This study aimed to identify the systemic and cerebral hemodynamic characteristics and their roles in high-altitude headache (HAH) among young Chinese men following acute exposure.
Methods
The subjects (n = 385) were recruited in June and July of 2012. They completed case report form questionnaires, as well as heart rate (HR), blood pressure, echocardiogram and transcranial Doppler examinations at 3700 m following a two-hour plane flight. A subgroup of 129 participants was examined at two altitudes (500 and 3700 m).
Results
HAH was characterized by increased HR and cardiac output (CO) and lower saturation pulse oxygen (SpO2) (all p < 0.05). The change in tricuspid regurgitation was also different between the HAH positive (HAH+) and HAH negative (HAH-) subjects. Furthermore, the HAH+ subjects exhibited faster mean (Vm), systolic (Vs) and diastolic (Vd) velocities in the basilar artery (BA; all p < 0.05) and a faster Vd ( 25.96 ± 4.97 cm/s vs. 24.76 ± 4.76 cm/s, p = 0.045) in the left vertebral artery (VA). The bilateral VA asymmetry was also significantly different between the two groups. The pulsatility index (PI) and resistance index (RI) of left VA were lower in the HAH subjects (p < 0.05) and were negatively correlated with HAH (p < 0.05). Baseline CO and Vm in left VA (or right MCA in different regressions) were independent predictors for HAH, whereas CO/HR and ΔVd (Vd difference between bilateral VAs) were independent risk factors for HAH at 3700 m.
Conclusions
HAH was characterized, in part, by increased systemic hemodynamics and posterior cerebral circulation, which was reflected by the BA and left VA velocities, and lower arterial resistance and compliance. Furthermore, baseline CO and Vm in left VA or right MCA at sea level were independent predictors for HAH, whilst bilateral VA asymmetry may contribute to the development of HAH at high altitude.
The online version of this article (doi:10.1186/s10194-015-0527-3) contains supplementary material, which is available to authorized users.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SZB and LH participated the design of this research. SZB also has drafted the manuscript and performed the statistical analysis. JJ, XHZ and JQ have reviewed and revised this manuscript critically for important intellectual content. JY, XHZ, JQ and SZB carried out the filling of case report form and the measurements of blood pressure, HR and SpO2. RSR and SYY carried out the echocardiography examinations. The transcranial Doppler examinations were performed by CFT and QNL. All authors read and approved the final manuscript.
Authors’ information
SZB, MD, Physician and instructor from Institute of Cardiovascular Diseases of PLA; Department of Cardiology, Xinqiao Hospital, Third Military Medical University. His research areas include cardiovascular diseases, acute mountain sickness and high altitude headache and he has published two articles in Journal of headache and pain and European journal of Applied Physiology [8, 28].
LH, PhD, MD, FACC; Professor and Director of Institute of Cardiovascular Diseases of PLA; Department of Cardiology, Xinqiao Hospital, Third Military Medical University. His interests focus on basic and clinical researches in cardiovascular diseases, acute mountain sickness and high altitude headache.
Abkürzungen
BA
Basilar artery
CO
Cardiac output
DBP
Diastolic blood pressure
EF
Ejection fraction
HAH
High-altitude headache
HAH+
HAH positive or with HAH
HAH-
HAH negative or without HAH
HR
Heart rate
LA
End-diastolic internal diameters of left atrium
LV
End-diastolic internal diameters of left ventricle
MCA
Middle cerebral artery
PA
End-diastolic internal diameters of pulmonary artery
PI
Pulsatility index
RA
End-diastolic internal diameters of right atrium
RI
Resistance index
RV
End-diastolic internal diameters of right ventricle
SBP
Systolic blood pressure
SpO2
Saturation pulse oxygen
SV
Stroke volume
VA
Vertebral artery
Vd
Diastolic velocity
Vm
Mean velocity
Vs
Systolic velocity
ΔVd
Difference in diastolic velocity between bilateral isonym cerebral arteries
ΔVm
Difference in mean velocity between bilateral isonym cerebral arteries
ΔVs
Difference in systolic velocity between bilateral isonym cerebral arteries
Background
High-altitude headache (HAH) is the primary critical complaint after high altitude exposure [1]. It is defined as a headache that occurs within 24 hours after ascending to 2500 m or higher [2]. HAH affects tourists’ and labor workers’ daily life and work due to its high incidence and discomfort experience [3]. HAH has also been defined as the primary symptom in diagnosis of acute mountain sickness [4].
Over the past several decades, epidemiology, clinical characteristics, risk factors, prevention and treatment aspects of HAH have been systematically studied in mountaineers [5, 2, 6, 7]. Clinical characteristics studies have showed that HAH presents as a sudden attack of migraine that is accompanied by nausea [6]. Previous studies have demonstrated that increased heart rate (HR) and self-anxiety scores, lower saturation pulse oxygen (SpO2) and a history of primary headache are all independent risk factors for HAH [8, 9]. Though oxygen inhalation, acetaminophen and aspirin have been used to treat HAH, the effects are quite often inconsistent [10, 11]. Despite accumulating evidence regarding HAH and related issues, the underlying mechanisms remain elusive [12, 13, 1].
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HAH exhibits an impulsivity property [14], which may be related to the hemodynamics (or blood flow in artery) of patients. While most previous studies have focused on the risk factors and epidemiology of HAH, few of them give proper attentions to the hemodynamic characteristics of HAH [8, 9, 7]. Furthermore, most of these studies have been conducted in mountaineers, which may not reflect representative properties of HAH [5, 9, 12].
To the best of our knowledge, the hemodynamic characteristics of and their roles in HAH has not been fully uncovered. Thus, we postulate that hemodynamics especially cerebral hemodynamic parameters are related HAH and they may be predictors for HAH. Therefore, we performed this large sample size cohort study to explore the hemodynamic characteristics of HAH via examinations of the systemic and cerebral hemodynamic parameters using echocardiogram and transcranial Doppler sonography, respectively, following acute high altitude exposure (within 24 h after arrival at 3700 m) to facilitate our understanding of the disease process and provide insight into the specific phenotypes associated with the disease course.
