Nervous System
Cardiovascular Regulation During Apnea in Elite Divers
Karsten Heusser, Gordan Dzamonja, Jens Tank, Ivan Palada, Zoran Valic, Darija Bakovic, Ante Obad,
Vladimir Ivancev, Toni Breskovic, André Diedrich, Michael J. Joyner, Friedrich C. Luft,
Jens Jordan, Zeljko Dujic
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Abstract—Involuntary apnea during sleep elicits sustained arterial hypertension through sympathetic activation; however,
little is known about voluntary apnea, particularly in elite athletes. Their physiological adjustments are largely unknown.
We measured blood pressure, heart rate, hemoglobin oxygen saturation, muscle sympathetic nerve activity, and vascular
resistance before and during maximal end-inspiratory breath holds in 20 elite divers and in 15 matched control subjects.
At baseline, arterial pressure and heart rate were similar in both groups. Maximal apnea time was longer in divers
(1.7⫾0.4 versus 3.9⫾1.1 minutes; P⬍0.0001), and it was accompanied by marked oxygen desaturation (97.6⫾0.7%
versus 77.6⫾13.9%; P⬍0.0001). At the end of apnea, divers showed a ⬎5-fold greater muscle sympathetic nerve
activity increase (P⬍0.01) with a massively increased pressor response compared with control subjects (9⫾5 versus
32⫾15 mm Hg; P⬍0.001). Vascular resistance increased in both groups, but more so in divers (79⫾46% versus
140⫾82%; P⬍0.01). Heart rate did not change in either group. The rise in muscle sympathetic nerve activity correlated
with oxygen desaturation (r2⫽0.26; P⬍0.01) and with the increase in mean arterial pressure (r2⫽0.40; P⬍0.0001). In
elite divers, breath holds for several minutes result in an excessive chemoreflex activation of sympathetic vasoconstrictor activity. Extensive sympathetically mediated peripheral vasoconstriction may help to maintain adequate oxygen
supply to vital organs under asphyxic conditions that untrained subjects are not able to tolerate voluntarily. Our results
are relevant to conditions featuring periodic apnea. (Hypertension. 2009;53:719-724.)
Key Words: baroreflex 䡲 breath-hold diving 䡲 chemoreflex 䡲 diving response 䡲 sympathetic nervous system
.
“I
nvoluntary” sleep apnea episodes trigger sympathetically mediated blood pressure surges1 and predispose to
cardiovascular and cerebrovascular morbidity and mortality.2– 4 The state of affairs is disturbing, because healthy
people, including underwater hockey players, synchronized
swimmers, and elite breath-hold divers practice “voluntary”
apnea on a regular basis. Freestyle swimmers may hold their
breath throughout 50-m sprint competitions. Elite breath-hold
divers can hold their breath for several minutes. In these
unique individuals, arterial oxygen saturation may decrease to
⬍50%, whereas alveolar carbon dioxide partial pressure
increases substantially.5 Typically, diving fish-catching competitions last for 5 hours with cumulative apnea duration of
⬇1 hour.
Breath holding elicits complex cardiovascular adaptations
even before relevant changes in arterial blood gases occur.
The response includes bradycardia, reduced cardiac output,
and peripheral vasoconstriction through sympathetic activation.6,7 The so-called diving response seems to conserve
oxygen.8 –10 Breath holding without water immersion also
increases sympathetic vasomotor tone.11–19 Hypoxemia16,20
and hypercapnia16,18 provide additional stimuli to the sympathetic nervous system through central and peripheral chemoreflex mechanisms. However, in untrained individuals,
breath-hold duration is too short to elicit a relevant decrease
in arterial oxygen saturation.21 We tested the hypothesis that
the sympathetic vasomotor response to maximal breath holding is increased in apnea divers compared with control
subjects.
Methods
Study Population
We recruited 43 young white subjects. Twenty two were active
apnea divers. Within the preceding months, they participated in ⱖ7
diving competitions and ⱖ70 training sessions, each consisting of 30
to 40 maximal apneas, separated by variable interapneic periods.
