Association between hemoglobin concentration and hypertension risk in native Tibetans at high altitude

Abstract

Previous studies examining the association between hemoglobin concentration and hypertension have yielded inconsistent results. There is still a lack of evidence regarding the association between hemoglobin concentration and hypertension risk in native Tibetans at high altitude. We performed this cross‐sectional study in Luhuo County of Ganzi Tibetan Autonomous Prefecture (average altitude of 3500 m). In this study, we enrolled 1547 native Tibetans. The association between hemoglobin concentration and hypertension risk was examined by multivariate binary logistic regression and smooth curve fitting. Native Tibetans with hypertension had significantly higher hemoglobin concentrations than those without hypertension (165.9 ± 21.5 g/L vs. 157.7 ± 19.2 g/L, P < 0.001). An increase in hemoglobin concentration of 1 g/L was associated with hypertension (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01–1.02) after confounder adjustment. The highest hemoglobin concentration group (exceeding 173 g/L) was associated with an increased hypertension risk compared with the bottom quartile of hemoglobin concentration (OR 2.39, 95% CI 1.48–3.85). Hemoglobin concentration (per 1 g/L change) exceeding 176 g/L was significantly associated with an increased hypertension risk (OR 1.04, 95% CI 1.03–1.06). Additionally, high‐altitude polycythemia significantly increased the hypertension risk compared with a normal hemoglobin concentration (OR 2.92, 95% CI 1.25–6.86). A similar result was observed for mild polycythemia (OR 1.74, 95% CI 1.29–2.34). In conclusion, hemoglobin concentration was associated with hypertension risk in native Tibetans. When the hemoglobin concentration exceeded a certain value (approximately 176 g/L), the risk of hypertension was significantly increased.

1. INTRODUCTION

Hypertension is one of the most important modifiable risk factors for cardiovascular disease (CVD), ¹ and it significantly increases the risk of stroke, ischemic heart disease, CVD‐related mortality, and all‐cause mortality. ² Hypertension is a highly heterogeneous disorder with a multifactorial etiology. ³ The development of hypertension is influenced by genetic, racial, and environmental factors, including high altitude. ⁴ It is estimated that 140 million people permanently live in high‐altitude regions of >2500 m, including the Andean Altiplano, Ethiopian Highlands, and Himalayan Plateau. ⁵ These highlanders are chronically exposed to a hypobaric and hypoxic environment, which has important effects on systemic blood pressure (BP) regulation. ⁴ Epidemiological data have shown that hypertension is prevalent among permanent highlanders, especially Tibetans. ⁶ , ⁷ , ⁸ However, our understanding of the factors leading to hypertension at high altitude is limited. Therefore, identifying the potential risk factors for hypertension at high altitude can help us to understand the physiological mechanisms associated with BP regulation at high altitude and improve hypertension management.

The high prevalence of hypertension at high altitude may be linked to the hypobaric and hypoxic environment. ⁴ Environmental hypoxia leads to hypoxemia and tissue hypoxia for some highlanders. ⁹ Hemoglobin can be considered a surrogate marker of hypoxia, ¹⁰ , ¹¹ and it is the most important determinant of blood viscosity. ¹² Therefore, high hemoglobin concentrations may be a potential risk factor for hypertension. According to some studies conducted among the general population lived in the plain, hemoglobin concentration is elevated in humans with hypertension and promotes hypertension development. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ However, other studies have yielded different results, suggesting that no association exists between them. ¹⁷ , ¹⁸ Importantly, studies on the association between hemoglobin concentration and the risk of hypertension at high altitude are scarce, ¹⁹ , ²⁰ and no studies have examined the relationship between hypertension and hemoglobin concentration in native Tibetans at high altitude. Thus, the purpose of this study is to investigate whether the hemoglobin concentration is associated with hypertension in native Tibetans and what degree of hemoglobin elevation increases hypertension risk.

