Baseline Parameters at 490 m

Baseline characteristics at low altitude are depicted in Table 1. Compared to control subjects, HAPE-S subjects were older and showed a higher A velocity. Furthermore, E/E’ trended to be different between groups (Table 1). However, none of the participants exhibited Doppler echocardiographic criteria of diastolic dysfunction. When only those 10 HAPE-S subjects with comparable age (mean, 33 ± 2 years; p = 0.33 vs control subjects) were considered for the comparison of baseline parameters, A velocity (46 ± 9 cm/s, p = 0.31 vs control subjects) and E/E’ (8.7 ± 2.0 cm/s, p = 0.53 vs control subjects) were similar in both groups.

Response to Exercise at 490 m

During exercise, changes in heart rate, BP, and LVEF were similar between HAPE-S and control subjects (data not shown). Whereas resting RVPG values were similar, the gradient increased to significantly higher levels during exercise in HAPE-S compared to control subjects (p < 0.001; Fig 1, top left, A). In contrast, the decrease in E/A (p = 0.12; Fig 1, top right, B) and the increase in E’ (p = 0.96; Fig 1, bottom left, C) in response to exercise were similar in both groups. There was a small increase in the E/E’ ratio during exercise, with no difference between the two groups (p = 0.62; Fig 1, bottom right, D).

Assessment of Subjects at High Altitude Under Resting Conditions and During Exercise

At 4,559 m, heart rate significantly increased in control subjects and HAPE-S subjects receiving tadalafil or placebo but not in those subjects receiving dexamethasone (Table 2). BP and LVEF were not different between groups at both altitudes (Table 2). At high altitude, RVPG increased in all subjects; this increase was significantly less in treated HAPE-S and control subjects compared to HAPE-S subjects receiving placebo (p < 0.05; Fig 2, left, A). In contrast, changes in LV diastolic parameters from low to high altitude followed a different pattern. In control subjects, the E/A ratio decreased by 13 ± 20%. The decrease tended to be larger in placebo-treated HAPE-S subjects (23 ± 15%) and in the tadalafil group (23 ± 14%) but was significantly less in dexa-methasone-treated HAPE-S subjects (decrease, 4 ± 15%; p = 0.01 compared to all other subjects [placebo, tadalafil, and control]; Fig 2, center, B). Changes in pulmonary venous flow were small and limited to a slight, though significant increase in atrial reversal velocities (Table 3). Again, the pattern did not follow the changes in RVPG. Changes in RVPG from low to high altitude showed no correlation with changes in E/A ratio (Fig 2, right, C) or changes in atrial reversal (r2 = 0.06, p = 0.17). The observed changes in E/A were related to increases in A velocity. In contrast, exposure to 4,559 m had no significant effect on E and E’ (Table 3). A power calculation based on our data revealed that the study had a statistical power of 80% to detect a difference in E/E’ between low and high altitude of 1.75, which is a relatively small increment. Moreover, the statistical power of our findings to truly represent absence of a significant difference between groups was 92%.

Exercise at high altitude resulted in an additional increase in RVPG (p < 0.001 vs rest at high altitude).

Whereas the absolute values during exercise were significantly different between the groups, the increase in response to exercise was similar (placebo, 48 ± 13 to 66 ± 21 mm Hg; dexamethasone, 32 ± 9 to 48 ± 9 mm Hg; tadalafil, 38 ± 14 to 54 ± 13 mm Hg; control subjects, 33 ± 5 to 48 ± 10 mm Hg; p = 0.04, for difference in absolute values during exercise; p = 0.8, for difference in increase in response to exercise). This further increase to a level of significant pulmonary hypertension in the majority of the cases was accompanied by a small but not significant decrease in E/A (mean of all groups, 1.33 ± 0.33 to 1.22 ± 0.31; p = 0.08) with no differences between the groups. Similar to the response at low altitude, E/E’ slightly increased with exercise (9.1 ± 3.3 to 10.4 ± 2.7, p = 0.007). Again, no differences between the groups were seen. LVEF significantly increased with exercise (64 ± 7 to 73 ± 7%, p = 0.02). The response was similar among the study groups.

Fig-1

Figure 1. Doppler echocardiographic parameters recorded in HAPE-S and control subjects at rest and during exercise at low altitude. Note the significantly higher increase in RVPG levels in HAPE-S subjects compared to control subjects (top left, A) as opposed to the similar changes in E/A ratio (top right, B), E’ (bottom left, C), and E/E’ ratio (bottom right, D). For difference resting vs exercise in both groups, *p < 0.001 and §p < 0.01. For difference between groups in changes induced by exercise, fp = 0.001 HAPE-S vs control subjects, and jp = not significant, HAPE-S vs control subjects.

Fig2

Figure 2. Left, A: Resting RVPG calculated from the gradient across the tricuspid valve. Center, B: E/A ratio recorded at rest in the four different study groups at 490 m and 4,559 m. Changes in RVPG from low to high altitude did not correlate with E/A changes (right, C). For changes induced by high altitude, *p < 0.05 vs other groups, and fp = 0.01 vs other groups. Dexa = dexamethasone; Tadal = tadalafil; Д = changes from 490 to 4,559 m.

