Echocardiographic Right Ventricular Outflow Track Notch Formation and the Incidence of Acute Mountain Sickness

Abstract

Yuan, Fangzhengyuan, Zhexue Qin, Chuan Liu, Shiyong Yu, Jie Yang, Jun Jin, Shizhu Bian, Xubin Gao, Jihang Zhang, Chen Zhang, Mingdong Hu, Jingbin Ke, Yuanqi Yang, Jingdu Tian, Chunyan He, Wenzhu Gu, Chun Li, Rongsheng Rao, and Lan Huang. Echocardiographic right ventricular outflow track notch formation and the incidence of acute mountain sickness. High Alt Med Biol. 22:263–273, 2021.

Background:

High-altitude exposure causes acute mountain sickness (AMS) and increases pulmonary arterial pressure (PAP). The notching of echocardiographic right ventricular outflow tract flow velocity envelope (right ventricular outflow tract [RVOT] notching), is related to increased PAP. We speculate that acute high-altitude exposure may trigger RVOT notching, which may be associated with AMS.

Methods:

All 130 subjects, ascended to 4,100 m from low altitude by bus within 7 days, underwent physiological and echocardiographic testing. The subjects with a total score of 3 or above and in the presence of a headache were diagnosed with AMS according to Lake Louise criteria.

Results:

After high-altitude exposure, the incidence of RVOT notching and AMS was 20% and 28.5%, respectively. The subjects with AMS had a higher incidence (37.8%) of RVOT notching than those without AMS (12.9%). Multivariate logistic regression analysis showed that RVOT notching was associated with systolic pulmonary artery pressure (SPAP) (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.05–1.17; p < 0.001) and the occurrence of AMS (OR, 5.48; 95% CI, 1.96–15.35; p = 0.001). Although linear regression analysis showed a weak correlation between SPAP and Lake Louise AMS score in the overall population (r = 0.20, p = 0.020), this correlation was more pronounced in the subpopulation with RVOT notching (r = 0.44, p = 0.023) and SPAP was not related to Lake Louise AMS score in the subpopulation without RVOT notching (r = 0.03, p = 0.698). Among AMS symptoms, the incidence of headache and fatigue were higher in subjects with RVOT notching than those in subjects without RVOT notching.

Conclusions:

We first observe that high-altitude exposure triggers RVOT notching formation, which is associated with AMS occurrence. Clinical Trials.gov ID: ChiCTR-RCS-12002232

Introduction

An increasing number of people ascend to high altitude for traveling, business, and other activities with the readily available transportation. However, sea-level residents without acclimatization are vulnerable to develop acute mountain sickness (AMS), and even life-threatening high-altitude illness, such as high-altitude pulmonary edema and high-altitude cerebral edema (Swenson and Bartsch, 2012; Bartsch and Swenson, 2013). Additionally, acute high-altitude exposure disturbed pulmonary hemodynamics, accompanied with the elevated pulmonary artery pressure (PAP) (Smith et al., 2009), which is associated with lower work capacity (Yang et al., 2015) and higher incidence of high-altitude pulmonary edema (Dehnert et al., 2005), but its association with AMS is still unclear.

AMS is evaluated by the severity of clinical symptoms, including headache, gastrointestinal symptoms, fatigue/weakness, and dizzy/lightheadedness (Roach et al., 2018). Naeije et al. and our studies demonstrated that borderline or high PAP limits work/exercise capacity, which might be associated with AMS symptom of fatigue (Naeije et al., 2010; Yang et al., 2015). According to a previous study, the subjects with high systolic pulmonary artery pressure (SPAP >40 mmHg) suffered from AMS, in contrast, the subjects with SPAP <40 mmHg were free of AMS upon high-altitude exposure (Tannheimer et al., 2012). Additionally, the association of higher cardiac natriuretic peptides with high SPAP and the presence of AMS indicated that high PAP was potentially linked with AMS occurrence (Mellor et al., 2014).

However, reducing PAP with pulmonary blood pressure-lowering medication decreased (dexamethasone and sitaxsentan) or unaffected (tadalafil) the Lake Louise AMS score compared with placebo (Maggiorini et al., 2006; Naeije et al., 2010). Thus, more factors were involved in the relationship between pulmonary hemodynamics and AMS other than just PAP.

The right ventricular outflow tract (RVOT) was usually measured to reflect pulmonary hemodynamics with transthoracic echocardiography (TTE). The RVOT systolic Doppler flow velocity envelope becomes notched with systolic flow deceleration corresponding to reflected waves from distal pulmonary vascular beds. The notching of the RVOT systolic Doppler flow velocity envelope (RVOT notching) strongly suggested elevated PAP and increased pulmonary vascular resistance (PVR) (Arkles et al., 2011). Interestingly, acute exposure to high altitude triggered hypoxic pulmonary vasoconstriction (HPV) and thus led to higher PVR and elevated PAP (Sommer et al., 2008; Huez et al., 2009). Therefore, it is very likely that RVOT notching might be present in subjects ascending to high altitude.

The RVOT notching is present in pulmonary hypertension (PH) with a high likelihood, ranging from 42.6% to 94.3% (Hardziyenka et al., 2007; Arkles et al., 2011; Kushwaha et al., 2016; Takahama et al., 2017). The prevalence of notch in PH is not consistent with the level of PAP, suggesting that the notched envelope might contain differentiated information about the interaction between the right ventricle and pulmonary circulation from PAP. Furthermore, the timing of notch occurrence in the RVOT envelope was related to the severity of pulmonary vascular diseases (Lopez-Candales and Edelman, 2012). Given the wealth of information contained in the RVOT notching, its association with AMS is worthy of investigation.