2. METHODS

2.1. Study subjects

We performed this cross‐sectional study in Luhuo County of Ganzi Tibetan Autonomous Prefecture (average altitude of 3500 m) to investigate the association between the risk of hypertension and hemoglobin concentration in native Tibetans. A multistage, stratified, and random cluster sampling survey was conducted. The number of villages was listed and selected using a random number table. All eligible participants aged ≥18 years were enrolled. A total of 1781 participants were recruited from different villages from 2019 to 2022. We excluded subjects with CVD, cerebrovascular disease, chronic obstructive pulmonary disease, anemia, and severe hepatic or renal dysfunction, as well as those with missing hemoglobin data. We ultimately enrolled 1547 native Tibetans in the analysis. This research was approved by the Ethics Committee of West China Hospital, Sichuan University (Chengdu, China). All participants provided written informed consent.

2.2. Data collection

Data were collected by investigators during face‐to‐face interviews using a standardized questionnaire. Peripheral capillary oxygen saturation (SpO₂) was measured by pulse oximetry, and SpO₂ readings were recorded when a stable reading was displayed on the digital display. BP was measured using a standardized automatic electronic sphygmomanometer (Omron HEM‐770A) between 8:00 am and 12:00 am. The right arm of the participant was selected for BP measurement. Before measurement, the participants were required to be in a sitting position at rest for at least 5 min. Readings were taken three times at 2‐min intervals. The mean of the three systolic BP (SBP) and diastolic BP (DBP) readings was used for the analysis. Weight and height were measured to the nearest 0.1 kg and 1 cm, respectively. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters.

2.3. Laboratory measurements

Blood samples were obtained in the morning after at least 8 h of overnight fasting. Biochemical parameters, including hemoglobin, total cholesterol (TC), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), creatinine (Cr), and fasting blood glucose (FBG), were measured in the laboratory at West China Hospital (Chengdu, China).

2.4. Definitions

Hypertension was defined as an SBP ≥140 mmHg and/or a DBP ≥90 mmHg, or current treatment with antihypertensive medications according to 2018 European Society of Cardiology/European Society of Hypertension guidelines for the management of arterial hypertension. ²¹ Current smoker was defined as smoking at least one cigarette per day during the last year. ²² Current drinker was defined as drinking alcohol at least 12 times during the last year. ²³ A hemoglobin concentration ≥210 g/L in males and ≥190 g/L in females was diagnosed as high‐altitude polycythemia according to the Qinghai standard of chronic mountain sickness. ²⁴ Mild polycythemia was defined as 210 g/L > hemoglobin ≥180 g/L in men and 190 g/L > hemoglobin ≥160 g/L in women. ²⁵ , ²⁶ , ²⁷ Anemia was defined as a hemoglobin concentration < 120 g/L in men and < 110 g/L in women. ²⁸

2.5. Statistical analysis

Continuous variables are reported as the mean ± standard deviation or median (interquartile range). Categorical variables are expressed as percentages. The baseline data were evaluated using the Student's t‐test, Mann–Whitney U test, or χ2 test depending on the data distribution. Binary logistic regression was performed to assess the association between hemoglobin concentration (as a continuous variable) and hypertension. Variables for adjustment were selected from the univariate analysis when their probability values were < 0.1. The association between hemoglobin concentration (as a categorical variable) and hypertension was determined by multivariate logistic regression. Model 1 was not adjusted; Model 2 was adjusted for age, sex, and BMI; and Model 3 was adjusted for current smoker, current drinker, FBG, TG, LDL‐C, estimated glomerular filtration rate (eGFR), and heart rate (HR), as well as those factors adjusted for in Model 2. Additionally, we explored the relationship between hemoglobin concentration and hypertension by smooth curve fitting. Two‐piecewise logistic regression models were also used to examine the threshold effects according to the smooth curve fitting. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to present the risk of hypertension. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, US) and EmpowerStats software (www.empowerstats.com, X&Y Solutions Inc., Boston, MA, US).

3. RESULTS

3.1. Baseline characteristics

A total of 1547 eligible native Tibetans were enrolled in this study. Overall, the mean age of the population was 47.3 years, and 49.3% of the participants were male. According to their BP measurements and medical history, the population was divided into the hypertension group (n = 628, 40.59%) and the non‐hypertension group (n = 919, 59.41%). A comparison of the baseline characteristics is summarized in Table 1. The subjects with hypertension were more likely to be older; had a higher proportion of males and current drinkers; had a lower proportion of current smokers; had higher BMI, hematocrit, FBG, TG, TC, LDL‐C, Cr, SBP, DBP, and HR values; and had a lower eGFR. The subjects with hypertension had a higher hemoglobin concentration than those without hypertension (165.9 ± 21.5 g/L vs. 157.7 ± 19.2 g/L, P < 0.001), as shown in Table 1.

