Retrospective cohort analysis of heart rate variability in patients with high altitude pulmonary hypertension in Tibet

Abstract Background Studies from both humans and animals experiments have offered abundant evidence supporting that mountain sickness is associated with changes in autonomic nervous function (ANF), which can be measured by heart rate variability (HRV). Hypothesis We aimed to assess changes of ANF in chronic mountain disease by measuring HRV in patients with high altitude pulmonary hypertension (HAPH). Methods From November 2018 to March 2019, 120 patients in the cardiac care unit of the People's Hospital of Tibet Autonomous Region were selected as the observation group, and 50 patients without organic heart disease served as the control group. Pulmonary artery systolic pressure was evaluated by echocardiography in patients with HAPH, divided into three groups: mild (30‐49 mm Hg), moderate (50‐69 mm Hg) and severity (≥70 mm Hg) groups. A 24‐hour dynamic electrocardiogram (DCG) was obtained for each patient. HRV (SDNN, SDANN, RMSSD, PNN50, and HRVTI for time domain; TP, VLF, LF, HF, and LF/HF for frequency domain) indexes were measured and compared. Results Compared with the control group, time domain parameters including SDNN, SDANN, RMSSD, PNN50, and HRVTI were reduced, as well as frequency domain indexes such as TP, VLF, LF, and HF. LF/HF was highest in mild HAPH group and lowest in the moderate HAPH group, and the difference between the two groups was statistically significant. Conclusions The HRV of patients with chronic HAPH in high altitude areas in Tibet is significantly reduced relative to healthy controls, and significantly negatively correlated with the severity of pulmonary artery hypertension.

(HAPH). 1 Studies by Wu Tian Yi et al showed that the prevalence of HAPH is higher in children than adults in Qinghai, China, and the difference is more obvious with the increase of altitude. 2 There are currently no relevant clinical studies focusing on autonomic changes in HAPH. Research is limited to changes in ANF in acute mountain sickness. In the development of HAPH, due to the low-oxygen hypobaric environment and pulmonary vascular remodeling, the right heart load is aggravated, affecting the sympathetic and vagus nerves that innervate the heart, and disrupting the balance of cardiac autonomic nervous system regulation. This leads to arrhythmia, cardiac disease, and sudden death. Therefore, it is imperative to explore ANF for chronic mountain disease, especially chronic HAPH.

| Ethics statement
The current survey was officially implemented after approval from the Medical Ethics Committee of the People's Hospital of Tibet Autonomous Region, China (approval number, ME-TBHP-36). All subjects or their families fully understood the purpose and methods of the study, and provided signed informed consent. There were no health interventions involving the subjects. All individual data were anonymous prior to analysis.

| HRV exam
Subject information was collected using a 12-lead 24-hour full information DCG system (Holter, Del Mar Reynolds Medical, Lifecard CF).
Sampling requirements were: starting point at 9-11 AM and rest for 15 minutes before inspection. The DCG was recorded and replayed on a computer, excluding ventricular/supraventricular premature or other arrhythmias. The 24-hour continuous DCG was recorded, and the ventricular/supraventricular premature contraction and interference were automatically eliminated by the software.

| HRV results
After adjustment for oxygen saturation (SaO 2 ), time domain indexes such as SDNN, SDANN, RMSSD, PNN50, and HRVTI progressively decreased from mild to severe groups of HAPH patients compared with control values, with statistically significant differences (P ≤ .001).
Similarly, after adjustment for SaO 2 , frequency domain indexes such as TP, VLF, LF, and HF progressively decreased from mild to severe groups of HAPH patients compared with control values, and the differences were statistically significant (P ≤ .001). In patients with mild pulmonary hypertension, the LF/HF ratio was slightly elevated compared with controls (P = .03). Meanwhile, this ratio was lowest in patients with moderate pulmonary arterial pressure followed by the severe diseased patients; both groups showed significantly lower LF/HF ratios compared with control values (P < .001). These data are detailed in Table 2.

| Correlation between HRV index and elevated pulmonary arterial pressure
The mean values of each group were consistent with normal distribu- Individuals living at high altitudes for a long time could have a series of physiological or pathological changes due to low pressure, low oxygen concentration, dry and cold weather, elevated solar radiation and ultraviolet radiation, which affect pulmonary artery pressure. At present, the important role of autonomic nervous regulation in its development is not clear.
HRV is currently the most widely used method for the evaluation of ANF. As a noninvasive quantitative indicator for judging cardiac autonomic nervous activity, HRV has been confirmed by many clinical trials. 5,6 It is used to evaluate a variety of cardiovascular diseases because of its noninvasive, simple, and reproducible characteristics. 7 More importantly, HRV is closely related to clinically meaningful outcome variables, such as heart events, morbidity, and mortality.
In the time domain of HRV, HRVTI represents the overall change of heart rate. SDNN and SDANN represent enhanced sympathetic activity. RMSSD and PNN50 represent weakened vagal activity, while RMSSD is more often used to evaluate vagal nerve function because of its good stability. The time domain analysis in this study was performed on a 24-hour time course, so assessment of long-term ANF in patients with HAPH is more accurate.
In this study, with the increase of pulmonary artery pressure, all time domain indexes of patients with HAPH were significantly reduced.
We observed a significant decrease in ANF in patients with chronic HAPH. HRV frequency domain analysis often uses short-term studies, so it is more suitable for short-term evaluation of ANF in patients with HAPH. The TP in the frequency domain represents the sum of high frequency, very low frequency, and ultralow frequency. LF was once used as a very important indicator of HRV to reflect the functional status of the sympathetic nerve. However, with further research, LF is no more considered an effective marker of autonomic nervous activity itself, because besides autonomic nervous system, it is also affected by baroreceptor activity. 8

| Limitations
We used noninvasive methods to assess pulmonary artery pressure and cardiac function in this study. These methods tend to underestimate the level of pulmonary arterial pressure, which is not as accurate as invasive measurement methods. 12 For ethical reasons, invasive measurement methods cannot be used in healthy individuals. Although the effects of drugs and other factors have been excluded, in addition to the effects of HAPH, the effect of hypoxia on HRV cannot be ruled out, and the complexity of the relationship between the two is often inconsistent. Due to the complexity of the relationship between hypoxia and HRV, inconsistent results are often found in the literature. [13][14][15][16] However, patients with chronic HAPH with an average duration of 5.00 (+0.65) years were selected in this study because they had achieved long-term adaptation to hypoxia. In general, hypoxia is considered to be effective in stimulating the sympathetic nervous system, resulting in a decrease in HRV variability (LF and HF components) and an increase in LF/HF ratios, which is inconsistent with the results of this study and fully demonstrates hypoxia in chronic altitude sickness. In this study, due to the limited sample size, we could not assess associations of HRV with hemoglobin levels and SaO 2 . Further validation studies are needed to verify these findings.

CONFLICT OF INTEREST
The authors have declared that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.