Global pulmonary arterial hypertension trends and projections to 2046: a multi-method analysis of epidemiologic and demographic drivers using GBD 2021

Introduction

Pulmonary arterial hypertension (PAH), a complicated and progressive disease characterized by elevated mean pulmonary arterial pressure, affects millions of individuals worldwide, with substantial variations in prevalence, diagnosis, treatment, and outcomes across different regions and income levels (1). Over the past three decades, PAH incidence has increased as a result of sophisticated diagnostic instruments and greater disease awareness. At the same time, the mortality has been decreased owing to advancements in medical tools and early diagnosis (2). Nevertheless, obstacles persist, particularly for PAH associated with other underlying conditions or unknown origins. While high-income countries have made strides in managing PAH, low- and middle-income countries encounter substantial difficulty in finding and treating PAH. High-income countries, with their advanced healthcare systems, are able to diagnose and treat PAH earlier and more effectively. In contrast, low- and middle-income countries face challenges, including delayed diagnosis and insufficient treatment resources, highlighting the need for more support from the international community and local governments in healthcare resource allocation and disease management (3).

The Global Burden of Disease (GBD) study is a multinational collaboration that facilitated the better understanding of the global PAH landscape by predicting the disease burden of individual countries worldwide (4). The GBD project, led by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, endeavors to quantify the burden of diseases, injuries, and risk factors worldwide. GBD 2021 provided a comprehensive analysis of 369 diseases and injuries, 286 causes of death, and 87 risk factors from 1980 to 2021, encompassing 21 regions and 204 countries and territories (4). Data extracted from GBD can be utilized to describe the burden in prevalence, mortality and disability-adjusted life years (DALYs) by region, sex, and age, as well as to project the PAH-related disease burden from 2022 to 2046 and monitor health inequality.

PAH imposes a substantial clinical and economic burden worldwide. Following the public release of the GBD 2021 data set—which, for the first time, includes distinct estimates for Group 1 PAH—baseline global prevalence, mortality, and DALYs estimates have been reported elsewhere (5,6). Building upon these baseline estimates, we applied Joinpoint regression, Bayesian age–period–cohort modelling, decomposition techniques, and frontier-efficiency analysis to delineate long-term temporal trajectories, partition the influence of population ageing, population expansion, and epidemiological change, project the global PAH burden through 2046, and benchmark national performance against their socio-demographic development. By explicitly distinguishing between age-standardised rates and absolute counts—and clarifying the policy relevance of each—this study provides evidence to guide resource allocation and inform the design of next-generation PAH prevention and control strategies. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-305/rc).

Methods

Study design

The original data were sourced from the Global Health Data Exchange (GHDx) online query tool provided by IHME (https://ghdx.healthdata.org/gbd-results-tool). In this research, data were extracted to calculated the prevalence, mortality, DALYs, and corresponding age-standardized rates (per 100,000 population) with 95% uncertainty intervals (UI), including the age-standardized prevalence rate (ASPR), age-standardized death rate (ASDR), and age-standardized rate of DALYs (ASDALYs) from GBD 2021. Subgroup analyses were stratified by sex (male and female), socio-demographic index (SDI) categories (high, high-middle, middle, low-middle, and low), 21 GBD regions (South Asia, East Asia, North Africa, Middle East, Western Sub-Saharan Africa, Southeast Asia, Eastern Sub-Saharan Africa, Central Latin America, Tropical Latin America, Central Sub-Saharan Africa, Western Europe, High-income North America, Central Asia, Eastern Europe, Southern Sub-Saharan Africa, High-income Asia Pacific, Central Europe, Andean Latin America, Caribbean, Southern Latin America, Oceania, and Australasia), and 204 countries and territories.

Definition

In GBD 2021, a Bayesian meta-regression disease modeling tool, DisMod-MR-2.1, was employed to estimate the prevalence, mortality, and DALYs associated with PAH based on a diverse range of data sources, including population surveys, cohort studies, registries, health system administrative data, and microdata from registry and cohort studies.