This study was to determine the changes in the RVOT systolic Doppler flow velocity envelope in subjects ascending rapidly from low altitude to high altitude and to establish the relationship between echocardiographic RVOT notching and AMS.

Methods

Study design and participants

This study was approved by the Clinical Research Ethics Board at the Army Medical University (Third Military Medical University) (No: 2012015) and performed according to the Declaration of Helsinki. All the participants signed written informed consent voluntarily before the study. The study was registered under the Chinese Clinical Trial Registration.

In this study, subjects were enrolled if they fulfilled the following criteria: Chinese young men (Han ethnic) who were born and lived at low altitude without high-altitude exposure history in the last 6 months, subjects in normal sinus rhythm and with normal baseline echocardiography at low altitude, and subjects not taking medication or receiving any intervention before ascending to a high altitude. Exclusion criteria included subjects with any of the following diseases, cerebrovascular diseases, cardiovascular diseases, respiratory diseases, or malignant tumors. All the subjects ascended to 4,100 m (Litang, Sichuan, China) from low altitude (400 m, Yanggongqiao, Chongqing, China) by bus with a stairs type within 7 days. Data collection was performed in June 2013 at low altitude and 5 ± 2 hours after arrival at 4,100 m. Each set of data consisted of oxygen saturation, systolic blood pressure, diastolic blood pressure, heart rate (HR), TTE, and the Lake Louise AMS score questionnaires.

Physiological parameter measurement

The oxygen saturation was measured using a pulse oximeter (NONIN-9550; Nonin Onyx) when the echocardiographic examination was performed. The value of oxygen saturation was recorded after it was stabilized. The systolic blood pressure and diastolic blood pressure were measured using a sphygmomanometer (HEM-6200; OMRON, China) with the subject sitting upright after a 5-minute rest period following the then latest guideline in 2013 (Mancia et al., 2013). The HR was recorded by synchronous electrocardiogram.

Lake Louise AMS scoring

Symptoms of acute high-altitude exposure were quantified according to the Lake Louise AMS scoring system (Roach et al., 2018). The Lake Louise AMS scoring system allocates a score of 0–3 (symptom not present to severe) for symptoms of AMS (headache, gastrointestinal symptoms, fatigue/weakness, dizzy/lightheadedness). The subjects with a total score of 3 or above and in the presence of a headache were diagnosed with AMS.

Echocardiographic examination

Subjects underwent a standard TTE in the left lateral decubitus position by two sophisticated ultrasonologists equipped with a 2.5 MHz adult transducer using CX50 ultrasound systems (Philips Ultrasound System, Andover, MA). Examinations were performed following the recommendations of the American Society of Echocardiography (Rudski et al., 2010; Mitchell et al., 2019). Images were stored for subsequent off-line data extraction using QLAB 10.5 (Philips Healthcare, Andover, MA) in a blinded, random fashion. Tricuspid regurgitation velocity (TRV) was recorded by continuous wave Doppler from multiple windows, and the highest velocity was then used to estimate SPAP using the modified Bernoulli equation SPAP = 4 × (TRV)² + 5 (Yock and Popp, 1984). Mean pulmonary artery pressure (mPAP) was calculated by the equation mPAP = 0.61 × SPAP +2 (Bossone et al., 2013). Left ventricular end-diastolic volume and end-systolic volume were obtained as previously described (Yang et al., 2015). Stroke volume (Stroke volume = left ventricular end-diastolic volume − left ventricular end-systolic volume), cardiac output (CO = Stroke volume × HR), and left ventricular ejection fraction (LVEF = Stroke volume/left ventricular end-diastolic volume × 100) were also calculated.

The pulsed-wave sample was positioned at the tips of the mitral or tricuspid valve leaflets to measure early diastolic peak transvalvular flow velocity (E) and late diastolic peak transvalvular flow velocity (A). Tissue Doppler-derived early diastolic peak annulus velocity (e′) and systolic peak annulus velocity (s′) were obtained in the apical four-chamber view on the lateral aspect of mitral or tricuspid annulus. Tricuspid tissue motion annular displacement (TMAD) was obtained from the apical four-chamber view using tissue tracking technique (Rudski et al., 2010). Three points, including the septal and lateral tricuspid annulus and RV apex were located to acquire tricuspid TMAD using QLAB software. TMAD measured at the lateral tricuspid annulus was recorded. The lateral tricuspid TMAD is an angle independent method to assess right ventricular systolic function and was proved to be strongly correlated with tricuspid annular plane systolic excursion (Rudski et al., 2010; Shen et al., 2018). Pulmonary capillary wedge pressure (PCWP) was calculated by equation PCWP = 1.9 + 1.24 × mitral E/e′ (Bossone et al., 2013). PVR was calculated as PVR = (mPAP − PCWP)/CO (Bossone et al., 2013). Fraction area change (FAC) was determined by tracing the RV endocardium to obtain the area in systole and diastole and calculated by equation percentage FAC = (end-diastolic area – end-systolic area)/end-diastolic area × 100.

Interrogation of the RVOT was performed by placing the pulsed Doppler sample volume ∼5–10 mm proximal to the pulmonic valve from the parasternal short-axis view. The investigators recorded images of three consecutive cardiac cycles of RVOT Doppler flow velocity envelopes from each subject. To investigate the presence of RVOT notching, all the three envelopes were visually checked for categorizing by the same reader in an off-line mode. The morphologies of the RVOT systolic flow Doppler profiles were categorized into three types: no notch (NN) with a parabolic or triangular Doppler envelope profile (1)]; mid systolic notch (MSN), a notched profile dividing the flow profile into two distinct peaks in the early or mid systolic period (2a)]; and late systolic notch (LSN), an inflection point without two distinct peaks in the late systolic period (2b)]. When the same pattern (MSN, LSN, or NN) was present in three consecutive envelopes, the corresponding type of RVOT notching was categorized accordingly. When different patterns were present in three consecutive envelopes, the worst type (MSN > LSN > NN, according to the pathological severity) of RVOT notching (Arkles et al., 2011) was recorded and categorized accordingly. RVOT systolic flow profiles were further categorized as notch (+) (MSN and LSN) and notch (−) (NN) (Fig. 1B) (Arkles et al., 2011).

