Travelers typically flock to high-altitude (HA) areas. However, hypobaric hypoxia at HA stresses the cardiopulmonary system (Parati et al., 2018). Due to HA-induced hypoxic pulmonary vasoconstriction (HPV), the pulmonary artery pressure (PAP) increases (Naeije, 2019), filling of the left ventricle and right ventricle decreases, and the left ventricular (LV)/right ventricular (RV) diastolic function is altered (Maufrais et al., 2017). In contrast, the LV/RV contractile function remains well-preserved (Osculati et al., 2016; Maufrais et al., 2019; Williams et al., 2019; Sareban et al., 2020). According to previous studies, mild pulmonary hypertension (PH) could decrease RV function, and the RV dysfunction progresses regardless of the treatment of lowering pulmonary vascular resistance (PVR) (van de Veerdonk et al., 2011; Huston et al., 2019).
Notching of the right ventricular outflow tract flow velocity Doppler envelope (RVOT notch) has been widely reported in patients with PH. The RVOT notch is caused by the reflected wave propagating to the pulmonary valve prior to the closure of the valve during a systole. The RVOT notch forms in the context of increased PAP and PVR, decreased pulmonary vascular compliance, and the presence of a reflecting site close enough to the pulmonary valve to allow for the velocity of the reflecting wave (Arkles et al., 2011; Ghimire et al., 2016).
The formation of the RVOT notch was mainly attributed to high PAP (Lopez-Candales and Edelman, 2012). As for patients with PH, it has been reported that the presence of an RVOT notch is associated with deteriorated RV function, such as reduced tricuspid annulus plane systolic excursion (TAPSE), RV fractional area change (FAC), peak systolic velocity of the tricuspid annulus (tricuspid s’), and the ratio of stroke volume index to RV end-diastolic area (Arkles et al., 2011; Lopez-Candales and Edelman, 2012). Even though PAP also increased in healthy subjects upon acute HA exposure, the amount of increase only ranged from mild to moderate. It is unclear whether this moderate increase of PAP induced by HPV led to RVOT notch formation. Additionally, since the RV function in healthy subjects upon acute HA exposure was reported to be well preserved; whether the presence of the RVOT notch in healthy subjects upon acute HA exposure is associated with deteriorated RV function is also unclear. Thus, the mechanism of RVOT notch formation and the relationship between RVOT notch and RV function at HA are worthy to investigate.
In a previous study, we had preliminarily reported that compared to the RVOT notch negative population, the correlation between PAP and intraventricular RV dyssynchrony was much greater in people with an RVOT notch. In this study, we tended to formally characterize the RVOT notch and comprehensively unravel the association between HA-induced RVOT notch and cardiac function.
Materials and Methods
Participants and Study Design
This study was approved by the Clinical Research Ethics Board of Army Medical University (Identification Code 201907501) and was registered at www.chictr.org.cn (ChiCTR-TRC-No.1900025728). In June 2019, we conducted this prospective cohort study on the Qinhai–Tibet Plateau. Han Chinese people who were born and permanently lived at a low altitude (≤500 m) were invited to participate in this study. A total of 111 participants were recruited at low altitudes (Chengdu, China, 500 m) to ascend to HA (Litang, China, 4100 m). Of all 111 subjects, five subjects withdrew from the study prior to ascending, and two subjects returned to low altitude because of severe HA illness. Ultimately, 104 subjects successfully ascended to 4100 m (Litang, China) by bus over a 2-day period. Due to the lack of suitable echocardiographic images in five subjects, the final analysis included 99 subjects. These subjects were healthy adults without HA exposure history in the past 6 months and had no recent medication use. Exclusion criteria included the presence of cardiopulmonary disease, cerebrovascular disease, liver disease, kidney disease, or malignant tumors. All physiological and transthoracic echocardiography examinations were performed 1 day prior to ascension at low altitude and 15 ± 3 h after arrived at HA. This study was conducted in accordance with the Declaration of Helsinki, and all subjects provided written informed consent.