Methods
Participants and procedures
Participants
Three hundred eighty-five participants were recruited in June and July of 2012 according to specific inclusion and exclusion criteria. The inclusion criteria were as follows: healthy males between the ages of 18 and 60 years who had no high-altitude exposure in recent two years. Individuals with any of the following conditions were excluded: neuropsychosis, cerebrovascular diseases, cardiovascular diseases, respiratory diseases, malignant tumors and liver or kidney disorders.
The study was reviewed and approved by the Ethics Committee of Xinqiao Hospital of Third Military Medical University. The study was thoroughly explained to all subjects who agreed to participate, and all volunteers signed informed consent forms prior to study participation.
Procedures
The subjects were transported to an altitude of 3700 m by plane over two hours of travel in June and July of 2012. None of the subjects drinks coffee regularly. The coffee, tea, and other caffeine-containing drinks as well as alcohol were avoided before the examinations. Baseline measurements of systemic and cerebral hemodynamic parameters were examined one week prior to the departure at sea level (Chengdu, 500 m) in a subgroup of 129 participants. The participants will receive regular training after a three days’ rest. They did the daily life activities and avoided any heavy exercises or physical labor in the first 72 hours at 3700 m. The field trials were performed within 18 to 24 hours after their arrivals at 3700 m. Structured case report questionnaires were used to record the subjects’ demographic information (i.e., age, body mass index (BMI), smoking and alcohol consumption), primary headache history [None of them takes medication regularly due to primary headache. However, severe headache (HAH) subjects were treated with NSAIDs or Sanlietong (Taiji medicine, Xi’an, China) as necessary at 3700 m] and HAH symptoms (0 = no headache; 1 = mild headache; 2 = moderate headache; 3 = severe headache).
Measurements of systemic hemodynamic parameters
The subjects’ systolic blood pressure (SBP), diastolic blood pressure (DBP), HR and SpO2 were measured using a sphygmomanometer (HEM-6200, OMRON, China) and a pulse oximeter (NONIN-9550, Nonin Onyx, USA) after the subjects had sat at rest for 30 min. Each subject received an echocardiogram examination (ultrasonography system, CX50, Philips, USA) that involved measurements of the end-diastolic internal diameters of the left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and pulmonary artery (PA), in addition to the stroke volume (SV), cardiac output (CO) and ejection fraction (EF).
Measurements of cerebral hemodynamic parameters
The examinations at both altitudes were performed in the morning after an overnight fast and caffeine containing drinks were avoided.
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Transcranial Doppler sonography examinations were performed by the same technician using an ultrasonography system with a 2 Hz probe (EME TC2021-III, NICOLET, USA). For each subject, the following parameters were recorded: the mean velocity (Vm), systolic velocity (Vs), diastolic velocity (Vd), pulsatility index (PI) and resistance index (RI). These measurements were taken in the bilateral middle cerebral artery (MCA) for anterior circulation and in the vertebral artery (VA) and basilar artery (BA) for posterior circulation.
The asymmetry of the MCA and VA was calculated as ΔV = left velocity - right velocity for each lateral MCA or VA, whereas the asymmetry index (AI) was calculated as AI = ΔV/ [(left Vm + right Vm)/2]. The cerebrovascular conductance index was calculated as the Vm_MCA/mean arterial blood pressure.
Statistical analysis
The case report forms were excluded if the demographic information was not completed, the velocity could not be identified at the depths previously described or the systemic hemodynamic parameters were not measured.
The normally distributed measurement variables (age, BMI, SBP, DBP, SpO2, HR, echocardiography parameters and velocities, PIs and RIs of the BA, MCAs and VAs) were expressed as the mean ± standard deviation (SD). The non-normally distributed variables were presented as the medians (interquartile range). The enumerated data are expressed as the rate of occurrence (%).
The normally distributed variables for the systemic and cerebral circulation measurements were compared using a paired Student’s t-test between the 500 and 3700 m altitudes and were analyzed using an independent samples t-test between the HAH positive (HAH+) and HAH negative (HAH-) groups at both altitudes. The asymmetries, AIs and tricuspid regurgitation measurements were compared using a Mann–Whitney U test. The relationships between HAH and the previously described parameters at 500 m and 3700 m were analyzed using Spearman’s correlations. Variables with a p < 0.05 in correlation analyses or significant difference between HAH+ and HAH- groups were included in univariate logistic regression. Adjusted logistic analyses were used to identify independent predictors or risk factors for HAH after univariate logistic regression (Fig 1). Variables with colinearity were analyzed in different models (adjusted by primary variables or calculated variables respectively) to reduce the bias.
Fig. 1
The fluidogram of the statistical analysis
×
The statistical analyses were performed using SPSS 19.0 software for Windows. P ≤ 0.05 was considered statistically significant. Statisticians from Third Military Medical University were consulted regarding the statistical methods and results.
Results
Clinical characteristics of the subjects
Three hundred eighty-five subjects received both echocardiography and transcranial Doppler examinations at 3700 m of elevation (363 subjects had completely valid transcranial Doppler and echocardiography parameters). Baseline measurements at 500 m were also recorded among 129 individuals. The subjects in this study were characterized by a mean age of 23.35 ± 4.37 years and a mean BMI of 21.81 ± 2.50 kg/m2. The ethnicity of the population was primarily Han Chinese (83.2%). Overall, in our study, the incidence of HAH following acute exposure to 3700 m was 75.2% (273 of 363).
Alterations in systemic and cerebral hemodynamics
Both systemic and cerebral circulations were dramatically altered following acute exposure to high altitude from sea level. However, the blood pressure parameters, including the SBP, DBP, pulse pressure and mean arterial blood pressure, did not significantly increase after the acute exposure. The SpO2 decreased from 98.34 ± 1.06% to 88.72 ± 2.71% (p < 0.001). The LA, RA and RV all significantly decreased (all p < 0.001). However, the EF and CO significantly increased, as well as the velocity in the bilateral MCAs. In VAs and BA, the Vd exhibited a significant increase. However, the VAs asymmetries did not dramatically change. The changes in the hemodynamic parameters are summarized in Table 1.
