmHg for 3 participants and -80 mmHg for 4 participants. Table 1 describes changes in haemodynamic and arterial stiffness parameters over LBNP. Briefly, MAP did not change over LBNP (P = 0.89). Central PWV increased significantly at LBNPmax but not LBNP50 (Fig. 1). Total arterial compliance decreased significantly over LBNP (Table 1). Heart rate significantly increased at LBNP50 and again at LBNPmax (Table 1). There was an increase in SBPLF over LBNP (P = 0.048) (Fig. 1). The mean correlation r between cPWV and SBPLF was 0.90 ± 0.03. The 95 % confidence interval for the correlation r between cPWV and SBPLF during LBNP was 0.79–0.99 (Fig. 2). The mean correlation between cPWV and MAP was 0.37 ± 0.23. The 95 % confidence interval for the correlation between cPWV and MAP during LBNP was -0.15 and 0.87. The mean correlation r between C and SBPLF was -0.63 ± 0.18 with a 95 % confidence interval for r of -0.98 to -0.28.

Discussion Our study has two main findings: (1) Central arterial distensibility is reduced during severe LBNP. (2) Indirect markers of sympathetic vasomotor modulation are associated with changes in central arterial distensibility. As distending pressure (i.e. MAP) did not increase during LBNP, this information suggests that the central large elastic arterial segment may be regulated by sympathetic modulation. Central arterial stiffness was not augmented during LBNP50, which is in agreement with other work using similar moderate intensity LBNP. To our knowledge, no other published research has examined aortic stiffness

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during severe LBNP. It was first recognized in 1898 that sympathetic post-ganglionic neurons terminate in the aorta (Tebbs 1898). As Cooke and colleagues have demonstrated, muscle sympathetic nervous system activity (MSNA) dramatically increases at negative pressure below -60 mmHg (Cooke et al. 2009). Due to reduced smooth muscle as well as decreased a-adrenergic receptor density when examining ever more proximal arterial segments, central arterial tone has previously been shown to be less responsive than relatively peripheral arterial segments during increases in sympathetic tone (Bjarnegard et al. 2004; Guimaraes and Moura 2001). In light of this, it is not surprising that severe LBNP is required to induce a sympathetically modulated change in cPWV without concomitant changes in distending pressure. Our study is in agreement with work from Steinback et al. showing small but significant reductions in direct measures of carotid arterial distensibility during postural change. These authors also postulated that augmented vessel stiffness was due to increased sympathetic activation (Steinback et al. 2005). Several other studies have associated sympathetic activation with central arterial stiffness however these studies are confounded by concomitant increases in blood pressure, assuring that the inherent elastance properties are not accurately detected (Mahmud and Feely 2001; Vlachopoulos et al. 2003, 2004). To our knowledge, our study is the first to clearly show that aortic stiffness increases during severe LBNP and is associated with indirect markers of sympathetic modulation. It was largely expected that total arterial compliance was reduced during LBNP. We, as well as others, have shown that SV reduces to a greater extent than PP during LBNP (Convertino et al. 2006; Cote et al. 2012). The change in C was also associated with SBPLF. This association is likely due to a combination of both the widely

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Fig. 2 The mean relationship between PWV and SBPLF during LBNP for each individual

accepted increase in peripheral resistance during LBNP (Stevens and Lamb 1965), as well as reduced central arterial compliance induced by increases in aortic stiffness as shown in the present study. Certainly, it would have been of interest to include measures of peripheral vascular stiffness during LBNP. Technical considerations however prohibited this due to our recent work showing that Finometer-based estimations of pulse transit time are not valid (Phillips et al. 2012a). As mentioned earlier, prior studies have suggested a differential response of peripheral vasculature where the proximal brachial artery is less responsive than the distal portion to LBNP-induced increases in sympathetic tone (Bjarnegard et al. 2004; Boutouyrie et al. 1994). As LBNP in these studies was low, at only -45 mmHg, we would expect increased tone would occur during greater sympathetic activation. This would be an interesting line of future research. Implications

Fig. 1 Haemodynamic and arterial stiffness responses to moderate (LBNP50) and severe (LBNPmax) lower body negative pressure; MAP mean arterial pressure (top); PWV carotid-femoral pulse wave velocity (middle); SBPLF total power (bottom). *Denotes P value less than 0.05. *Above point denotes significantly different from baseline and LBNP50, while *beside point denotes significant effect of time (LBNP)