TABLE 1.

Baseline characteristics.

	Total	Hypertension	Non‐hypertension
Variable	(n = 1547)	(n = 628)	(n = 919)	P value
Age (year)	47.3 ± 16.7	57.8 ± 13.2	40.1 ± 15.1	<0.001
Male(%)	49.30	52.1	47.3	0.067
Current smoker(%)	14.70	11.6	16.8	0.008
Current drinker(%)	8.70	11.9	6.4	<0.001
Height(cm)	163.8 ± 9.1	162.5 ± 9.5	164.7 ± 8.7	<0.001
Weight(kg)	68.9 ± 13.3	72.3 ± 14.0	66.6 ± 12.3	<0.001
BMI (kg/m2)	25.6 ± 4.5	27.7 ± 4.5	24.5 ± 4.1	<0.001
Hb (g/L)	161.1 ± 20.6	165.9 ± 21.5	157.7 ± 19.2	<0.001
HCT(%)	48.3 ± 6.2	49.3 ± 6.7	47.7 ± 5.7	<0.001
SpO2(%)	90.9 ± 3.3	90.8 ± 3.3	90.9 ± 3.2	0.288
FBG (mmol/L)	4.31(3.76–4.93)	4.69(4.13–5.44)	4.06(3.62–4.56)	<0.001
TG (mmol/L)	1.10(0.77–1.61)	1.37(1.01–1.95)	0.93(0.65–1.34)	<0.001
TC (mmol/L)	5.21 ± 1.15	5.68 ± 1.09	4.89 ± 1.07	<0.001
LDL‐C (mmol/L)	3.07 ± 0.92	3.38 ± 0.91	2.86 ± 0.86	<0.001
HDL‐C (mmol/L)	1.46 ± 0.35	1.45 ± 0.36	1.46 ± 0.33	0.396
Crea (μmoI/L)	73.5 ± 16.1	76.4 ± 15.6	71.6 ± 16.1	<0.001
eGFR(ml/min/1.73 m2)	97.1 ± 18.1	87.4 ± 16.2	103.8 ± 16.2	<0.001
SBP(mmHg)	128.4 ± 23.3	148.6 ± 20.8	114.6 ± 12.1	<0.001
DBP(mmHg)	81.0 ± 13.4	91.3 ± 12.6	73.9 ± 8.3	<0.001
HR (bpm)	75.4 ± 12.7	77.7 ± 13.4	73.9 ± 11.9	<0.001

Abbreviations: BMI, body mass index; Crea, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate ; FBG, fasting blood glucose; Hb, hemoglobin; HCT, hematocrit; HDL‐C, high density lipoprotein cholesterol; HR, heart rate.; LDL‐C, low density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.

3.2. Risk factors for hypertension

To elucidate whether the hemoglobin concentration was associated with hypertension in native Tibetans, we performed the binary logistic regression analysis. Variables with P values < 0.1 in Table 1 were selected as potential covariates, and collinearity among the variables was considered before the analysis. We eventually included 10 variables in the multivariate logistic regression model, including age, male sex, current smoking status, current alcohol consumption status, BMI, hemoglobin, FBG, TG, LDL‐C, eGFR, and HR. After adjusting for potential confounders, multivariate logistic regression revealed that age (OR 1.06, 95% CI 1.05−1.08), BMI (OR 1.10, 95% CI 1.07−1.14), current drinking (OR 1.68, 95% CI 1.04−2.70), hemoglobin (OR 1.02, 95% CI 1.01−1.02), FBG (OR 1.13, 95% CI 1.02−1.21), and HR (OR 1.02, 95% CI 1.01−1.03) were independent risk factors for hypertension (Table 2).

TABLE 2.

Odds ratio estimating the effect of risk factors on hypertension.