Matched, untrained subjects served as controls. All of the participants were healthy nonsmokers and ingested no medications. The
Received December 4, 2008; first decision December 27, 2008; revision accepted February 2, 2009.
From the Institute of Clinical Pharmacology (K.H., J.T., J.J.), Hannover Medical School, Hannover, Germany; Department of Neurology (G.D.),
Clinical Hospital Split, Split, Croatia; Department of Physiology (I.P., Z.V., D.B., A.O., V.I., T.B., Z.D.), University of Split School of Medicine, Split,
Croatia; Autonomic Dysfunction Service (A.D.), Vanderbilt University, Nashville, Tenn; Department of Anesthesiology (M.J.J.), Mayo Clinic College
of Medicine, Rochester, Minn; Experimental and Clinical Research Center (F.C.L.), Charité, Max-Delbrueck-Centrum, Berlin, Germany; and HELIOS
Klinikum (F.C.L.), Berlin, Germany.
K.H. and G.D. contributed equally to this work.
Correspondence to Karsten Heusser, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover,
Germany. E-mail [email protected]
© 2009 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.108.127530
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Figure 1. Original recordings of beat-to-beat arterial blood pressure (ABP; Finometer) and MSNA in 3 subjects. Upper trace, Control
subject. Lower traces, Apnea divers. Note the sympathetic activation during the first 15 to 20 seconds of apnea. The activation is
baroreflex triggered by the blood pressure drop immediately after starting the breath hold. The lowest trace demonstrates that early
sympathetic activation is achieved by an increase in burst frequency (bursts per minute). During the last minute of apnea, a rise in
spike frequency dominates, as reflected by the increasing amplitude of the bursts.
ethical committee of the University of Split School of Medicine
approved the study, and written informed consent was obtained.
Protocol
The participants arrived at the laboratory in the postabsorptive state
and had abstained from caffeine for ⱖ12 hours. After emptying their
bladders, they remained in the supine position throughout the
experiments. They were instrumented, including searching for a
suitable muscle sympathetic nerve activity (MSNA) recording site.
After baseline measurements had been obtained, volunteers performed 2 to 3 bouts of maximal static apnea separated by 5-minute
recovery periods. The first bouts were for practice. Apnea was
performed with a nose clip and closed lips to avoid air leaks.
Immediately before the breath holds, the participants were allowed to
perform a maximal inspiration without previous hyperventilation or
glossopharyngeal pistoning, a breathing maneuver that is common
among experienced apnea divers to maximally increase total lung
capacity.22 At the end of the experiment we measured the forced vital
capacity (FVC) with the subjects still in the supine position.
Measurements
Heart rate was determined using a standard ECG. Arterial blood
pressure was measured noninvasively using continuous finger-pulse
photoplethysmography (Finometer, Finapres Medical Systems). Finger blood pressure was calibrated against brachial arterial pressure.
Arterial oxygen saturation (SpO2) was monitored continuously by
pulse oximetry (Poet II, Criticare Systems), with the probe placed on
the middle finger. Vascular resistance was estimated by the ratio
between mean arterial pressure (Finometer) and mean femoral blood
velocity (Doppler ultrasound device, Multigon) as described previously23 or by impedance cardiography (Cardioscreen, Medis
GmbH).24 A pneumatic chest belt was used to register thoracic and
abdominal movements. Especially in divers, involuntary breathing
movements are regularly seen during late apnea. Therefore, deter-
mination of apnea time was achieved by visual inspection of
the subjects.
To measure sympathetic activity, we used the technique of
microneurography.25 We obtained multiunit recordings of postganglionic sympathetic nerve activity with unipolar tungsten microelectrodes inserted selectively into muscle nerve fascicles of the right
peroneal nerve in the popliteal space. Nerve activity was amplified
with a total gain of 100 000, bandpass filtered (0.7 to 2.0 kHz),
rectified, and integrated with a time constant of 0.1 seconds. To
improve the signal:noise ratio, we shielded the lower body of the
subjects (Waveprotect sheet, Teha Textil GmbH). The sympathetic
bursts were identified in the mean voltage neurograms. The rate of
sympathetic nerve discharges during baseline was expressed as the
number of bursts per minute (burst frequency). During prolonged
apnea, every diastolic trough evokes a sympathetic burst (Figure 1,
insert). Hence, further sympathetic excitation is not properly reflected by the burst frequency. Therefore, we quantified end-apneic
responses also by means of total activity, ie, the cumulated area
under the sympathetic bursts in the integrated nerve signal as a
surrogate for spike frequency.