FIG. 1.

Incidence of RVOT notching and AMS after high-altitude exposure (A) The incidence of RVOT notching in healthy subjects at low altitude was 0%. After high-altitude exposure, the incidences of RVOT notching and AMS were 20% and 28.5%, respectively. (B) Morphologies of different RVOT systolic Doppler flow velocity envelopes. (B1) Normal RVOT systolic Doppler flow velocity envelope in healthy subjects with a parabolic or triangular contour was categorized as NN. (B2) Notched RVOT systolic Doppler flow velocity envelopes were categorized as MSN and LSN: MSN (B2a), a notched profile dividing the flow profile into two distinct peaks in the early or mid systolic period; LSN (B2b), an inflection point without two distinct peaks in the late systolic period. RVOT systolic flow profiles were further categorized as notch (+) (MSN and LSN) and notch (−) (NN). AMS, acute mountain sickness; NN, no notch; LSN, late systolic notch; MSN, mid systolic notch; RVOT, right ventricular outflow tract.

To assess the intraobserver variability, the same reader measured the randomly selected variables of 20 subjects again 3 months later without information on hemodynamic data. To quantify interobserver variability, two independent readers, blinded to each other, measured the same variables of 20 randomly selected subjects (Supplementary Table S1). To determine the interobserver variability of RVOT notching, RVOT notching patterns of all the subjects were assessed by two independent readers. The interobserver agreement in grading RVOT notching is good (weighted κ = 0.92 [(95% confidence interval (CI), 0.85–0.99]).

Statistical analyses

Statistical analyses were performed using SPSS software (Version 22.0; IBM Corp., Armonk, NY). Categorical variables are presented as the number of subjects and percentages, whereas χ² tests or Fisher's exact tests were used to compare proportions between groups as appropriate. Continuous variables were checked for normal distribution using the Kolmogorov–Smirnov test and presented as the mean ± SD in the case of a normal distribution, or otherwise as a median and interquartile range. Variable comparisons between groups were performed using an independent samples t-test or the Mann–Whitney U-test, as appropriate. Univariate logistic regression analysis was used to identify variables associated with AMS or RVOT notching. Variables with p-values <0.1 were included in a multivariate logistic regression analysis. The correlation between Lake Louise AMS score and SPAP was determined using linear regression analysis. Power analysis for the logistic regression of AMS occurrence with RVOT notching occurrence at high altitude was performed using PASS software (Version 15.0; NCSS Corp.). p-Values <0.05 were considered statistically significant.

Results

Population characteristics and the incidence of RVOT notching and AMS

Overall, this study included 130 participants, which were all male with a median age of 20 years (95% CI, 19–22 years). The demographic parameters of the cohort are presented in Table 1. After all the participants had ascended to the highest altitude (Litang, 4,100 m), 37 participants (28.5%) were diagnosed with AMS by the Lake Louise AMS score questionnaire (Roach et al., 2018). None of the subjects developed into high-altitude cerebral edema or high-altitude pulmonary edema. At low altitude, no participants were observed in the notched envelope by RVOT spectral Doppler signal analyses, while at high altitude 26 participants (20%) met the criteria for RVOT notching (Fig. 1). Among them, LSN and MSN cases were 18 (13.8%) and 8 (6.2%), respectively. The population with RVOT notching showed no differences in age, height, weight, body mass index, or smoking status compared with those in the population without RVOT notching (Table 1). Demographics were also comparable between the AMS (−) and AMS (+) groups in age, height, weight, and body mass index, but the proportion of smokers in subjects with AMS was higher than that in subjects without AMS (Table 1).

Table 1.

Characteristics of the Population

Baseline characteristics	Overall population	Notch (−) (n = 104)	Notch (+) (n = 26)	AMS (−) (n = 93)	AMS (+) (n = 37)	p1-Value	p2-Value
Age, years	20.00 (19.0–22.0)	20.00 (19.0–22.0)	20.00 (19.0–22.5)	20.00 (19.0–22.0)	20.00 (19.0–22.0)	0.974	0.313
Height, mm	172.0 ± 4.2	172.1 ± 4.2	171.7 ± 4.5	172.1 ± 4.4	171.6 ± 3.8	0.665	0.548
Weight, kg	63.0 ± 6.5	62.6 ± 6.1	64.4 ± 7.8	63.2 ± 6.2	62.5 ± 7.1	0.202	0.574
BMI, kg/m²	21.3 ± 1.8	21.1 ± 1.7	21.8 ± 2.1	21.3 ± 1.7	21.2 ± 2.2	0.085	0.777
Smoking, n (%)	69 (53.1)	54 (51.9)	15 (57.7)	44 (47.3)	25 (67.6)	0.598	0.037

p1: comparison between notch (−) group and notch (+) group; p2: comparison between AMS (−) group and AMS (+) group.

AMS, acute mountain sickness; BMI, body mass index.

Physiological and cardiac parameter differences in populations with or without RVOT notching

At low altitude, no differences were observed in physiological and cardiac parameters between notch (−) and notch (+) groups (Table 2). At high altitude, physiological and left ventricular parameters showed no differences between notch (−) and notch (+) groups. However, the right ventricular parameters, including Tricuspid s′, TRV, SPAP, mPAP, and PVR, were higher in the notch (+) group than those in the notch (−) group (Table 2).