The SDI serves as a composite indicator of social and economic conditions across different locations. It is calculated as the geometric mean of three indices: the total fertility rate in females under 25 years old, the average years of education for individuals over 15 years old, and the lag-distributed income per capita. To categorize countries and territories into SDI quintiles, cutoff values were determined using data from countries with populations exceeding one million. The 204 countries and territories analyzed were classified into five SDI quintiles: high SDI (0.810 to 1), high-middle SDI (0.712 to <0.810), middle SDI (0.619 to <0.712), low-middle SDI (0.466 to <0.619), and low SDI regions (0 to <0.466). Additionally, based on socio-economic and geographic criteria, countries and regions globally were grouped into 21 GBD regions.

Metrics

To permit valid comparisons across time, sex, and SDI regions, we extracted two complementary sets of indicators. ASPR, ASDR, and DALYs per 100,000 population—standardised to the GBD reference population—were used to describe temporal and regional patterns independent of demographic change. In parallel, absolute counts of PAH cases, deaths, and DALYs were reported to illustrate the real-world volume of disease.

Statistical analysis

The estimated annual percentage change (EAPC) with a 95% confidence interval (CI) was used to evaluate the PAH burden, given its efficacy in summarizing and monitoring trends in age-standardised rates over a specific period. A key advantage of the EAPC lies in its ability to signify trends succinctly: an EAPC of 0 denotes a stable rate, a positive value indicates an increasing trend, while a negative value suggests a decreasing trend. Moreover, the magnitude of the EAPC reflects the pace of the rate changes over time, with larger absolute values indicating more rapid changes. Furthermore, a Pearson correlation analysis was conducted to explore the relationship between age-standardised rates and the SDI.

The Joinpoint regression program (version 4.9.0.0, National Cancer Institute, USA) was utilized to assess temporal trends in the PAH burden from 1992 to 2021 by estimating the average percent change (APC) and average annual percentage change (AAPC) in ASPR, ASDR, and ASDALYs (7). A Monte Carlo permutation method was employed to ascertain the statistical significance. If AAPC >0 and the P value <0.05, the age-standardised rates indicate an increasing trend throughout this study period; otherwise, if AAPC <0 and the P value <0.05, then the age-standardised rates suggest a decreasing trend. If P≥0.05, the rate signifies an unchanged trend. Additionally, the correlation between AAPC and SDI was assessed using Pearson correlation analysis.

The age-period-cohort analysis (8) and decomposition methodology (9), which isolate and statistically estimate the differential effects of age, period, and cohort, have been widely used to explore social change, disease etiology, aging, and demographic processes. Net drift and local drift represent key parameters in age-period-cohort models. Net drift encapsulates the overall log-linear trend across period and birth cohort, showing the annual percentage change of the expected age-adjusted rates over time. On the other hand, local drift delineates the log-linear trend specific to each period and cohort, offering a nuanced understanding of temporal variations. The longitudinal age curve serves as a pivotal component, illustrating age-specific relative risk in comparison to a designated reference age group within a reference cohort, and simultaneously accounting for period variations. Moreover, period (or cohort) rate ratios (RR) play a crucial role in age-period-cohort analyses, elucidating the relative risk of a particular cohort (or period) after adjusting for age and nonlinear period (or cohort) effects relative to the reference cohort or period. To gauge the significance of estimable parameters and functions, Wald chi-square tests were adapted, ensuring robust statistical assessment and interpretation within the age-period-cohort framework.

Frontier analysis was applied to establish benchmarks for the PAH burden by comparing regions against the best-performing counterparts (10). This method identifies leading regions, thereby setting standards and targets for others. We computed the “effective difference” for each region, indicating the gap between the current and potential PAH burden, as adjusted for SDI.

The Bayesian age-period-cohort (BAPC, version 0.0.34) analysis model with integrated nested Laplace approximation (INLA, version 23.04.24) was employed to forecast the disease burden trends from 2022 to 2046. The BAPC model, which leverages both sample and prior information, provides unique parameter estimates and reliable results (11). INLA employed alongside the BAPC model facilitated the approximation of the marginal posterior distribution, thereby avoiding some of the mixing and convergence issues associated with the Markov chain Monte Carlo sampling technique traditionally used in Bayesian methods.