Variable	OR	95% CI	P value
Age(year)	1.06	1.05–1.08	<0.001
Male(%)	1.13	0.81–1.57	0.475
BMI (kg/m2)	1.10	1.07–1.14	<0.001
Current drinker(%)	1.68	1.04–2.70	0.034
Hb (g/L)	1.02	1.01–1.02	<0.001
FBG (mmol/L)	1.13	1.02–1.21	0.014
TG (mmol/L)	1.1	0.98–1.25	0.097
LDL‐C (mmol/L)	1.02	0.87–1.19	0.856
eGFR (mL/min/1.73 m2)	0.98	0.97–0.99	<0.001
HR(bpm)	1.02	1.01–1.03	<0.001

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate.; FBG, fasting blood glucose; Hb, hemoglobin; HR, heart rate; LDL‐C, low density lipoprotein cholesterol; TG, triglyceride.

3.3. Categorized hemoglobin concentration and hypertension risk

The relationship between the hemoglobin concentration and hypertension risk was further explored in different logistic regression models (Table 3). The subjects were divided into quartile groups according to the hemoglobin concentration. Q1 was used as the reference quartile. We found that the highest hemoglobin concentration group (hemoglobin exceeding 173 g/L) had a significantly increased risk of hypertension after adjustment for confounders (OR 2.39, 95% CI 1.48−3.85).

TABLE 3.

Odds ratios for hypertension according to the quartiles of hemoglobin concentration.

Variable	Model 1			Model 2			Model 3
	OR	95%CI	P	OR	95%CI	P	OR	95%CI	P
Hb
Q1(<148 g/L)	1	Ref		1	Ref		1	Ref
Q2(148–160 g/L)	1.58	1.17–2.12	0.002	1.32	0.93–1.87	0.117	1.16	0.81–1.67	0.422
Q3(160–173 g/L)	1.4	1.04–1.88	0.026	1.54	1.04–2.30	0.031	1.36	0.90–2.06	0.136
Q4(>173 g/L)	2.74	2.04–3.67	<0.001	3.11	1.97–4.89	<0.001	2.39	1.48–3.85	<0.001

Model 1 was not adjusted; Model 2 was adjusted for age, sex and BMI; Model 3 was adjusted for Model 2 plus variables including, current smoker, current drinker, FBG, TG, LDL‐C, eGFR and HR.

3.4. Two‐piecewise analysis for hemoglobin concentration

We further assessed the relationship between hemoglobin concentration and hypertension by smooth curve fitting. A threshold effect was observed with a two‐stage change and an inflection point. The inflection point of the threshold effect was approximately 176 g/L (Figure 1). Because of the non‐linear relationship between the hemoglobin concentration and hypertension, a two‐piecewise logistic regression model was used on the basis of visual identification of the hemoglobin concentration value associated with changes in hypertension on the hemoglobin–hypertension curve. Hemoglobin concentration (per 1 g/L change) was only slightly associated with hypertension (OR 1.01, 95% CI 1.01−1.02, P = 0.0009) before the inflection point. However, hemoglobin concentration (per 1 g/L change) had a more significant effect on the increased risk of hypertension (OR 1.04, 95% CI 1.03−1.06, P < 0.0001) after the inflection point (Table 4). The further analysis in the situation of 171 and 181 g/L as inflection points was shown in Supplementary material 1.

FIGURE 1.

Relation between hemoglobin concentration and hypertension by smooth curve fitting. The red curve in the middle is the spline smoothing, and the blue curves on both sides represents the 95%CI confidence interval.

TABLE 4.

Threshold effect analysis of the relationship between hemoglobin concentration and the risk of hypertension.