Assessment of Physiological Parameters
Pulse oxygen saturation (SpO2) was recorded using a pulse oximeter (ONYX OR9500, Nonin, Plymouth, MN, United States). Blood pressure was measured with the subject in a sitting position using an electronic sphygmomanometer (Omron HEM-6200, Japan) after a 10-minute rest period. Heart rate (HR) data were recorded using the synchronous electrocardiogram during echocardiography. We measured height and weight with a height and weight scale (RGZ-120, I WISH, China) 1 day before ascension at a low altitude. The body mass index (BMI) was calculated as weight/(height)2.
Echocardiographic examinations were performed by two experienced sonographers equipped with a 2.5 MHz adult transducer using a CX50 ultrasound system (Philips Ultrasound System, Andover, MA, United States) with the subject in the left lateral decubitus position. The dynamic echocardiographic images, which consisted of three consecutive cardiac cycles, were stored digitally for offline analysis using QLAB 10.5 (Philips Healthcare, Andover, MA, United States) in a blinded fashion. All examinations and measurements were performed according to the recommendations of the American Society of Echocardiography (Rudski et al., 2010; Mitchell et al., 2019), and the value of each echocardiographic parameter was averaged from measurements of three consecutive cardiac cycles.
LV end-diastolic volume, LV end-systolic volume, RV basal transverse diameter (RVD base), and RVD mid were measured. RV end-diastolic and end-systolic areas were determined using the apical four-chamber view by manually tracing the RV endocardium. TAPSE was recorded as the peak excursion of the lateral tricuspid annulus, which was measured with M-mode echocardiography. The maximum tricuspid regurgitation velocity (TRV) was evaluated using continuous-wave Doppler. The LV and RV inflow were measured using the apical four-chamber view of pulsed-wave Doppler. The maximum early (E) and late (A) diastolic velocities were recorded. A pulse tissue Doppler was used to assess the velocities of the mitral and tricuspid annuli on the lateral and septal aspects in early diastole and systole. The peak early diastolic velocity of the annulus (e’), peak systolic velocity of the annulus (s’), and peak velocity of the isovolumic contraction period (ICV) were recorded as the average of the lateral and septal values. Stroke volume (SV), left ventricular ejection fraction (LVEF), and cardiac output (CO) were calculated using LV volume data and HR (Lang et al., 2015). RV FAC was calculated as follows: FAC = (end-diastolic area – end-systolic area)/end-diastolic area × 100. Systolic pulmonary artery pressure (SPAP) was calculated with the following modified Bernoulli equation: SPAP = 4 × (TRV)2+5 (Yock and Popp, 1984). The mean PAP (mPAP) was calculated as follows: mPAP = 0.61 × SPAP+2 (Bossone et al., 2013). Pulmonary capillary wedge pressure (PCWP) was calculated using the following equation: PCWP = 1.9+1.24 × mitral E/e’ (Bossone et al., 2013). PVR was derived according to the equation PVR = (mPAP-PCWP)/CO (Bossone et al., 2013).
To investigate the RVOT blood flow, the pulse Doppler sample volume probe was placed 0.5–1 cm proximally to the pulmonic valve in the parasternal short-axis view. The RVOT acceleration time (AT) and RVOT ejection time (ET) were measured. The shapes of the RVOT Doppler flow velocity envelope were categorized as notch (+) (in the presence of a notching pattern) and notch (−) (when no notching pattern was present), as previously described (Arkles et al., 2011). The specific notch relevant parameter mid-systolic flow deceleration time (mid-systolic DT) was measured (Takahama et al., 2017).
The LV global longitudinal strain (GLS) was defined as the mean of 17 segments that was calculated on the apical two-, three- and four-chamber images. The LV global circumferential strain (GCS) was defined as the average peak strain in each segment of the basal, mid-, and apical levels using parasternal short-axis images. The RV GLS was defined as the mean of six segments on the RV-focused four-chamber image.