Table 2.

Physiology and Cardiac Parameter Differences in Populations With or Without Right Ventricular Outflow Tract Notching at High Altitude

Variables	Total (n = 130)			Notch (−) (n = 104)			Notch (+) (n = 26)			p1-Value	p2-Value
Variables	Low altitude	High altitude	p-Value	Low altitude	High altitude	p-Value	Low altitude	High altitude	p-Value	p1-Value	p2-Value
HR, beats/min	63.0 (59.0–69.0)	71.5 (62.8–79.3)	<0.001	62.5 (59.0–68.0)	72.0 (63.0–77.8)	<0.001	65.5 (59.3–74.3)	70.0 (61.3–83.0)	0.161	0.414	0.999
SpO₂, %	98.0 (97.0–98.0)	89.0 (88.0–91.0)	<0.001	98.0 (97.0–98.0)	89.0 (88.0–91.0)	<0.001	97.5 (96.0–98.0)	88.0 (86.0–91.0)	<0.001	0.755	0.104
SBP, mmHg	111.0 (106.0–119.0)	120.0 (112.5–128.5)	<0.001	111.0 (106.0–119.0)	120.0 (112.3–128.0)	<0.001	112.5 (104.3–124.0)	123.0 (113.5–134.0)	0.005	0.858	0.175
DBP, mmHg	67.2 ± 8.7	79.5 ± 9.9	<0.001	67.2 ± 8.6	79.3 ± 9.5	<0.001	67.4 ± 9.0	80.4 ± 11.5	<0.001	0.914	0.640
CO, l/min	3.9 (3.1–4.8)	4.0 (3.1–4.8)	0.693	3.9 (3.2–4.9)	3.9 (3.2–4.7)	0.947	3.5 (2.5–4.5)	4.0 (3.1–5.1)	0.328	0.102	0.778
LVEF, %	63.4 (54.5–68.5)	66.0 (59.8–70.1)	0.004	63.9 (55.2–68.8)	66.1 (60.6–71.6)	0.015	61.3 (53.9–67.0)	63.1 (53.8–68.7)	0.379	0.320	0.072
Mitral E/A	1.9 (1.6–2.3)	1.6 (1.4–2.0)	<0.001	1.9 (1.6–2.3)	1.6 (1.3–2.0)	<0.001	2.0 (1.6–2.2)	1.7 (1.5–2.0)	0.091	0.992	0.299
Mitral s′, cm/s	12.6 ± 3.3	13.7 ± 3.2	0.029	12.6 ± 3.3	13.8 ± 3.2	0.027	12.4 ± 3.6	13.4 ± 3.2	0.369	0.866	0.652
Mitral e′, cm/s	20.0 (17.1–21.8)	20.3 (17.7–23.5)	0.419	20.4 (17.3–21.8)	20.2 (17.6–23.3)	0.672	17.8 (14.9–21.4)	20.8 (17.2–23.7)	0.334	0.206	0.966
RV FAC, %	45.5 (42.2–48.3)	41.4 (37.8–43.8)	<0.001	45.8 (42.6–48.6)	41.7 (37.8–43.6)	<0.001	44.1 (41.8–45.9)	40.1 (37.6–45.4)	0.020	0.171	0.771
Tricuspid TMAD, mm	20.6 (19.4–22.3)	18.6 (17.2–20.5)	<0.001	20.5 (19.4–22.1)	18.6 (17.3–20.4)	<0.001	21.3 (18.9–23.8)	18.6 (17.1–22.0)	0.017	0.216	0.843
Tricuspid E/A	2.1 (1.7–2.4)	1.8 (1.4–2.2)	<0.001	2.0 (1.7–2.5)	1.8 (1.4–2.3)	0.002	2.1 (1.8–2.3)	1.7 (1.5–2.3)	0.118	0.853	0.940
Tricuspid s′, cm/s	13.9 ± 2.6	14.1 ± 2.8	0.654	13.9 ± 2.4	13.8 ± 2.8	0.816	13.7 ± 3.3	15.4 ± 2.5	0.044	0.705	0.012
Tricuspid e′, cm/s	16.2 (13.7–17.8)	15.5 (13.6–17.9)	0.207	16.2 (13.7–17.7)	15.5 (13.0–17.9)	0.304	15.9 (13.9–18.4)	15.8 (14.5–19.1)	0.999	0.523	0.226
TRV, cm/s	220.6 (202.7–233.7)	243.1 (224.0–279.4)	<0.001	221.8 (204.2–233.8)	238.8 (223.3–262.1)	<0.001	218.5 (198.3–231.8)	282.4 (233.1–306.7)	<0.001	0.565	0.002
SPAP, mmHg	23.8 ± 5.0	30.5 ± 8.3	<0.001	23.9 ± 5.1	29.1 ± 7.2	<0.001	23.4 ± 4.8	36.1 ± 9.8	<0.001	0.686	<0.001
mPAP, mmHg	16.5 ± 3.1	20.6 ± 5.0	<0.001	16.6 ± 3.1	19.8 ± 4.4	<0.001	16.3 ± 2.9	24.0 ± 6.0	<0.001	0.686	<0.001
PCWP, mmHg	8.1 (7.3–8.9)	6.9 (6.1–7.8)	<0.001	8.0 (7.2–8.8)	6.9 (6.0–7.8)	<0.001	8.7 (7.7–9.1)	6.7 (6.2–8.1)	0.014	0.243	0.476
PVR, WU	2.0 (1.6–3.0)	3.5 (2.3–4.6)	<0.001	2.2 (1.6–3.3)	3.3 (2.2–4.3)	<0.001	1.6 (1.5–1.9)	4.5 (3.4–6.1)	<0.001	0.066	0.006
PV_RVOT, cm/s	105.7 (100.6–119.2)	101.6 (94.7–110.8)	<0.001	106.9 (100.6–119.2)	101.3 (94.6–110.4)	<0.001	105.7 (100.5–121.4)	103.4 (94.6–119.5)	0.690	0.723	0.144

p1: comparison between notch (−) group and notch (+) group at low altitude; p2: comparison between notch (−) group and notch (+) group at high altitude.