Table 1—Baseline Characteristics at Low Altitude in HAPE-S Subjects vs Control Subjects

Variables Control (n = 10) HAPE-S (n = 29) p Value
Age, yr 32 ± 3 43 ± 9 < 0.0001
Heart rate, beats/min 67 ± 10 60 ± 9 0.1
Systolic BP, mm Hg 124 ± 10 133 ± 13 0.06
Diastolic BP, mm Hg 80 ± 9 83 ± 9 0.29
LVEF, % 62 ± 3 63 ± 6 0.9
RVPG, mm Hg 18 ± 3 20 ± 5 0.22
E velocity, cm/s 71 ± 14 2
+ 1
5
7
0.35
A velocity, cm/s 42 ± 7 51 ± 11 0.02
E/A ratio 1.72 ± 0.42 1.52 ± 0.33 0.12
E’ medial, cm/s 9.0 ± 1.4 7.8 ± 2.1 0.1
E/E’ 8.1 ± 2.0 10.4 ± 3.5 0.052
IVRT, ms 83 ± 11 87 ± 1 0.44
Systolic PVF, cm/s 44 ± 8 49 ± 10 0.20
Diastolic PVF, cm/s 51 ± 11 50 ± 8 0.72
Atrial reversal, cm/s 24 ± 5 23 ± 5 0.70
Д A duration, ms 29 ± 18 36 ± 19 0.29

Table 2—Heart Rate, Systolic BP, and LVEF at Low and High Altitudes

Variables Placebo (n = 9) HAPE-S Dexamethasone (n = 10) Tadalafil
(n = 9)
Control (n = 10) p Value, Altitude p Value,
Between
HAPE-S
p Value, Placebo vs Control
Heart rate, beats/min
490 m 61 ± 8 59 ± 10 61 ± 13 67 ± 10
4,559 m 81 ± 11 56 ± 10 83 ± 13 78 ± 12 0.001 0.001 0.22
Systolic BP, mm Hg
490 m 132 ± 9 133 ± 13 136 ± 16 124 ± 10
4,559 m 137 ± 13 130 ± 9 128 ± 10 127 ± 10 0.78 0.05 0.31
LVEF, %
490 61 ± 5 60 ± 5 66 ± 5 62 ± 3
4,559 66 ± 6 64 ± 5 65 ± 5 63 ± 10 0.15 0.30 0.73

Table 3—Resting Diastolic Function Assessed by Doppler Echocardiography: Comparison Between Low and High Altitudes

Variables HAPE-S Control (n = 10) p Value, Altitude p Value, Between HAPE-S p Value, Placebo vs Control
I
Placebo (n = 9)
Dexamethasone (n = 10) Tadalafil (n = 9)
E velocity, cm/s
490 m 77 ± 12 73 ± 14 76 ± 13 71 ± 15
4,559 m 74 ± 22 78 ± 14 78 ± 13 72 ± 14 0.67 0.21 0.54
A velocity, cm/s
490 m 50 ± 12 49 ± 14 54 ± 9 41 ± 7
4,559 m 62 ± 22 55 ± 14 74 ± 9 50 ± 11 0.001 0.98 0.59
E/A ratio
490 m 1.6 ± 0.3 1.6 ± 0.4 1.4 ± 0.3 1.8 ± 0.4
4,559 m 1.2 ± 0.3 1.5 ± 0.2 1.1 ± 0.2 1.5 ± 0.4 0.001 0.05 0.49
E’ medial, cm/s
490 m 8.6 ± 2.8 8.2 ± 1.3 6.7 ± 1.6 9.0 ± 1.4
4,559 m 8.8 ± 1.3 8.5 ± 1.4 7.4 ± 2.5 9.0 ± 1.4 0.36 0.81 0.65
E/E’
490 m 10.2 ± 4.4 9.0 ± 1.6 12.6 ± 4.0 7.7 ± 1.7
4,559 m 8.3 ± 2.9 9.3 ± 2.2 12.2 ± 4.9 8.2 ± 2.3 0.55 0.33 0.31
Systolic PVF, cm/s
490 m 46 ± 6 51 ± 10 51 ± 13 44 ± 9
4,559 m 46 ± 13 52 ± 13 53 ± 13 52 ± 8 0.23 0.78 0.18
Diastolic PVF, cm/s
490 m 52 ± 6 52 ± 7 47 ± 11 53 ± 10
4,559 m 44 ± 7 59 ± 23 45 ± 13 45 ± 7 0.36 0.23 0.83
Atrial reversal, cm/s
490 m 23 ± 6 23 ± 4 23 ± 2 24 ± 5
4,559 m 27 ± 6 25 ± 3 29 ± 4 27 ± 7 0.001 0.86 0.67
A duration, ms
490 m 37 ± 16 29 ± 19 33 ± 19 29 ± 19
4,559 m 23 ± 29 24 ± 19 32 ± 23 20 ± 25 0.22 0.39 0.79
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