To analyze LV/RV dyssynchrony, the time from the onset of the QRS complexes to the peak strain of each segment on ECG was calculated and correlated to the R-R interval according to Bazett’s formula: corrected interval = measured time to peak strain/(RR interval)1/2. The standard deviation (SD) of the correlated interval for the 12 mid-basal LV segments was termed the TS-12SD (Zoroufian et al., 2014), whereas the SD for the four mid-basal RV segments was termed the RV-SD4 (Badagliacca et al., 2015).
To determine the intraobserver variability, data from 10 subjects at a low altitude and 10 subjects at a HA were randomly selected and evaluated twice by the same observer with a 1-month interval between evaluations. Interobserver variability was determined by comparing the evaluations conducted by two separate observers blinded to each other. The intra- and interobserver variabilities for the echocardiographic variables are presented in Supplementary Table S1.
The 99 subjects consisted of 69 men and 30 women with a median age of 25 years and an average BMI of 22.2 kg/m2. No subject was found to have an RVOT notch at low altitude. Upon HA exposure, an RVOT notch was identified in 20 subjects (20.2%) (Figure 1). There were no significant differences in age, sex, or BMI between the notch (+) and notch (−) groups. Following HA exposure, subjects in all groups had increased systolic blood pressure, diastolic blood pressure, and HR. Both groups also had decreased SpO2 following HA exposure, with the notch (+) group experiencing a lower SpO2 level than the notch (−) group ( = 0.039) (Table 1 and Figure 2).
After HA exposure, SV and LV GLS decreased, GCS did not change, and the LVEF, CO, mitral ICV, and TS-12SD increased in all subjects. The mitral s’ in the notch (−) group increased upon HA exposure, but the mitral s’ in the notch (+) group did not change. Following HA exposure, the mitral E, mitral E/A, and mitral E/e’ decreased in all subjects. However, the mitral A increased in all subjects following HA exposure, with a higher value in the notch (+) group than in the notch (−) group. The mitral E/A at HA in the notch (+) group was lower than that in the notch (−) group (Table 2).
Pulmonary Hemodynamics and RV Function
Determinants of RVOT Notch
In multivariate logistic regression analysis, SPAP (OR, 1.14; 95% CI, 1.05 to 1.23; = 0.001), RV GLS (OR, 0.74; 95% CI, 0.60 to 0.93; = 0.011), and tricuspid E/A (OR, 0.13; 95% CI, 0.03 to 0.68; = 0.016) were found to be independently associated with RVOT notch (Supplementary Table S3).
Following rapid elevation gain, an RVOT notch was found in 20 (20.2%) healthy subjects. SpO2, RV deformation, the level of RV-PA coupling, and RV intraventricular synchrony were decreased in all subjects, while the RV afterload, biventricular s’, and ICV were increased in all subjects. However, the increase in the RV afterload and the decrease in SpO2, RV deformation, RV-PA coupling, and RV intraventricular synchrony were more pronounced in subjects with an RVOT notch. Moreover, the mitral s’, tricuspid s’, and tricuspid ICV in subjects with an RVOT notch did not increase upon HA exposure. These results suggest that HA exposure induced the RVOT notch formation, which may be related to impaired RV function.