A, late diastolic transmitral or transtricuspid flow velocity; CO, cardiac output; DBP, diastolic blood pressure; E, early diastolic transmitral or transtricuspid flow velocity; e′, mitral or tricuspid annulus early diastolic velocity; FAC, fraction area change; HR, heart rate; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PV_RVOT, peak velocity of RVOT outflow; RV, right ventricular; RVOT, right ventricular outflow tract; s′, mitral or tricuspid annulus systolic velocity; SBP, systolic blood pressure; SPAP, systolic pulmonary artery pressure; SpO₂, pulse oxygen saturation; TMAD, tissue motion annular displacements; TRV, tricuspid regurgitation velocity.

The association between cardiac parameters and RVOT notching occurrence

At low altitude, no physiological and cardiac parameters were found to be associated with RVOT notching occurrence (Supplementary Table S2). At high altitude, in the multivariate logistic regression analysis, the occurrence of RVOT notching was associated with SPAP (odds ratio [OR], 1.11; 95% CI, 1.05–1.17; p < 0.001) (Table 3).

Table 3.

Logistic Regression Analysis of the Correlated Parameters with Notch Occurrence at High Altitude

Variables	Univariate analysis		Multivariate analysis
Variables	p-Value	OR (95% CI)	p-Value	OR (95% CI)
Age	0.587	1.04 (0.90–1.20)	Not selected
BMI	0.088	1.23 (0.97–1.56)	—
Smoking	0.598	1.26 (0.53–3.01)	Not selected
HR	0.927	1.00 (0.96–1.03)	Not selected
SpO₂	0.208	0.90 (0.75–1.06)	Not selected
SBP	0.176	1.03 (0.99–1.07)	Not selected
DBP	0.637	1.01 (0.97–1.06)	Not selected
CO	0.634	0.92 (0.64–1.32)	Not selected
LVEF	0.074	0.96 (0.91–1.00)	—
Mitral E/A	0.279	1.61 (0.68–3.79)	Not selected
Mitral s′	0.648	0.97 (0.84–1.12)	Not selected
Mitral e′	0.965	1.00 (0.91–1.11)	Not selected
RV FAC	0.769	0.98 (0.87–1.11)	Not selected
Tricuspid TMAD	0.840	1.02 (0.84–1.23)	Not selected
Tricuspid E/A	0.957	0.98 (0.45–2.15)	Not selected
Tricuspid s′	0.015	1.23 (1.04–1.46)	—
Tricuspid e′	0.225	1.08 (0.95–1.23)	Not selected
SPAP	<0.001	1.11 (1.05–1.18)	<0.001	1.11 (1.05–1.17)
PCWP	0.519	1.10 (0.82–1.47)	Not selected
PV_RVOT	0.146	1.02 (0.99–1.06)	Not selected

Other abbreviations as in Tables 1 and 2.

CI, confidence interval; OR, odds ratio.

Differences in physiological parameters and cardiac functions between the AMS (−) and AMS (+) groups

The physiological profiles and cardiac function were compared between the AMS (−) and AMS (+) groups. At low altitude, the FAC in subjects without AMS was higher than that in subjects with AMS (Table 4). At high altitude, the incidence of RVOT notching and HR were significantly higher in the AMS (+) group than those in the AMS (−) group (Table 4).

Table 4.

Differences in Physiology Parameters and Cardiac Functions Between the AMS (−) and AMS (+) Groups at High Altitude