Analog signals of the above-mentioned parameters were digitized
and stored on a computer. The data files were processed by use of a
program written by 1 of the authors (A.D.) that is based on
PV-WAVE (Visual Numerics), as described previously.26
We determined FVC using spirometry (Quark PFT, Cosmed) and
calculated normalized FVC as the ratio between the observed and
predicted FVCs of a subject. The calculation depends on height, age,
and sex.27
Statistics
In 8 subjects we were unable to find a stable recording site within the
nerve. Thus, only 15 male control subjects and 20 divers (3 women)
were included in the statistical analysis.
During apnea, the course of cardiovascular and autonomic reactions is highly dynamic. To trace these responses properly, we
Heusser et al
Table 1.
Voluntary Apnea
721
Resting Data
60
Controls
Divers
P
BMI, kg/m2
25.8⫾2.1
25.0⫾2.9
0.40
Sports, h/wk
4.7⫾4.8
7.9⫾4.0
0.16
SAP, mm Hg
122⫾12
127⫾14
0.26
MAP, mm Hg
90⫾10
93⫾10
0.36
DAP, mm Hg
80⫾8
79⫾9
0.98
HR, bpm
63⫾8
62⫾7
0.91
MSNA, bursts per min
28⫾12
26⫾9
FVC, %
96⫾9
112⫾11
0.48
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Results
Baseline measurements are given in Table 1. Body mass
index, hemodynamic variables, and MSNA were similar in
both groups. Divers had higher normalized FVC values than
control subjects.
Measurements obtained 1 minute into and at the end of
breath holding are presented in Table 2. Apnea time varied
from 57 seconds in a control subject to 5 minutes and 52
Apnea Data
Parameter, unit
Controls
Divers
P
End of first minute of apnea
SpO2, %
98.4⫾0.6
98.8⫾1.0
0.22
⌬CO, %
⫺38⫾12
⫺51⫾11
⬍0.05
⌬MAP, mm Hg
5.2⫾4.6
7.6⫾7.8
0.30
⌬HR, bpm
0.9⫾7.9
4.0⫾12.2
0.39
11.8⫾9.7
24.2⫾12.4
⬍0.01
⌬MSNA, au/min
2.2⫾1.9
3.2⫾2.0
0.15
VR, relative
1.7⫾0.5
2.8⫾1.0
⬍0.001
⬍0.0001
⌬MSNA, bursts per min
20
0
70
60
MSNA [au/min]
applied averaging periods of ⬇20 seconds as a compromise between
stable averages and sufficient time resolution. We decided to
examine 2 particular periods during apnea: the last 20 seconds of the
first minute of apnea and the last 20 seconds of apnea. All of the
values are given as means⫾SDs. Two-tailed unpaired t tests were
used to compare baseline data and apnea reactions of the groups.
Welch’s correction was applied in case of different variances. We
assessed linear association between variables by Pearson or Spearman correlation analysis, depending on the data distribution. A value
of P⬍0.05 was considered statistically significant. Prism 4 for
Windows (GraphPad Software, Inc) was used for statistical analyses.
40
-20
⬍0.01
Values are means⫾SDs. BMI indicates body mass index; DAP, diastolic
arterial pressure; MAP, mean arterial pressure; SAP, systolic arterial pressure;
HR, heart rate.
Table 2.
MAP [mmHg]
Parameter
50
40
30
20
10
0
-2
-1
0
1
2
t [min]
3
4
5
6
Figure 2. Individual courses of mean arterial pressure (Finometer) and MSNA during apnea (starting at 0 minutes). Circles
denote apnea termination points. E, control subjects; F, divers.