Table 1
Alterations in systemic and cerebral hemodynamics (N = 129)
Sea level
3700 m
p value
Systemic hemodynamics
SBP
116.32 ± 15.24
115.84 ± 11.84
0.782
DBP
74.65 ± 10.93
76.24 ± 9.40
0.156
ΔBP
41.67 ± 11.71
39.61 ± 8.05
0.131
MAP
88.54 ± 11.25
89.44 ± 9.55
0.444
HR
63.58 ± 10.19
83.98 ± 11.90
<0.001**
SpO2
98.34 ± 1.06
88.72 ± 2.71
<0.001**
LA
30.91 ± 1.73
30.00 ± 1.92
<0.001**
LV
46.47 ± 2.45
46.15 ± 2.04
0.184
RA
35.70 ± 2.23
34.21 ± 2.15
<0.001**
RV
35.49 ± 2.08
33.72 ± 2.42
<0.001**
PA
20.24 ± 1.60
19.92 ± 1.60
0.097
EF
62.94 ± 5.49
66.56 ± 3.92
<0.001**
SV
65.24 ± 12.22
67.30 ± 8.31
0.088
CO
4.16 ± 0.95
5.32 ± 1.09
<0.001**
Tricuspid regurgitation
0.500 (1.00)
0.500(0.500)
0.885
Cerebral hemodynamics
Left side MCA
Vm
62.08 ± 10.39
65.79 ± 11.78
<0.001**
Vs
95.95 ± 14.60
99.80 ± 15.93
0.002**
Vd
42.69 ± 7.91
46.47 ± 9.07
<0.001**
PI
0.867 ± 0.133
0.817 ± 0.133
<0.001**
RI
0.554 ± 0.048
0.534 ± 0.048
<0.001**
Left side VA
Vm_
32.77 ± 5.14
35.20 ± 5.83
<0.001**
Vs_
50.70 ± 7.50
51.57 ± 7.91
0.233
Vd_
21.91 ± 4.095
24.82 ± 4.86
<0.001**
PI
0.895 ± 0.181
0.770 ± 0.168
<0.001**
RI
0.570 ± 0.067
0.516 ± 0.061
<0.001**
Right side MCA
Vm
58.79 ± 10.18
63.25 ± 11.58
<0.001**
Vs
90.50 ± 14.18
94.71 ± 15.01
<0.001**
Vd
40.35 ± 7.49
44.55 ± 9.04
<0.001**
PI
0.864 ± 0.150
0.804 ± 0.130
<0.001**
RI
0.556 ± 0.055
0.530 ± 0.050
0.293
Right side VA
Vm
34.33 ± 4.77
36.47 ± 5.73
<0.001**
Vs
50.60 ± 6.55
51.78 ± 7.83
0.058
Vd
23.24 ± 4.12
25.90 ± 4.55
<0.001**
PI
0.808 ± 0.162
0.715 ± 0.117
<0.001**
RI
0.539 ± 0.061
0.499 ± 0.048
<0.001**
BA
Vm
39.66 ± 7.75
41.85 ± 9.58
0.002**
Vs
67.93 ± 13.57
66.19 ± 13.46
0.117
Vd
25.07 ± 5.85
28.59 ± 7.71
<0.001**
PI
1.093 ± 0.251
0.920 ± 0.220
<0.001**
RI
0.627 ± 0.068
0.567 ± 0.073
<0.001**
Asymmetry of the bilateral VAs
ΔVs
0.0 (11.0)
0.0 (12.0)
0.645
ΔVd
−1.0 (6.0)
−1.0 (6.0)
0.623
ΔVm
−1.0 (7.0)
−2.0 (8.0)
0.529
AI%
−3.5 (20.2)
−2.9 (18.1)
0.190
Conduction
CVCi
0.695 ± 0.145
0.730 ± 0.149
0.011*
BA: basilar artery; CO: cardiac output; CVCi : cerebrovascular conductance index; DBP: diastolic blood pressure; EF: ejection fraction; HAH: high-altitude headache; HAH+: HAH positive or with HAH; HAH-: HAH negative or without HAH;HR: heart rate; LA: end-diastolic internal diameters of left atrium; LV: end-diastolic internal diameters of left ventricle; MCA: middle cerebral artery; PA: end-diastolic internal diameters of pulmonary artery; PI: pulsatility index; RA: end-diastolic internal diameters of right atrium; RI: resistance index; RV: end-diastolic internal diameters of right ventricle; SBP: systolic blood pressure;SpO2: saturation pulse oxygen; SV: stroke volume; VA: vertebral artery; Vs: systolic velocity; Vd: diastolic velocity; Vm: mean velocity;ΔVs: difference in systolic velocity between bilateral isonym cerebral arteries; ΔVd: difference in diastolic velocity between bilateral isonym cerebral arteries;ΔVm: Difference in mean velocity between bilateral isonym cerebral arteries. Cerebrovascular conductance index (CVCi) = Vm_MCA/MAP
#: N = 129;
*p is 0.05 or less, **p is 0.01 or less
Most of the cerebral hemodynamic parameters altered dramatically from sea level to 3700 m and systemic hemodynamic parameters altered dramatically in part
Clinical and hemodynamic characteristics of HAH at 3700 m
Only age (p = 0.044) was significantly higher in the HAH+ group as compared with the HAH- group regarding demographic data. The HAH+ patients were characterized by increased HR (87.96 ± 13.02 vs. 84.41 ± 13.11 beats per min, p = 0.026) and decreased SpO2 (87.94 ± 3.19 vs. 88.70 ± 2.98%, p = 0.048). Regarding blood pressure, there was no significant difference between the HAH+ and HAH- groups in the SBP, DBP, pulse pressure or mean arterial blood pressure. Although the LA, LV, RA, RV, PA, EF, SV and tricuspid regurgitation were not significantly different in the HAH+ subjects compared with the HAH- subjects (all p > 0.05), the CO was significantly increased in the HAH+ group (p = 0.001).
Anterior circulation, which was assessed via measurements of velocities in MCAs, was similar in the HAH+ and HAH- groups in bilateral MCAs (all p > 0.05). The PIs and RIs in the right and left MCA were not different between the two groups. For posterior circulation, the velocities in BA, including Vs (65.46 ± 11.54 vs. 68.81 ± 14.84, p = 0.028), Vd (28.61 ± 7.46 vs. 30.47 ± 7.52, p = 0.042) and Vm (41.42 ± 8.64 vs. 44.18 ± 9.74, p = 0.017), were significantly different in the HAH- group as compared with the HAH+ group, respectively. Similar to the MCA, the PI (p = 0.151) and RI (p = 0.292) of the BA were not significantly different between the HAH+ and HAH- groups. Furthermore, the Vd in left VA was significantly increased in the HAH+ group compared with the HAH- group (25.96 ± 4.97 vs. 24.76 ± 4.76 cm/s, p = 0.045), whereas the Vs and Vm were not significantly different between the two groups. Additionally, the HAH+ patients also exhibited a lower RI and PI in the left VA (p = 0.040 and 0.025, respectively). However, in the right VA, the velocities and pulsate indexes showed no differences between HAH+ group and HAH- one (all p > 0.05, Table 2).