Variables	AMS (−) (n = 93)			AMS (+) (n = 37)			p1-Value	p2-Value
Variables	Low altitude	High altitude	p-Value	Low altitude	High altitude	p-Value	p1-Value	p2-Value
HR, beats/min	62.0 (59.0–68.0)	70.0 (61.0–77.5)	<0.001	65.0 (60.0–73.0)	75.0 (67.0–82.5)	0.002	0.375	0.020
SpO₂, %	98.0 (97.0–98.0)	89.0 (88.0–91.0)	<0.001	97.0 (96.0–98.0)	88.0 (87.0–91.0)	<0.001	0.083	0.373
SBP, mmHg	112.0 (107.0–119.8)	121.0 (113.0–129.0)	<0.001	111.0 (104.0–119.0)	120.0 (112.0–127.5)	<0.001	0.319	0.687
DBP, mmHg	67.6 ± 9.2	78.9 ± 10.0	<0.001	66.3 ± 7.4	81.1 ± 9.4	<0.001	0.447	0.242
CO, l/min	3.9 (3.1–4.9)	4.0 (3.1–4.6)	0.801	3.8 (2.9–4.6)	3.9 (3.1–5.0)	0.709	0.704	0.974
LVEF, %	63.5 (55.3–68.9)	66.1 (60.7–72.1)	0.021	62.5 (50.5–68.1)	65.4 (56.3–69.1)	0.201	0.421	0.213
Mitral E/A	1.9 (1.6–2.3)	1.6 (1.3–1.9)	<0.001	2.2 (1.6–2.6)	1.7 (1.4–2.2)	0.019	0.217	0.184
Mitral s′, cm/s	12.3 (9.7–15.1)	13.2 (11.3–15.2)	0.190	12.4 (10.5–13.8)	14.5 (12.1–16.3)	0.014	0.993	0.050
Mitral e′, cm/s	20.4 (16.9–21.9)	20.0 (17.3–23.6)	0.678	18.1 (17.4–21.6)	20.8 (17.8–22.8)	0.262	0.605	0.965
RV FAC, %	46.0 ± 3.8	41.1 ± 3.9	<0.001	43.6 ± 4.0	41.1 ± 4.1	0.023	0.005	0.961
Tricuspid TMAD, mm	20.6 (19.5–22.0)	18.7 (17.6–20.5)	<0.001	20.5 (18.6–23.0)	18.3 (17.0–20.6)	0.002	0.722	0.753
Tricuspid E/A	2.0 (1.6–2.4)	1.8 (1.5–2.4)	0.028	2.2 (1.8–2.7)	1.7 (1.4–2.2)	<0.001	0.120	0.384
Tricuspid s′, cm/s	13.9 ± 2.5	14.0 ± 2.8	0.869	13.9 ± 2.8	14.6 ± 2.8	0.240	0.940	0.220
Tricuspid e′, cm/s	15.8 (13.5–17.5)	15.3 (13.4–17.7)	0.523	17.3 (14.4–18.4)	15.8 (13.7–18.1)	0.474	0.086	0.186
TRV, cm/s	221.8 (201.8–234.4)	243.4 (223.0–267.6)	<0.001	218.5 (201.8–233.2)	242.8 (228.3–297.7)	<0.001	0.806	0.258
SPAP, mmHg	23.8 ± 5.2	29.9 ± 7.4	<0.001	24.0 ± 4.6	32.0 ± 10.1	0.001	0.861	0.190
mPAP, mmHg	16.5 ± 3.2	20.3 ± 4.5	<0.001	16.6 ± 2.8	21.5 ± 6.2	0.001	0.860	0.190
PCWP, mmHg	8.0 (7.2–8.9)	7.0 (6.1–7.9)	<0.001	8.4 (7.4–8.9)	6.7 (6.2–7.6)	0.002	0.909	0.761
PVR, WU	2.0 (1.5–3.2)	3.5 (2.2–4.6)	<0.001	2.2 (1.6–2.9)	3.4 (2.4–4.6)	0.004	0.996	0.801
RVOT notching, n (%)	0 (0)	12 (12.9)	<0.001	0 (0)	14 (37.8)	<0.001	—	0.001
PV_RVOT, cm/s	108.2 ± 14.0	103.0 ± 12.8	0.012	111.8 ± 13.9	104.4 ± 13.9	0.030	0.193	0.588

p1: comparison between AMS (−) group and AMS (+) group at low altitude; p2: comparison between AMS (−) group and AMS (+) group at high altitude.

Abbreviations as in Table 2.

Correlation between AMS and RVOT notching

At low altitude, in the multivariate logistic regression analysis, smoking (p = 0.037, OR = 2.88) and FAC (p = 0.007, OR = 0.83) were associated with AMS occurrence (Supplementary Table S3). At high altitude, the univariate logistic regression analyses between the physiological/cardiac parameters and the occurrence of AMS showed that smoking, HR, mitral s′, and RVOT notching occurrence might be related to AMS (p < 0.1). All the aforementioned parameters and the physiological parameters reported to be associated with AMS were selected into the multiple regression model. The multivariate logistic regression analysis showed that the occurrence of RVOT notching (p = 0.001, OR = 5.48) and HR (p = 0.007, OR = 1.05) were associated with AMS (Table 5). In the multivariate logistic regression model, logistic regression of RVOT notching with AMS occurrence achieves 96.1% power with the sample size of 130 subjects for an OR of 5.48 at a two-sided 0.05 significance level.

Table 5.

Logistic Regression Analysis of the Correlated Parameters with Acute Mountain Sickness Occurrence at High Altitude

Variables	Univariate analysis		Multivariate analysis
Variables	p-Value	OR (95% CI)	p-Value	OR (95% CI)
Age	0.256	0.92 (0.79–1.07)	—
BMI	0.775	0.97 (0.79–1.20)	—
Smoking	0.039	2.32 (1.04–5.16)	—
HR	0.010	1.04 (1.01–1.08)	0.007	1.05 (1.01–1.09)
SpO₂	0.370	0.93 (0.80–1.09)	—
SBP	0.684	0.99 (0.96–1.03)	Not selected
DBP	0.241	1.02 (0.98–1.07)	Not selected
CO	0.840	0.97 (0.71–1.33)	Not selected
LVEF	0.212	0.97 (0.93–1.02)	Not selected
Mitral E/A	0.151	1.79 (0.81–3.99)	Not selected
Mitral s′	0.053	1.13 (1.00–1.29)	—
Mitral e′	0.965	1.00 (0.92–1.09)	Not selected
RV FAC	0.961	1.00 (0.90–1.12)	Not selected
Tricuspid TMAD	0.749	0.97 (0.83–1.14)	Not selected
Tricuspid E/A	0.340	0.70 (0.34–1.46)	Not selected
Tricuspid s′	0.219	1.09 (0.95–1.26)	Not selected
Tricuspid e′	0.187	1.08 (0.96–1.21)	Not selected
SPAP	0.190	1.03 (0.99–1.08)	Not selected
RVOT notching	0.002	4.11 (1.67–10.10)	0.001	5.48 (1.96–15.35)
PCWP	0.783	0.96 (0.73–1.27)	Not selected
PV_RVOT	0.585	1.01 (0.98–1.04)	Not selected

Abbreviations as in Tables 1 and 2.

Correlation between Lake Louise AMS score and SPAP

In all subjects, the Lake Louise AMS score was positively correlated with SPAP (p = 0.020, r = 0.20) (Fig. 2). Furthermore, subgroup analyses showed that the association between SPAP and Lake Louise AMS score remained significant in the notch (+) subjects (p = 0.023, r = 0.44). However, SPAP in the notch (−) subgroup was not associated with Lake Louise AMS score (Fig. 2).