Note that the increase in blood pressure and MSNA in divers
does not reach a ceiling.
seconds in the best diver. As expected, divers held their
breath significantly longer than untrained subjects, leading to
a more pronounced oxygen desaturation. The time course of
arterial pressure and MSNA is shown in the Figures 1 and 2.
In both groups, MSNA and vascular resistance increased
during the first minute of apnea and remained elevated until
the end of apnea (P⬍0.001 for all comparisons). Cardiac
output showed a fast reduction within the first minute of
apnea that was more marked in divers; afterward, it recovered
partially. Blood pressure and MSNA continued to increase
with prolonged breath holding. Toward the end of breath
holding, both measurements increased much more in divers
(Figures 2 and 3). The rise in MSNA was correlated with
oxygen desaturation (r2⫽0.26; P⬍0.01) and with the increase
in mean arterial pressure (r2⫽0.40; P⬍0.0001; Figure 3).
Vascular resistance increased in both groups, but more so in
the divers (79⫾46% versus 140⫾82%; P⬍0.01). Total apnea
duration was positively correlated with the MSNA increase at
the end of the first apnea minute (r2⫽0.15; P⬍0.05).
End of apnea
1.7⫾0.4
3.9⫾1.1
SpO2, %
Time, min
97.6⫾0.7
77.6⫾13.9
⌬CO, %
⫺32⫾13
0.0001
⫺22⫾17
⬍0.23
⌬MAP, mm Hg
8.8⫾4.9
32.4⫾15.2
⬍0.0001
⌬HR, bpm
2.3⫾7.2
⫺5.3⫾16.8
0.08
16.4⫾12.8
27.6⫾14.7
⬍0.05
⌬MSNA, au/min
3.6⫾2.7
16.4⫾15.6
⬍0.01
VR, relative
1.8⫾0.5
2.4⫾0.8
⬍0.01
⌬MSNA, bursts per min
Values are means⫾SDs. CO indicates cardiac output; MAP, mean arterial
pressure; HR, heart rate; VR, vascular resistance.
Discussion
The important findings in our study are that prolonged apnea
in elite divers resulted in profound elevations of MSNA,
along with blood pressure, as they decreased their oxygen
saturation to 78%. The response was completely different
from that of untrained persons. The increase in arterial blood
pressure and MSNA was much greater in elite divers with no
ceiling on the rise in MSNA, whereas these parameters
remained fairly flat throughout the maneuver in control
subjects. Compared with baseline, the mean end-apneic
sympathetic traffic was ⬍4-fold in the control subjects but
722
Hypertension
April 2009
60
Inspiration
MAP [mmHg]
50
Intrathoracic
pressure
Lung
volume
40
CO 2
dilution space
30
O2
store
Training
Peripheral
vasoconstriction
20
O2
conservation
10
r² = 0.40
p < 0.0001
0
0
20
40
Urge
to breathe
60
MSNA [au/min]
Apnea duration
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Figure 3. Relationship between changes in mean arterial pressure (MAP) and MSNA at the end of apnea. E, control subjects;
F, divers. The data suggest that increasing sympathetic activity
contributes to the increase in arterial pressure.
Figure 4. Determinants of apnea duration. Schematic drawing of
factors that help to cope with the urge to breathe during apnea
without previous hyperventilation.
⬎20-fold in the divers. Furthermore, our study suggests that
sympathetic activation early and late into breath holding is
governed by different reflex mechanisms. Our work is the
first to investigate sympathetic nerve traffic in elite divers
during maximal voluntary apnea. The data provide insights
into cardiovascular reflex mechanisms that could not be
obtained in untrained subjects given their limited breath-hold
duration. We believe that our data may be relevant to other
athletic events characterized by breath holding, such as sprint
swimming, and addresses the question, “how do they do it?”