Table 2
Differences between HAH+ and HAH- groups in demographics, systemic and cerebral hemodynamics (N = 363)
Headachea
HAH-
HAH+
HAH intensities
p (H+ vs. H-)
Cases(n)
(90)
(273)
Mild (215)
Moderate (52)
Sever (6)
Demographic factors
Age
22.59 ± 3.95
23.60 ± 4.48
23.12 ± 4.26
25.47 ± 4.99
25.00 ± 3.69
0.044*
BMI
21.52 ± 2.11
21.90 ± 2.61
21.85 ± 2.55
21.96 ± 2.89
23.56 ± 2.09
0.199
Smoking(yes)
20(22.2%)
66(24.2%)
52(24.2%)
11(21.2%)
3(50.0%)
0.705
Alcohol consumption(yes)
54(60.0%)
159(58.2%)
126 (58.6%)
28(53.8%)
5(83.3%)
0.796
Systemic hemodynamics
SBP
117.28 ± 11.62
118.66 ± 12.03
118.84 ± 12.38
118.17 ± 11.04
116.67 ± 7.76
0.340
DBP
77.52 ± 10.83
78.86 ± 9.97
78.89 ± 10.21
78.92 ± 9.26
77.33 ± 8.43
0.279
ΔBP
39.76 ± 7.14
39.80 ± 6.59
39.94 ± 7.04
39.25 ± 4.54
39.33 ± 5.24
0.958
MAP
90.77 ± 10.57
92.13 ± 10.24
92.21 ± 10.47
92.01 ± 9.65
90.44 ± 7.83
0.280
HR
84.41 ± 13.11
87.96 ± 13.02
87.35 ± 12.65
89.35 ± 13.26
98.00 ± 20.66
0.026*
SpO2
88.70 ± 2.98
87.94 ± 3.19
88.16 ± 3.01
87.06 ± 3.81
87.83 ± 3.06
0.048*
LA
29.82 ± 2.12
29.70 ± 2.18
29.75 ± 1.99
29.40 ± 2.84
30.33 ± 2.50
0.632
LV
45.78 ± 2.27
46.00 ± 2.25
46.04 ± 2.21
45.85 ± 2.44
45.83 ± 2.32
0.425
RA
33.98 ± 2.04
34.10 ± 2.32
34.14 ± 2.27
34.06 ± 2.56
33.17 ± 2.32
0.661
RV
33.48 ± 2.24
33.70 ± 2.56
33.78 ± 2.56
33.50 ± 2.60
32.50 ± 2.07
0.469
PA
19.83 ± 1.14
19.95 ± 1.42
19.93 ± 1.42
19.98 ± 1.48
20.33 ± 1.03
0.452
EF
66.38 ± 4.28
67.16 ± 4.72
67.29 ± 4.82
66.87 ± 4.40
64.83 ± 3.31
0.165
SV
65.92 ± 8.96
67.32 ± 9.72
67.57 ± 9.79
66.66 ± 9.42
64.17 ± 10.63
0.230
CO
5.16 ± 1.14
5.60 ± 1.02
5.60 ± 1.03
5.65 ± 1.02
5.60 ± .663
0.001**
Tricuspid regurgitation
0.50(0.80)
0.50(0.60)
0.50(0.60)
0.50(0.80)
0.40(0.68)
0.135
Cerebral hemodynamics
Left side MCA
Vm
67.46 ± 12.18
67.41 ± 11.74
66.91 ± 10.87
69.35 ± 14.87
68.50 ± 11.47
0.973
Vs
102.17 ± 14.94
101.41 ± 15.91
100.79 ± 15.15
103.92 ± 18.83
102.00 ± 15.82
0.693
Vd
48.0 ± 10.12
47.96 ± 9.10
47.51 ± 8.37
49.46 ± 11.67
51.00 ± 8.60
0.964
PI
0.820 ± 0.169
0.800 ± 0.130
0.802 ± 0.127
0.799 ± 0.141
0.750 ± 0.130
0.260
RI
0.531 ± 0.063
0.527 ± 0.0490
0.528 ± 0.048
0.526 ± 0.051
0.499 ± 0.057
0.532
Left side VA
Vm
35.18 ± 5.57
36.38 ± 6.19
35.93 ± 5.66
37.63 ± 6.59
41.67 ± 14.40
0.103
Vs
51.28 ± 7.05
52.16 ± 8.49
51.75 ± 7.93
53.19 ± 9.20
57.83 ± 17.59
0.374
Vd
24.76 ± 4.76
25.96 ± 4.97
25.46 ± 4.49
27.35 ± 5.08
32.00 ± 11.93
0.045*
PI
0.765 ± 0.159
0.727 ± 0.153
0.738 ± 0.153
0.690 ± 0.150
0.640 ± 0.102
0.040*
RI
0.517 ± 0.065
0.500 ± 0.061
0.505 ± 0.058
0.482 ± 0.070
0.454 ± 0.053
0.025*
Right side MCA
Vm
63.51 ± 13.67
64.46 ± 11.45
64.24 ± 11.26
64.87 ± 11.57
68.67 ± 17.61
0.518
Vs
95.59 ± 17.61
96.24 ± 15.67
96.17 ± 15.55
96.13 ± 15.65
99.83 ± 22.29
0.740
Vd
45.11 ± 10.96
45.75 ± 8.73
45.53 ± 8.52
46.12 ± 8.95
50.67 ± 13.74
0.573
PI
0.812 ± 0.144
0.792 ± 0.124
0.796 ± 0.121
0.780 ± 0.125
0.734 ± 0.190
0.191
RI
0.530 ± 0.053
0.526 ± 0.051
0.527 ± 0.051
0.521 ± 0.047
0.493 ± 0.076
0.440
Right side VA
Vm
37.27 ± 6.18
37.27 ± 6.02
37.00 ± 5.80
38.63 ± 6.89
35.17 ± 4.66
0.991
Vs
52.51 ± 7.69
52.26 ± 8.29
52.11 ± 8.09
53.42 ± 9.21
47.50 ± 6.06
0.800
Vd
26.72 ± 5.09
26.55 ± 4.74
26.26 ± 4.56
27.75 ± 5.33
26.33 ± 4.89
0.764
PI
0.716 ± 0.208
0.693 ± 0.117
0.702 ± 0.117
0.669 ± .114
0.606 ± 0.056
0.202
RI
0.500 ± 0.119
0.491 ± 0.053
0.494 ± 0.052
0.480 ± .053
0.448 ± 0.037
0.317
BA
Vm
41.42 ± 8.64
44.18 ± 9.74
43.80 ± 9.42
46.33 ± 10.91
38.83 ± 8.06
0.017*
Vs
65.46 ± 11.54
68.81 ± 14.84
68.60 ± 14.32
70.81 ± 16.13
59.17 ± 19.63
0.028*
Vd
28.61 ± 7.46
30.47 ± 7.52
30.07 ± 7.31
32.29 ± 8.31
28.83 ± 6.27
0.042*
PI
0.914 ± 0.224
0.879 ± 0.193
0.890 ± 0.192
0.844 ± 0.183
0.760 ± .262
0.151
RI
0.564 ± 0.078
0.554 ± 0.068
0.559 ± 0.066
0.542 ± 0.069
0.496 ± .086
0.292
Asymmetry of the bilateral VAs
ΔVs
−1.00 (8.00)