Association of RVOT Notch, PAP, and SpO2 Upon HA Exposure
In previous studies, the RVOT notch was mainly observed in patients with chronic PH, especially in those with pulmonary vascular disease (Arkles et al., 2011; Takahama et al., 2017). Patients with low arterial compliance, high arterial resistance, and/or a pulmonary embolism proximal to the pulmonary valve may have a pulmonary vascular reflected wave on Doppler, which is seen as a notched Doppler flow velocity contour in the RVOT if the reflected wave rapidly propagates to the pulmonary valve prior to its closure (Torbicki et al., 1999; Arkles et al., 2011). In this study, we found that RVOT notch formation in subjects upon HA exposure is associated with higher SPAP, which is in accordance with the previous finding in PH patients (Lopez-Candales and Edelman, 2012). Upon HA exposure, alveolar hypoxia-induced HPV and inhomogeneous pulmonary vasoconstriction facilitated the ventilation–perfusion matching in the regional lung (Sommer et al., 2008). According to previous studies, SpO2 decreases and SPAP increases with rising altitude (Penaloza and Arias-Stella, 2007). Furthermore, in patients receiving bosentan for PH, SpO2 levels significantly increase with an increase in altitude (Modesti et al., 2006; Mellor et al., 2014). Thus, patients with lower SpO2 are more likely to experience HPV of greater magnitude as an attempt to maintain the ventilation–perfusion balance, which leads to higher SPAP and PVR. Although the presence of an RVOT notch in patients with PH indicates a high SPAP (Kubba et al., 2016), the uneven HPV at HA might induce a reflection site proximal to the pulmonary valve, which leads to the formation of an RVOT notch.
Similar to previous studies, our results indicated that LV filling is decreased and LV contractile function is preserved in subjects upon HA exposure (Maufrais et al., 2017, 2019). Although the LV filling is decreased, the HR is increased. The maintained LV function might due to the increase of sympathetic activation. According to a previous study, LV function is not related to RVOT notch formation due to the absence of an RVOT notch in left-heart-disease-associated PH (Kushwaha et al., 2016). However, hypoxia may affect LV function in notch (+) subjects with a lower SpO2. Thus, the increase of mitral s’ in the notch (+) group was blunted in this study. At HA, no difference in TS-12SD was found between the two groups in this study, indicating that upon HA exposure, the SpO2 has little effect on LV dyssynchrony.
Impact of RVOT Notch on RV Function Evaluated by Conventional Echocardiography
In our study, we found that the presence of an RVOT notch indicates impaired RV function in healthy subjects upon HA exposure, which is consistent with previous studies that reported advanced RV dysfunction in PH patients with RVOT notch (Arkles et al., 2011; Lopez-Candales and Edelman, 2012). Previous reports of the changes in RV FAC and TAPSE vary from a decrease (Kurdziel et al., 2017; Netzer et al., 2017), to no change (Maufrais et al., 2017, 2019), and to an increase upon HA exposure (Sareban et al., 2020). These inconsistent results may be due to different exposure times and ascending altitudes, or states of dehydration, all of which have been associated with RV adaptation upon HA exposure. In the present study, we found that the TAPSE and RV FAC decreased upon HA exposure. Although RV contractility may increase in response to the acutely increased RV afterload to maintain the pump function and RV-PA coupling (Naeije et al., 2014), the appropriately increased RV contractility upon HA exposure that is mirrored by load-dependent RV FAC and TAPSE may be under detected due to hypovolemia-induced RV FAC and TAPSE reduction via the Frank-Starling mechanism in patients with moderately increased PAP (Rudski et al., 2010; Najafian et al., 2015; Stembridge et al., 2016; Zhao et al., 2019).
TAPSE/SPAP is noninvasively measured for the evaluation of RV-PA coupling and correlates well with the gold standard multi-beat end-systolic/arterial elastance ratio in patients with PH (Tello et al., 2019; Richter et al., 2020). In this study, the decrease of TAPSE/SPAP in all subjects indicates that the level of RV-PA coupling was decreased in healthy subjects upon HA exposure. The more significant decrease of TAPSE/SPAP in the notch (+) group was attributed to the higher SPAP. The comparable TAPSE between notch (−) and notch (+) groups suggests that the RV contractility in the notch (+) group is maladaptive to the higher RV afterload upon HA exposure. TAPSE/SPAP has been reported to be positively correlated with VO2 peak and workload during cardiopulmonary exercise testing (Martens et al., 2018; Tello et al., 2018). Thus, although TAPSE/SPAP was maintained within a normal range, lower TAPSE/SPAP in the notch (+) subjects upon HA exposure may indicate lower work capacity.