	The risk of hypertension
Hemoglobin concentration (g/L)	OR (95%CI)	P value
Fitting model by two‐piecewise linear regression
Inflection point (K)	176
<176 slope 1	1.01 (1.00–1.02)	0.0009
>176 slope 2	1.04 (1.02–1.06)	<0.0001
Effect difference between slope 2 and slope 1	1.03 (1.01–1.05)	0.0062
Logarithm likelihood ratio test		0.005

3.5. Polycythemia and hypertension risk

The subjects were divided into three groups according to sex‐specific hemoglobin concentrations (normal hemoglobin, mild polycythemia, and high‐altitude polycythemia). The normal hemoglobin group was used as the reference group. The relationship between polycythemia and hypertension risk was further explored in different logistic regression models (Table 5). We found that high‐altitude polycythemia significantly increased the risk of hypertension after adjustment for confounders (OR 2.92, 95% CI 1.25−6.86). A similar result was also observed in subjects with mild polycythemia (OR 1.74, 95% CI 1.29−2.34) (Table 5).

TABLE 5.

Odds Ratios for hypertension according to hemoglobin concentration group.

Variable	Model 1			Model 2			Model 3
	OR	95%CI	P	OR	95%CI	P	OR	95%CI	P
Hb
Normal Hb	1	Ref		1	Ref		1	Ref
Mild polycythemia	2.2	1.73–2.79	<0.001	1.98	1.49–2.65	<0.001	1.74	1.29–2.34	<0.001
High‐altitude polycythemia	6.86	3.25–14.48	<0.001	3.12	1.37–7.10	0.007	2.92	1.25–6.86	0.014

Model 1 was not adjusted; Model 2 was adjusted for age, sex and BMI; Model 3 was adjusted for Model 2 plus variables including, current smoker, current drinker, FBG, TG, LDL‐C, eGFR and HR.

4. DISCUSSION

In this study, hemoglobin concentration was associated with hypertension in native Tibetans at high altitude. In the smooth curve fitting and threshold effect analysis, we identified an inflection point for hemoglobin concentration at 176 g/L. Hemoglobin concentration exceeding that value was significantly associated with an increased risk of hypertension (OR 1.04, 95% CI 1.03−1.06). In addition, high‐altitude polycythemia increased the risk of hypertension, even in subjects with mild polycythemia.

Some observational studies have shown that hemoglobin concentration is significantly correlated with BP. ¹³ , ¹⁴ , ¹⁵ However, these observational data lacked confounding factor adjustment. The present study indicated that hemoglobin concentration was associated with hypertension in native Tibetans at high altitude, even after adjusting for acknowledged risk factors for hypertension, such as age, BMI, FBG, and lower eGFR. Two previous studies among the general population lived in the plain support our findings. ¹⁶ , ²⁹ In addition, a previous study has shown that compensatory elevation in hemoglobin concentration within a certain range is considered a fundamental physiological response to high‐altitude hypoxia, ³⁰ which is beneficial to increase the oxygen‐carrying capacity of the blood and improve tissue oxygenation without increasing cardiac output. ²⁷ However, when the hemoglobin concentration is >180 g/L, increasing the hemoglobin concentration becomes progressively less effective, and an increase in cardiac output is required to maintain oxygen transport. ²⁶ An increase in cardiac output would contribute to BP elevation. The above theoretical basis confirms our finding that a hemoglobin concentration exceeding 176 g/L significantly increases the risk of hypertension.

Although data on the association between high‐altitude polycythemia and hypertension are scarce, the findings of two recent studies are in line with our results. A cross‐sectional study including 342 males from Cerro de Pasco, Peru, at 4340 m showed that the ORs of systolic and diastolic hypertension were substantially higher in the excessive erythrocytosis group than in healthy highlanders when adjusted for overweight and obesity, age, and SpO₂.¹⁹ In the HIGHCARE‐ANDES Highlanders Study, excessive erythrocytosis was identified as an independent predictor of ambulatory hypertension. ²⁰ Although both of these studies included Andes highlanders, they support our findings to some extent. In addition, our research found that mild polycythemia increased the risk of hypertension. To our knowledge, this is the first report of this phenomenon. It seems that a hemoglobin concentration of 180–210 g/L for males and 160–190 g/L for females threatens the wellbeing of altitude residents ²⁶ , ²⁷ ; therefore, this area is worthy of further research.