Within the first 15 to 20 seconds of end-inspiratory apnea,
the time course of blood pressure and MSNA resembled the
response to a Valsalva maneuver with an initial blood
pressure decrease. Thereafter, maintained intrathoracic pressure kept cardiac output low28 (Table 2). Arterial pressure
was then stabilized by moderately increased MSNA, as in
previous observations.14,29 The vasoconstrictor sympathetic
activity at the end of the first minute was greater in the divers,
and it correlated with breath-holding duration. It has been
shown that training may increase sympathetic responsiveness.30,31 However, the phenomenon may be secondary:
divers took a deeper breath before apnea, causing higher
intrathoracic pressures, resulting in reduced cardiac output28
and, finally, a more pronounced baroreflex-mediated sympathetic activation. Unloading of low-pressure cardiopulmonary
receptors may also contribute to the sustained sympathetic
excitation.29 Thus, in the early, normoxic stage of breath
holding, hemodynamic changes appear to drive the increase
in sympathetic traffic through baroreflex mechanisms possibly facilitated by central neural mechanisms acquired by
training.
Only trained divers attain the late phase of apnea. Chemoreflex engagement through hypoxia,16,20 hypercapnia,16,18,32 and the lack of ventilatory MSNA inhibition15,18,33,34 may all serve to explain the steady MSNA
increase. In this period, changes in MSNA and blood pressure
were directly correlated with one another. Hence, MSNA
appears to drive blood pressure. The observation is consistent
with a resetting of the sympathetic baroreflex to higher blood
pressure values. Other investigators have argued that baroreflex resetting has priority over ordinary blood pressure
regulation to subserve oxygen conservation.6 Additional studies found that the sympathetic baroreflex maintains its gain
under moderate hypoxia despite a higher operational pressure.17,35,36 Hence, it appears that the arterial baroreflex
continues to operate during the steady increase in vasoconstrictor outflow.29 In this context, it is likely that a number of
sympathoexcitatory factors interact synergistically to promote elevations in MSNA during apnea. Such factors most
likely include hypoxia and hypercapnia,18 whereas others are
of less importance, as has been found for the low-pressure
receptors16 and lung afferents.12 Along these lines, sympathetic activation during long breath holds does not reach a
ceiling (Figures 1 and 2), which is in contrast to previous
suggestions.18 In the later stage of breath holding, sympathetic activity was not associated with a concomitant increase
in leg vascular resistance. It is very likely that the sympathetically mediated vasoconstriction has been attenuated by the
direct vasodilator effect that results from hypoxia,37 as well as
from impeded vasoconstrictor transduction induced by hypercapnia.38 Thus, the rising arterial pressure is presumably
attributable to (partially) recovered cardiac output by increased venous return because of involuntary breathing
movements39 backed by sympathetically maintained peripheral resistance (Table 2).
Hypoxemia in the divers was profound compared with
controls. None of the controls had SpO2 values ⬍90% at the
end of maximal apnea; in the divers, almost all did. Five
divers reached SpO2 levels ⬍70%, which is less than normal
mixed-venous blood. Their hypoxemia is necessarily acute,
and how they acclimatize to this hypoxia, compared with
untrained controls, is uncertain. The values recorded in the
divers equal or exceed the hypoxemia observed in severe
sleep-apnea patients, who suffer from similar deoxygenation
and also have substantially increased MSNA. We found that
repeated bouts of hypoxemia in divers did not lead to
sustained sympathetic activation or arterial hypertension.
Heusser et al
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Thus, we have no reason to believe that the repeated apnea
episodes in our subjects increase their risk for comorbidities.
Previous studies suggested that water contact of the face
during breath holding is the major determinant of peripheral
vasoconstriction40 and that the MSNA increase results from
mutual reinforcement of responses to facial receptor activation and apnea.6 Our findings suggest that face submersion is
not necessary to provoke a substantial increase in MSNA
with breath holding. On the other hand, we and others39,41 did
not observe bradycardia, which is characteristic for a complete diving response.42
Consistent with previous studies, sympathetic activity was
rapidly suppressed when subjects started to breathe
again.6,12,17,19,20,43 The response was too fast for a chemoreflex mechanism. Respiration itself and baroreflex mechanisms are a more likely explanation for the first 4 to 5 seconds
of suppression.19 For instance, pulmonary vagal afferents
activated by postapneic inhalation contribute to the sympatholytic response.12
Our study necessarily has limitations. We did not measure
expired gas concentrations as subjects resumed breathing.