FIG. 2.

Correlation between Lake Louise AMS score and SPAP. (A) The SPAP in total subjects was related to Lake Louise AMS score (r = 0.20, p = 0.020). (B) The SPAP in subjects with RVOT notching was related to Lake Louise AMS score (r = 0.44, p = 0.023). The SPAP in subjects without RVOT notching was not related to Lake Louise AMS score. SPAP, systolic pulmonary artery pressure.

Comparison of AMS symptoms between notch (−) and notch (+) groups

The incidence of AMS and the median score were significantly higher in notch (+) subjects than those in the notch (−) subjects according to the Lake Louise AMS scoring system (Table 6). The association between RVOT notching and AMS might be attributed to the higher frequency of headache and fatigue in the notch (+) group (Table 6). No significant difference was observed in dizziness and gastrointestinal symptoms between the two groups (Table 6).

Table 6.

Comparison of Acute Mountain Sickness and its Related Symptoms Between Notched Envelope or Non-Notched Population at High Altitude

	Notch (−) (n = 104)	Notch (+) (n = 26)	p-Value
Lake Louise AMS score	1 (0–2)	3 (1–4)	<0.001
AMS patients	23 (22.1%)	14 (53.8%)	0.001
Headache	39 (37.5%)	19 (73.1%)	0.001
Dizziness	48 (46.2%)	16 (61.5%)	0.160
GI symptoms	7 (6.7%)	4 (15.4%)	0.306
Fatigue	47 (45.2%)	19 (73.1%)	0.011

Other abbreviation as in Table 1.

GI, gastrointestinal.

Discussion

This cohort with echocardiography measurements observed that rapidly ascending to high altitude would induce RVOT notching. The presence of RVOT notching is positively associated with SPAP and AMS. Subgroup analysis further revealed that SPAP in the notch (+) group is positively associated with the AMS score. Subjects in the notch (+) group had a higher likelihood of developing headaches and fatigue.

The RVOT flow velocity envelope was profiled as a parabolic or triangular contour in the normal population, and RVOT notching at the systolic period is frequently observed in PH patients. After decades of investigation, RVOT notching formation is considered a reflected wave propagating to the pulmonary valve before its closure. The occurrence of RVOT notching could be observed under certain clinical circumstances, such as pulmonary arterial hypertension, increased PVR, and poor vascular compliance (Arkles et al., 2011). However, not all pulmonary arterial hypertension patients experience RVOT notching. The absence of Doppler flow notching was highly associated with lower PVR with pulmonary venous hypertension in a PH-left heart disease cohort (Kushwaha et al., 2016). Furthermore, the timing of notch position and morphology of notch are associated with the severity of pulmonary vascular disease and worse clinical outcomes (Hardziyenka et al., 2007; Takahama et al., 2017). Moreover, the occurrence of RVOT notching is not proportionate to the degree of PH, and mild or moderate PH would also cause RVOT notching, as shown in our study.

PAP elevation is widely accepted as an early and inevitable consequence of ascent to high altitude. Resting SPAP increases to ∼35 mmHg (95% CI, 31–40 mmHg) at 4,559 m (Agostoni et al., 2010), and this study showed that 4,100 m high-altitude exposure induces the elevation of SPAP to 29 mmHg (95% CI, 25–36 mmHg). Consistently, we also revealed that the incidence of borderline PH (mPAP between 20 and 25 mmHg) was 29% for acute exposures at 3,700 m (Yang et al., 2015). The increase in PAP upon acute exposure to high altitude is attributed to HPV, rather than vascular remodeling. HPV was initiated seconds after hypoxia exposure and reached maximum vasoconstriction during the prolonged phase within several hours (Weissmann et al., 1995). Mechanistically, HPV participates in optimizing ventilation–perfusion matching during regional hypoxia in the lung (Kylhammar and Radegran, 2017). At high altitude, the magnitude of HPV significantly contributed to the severity of high-altitude PH (Will et al., 1975). Thus, RVOT notching occurrence at high altitude is associated with intensive HPV. Moreover, the contraction of the precapillary smooth muscle layer of the resistance vessels is at the distal position to the pulmonary valve (Hillier et al., 1997). This finding might further support that the majority of RVOT notching at high altitude was located in the late systolic period (18 in 26 cases). Importantly, compared with RVOT notching observed in chronic diseases, the HPV-induced RVOT notching might be temporary and reversible, without significant changes in RV function (Table 2).

RVOT notching is associated with increased PVR, PAP, and decreased pulmonary artery compliance. We extended the association to high altitude-induced pulmonary hemodynamics. We and others found that the SPAP, rather than RV function parameters, is independently associated with RVOT notching formation when including pulmonary circulation and RV function parameters in the multivariate logistic regression analysis (Lopez-Candales and Edelman, 2012). In this study, RV function in subjects with RVOT notching was not significantly lower than that in subjects without RVOT notching at high altitude, which might be attributed to the transient high-altitude exposure time. This indicated that the formation of RVOT notching is mainly attributed to high RV afterload and the lower RV function might be due to the impact of high RV afterload in a long term.

In the present study, not only did the notch group had a higher level of SPAP, but they also had a higher rate of AMS, including symptoms of headache and fatigue. Naeije et al. (2010) found that the selective endothelin A receptor antagonist sitaxsentan decreased PVR, SPAP, and Lake Louise AMS score by inhibiting pulmonary vasoconstriction. Consistent with this finding, although limited by small sample size, the subjects treated with sildenafil still showed a trend to decrease in Lake Louise AMS score on day 5 and day 6 after high-altitude exposure (p = 0.054) (Richalet et al., 2005). Similarly, in subjects taking dexamethasone, the decrease of SPAP was accompanied with the decrease of Lake Louise AMS score upon high-altitude exposure (Maggiorini et al., 2006). Diverse PAP-lowering strategies decreased Lake Louise AMS score, which indicated the key role of PAP in affecting AMS symptoms.