The potential pathophysiological mechanism linking hemoglobin concentration to hypertension has not yet been clearly established. However, some hypotheses may be suggested. Hemoglobin has a high affinity for nitric oxide (NO). ³¹ Scavenging of NO by hemoglobin triggers systemic vasoconstriction, ³² , ³³ which contributes to BP elevation. A clinical study also showed that accelerated scavenging of NO by hemoglobin might be a key factor determining hypertension development in people with polycythemia vera. ³⁴ In addition, hemoglobin concentration is associated with blood viscosity, and increased blood viscosity is considered a determinant of peripheral vascular resistance, which is expected to contribute to BP elevation. ³⁵ Donadee et al. found that cell‐free hemoglobin reacts with endothelial NO about 1000‐times faster than hemoglobin in intact erythrocytes. ³⁶ Deoxygenated hemoglobin also scavenges NO faster than oxygenated hemoglobin. ³⁷ In the hypobaric, hypoxic environment, cell‐free hemoglobin is increased due to microcirculatory dysfunction in subjects with high‐altitude polycythemia. ²⁴ At the same time, the arterial oxygen saturation of Tibetans is lower than that of the Andes and general populations lived in the plains. ³⁸ Therefore, for Tibetans living in plateau areas with the same hemoglobin concentration, the concentration of deoxygenated hemoglobin is much higher than the general people living in plain areas. ³⁹ The mechanism by which mild polycythemia and high‐altitude polycythemia increase the risk of hypertension might be that high levels of deoxyhemoglobin and cell‐free hemoglobin accelerate NO scavenging, leading to vasoconstriction and eventually contributing to an increase BP.

One study showed that high blood hemoglobin concentration is a specific risk factor for major atherosclerotic cardiovascular events. ⁴⁰ Kawamoto also reported that hemoglobin concentration is strongly related to arterial stiffness. ⁴¹ There is a very strong link between hypertension and atherosclerosis and arterial stiffness. Thus, hemoglobin concentration‐related atherosclerosis and arteriosclerosis might also be the potential causes of BP elevation. In plateau areas, hemoglobin concentration is compensatively elevated due to the hypobaric, hypoxic environment. When the compensation reaches a certain level, it is necessary to increase cardiac output to maintain oxygen supply which could contribute to BP elevation. ²⁶

The lack of ambulatory BP monitoring is the main limitation of the present study. In addition, it is difficult to draw a conclusion about the causal role of hemoglobin concentration in hypertension due to the cross‐sectional design of the study. The specific mechanisms by which hemoglobin concentration contributes to hypertension should be further explored by a series of follow‐up studies. Despite these limitations, this study has several strengths. First, the sample size of the study was large, which increased the statistical reliability of the results. Second, we adjusted for other traditional risk factors for hypertension and eliminated the possible effects of confounding factors on the association between hemoglobin concentration and BP. Last but not least, The present study is the first time to investigate the relationship between hemoglobin concentration and hypertension in native Tibetans living in plateau area. The study provides guidance for the BP regulation and the management of hypertension in plateau areas.

5. CONCLUSION

In this study, the hemoglobin concentration was associated with hypertension risk in native Tibetans. When the hemoglobin concentration exceeded a certain value (approximately 176 g/L), the risk of hypertension increased. Mild polycythemia and high‐altitude polycythemia were both risk factors for hypertension. Further studies are needed to confirm the exact pathophysiological mechanism underpinning the association between hemoglobin concentration and hypertension.

AUTHOR CONTRIBUTIONS

Xueting Liu and Changqiang Yang contributed equally to the manuscript. Xiaoping Chen and Qingtao Meng shared the corresponding author. Concept and design: Xiaoping Chen, Qingtao Meng, and Xin Zhang. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Xueting Liu, and Changqiang Yang. Critical revision of the manuscript for important intellectual content: Xiaoping Chen and Qingtao Meng. Statistical analysis: Changqiang Yang, Xueting Liu, and Xin Zhang. All authors read and approved the final manuscript.

We are grateful to the study participants for their involvement in the study. We thank the public health workers at Luhuo County People's Hospital, Ganzi Tibetan Autonomous Prefecture, People's Republic of China, for their support of participant recruitment and sample collection.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

Liu X, Yang C, Zhang X, et al. Association between hemoglobin concentration and hypertension risk in native Tibetans at high altitude. J Clin Hypertens. 2024;26:17–23. 10.1111/jch.14726

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author.