Our work has important implications for both basic research examining the functional properties of the vasculature and its autonomic control, and also clinical research studying orthostatic tolerance, blood pressure regulation, and the development of prognostic haemodynamic parameters. For example, aortic stiffening during severe LBNP may work in opposing ways to both propagate and delay the eventual syncopal event. Firstly, increasing aortic stiffness places a greater work requirement on the heart (Nichols and O’Rourke 2005), and Q is thought to play an important role in determining orthostatic

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tolerance (Verheyden et al. 2008). Also, increased aortic stiffness reduces the sensitivity of the arterial baroreflex, a key mechanism for maintenance of blood pressure which has shown to be reduced during orthostatic challenge (Lucini et al. 2004). Alternatively, acutely increased aortic stiffness may help delay the development of syncope during orthostatic challenge by increasing pulsatile flow to the brain, which is thought to play an important role maintaining cerebral perfusion at low perfusion pressures (Lucas et al. 2010; Rickards et al. 2011). More work is needed to clarify how acute changes in aortic stiffness influence cerebral and systemic blood flow pulsatility as well as baroreflex sensitivity and cardiac output. Limitations A couple limitations exist within this study requiring consideration. Firstly, the use of power spectral analysisderived markers of sympathetic modulation may be criticized, as on an individual basis SBPLF has been shown to relate poorly to muscle sympathetic nervous system activity (MSNA) parameters (Ryan et al. 2011). We chose to represent sympathetic vasomotor modulation by SBPLF as a marker of efficacious vasomotor tone. On a group level, several studies have shown SBPLF to strongly relate to muscle sympathetic nervous activity (MSNA) during both pharmacological alterations of blood pressure and orthostatic challenge (Furlan et al. 2000; Pagani et al. 1997; Ryan et al. 2011) however it has recently been shown to relate poorly on an individual basis to MSNA using parametric statistics (Ryan et al. 2011). We agree with this study highlighting that SBPLF is a poor marker of MSNA on an individual basis and indeed it suggests SBPLF may not be suitable for experiments examining the generalized sympathetic outflow. The purpose of our study however was not to relate presynaptic sympathetic activity to arterial stiffness (Kiviniemi et al. 2011). Instead the purpose was to relate arterial stiffness to effective arterial sympathetic tone (in other words efficacious sympathetic outflow actively altering vasomotor tone) under constant distending pressure. As LF oscillations in SBP are certainly related to post-synaptic sympathetic vasomotor tone, SBPLF is suitable marker for the purpose of this study (Cevese et al. 2001). This is particularly salient when considering that hypoxia, which is known to occur due to hyperventilation during LBNP, alters adrenergic receptor sensitivity and that uncoupling between sympathetic efferent traffic and vasomotor responsiveness has suspected (Convertino et al. 2009; Cooke et al. 2009; Heistad and Wheeler 1970). Also, we evaluated total arterial compliance from brachialderived pulse pressure and SV. Although this technique has been shown to provide meaningful compliance values (de Simone et al. 1999; Lind et al. 2004), we realize we may

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have overestimated true aortic PP from the brachial site of collection (Vasan 2008). Because our compliance values are not for identifying risk, and meant solely to illustrate acute changes in response to LBNP, it is likely our results provide a valid marker of haemodynamic changes occurring in total arterial compliance.

Conclusion In conclusion, our study shows that both central and total arterial stiffness increase during severe LBNP. Further, our work indicates that increased aortic stiffness is related to increases in an indirect measure of sympathetic vasomotor tone. Further work should examine segmental aortic stiffness during severe LBNP in those with high level complete spinal cord injury (or other sympathetic nervous system dysfunction) with simultaneous recoding of MSNA and SBPLF. Acknowledgments We would like to acknowledge Dr. Maria Trache for her statistical guidance in the preparation of this manuscript. This research was supported by funding from the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, and the BC Knowledge Development Fund. AA Phillips was supported by funding from the Natural Sciences and Engineering Research Council of Canada and Mathematics of Information Technology and Complex Systems (Canada). DER Warburton was supported by salary awards from the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research. Conflict of interest The authors declare no conflict of interest with the present research.

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