0. 00 (9.00)
0.00(9.00)
0.00 (10.50)
5.00 (28.5)
0.126
ΔVd
−3.00 (6.25)
−1.00 (6.00)
−1.00(7.00)
−1.00 (3.75)
2.00 (18.5)
0.010*
ΔVm
−2.50 (8.00)
−1.00 (6.00)
−1.00(6.00)
−1.00 (4.75)
1.00 (23.75)
0.046*
AI%
−6.6(22.0)
−2.7 (18.0)
−2.9(18.4)
−2.1(13.8)
2.8 (52.2)
0.040*
Conduction
CVCi
0.729 ± 0.145
0.724 ± 0.140
0.719 ± 0.135
0.737 ± 0.153
0.767 ± 0.191
0.758
*p is 0.05 or less, **p is 0.01 or less
HAH was characterized with higher velocity in posterior cerebral circulation and higher HR but lower SpO2
The asymmetry of the bilateral VAs, including the ΔVd (p = 0.010), ΔVm (p = 0.046) and AI (p = 0.040), in the HAH patients was significantly different than the HAH- subjects. The cerebrovascular conductance index (0.724 ± 0.140 vs.0.729 ± 0.145, respectively, p = 0.758) was similar in the HAH+ and HAH- subjects (Table 2).
The Spearman’s correlation analyses demonstrated that age (r = 0.178, p = 0.001), HR (r = 0.143, p = 0.006) and CO (r = 0.175, p = 0.001) exhibited significantly positive relationships with the HAH severity, whereas the SpO2 (r = −0.148, p = 0.005) exhibited an inverse relationship. The other parameters in systemic hemodynamics were not closely associated with HAH (all p > 0.05). The anterior circulation parameters, including the velocities, PIs and RIs in the bilateral MCA, had no associations with HAH severity. With the exception of the Vs, the other parameters (Vm, Vd, PI and RI) of the BA exhibited significant associations with HAH (p was 0.023, 0.021, 0.045 and 0.042, respectively). On the left side VA, the Vd (r = 0.157, p = 0.003) and Vm (r = 0.120, p = 0.022) exhibited positive relationships with HAH, whereas the PI (r = −0.152, p = 0.004) and RI (r = −0.166, p = 0.001) were negatively correlated with HAH. The parameters on the right side of the VA were not as closely correlated with HAH. Furthermore, associations between VA asymmetries and HAH were also identified in the bilateral VAs: ΔV of Vd (r = 0.137, p = 0.009), ΔV of Vm (r = 0.105, p = 0.046) and AI (r = 0.106, p = 0.043). The relationships between HAH and the hemodynamic parameters are shown in Table 3.
Table 3
Relationships between HAH and demographic, systemic and cerebral hemodynamic parameters (N = 363)
Headache score
r
p
r
p
Demographic factors
PI
−0.152
0.004**
Age
0.178
0.001**
RI
−0.166
0.001**
BMI
0.075
0.155
Right side MCA
Systemic hemodynamics
Vm
0.078
0.136
SBP
0.031
0.561
Vs
0.055
0.297
DBP
0.031
0.560
Vd
0.086
0.103
ΔBP
0.009
0.865
PI
−0.099
0.059
MAP
0.033
0.535
RI
−0.087
0.097
HR
0.143
0.006**
SpO2
−0.148
0.005**
Right side VA
LA
−0.035
0.507
Vm
0.039
0.455
LV
0.027
0.610
Vs
<0.001
0.997
RA
0.010
0.851
Vd
0.036
0.499
RV
0.001
0.992
PI
−0.083
0.115
PA
0.058
0.275
RI
−0.065
0.215
EF
0.045
0.390
SV
0.035
0.506
BA
CO
0.175
0.001**
Vm
0.119
0.023*
Tricuspid regurgitation
0.044
0.400
Vs
0.077
0.141
Vd
0.121
0.021*
Cerebral hemodynamics
PI
−0.105
0.045*
Left side MCA
RI
−0.107
0.042*
Vm
0.033
0.536
Vs
0.018
0.733
Asymmetry of VAs
Vd
0.039
0.454
ΔVs
0.080
0.130
PI
−0.039
0.458
ΔVd
0.137
0.009**
RI
−0.050
0.345
ΔVm
0.105
0.046*
AI%
0.106
0.043*
Left side VA
Vm
0.120
0.022*
Conduction
Vs
0.067
0.203
CVCi
0.019
0.716
Vd
0.157
0.003**
*p is 0.05 or less, **p is 0.01 or less
HAH was positively associated with HR, CO and cerebral velocities while it negatively correlated with SpO2, PIs and RIs in BA and left side VA
Anzeige
Risk factors for HAH at 3700 m
Univariate logistic regression was performed for variable with a p < 0.05 in correlation analyses or significant difference between HAH+ and HAH- groups. HR, SpO2, CO, Vd, PI and RI of left side VA, velocities in BA (Vm, Vd) and ΔVd were risk factors for HAH. After adjusted regression analyses, only HR (or CO) and ΔVd were independent risk factors for HAH (Table 4).