Therefore, we cannot dissect the relative contribution of
hypoxia and hypercapnia to late sympathoexcitation. Face
immersion in cold water augments the sympathetic response.8
However, we purposely avoided this maneuver, because it
could have affected the response to apnea differently in the 2
study groups.10 Even more so, our data do not reflect real
diving situations with whole-body immersion in water of
certain depth and temperature.
Perspectives
Maximal end-inspiratory dry apnea leads to increased sympathetic vasoconstrictor activity. In elite divers, breath holds
for several minutes result in an excessive chemoreflex activation of sympathetic vasoconstrictor activity. The increase is
⬎5 times higher in the elite divers than in untrained control
subjects, and it does not reach a ceiling. Such extensive
sympathetically mediated peripheral vasoconstriction may
help to maintain adequate oxygen supply to vital organs
under asphyxic conditions that untrained subjects are not able
to tolerate voluntarily. Taken together it appears that, in elite
divers, a suite of factors prolongs their ability to resist the
urge to breathe, resulting in breath-hold times of several
minutes (Figure 4).
In contrast to involuntary apnea in sleep apnea patients,
elite divers who reiterate apneas voluntarily do not suffer
from sustained sympathetic activation and hypertension. Factors other than frequent asphyxia, eg, excessive daytime
sleepiness and impaired baroreflex function in the patients,
may contribute to the discrepancy.44 The mechanisms deserve
further study.
Sources of Funding
The Croatian Ministry of Science, Education, and Sports (grants
216-2160133-0330 and 216-2160133-0130) supported the work. The
Deutsche Forschungsgemeinschaft supported K.H., J.T., and J.J., and
the Mayo Foundation supported M.J.J.
Disclosures
None.
Voluntary Apnea
723
References
1. Watanabe T, Mano T, Iwase S, Sugiyama Y, Okada H, Takeuchi S, Furui
H, Kobayashi F. Enhanced muscle sympathetic nerve activity during
sleep apnea in the elderly. J Auton Nerv Syst. 1992;37:223–226.
2. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the
association between sleep-disordered breathing and hypertension. N Engl
J Med. 2000;342:1378 –1384.
3. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea:
implications for cardiac and vascular disease. JAMA. 2003;290:
1906 –1914.
4. Donadio V, Liguori R, Vetrugno R, Elam M, Falzone F, Baruzzi A,
Montagna P. Parallel changes in resting muscle sympathetic nerve
activity and blood pressure in a hypertensive OSAS patient demonstrate
treatment efficacy. Clin Auton Res. 2006;16:235–239.
5. Ferretti G. Extreme human breath-hold diving. Eur J Appl Physiol.
2001;84:254 –271.
6. Fagius J, Sundlof G. The diving response in man: effects on sympathetic
activity in muscle and skin nerve fascicles. J Physiol. 1986;377:429 – 443.
7. Gooden BA. Mechanism of the human diving response. Integr Physiol
Behav Sci. 1994;29:6 –16.
8. Andersson JP, Liner MH, Runow E, Schagatay EK. Diving response and
arterial oxygen saturation during apnea and exercise in breath-hold divers.
J Appl Physiol. 2002;93:882– 886.
9. Palada I, Obad A, Bakovic D, Valic Z, Ivancev V, Dujic Z. Cerebral and
peripheral hemodynamics and oxygenation during maximal dry breathholds. Respir Physiol Neurobiol. 2007;157:374 –381.
10. Schagatay E, Andersson J. Diving response and apneic time in humans.
Undersea Hyperb Med. 1998;25:13–19.
11. Katragadda S, Xie A, Puleo D, Skatrud JB, Morgan BJ. Neural
mechanism of the pressor response to obstructive and nonobstructive
apnea. J Appl Physiol. 1997;83:2048 –2054.