Although, a study in subjects receiving tadalafil upon high-altitude exposure also reported that with decreasing SPAP, tadalafil failed to decrease Lake Louise AMS score (Maggiorini et al., 2006). This might be due to the fact that headache is also the main side effect of taking tadalafil. This is in accordance with the observation that with the decreasing of SPAP, tadalafil did not decrease the headache score, however, the dexamethasone did (Maggiorini et al., 2006). Herein, we reasoned that the relationship between RVOT notching and AMS might be partially attributed to higher PVR and SPAP in subjects with RVOT notching. This finding is supported by a subgroup analysis showing that the SPAP in the notch (+) group was still correlated with the AMS score. Although the correlation is moderate (r = 0.44), the SPAP in subjects without RVOT notching is not correlated with AMS score, which indicated that high PAP was involved in the presence of AMS symptoms. This is consistent with the finding that higher cardiac natriuretic peptides were associated with high SPAP and the presence of AMS or severe AMS (Mellor et al., 2014).

Considering the AMS score evaluated by the severity of AMS symptoms, the higher AMS score and AMS occurrence were attributed to the higher incidence of fatigue and headache in the notch (+) group. Fatigue is a common symptom in patients with PH (Tartavoulle et al., 2018). Thus, the subjects in notch (+) groups with higher SPAP were more likely to experience fatigue at high altitudes. Naeije et al. confirmed high PAP limits exercise capacity at a high altitude (Faoro et al., 2009; Naeije et al., 2010). Additionally, our previous study found that PWC170 (predicted work capacity at a HR of 170 beats per minute) is negatively correlated with mPAP, indicating a lower work capacity in subjects with higher mPAP, which might be associated with fatigue upon high-altitude exposure (Yang et al., 2015). Consistent with our finding, the fatigue score in subjects receiving sildenafil with lower SPAP was slightly lower than that in the subjects receiving placebo with higher SPAP (Richalet et al., 2005). Headache is an indispensable symptom in AMS patients. In a previous study, the headache score in the subjects treated with dexamethasone with lower SPAP was found to be lower than that in the subjects treated with placebo with higher SPAP upon high-altitude exposure. The higher frequency of headache might be induced by higher levels of headache trigger factors, including thromboxane A2, histamine, serotonin, and arachidonic acid metabolites, which were associated with pulmonary vasoconstriction and contributed to a greater magnitude of HPV (Sanchez del Rio and Moskowitz, 1999; Kylhammar and Radegran, 2017).

The occurrence and profiles of RVOT notching at high altitude depict the hemodynamic changes in RVOT after acute hypobaric hypoxia exposure. This new finding fulfilled the comprehensive understanding of RVOT notching, which is widely accepted as a symbol of worse clinical outcomes. The positive correlation between RVOT notching and AMS indicated that cardiopulmonary hemodynamics is potentially linked with the presence of AMS upon high-altitude exposure. The RVOT notching profiles obtained from RVOT pulse Doppler images are helpful to comprehensively understand AMS occurrence. However, the mechanism underlying the RVOT notching and AMS still need further investigation.

Several limitations to this cohort analysis should be noted. The included subjects were all young Chinese men. The results might not apply to the whole population, especially for females. Observational studies have inherent limitations, including unexpected or unmeasured variables. A cardiac catheter was not used to measure the cardiac hemodynamics in subjects at a high altitude. However, echocardiography is noninvasive and convenient compared with the cardiac catheter test. To investigate the levels of circulation biomarkers in different subgroups [AMS (−) vs. AMS (+) or notch (−) vs. notch (+)] is helpful to interpret the mechanism underlines RVOT notching and AMS. In this study, we had not performed the examination of circulating biomarkers from blood samples, which needs to be investigated in the future. In addition, the RVOT notching presence is reportedly accompanied by worse clinical outcomes. Therefore, a longer follow-up to observe unfavorable endpoints is necessary.

Conclusion

To the best of our knowledge, we first observed an alteration of the RVOT profile characterized by notch formation upon high altitude, which is associated with the increased PAP. Moreover, the occurrence of RVOT notching is associated with the occurrence of AMS, which might be attributed to the higher frequency of headache and fatigue in subjects with RVOT notching. Our findings might provide a novel insight into the understanding of pulmonary hemodynamic changes upon high-altitude hypoxic exposure and the accompanying increased PAP underlying the association between RVOT notching and AMS incidence.

Footnotes

Authors' Contributions

L.H., F.Y., Z.Q., and C.L. contributed to the conception or design of the work. F.Y., J.K., Y.Y., J.T., C.H., W.G., C.L., and R.R. contributed to the acquisition of data for the work. C.Z., J.Y., and S.B. performed statistical analyses. Z.Q., C.L., S.Y., J.J., X.G., J.Z., and M.H. interpreted the results of statistical analyses. F.Y., Z.Q., and C.L. drafted the article. L.H., F.Y., Z.Q., and C.L. critically revised the article. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

L.H. confirms that all coauthors have reviewed and approved of the article before submission.

Ethics Approval

Acknowledgment

The authors thank all the participants in this study for their scientific contributions.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by grants from the National Natural Science Foundation of China (Grant No: 81730054); Military Logistics Research Project, PLA (Grant No: BLJ18J007); and the Special Health Research Project, Ministry of Health of PR China (Grant No: 201002012).

Supplementary Material

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