Table 4
Univariate and adjusted logistic regression for variables at 3700 m (N = 363)
Risk factors
β-coefficient
Odds ratio
(95% CI)
p value
Lower
Upper
Univariate logistic regression
HR
0.022
1.022
1.003
1.042
0.027*
SpO2
−0.081
0.922
0.851
1.000
0.049*
CO
0.422
1.524
1.195
1.944
0.001**
Left VA
Vd
0.052
1.053
1.001
1.108
0.046*
PI
−1.562
0.210
0.047
0.944
0.042*
RI
−4.476
0.011
0.000
0.591
0.026*
BA
Vm
0.032
1.033
1.005
1.061
0.018*
Vd
0.044
1.036
1.001
1.071
0.035*
Asymmetry of VAs
ΔVd
0.063
1.065
1.011
1.122
0.018*
Adjusted logistic regression
Model 1
HR
0.025
1.025
1.005
1.045
0.012*
Model 2
HR
0.023
1.023
1.003
1.044
0.026*
ΔVd
0.065
1.068
1.013
1.126
0.015*
Model3
CO
0.417
1.517
1.189
1.937
0.001**
ΔVd
0.063
1.065
1.009
1.124
0.022*
*p is 0.05 or less, **p is 0.01 or less
Model 1: Adjusted by primary variables (SpO2, Vd in left side VA and BA);
Model 2: Adjusted by primary variables and an asymmetry data (ΔVd);
Model 3: Avoided the colinearity between HR and CO, indicated that CO and ΔVd were independent risk factors for HAH;
We just listed the variable with a p < 0.05
Associations between hemodynamic parameters and HAH in a subgroup of 129 subjects
In the baseline parameters, CO, Vm, PI and RI in left side VA, velocities [Vm (60.20 ± 10.37 vs. 54.29 ± 7.03 cm/s, p = 0.004), Vs (92.11 ± 14.53 vs. 85.64 ± 10.46 cm/s, p = 0.023) and Vd (41.42 ± 7.60 vs. 37.19 ± 5.50 cm/s, p = 0.005)] in right MCA were significant different between HAH+ and HAH- groups. Furthermore, CO showed a positive relationship with HAH (Table 5).
Table 5
Associations between baseline parameters and HAH (N = 129)
Differences between HAH+
Correlation with HAH intensities
and HAH- groups
Headache Cases(n)
HAH-(31)
HAH+(98)
p value
r
p value
Demographic factors
Age
22.71 ± 3.21
23.13 ± 4.31
0.616
0.093
0.297
BMI
21.41 ± 1.67
22.07 ± 2.52
0.175
0.153
0.084
Smoking(yes)
7(22.5%)
23(23.5%)
0.919
/
/
Alcohol consumption(yes)
21(67.7%)
58(59.2%)
0.396
/
/
Primary headache(yes)
4(12.9%)
23(23.5%)
0.209
/
/
Systemic hemodynamic
SBP
118.35 ± 10.81
117.32 ± 12.37
0.676
0.018
0.843
DBP
74.00 ± 9.22
75.18 ± 11.31
0.598
0.059
0.509
ΔBP
44.35 ± 6.47
42.13 ± 6.37
0.094
−0.137
0.122
MAP
88.78 ± 9.29
89.22 ± 11.28
0.843
0.061
0.490
HR
63.32 ± 11.35
64.42 ± 10.10
0.607
0.008
0.930
SpO2
98.35 ± 1.02
98.30 ± 1.10
0.793
0.038
0.670
LA
31.06 ± 1.55
30.87 ± 1.78
0.581
−0.062
0.484
LV
45.81 ± 2.14
46.71 ± 2.50
0.071
0.183
0.037*
RA
35.45 ± 1.98
35.78 ± 2.27
0.478
0.153
0.082
RV
35.29 ± 1.85
35.55 ± 2.13
0.542
0.109
0.217
PA
20.06 ± 1.46
20.30 ± 1.63
0.481
0.094
0.288
EF
62.90 ± 5.98
63.10 ± 5.34
0.865
0.002
0.978
SV
62.53 ± 16.31
66.55 ± 10.61
0.113
0.088
0.322
CO
3.79 ± 1.01
4.33 ± 0.93
0.007**
0.177
0.045*
Tricuspid regurgitation
0.50(1.00)
0.45(1.00)
0.372
−0.030
0.739
Cerebral hemodynamic
Left side MCA
Vm
59.61 ± 8.24
63.24 ± 10.92
0.091
0.060
0.501
Vs
93.48 ± 12.13
97.00 ± 15.21
0.246
0.062
0.488
Vd
40.93 ± 6.20
43.62 ± 8.37
0.102
0.058
0.513
PI
0.889 ± 0.154
0.852 ± 0.125
0.180
−0.004
0.960
RI
0.562 ± 0.051
0.550 ± 0.047
0.221
−0.015
0.862
Left side VA
Vm
30.94 ± 5.25
33.23 ± 4.97
0.029*
0.171
0.053
Vs
49.64 ± 7.11
50.82 ± 7.56
0.444
0.083
0.351
Vd
20.68 ± 4.17
22.26 ± 3.95
0.056
0.142
0.107
PI
0.957 ± 0.193
0.873 ± 0.169
0.022*
−0.150
0.090
RI
0.594 ± 0.075
0.561 ± 0.056
0.010*
−0.159
0.072
Right side MCA
Vm
54.29 ± 7.03
60.20 ± 10.37
0.004**
0.155
0.080
Vs
85.64 ± 10.46
92.11 ± 14.53
0.023*
0.125
0.157
Vd
37.19 ± 5.50
41.42 ± 7.60
0.005**
0.114
0.200
PI
0.888 ± 0.150
0.855 ± 0.146
0.276
−0.078
0.380
RI
0.574 ± 0.062
0.586 ± 0.053
0.592
−0.093
0.292
Right side VA
Vm
32.77 ± 5.30
34.84 ± 4.40
0.032
0.126
0.155
Vs
49.38 ± 6.88
51.03 ± 6.33
0.220
0.073
0.411
Vd
22.09 ± 4.29
23.64 ± 3.95
0.065
0.110
0.216
PI
0.849 ± 0.160
0.793 ± 0.156
0.086
−0.141
0.110
RI
0.555 ± 0.055
0.534 ± 0.061
0.081
−0.134
0.130
BA
Vm
37.55 ± 7.36
40.50 ± 7.80
0.065
0.154
0.082
Vs
66.29 ± 13.65
68.53 ± 13.87
0.433
0.054
0.546
Vd
23.48 ± 5.08
25.69 ± 5.97
0.066
0.139
0.115
PI
0.964 ± 0.210
0.885 ± 0.197
0.092
−0.104
0.239
RI
0.644 ± 0.055
0.621 ± .0714
0.108
−0.074
0.404
Asymmetry of bilateral VAs
ΔVs
2.0 (15.0)
0.0(9.25)
0.795
0.042
0.634
ΔVd
0.0(6.0)
−2.0 (6.0)
0.703
0.017
0.851
ΔVm
−2.0 (8.0)
−1.0 (7.0)
0.934
0.064
0.468
AI%
−0.061 (0.224)
−0.034(0.200)
0.815
0.075
0.398
Conduction
CVCi
0.648 ± 0.103
0.704 ± 0.145
0.048*
0.097
0.275
/:binary variables that were not analyzed by Spearman’s correlation
*p is 0.05 or less, **p is 0.01 or less
Univariate logistic regression revealed that CO, Vm in both VAs and velocities in right side MCA were risk factors for HAH. However, adjusted analyses showed that CO (adjusted by Vs and Vd of right side MCA, OR: 1.613, p = 0.036 or adjusted by Vm of right side MCA OR: 1.811, p = 0.024) and Vm in right MCA (OR: 1.066, p = 0.011) or left VA (OR: 1.099, p = 0.035) were still independent predictors for HAH (Table 6).
Table 6
Univariate and adjusted logistic regression for variables at baseline to predict HAH. (N = 129)