12. Khayat RN, Przybylowski T, Meyer KC, Skatrud JB, Morgan BJ. Role of
sensory input from the lungs in control of muscle sympathetic nerve
activity during and after apnea in humans. J Appl Physiol. 2004;97:
635– 640.
13. Leuenberger UA, Hardy JC, Herr MD, Gray KS, Sinoway LI. Hypoxia
augments apnea-induced peripheral vasoconstriction in humans. J Appl
Physiol. 2001;90:1516 –1522.
14. Macefield VG, Gandevia SC, Henderson LA. Neural sites involved in the
sustained increase in muscle sympathetic nerve activity induced by
inspiratory capacity apnea: a fMRI study. J Appl Physiol. 2006;100:
266 –273.
15. Macefield VG, Wallin BG. Modulation of muscle sympathetic activity
during spontaneous and artificial ventilation and apnoea in humans.
J Auton Nerv Syst. 1995;53:137–147.
16. Morgan BJ, Denahan T, Ebert TJ. Neurocirculatory consequences of
negative intrathoracic pressure vs. asphyxia during voluntary apnea.
J Appl Physiol. 1993;74:2969 –2975.
17. Muenter SN, Cutler MJ, Fadel PJ, Wasmund WL, Ogoh S, Keller DM,
Raven PB, Smith ML. Carotid baroreflex function during and following
voluntary apnea in humans. Am J Physiol Heart Circ Physiol. 2003;285:
H2411–H2419.
18. Somers VK, Mark AL, Zavala DC, Abboud FM. Contrasting effects of
hypoxia and hypercapnia on ventilation and sympathetic activity in
humans. J Appl Physiol. 1989;67:2101–2106.
19. Watenpaugh DE, Muenter NK, Wasmund WL, Wasmund SL, Smith ML.
Post-apneic inhalation reverses apnea-induced sympathoexcitation before
restoration of blood oxygen levels. Sleep. 1999;22:435– 440.
20. Hardy JC, Gray K, Whisler S, Leuenberger U. Sympathetic and blood
pressure responses to voluntary apnea are augmented by hypoxemia.
J Appl Physiol. 1994;77:2360 –2365.
21. Andersson J, Schagatay E. Arterial oxygen desaturation during apnea in
humans. Undersea Hyperb Med. 1998;25:21–25.
22. Overgaard K, Friis S, Pedersen RB, Lykkeboe G. Influence of lung
volume, glossopharyngeal inhalation and P(ET) O2 and P(ET) CO2 on
apnea performance in trained breath-hold divers. Eur J Appl Physiol.
2006;97:158 –164.
23. Bush VE, Wight VL, Brown CM, Hainsworth R. Vascular responses to
orthostatic stress in patients with postural tachycardia syndrome (POTS),
in patients with low orthostatic tolerance, and in asymptomatic controls.
Clin Auton Res. 2000;10:279 –284.
24. Mathews L, Singh RK. Cardiac output monitoring. Ann Card Anaesth.
2008;11:56 – 68.
724
Hypertension
April 2009
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
25. Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG. Somatosensory,
proprioceptive, and sympathetic activity in human peripheral nerves.
Physiol Rev. 1979;59:919 –957.
26. Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Kruger N, Strauss A,
Stoffels G, Luft FC, Jordan J. Influence of sibutramine treatment on
sympathetic vasomotor tone in obese subjects. Clin Pharmacol Ther.
2006;79:500 –508.
27. Kuster SP, Kuster D, Schindler C, Rochat MK, Braun J, Held L, Brandli
O. Reference equations for lung function screening of healthy neversmoking adults aged 18 – 80 years. Eur Respir J. 2008;31:860 – 868.
28. Ferrigno M, Hickey DD, Liner MH, Lundgren CE. Cardiac performance
in humans during breath holding. J Appl Physiol. 1986;60:1871–1877.
29. Macefield VG, Wallin BG. Effects of static lung inflation on sympathetic
activity in human muscle nerves at rest and during asphyxia. J Auton Nerv
Syst. 1995;53:148 –156.