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Impact of RVOT Notch on RV Function Evaluated by TDI
Upon HA exposure, the load-independent tricuspid s’ and ICV increased in the context of increased PAP (Abali et al., 2005; Rudski et al., 2010; Negishi et al., 2017), which indicates an increased RV inotropic function in response to the elevated RV afterload (Vonk Noordegraaf et al., 2017). This enhancement of myocardial contractility may be attributed to homeometric autoregulation or sympathetic activation (Rex et al., 2007, 2008). The association of RV contractility with sympathetic activation upon HA exposure is supported by a previous report, which suggests that the tricuspid s’ is correlated with HR (Sareban et al., 2020). However, in the notch (+) group, the tricuspid s’ and ICV did not increase to match the increased RV afterload, leading to a blunted RV contractile response upon HA exposure. This may be due to the fact that the positive inotropic effect of homeometric autoregulation or sympathetic activation was overwhelmed by the negative inotropic effect of hypoxia in notch (+) subjects with lower SpO2 (Silverman et al., 1997).
Impact of RVOT Notch on RV Function Evaluated by 2D-STE
Impact of Mid-Systolic DT on Cardiac Function
Several limitations in this study should be noted. For ethical reasons, cardiac catheterization, the gold standard for the measurement of cardiac hemodynamics, was not performed in this study. As 30 females (30.3% of total subjects) were included in this study and the menstrual cycle in female participants may affect heart physiology, menstrual cycle information should be collected, and its association with RVOT notch needs to be investigated. Acute mountain sickness was reported to be associated with reduced LV function, whereas, as this study mainly focused on the association of RVOT notch with RV function, acute mountain sickness cases were not excluded. As the subjects in this study returned to low altitude within two months, the long-term association of an RVOT notch with RV function was not studied. It is not clear whether the subjects with RVOT notch are more likely to develop HA heart disease. Furthermore, the cardiopulmonary exercise test to investigate RV contractile reserves in subjects with an RVOT notch should be performed in future studies as the RV function in these subjects is maladapted to HA exposure. It would be valuable to see whether the RVOT notch would reverse to normal after notch (+) subjects returned to sea level and whether a lower exercise capacity could be observed in the notch (+) subjects at sea level via cardiopulmonary exercise test.
Our study revealed that HA exposure-induced RVOT notch formation may be attributed to high PAP and low SpO2. The presence of an RVOT notch upon HA exposure was associated with impaired RV function as the tricuspid ICV and s’ did not increase, the RV deformation reduced, the RV-PA coupling deteriorated, and RV intraventricular dyssynchrony was observed. Therefore, an RVOT notch may be a potential echocardiographic sign representing impaired RV function at HA. However, whether the impaired RV function in subjects with RVOT notch upon HA exposure persists or is transient still needs further investigation.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by the Clinical Research Ethics Board of Army Medical University. The patients/participants provided their written informed consent to participate in this study.
LH, FY, and CL contributed to the conception or design of the work. FY, CL, JK, YY, CH, CZ, RR, ZL, and JuY conducted the experiments. FY and CL performed the statistical analyses and drafted the manuscript. SY, SB, JiY, XD, JZ, and HT interpreted the results of the statistical analyses. LH critically revised the manuscript. All authors approved of the final version of the manuscript and agreed to be accountable for all aspects of the work.
This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81730054); Military Logistics Research Project, PLA (Grant No. BLJ18J007); the Special Health Research Project, Ministry of Health of the P.R. China (Grant No. 201002012); and the PLA Youth Training Project for Medical Science (Grant No. 15QNP062).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank all participants in this study for their contributions to medical science.
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphys.2021.639761/full#supplementary-material