Predictors
β-coefficient
Odds ratio
(95% CI)
P value
Lower
Upper
Univariate logistic regression
CO
0.650
1.915
1.158
3.168
0.011*
Left side VA
Vm
0.095
1.099
1.008
1.198
0.031*
Right side MCA
Vm
0.071
1.073
1.021
1.127
0.005**
Vs
0.039
1.040
1.005
1.076
0.026*
Vd
0.087
1.091
1.024
1.161
0.007**
Right side VA
Vm
0.099
1.104
1.007
1.211
0.035*
Adjusted logistic regression
Model 1
Left VA
Vm
0.094
1.099
1.007
1.199
0.035*
CO
0.478
1.613
1.031
2.522
0.036*
Model 2
Right side MCA
Vm
0.064
1.066
1.015
1.121
0.011*
CO
0.594
1.811
1.080
3.036
0.024*
Model 1: Adjusted by primary variables (Vs and Vd of right side MCA)
Model 2: Adjusted by calculated variable (Vm of right side MCA)
Baseline CO was an independent predictor for HAH at 3700 m, whereas, Vm in left VA or right MCA was also independent predictors for HAH in different models
Only the variable with a significant statistically has been listed above
* p is 0.05 or less, ** p is 0.01 or less
Furthermore, in the subgroup analysis, the change in tricuspid regurgitation from sea level to 3700 m was significantly different between the HAH+ and HAH- groups. The alterations of ΔV in Vd and Vs of the VAs and the Vm and Vd of the BA were also significantly different between the HAH+ and HAH- groups (see Additional file 1: Table S1A).
Anzeige
Discussion
Alterations in both systemic and cerebral hemodynamics
In the current study, we identified alterations in both systemic and cerebral hemodynamics. The HR dramatically increased between sea level and high altitudes, which is consistent with a previous study that reported a significant increase in HR after exposure to high altitude because of the activation of the parasympathetic nervous system by hypobaric hypoxic stress [15, 4, 16]. However, the SV was similar at both altitudes, which indicates the increased CO was primarily caused by the increased HR [16]. Conversely, the hypoxia also induced a reduction in the SpO2, which may result in a decrease in the delivery of oxygen and energy to organs and tissues. Furthermore, the diastolic function of the heart has been reported to decrease in high altitude environments, which may be because of the shortened cardiac diastolic phase caused by the increased HR [17, 16].
Following acute hypoxic stress, parasympathetic nervous system activation, combined with a disequilibrium in the synthesis and expression of certain vasoconstrictors and vasodilators, results in endothelial cell dysfunction (e.g., increased endothelin-1 expression vs. decreased nitric oxide level) [18, 19]. Therefore, the vasoconstriction of systemic and cerebral arteries exhibits a significant impact on the measured velocities of blood flow [20]. We demonstrated that most velocities in both the anterior and posterior cerebral circulations significantly increased. These results are similar to previous studies in which cerebral blood flow increased dramatically after high altitude exposure [21‐23].
Associations between HAH occurrence and demographical data
As previously reported by our team and other researchers, HAH patients are typically older in age, which is consistent with the risk factors of primary headache at sea level and high altitude [8, 9]. Although a history of smoking and alcohol consumption did not exhibit associations with HAH, they were not precisely measured, which could be improved in future studies.
HAH is partially associated with systemic hemodynamics
HAH is a regional symptom that comprises the primary diagnostic criteria of acute mountain sickness, which is typically induced by a local and systematic factor [5, 24]. Therefore, systemic hemodynamics may be a cause of HAH because it functions to deliver blood to all organs, including the brain, which is an organ with considerably high metabolism and energy consumption. First, an increased HR exhibited a strongly positive correlation with HAH, which is consistent with the relationship between CO and HAH. The HAH patients were also characterized by increased HR and CO. Further analyses indicated that baseline CO and LV were correlated with HAH significantly. These results may be because of the nervous system changes that lead to alterations in systemic hemodynamics [19, 25, 16]. In addition, the SpO2 was inversely correlated with HAH; however, the SBP and DBP were not related to HAH, which was similar to previous studies [8, 15, 25]. A reduced SpO2 and increased HR are independent risk factors for HAH [8, 9]. These changes could result from sympathetic nervous system activation and a decreased partial pressure of oxygen, which results in a decrease in oxygen delivery to the brain, where oxygen consumption is increased during hypoxic stress [5, 9, 6]. The change in tricuspid regurgitation in HAH patients differed from the non-HAH subjects, which indicates alterations in cardiac function induced by hypoxia may be risk factors for HAH (see Additional file 1).