30. Furlan R, Piazza S, Dell’Orto S, Gentile E, Cerutti S, Pagani M, Malliani
A. Early and late effects of exercise and athletic training on neural
mechanisms controlling heart rate. Cardiovasc Res. 1993;27:482– 488.
31. Saito M, Iwase S, Hachiya T. Resistance exercise training enhances
sympathetic nerve activity during fatigue-inducing isometric handgrip
trials. Eur J Appl Physiol. 2009;105:225–234.
32. Dujic Z, Ivancev V, Heusser K, Dzamonja G, Palada I, Valic Z, Tank J,
Obad A, Bakovic D, Diedrich A, Joyner MJ, Jordan J. Central chemoreflex sensitivity and sympathetic neural outflow in elite breath-hold
divers. J Appl Physiol. 2008;104:205–211.
33. Somers VK, Mark AL, Zavala DC, Abboud FM. Influence of ventilation
and hypocapnia on sympathetic nerve responses to hypoxia in normal
humans. J Appl Physiol. 1989;67:2095–2100.
34. St Croix CM, Satoh M, Morgan BJ, Skatrud JB, Dempsey JA. Role of
respiratory motor output in within-breath modulation of muscle sympathetic nerve activity in humans. Circ Res. 1999;85:457– 469.
35. Halliwill JR, Minson CT. Effect of hypoxia on arterial baroreflex control
of heart rate and muscle sympathetic nerve activity in humans. J Appl
Physiol. 2002;93:857– 864.
36. Halliwill JR, Morgan BJ, Charkoudian N. Peripheral chemoreflex and
baroreflex interactions in cardiovascular regulation in humans. J Physiol.
2003;552:295–302.
37. Lahana A, Costantopoulos S, Nakos G. The local component of the acute
cardiovascular response to simulated apneas in brain-dead humans. Chest.
2005;128:634 – 639.
38. Simmons GH, Minson CT, Cracowski JL, Halliwill JR. Systemic hypoxia
causes cutaneous vasodilation in healthy humans. J Appl Physiol. 2007;
103:608 – 615.
39. Palada I, Bakovic D, Valic Z, Obad A, Ivancev V, Eterovic D, Shoemaker
JK, Dujic Z. Restoration of hemodynamics in apnea struggle phase in
association with involuntary breathing movements. Respir Physiol
Neurobiol. 2008;161:174 –181.
40. Campbell LB, Gooden BA, Horowitz JD. Cardiovascular responses to
partial and total immersion in man. J Physiol. 1969;202:239 –250.
41. Badra LJ, Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen
KU, Eckberg DL. Respiratory modulation of human autonomic rhythms.
Am J Physiol Heart Circ Physiol. 2001;280:H2674 –H2688.
42. Stromme SB, Kerem D, Elsner R. Diving bradycardia during rest and
exercise and its relation to physical fitness. J Appl Physiol. 1970;28:
614 – 621.
43. Leuenberger U, Jacob E, Sweer L, Waravdekar N, Zwillich C, Sinoway
L. Surges of muscle sympathetic nerve activity during obstructive apnea
are linked to hypoxemia. J Appl Physiol. 1995;79:581–588.
44. Donadio V, Liguori R, Vetrugno R, Contin M, Elam M, Wallin BG,
Karlsson T, Bugiardini E, Baruzzi A, Montagna P. Daytime sympathetic
hyperactivity in OSAS is related to excessive daytime sleepiness. J Sleep
Res. 2007;16:327–332.
Cardiovascular Regulation During Apnea in Elite Divers
Karsten Heusser, Gordan Dzamonja, Jens Tank, Ivan Palada, Zoran Valic, Darija Bakovic, Ante
Obad, Vladimir Ivancev, Toni Breskovic, André Diedrich, Michael J. Joyner, Friedrich C. Luft,
Jens Jordan and Zeljko Dujic
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Hypertension. 2009;53:719-724; originally published online March 2, 2009;
doi: 10.1161/HYPERTENSIONAHA.108.127530
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