Anzeige
Cerebral hemodynamic characteristics of HAH
In the present study, we demonstrated that the velocities in both the BA and left VA in the posterior cerebral circulation were strongly associated with HAH, which is partly consistent with previous reports [26, 22, 27]. The HAH patients were characterized by an increased Vd but decreased RI and PI in the left VA. These findings imply that HAH is associated with higher blood flow but lower resistance and compliance. At the baseline, HAH+ patients were also featured with a higher Vm in VAs on both sides indicating that posterior circulation plays critical roles in HAH or it is a pathophysiological process of HAH. Furthermore, the HAH+ group also exhibited increased Vs and Vd in the BA, which supplies blood and oxygen to the cerebellum. These results are consistent with the clinical characteristics that HAH often presents (i.e., a pulsing headache), which may be caused by diastolic dysfunction in the arteries [5, 6]. The relationship between HAH and posterior, rather than anterior, cerebral circulation contributed to HAH occurrence.
Of note, velocities in right MCA at baseline in HAH+ group were differed significantly from those in HAH- group. In partial agreement with the results reported for acute mountain sickness, including HAH, we did not identify an association between HAH and anterior circulation as assessed by the velocities, PI and RI of the bilateral MCAs [28]. However, these results were inconsistent with the previously reported that acute mountain sickness related headache usually presents as frontal headache [5]. The inconsistence may be caused by the sample size in the subgroup of 129 participants.
Though the baseline conduction from systemic to cerebral blood flow, which was evaluated using the cerebrovascular conductance index, showed a significant difference between HAH+ and HAH- groups, it is not predictor for HAH. Furthermore, it was not associated with HAH at 3700 m, which indicates cerebral blood flow plays a primary role in HAH and has more critical importance than systemic hemodynamics.
Predictors and risk factors for HAH
After adjusted regression analyses at baseline, we identified that CO and Vm in left VA (or right MCA in different regressions) were independent predictors for HAH. However, the posterior and anterior circulations were not valuable in a same model.
Other adjusted analyses at 3700 m revealed that only HR (or CO) and ΔVd were independent risk factors for HAH, which is partly consistent with our and others’ previous studies. However, ΔVd was found to be a novel risk factor for HAH which may be caused by the hypoxia induced local expressions of vasoactive substances. Furthermore, the variation in VAs of Chinese Han in anatomy may also be a reason for our findings.
Relationship between HAH and VA asymmetry
We report a novel finding in that VA asymmetry was closely related to HAH. An asymmetry in the bilateral isonym VA exists under normal physiological conditions [21, 28, 29]. However, this physiological asymmetry could become a considerable or pathological irregularity because of its amplification by hypoxia-induced vasodilatation and an impaired auto-regulation of cerebral blood flow following acute high-altitude exposure [21].
Furthermore, HAH severity was closely associated with the VA asymmetry, which represents a characteristic that has not been previously reported. This finding may be associated with the region of blood flow and perfusion in the cortex and cerebellum. It may also be related to the clinical characteristics of the migraine pattern present in many HAH patients [5]. The variance between the isonym VAs may contribute to the development of HAH and requires further examination to identify its precise pathophysiological mechanisms.
HAH comprises multifactorial components [30, 12, 31, 14]. Therefore, the cerebral and systemic hemodynamic characteristics of HAH may be relevant to the disease development, as well as its pathophysiological processes and clinical manifestations.
Limitations
Our study was restricted to young Chinese men, which could potentially generate a bias regarding age or gender; thus, this issue should be addressed in future studies. Another limitation is that a key modulator of cerebral perfusion, partial pressure of carbon dioxide (PaCO2), was not measured in the present study. This modulator could be included in future mechanistic studies. Another limitation is that headache satisfied the diagnostic criteria of the International Classification of Headache Disorders basically. Although the descent was not performed immediately after the onset of the headache, cephalalgia almost resolved as time went on. Furthermore, the subjects were all newcomers from sea level, thus none of them with a history of HAH or acute mountain sickness history, which should be improved in future study.
Conclusions
HAH is characterized, in part, by increased systemic hemodynamics and posterior cerebral circulation as reflected by the velocities in the BA and left VA, as well as lower arterial resistance and compliance. Furthermore, baseline CO and Vm in left VA or right MCA at sea level are independent predictors for HAH, whilst bilateral VA asymmetry may contribute to the development of HAH at high-altitude.
Acknowledgements
This work was supported by the Ministry of Health of the P.R. China [Grant No. 201002012]. We would like to thank all individuals who participated in this study for their support. We are grateful to professor Xia Zhang, Mr. Can Chen, Mr. Bai-Da Xu and Miss Shuang-Fei Li for their helps. We also thank Mr. Ru-Fu Xu for his suggestions regarding the statistical analyses.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
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The authors declare that they have no competing interests.
Authors’ contributions
SZB and LH participated the design of this research. SZB also has drafted the manuscript and performed the statistical analysis. JJ, XHZ and JQ have reviewed and revised this manuscript critically for important intellectual content. JY, XHZ, JQ and SZB carried out the filling of case report form and the measurements of blood pressure, HR and SpO2. RSR and SYY carried out the echocardiography examinations. The transcranial Doppler examinations were performed by CFT and QNL. All authors read and approved the final manuscript.
Authors’ information
SZB, MD, Physician and instructor from Institute of Cardiovascular Diseases of PLA; Department of Cardiology, Xinqiao Hospital, Third Military Medical University. His research areas include cardiovascular diseases, acute mountain sickness and high altitude headache and he has published two articles in Journal of headache and pain and European journal of Applied Physiology [8, 28].
LH, PhD, MD, FACC; Professor and Director of Institute of Cardiovascular Diseases of PLA; Department of Cardiology, Xinqiao Hospital, Third Military Medical University. His interests focus on basic and clinical researches in cardiovascular diseases, acute mountain sickness and high altitude headache.