All statistical analyses were conducted using the R program (Version 4.3.0, R Core Team), and a two-tailed P<0.05 was considered statistically significant.

Ethical information

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All methods in this paper were performed following the relevant guidelines and regulations.

Results

Overview of the global burden

Globally, the absolute number of PAH cases rose from 110,099.11 (95% UI: 90,103.87–135,861.57) in 1992 to 191,808.22 (95% UI: 155,356.95–235,787.14) in 2021, an increase of roughly 74%, even though the ASPR remained essentially flat, shifting only from 2.30 (95% UI: 1.87–2.82) to 2.28 (95% UI: 1.85–2.80) cases per 100,000 individuals, with an EAPC of 0.04 (95% CI: 0.02–0.06). Mortality cases climbed from 15,166.01 (95% UI: 12,726.08–17,840.94) to 22,020.53 (95% UI: 18,239.16–25,351.58), yet the ASDR fell from 0.35 (95% UI: 0.29–0.41) per 100,000 people in 1992 to 0.27 (95% UI: 0.23–0.32) per 1000,000 people in 2019, with an EAPC of −0.58 (95% CI: −0.76 to −0.41). Total PAH-related DALYs cases decreased modestly from 684,266.14 (95% UI: 551,247.50–813,514.03) to 642,104.29 (95% UI: 552,272.69–728,993.24), while the ASDALYs dropped sharply from 12.94 (95% UI: 10.68–15.06) per 100,000 population to 8.24 (95% UI: 7.14–9.39) per 1000,000 population, with an EAPC of −1.33 (95% CI: −1.46 to −1.19) (Figure 1; Table S1).

Figure 1 Sex‑specific age‑standardised rates of PAH burden by SDI quintile, 1992–2021. ASDR, age-standardized death rate; ASDALYs, age-standardized rate of disability-adjusted life years; ASPR, age-standardized prevalence rate; ASR, age-standardized rate; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

Sex‑specific patterns

Sexual difference in the trends of PAH prevalence number was significantly shown between 1992 and 2021, where males was in an upward trend, with an EAPC of 0.15 (95% CI: 0.12 to 0.18). While, females exhibited a downward trend, with an EAPC of −0.02 (95% CI: −0.04 to 0.00). Despite this decline, the PAH prevalence number in females remained higher than that in males. Similarly, the PAH mortality number in females was higher than in males. In 2021, the mortality number for females was nearly 1.6 times higher than in 1992, whereas for males, it increased by only 1.3 times. However, ASDR for both genders showed a downward trend, with an EAPC of −0.73 (95% CI: −0.94 to −0.52) for males and −0.46 (95% CI: −0.61 to −0.31) for females. In 1992, the DALYs number for males exceeded that of females. However, by 2021, the DALYs number for males had significantly decreased, falling below that of females, while the number for females showed a slight increase. The ASDALYs for both genders exhibited a downward trend, with a more pronounced decline in males [male: −1.55 (95% CI: −1.71 to −1.39); female: −1.09 (95% CI: −1.21 to −0.97)] (Figures 1,2; Table S1).

Figure 2 Global PAH burden by sex, age group, and SDI region. (A-C) Age-standardised prevalence rates (ASPR, per 100,000) and accompanying absolute case counts for 1992, 2019, and 2021. (D-F) Age-standardised death rates (ASDR, per 100,000) and absolute death counts for 1992, 2019, and 2021. (G-I) Age-standardised DALY rates (ASDALYs, per 100,000) and absolute DALY counts for 1992, 2019, and 2021. ASDR, age-standardized death rate; ASDALYs, age-standardized rate of disability-adjusted life years; ASPR, age-standardized prevalence rate; PAH, pulmonary arterial hypertension; DALYs, disability-adjusted life years; SDI, socio-demographic index; y, years.

Age-group trends

In the analysis of subgroups based on age, in both 1992 and 2021, the highest PAH prevalence number was 75–79 years age group [1992: 8.31 (5.63–11.94); 2021: 7.94 (5.54–11.02)]. Unsurprisingly, the 95+ years age group had the highest PAH ASDR [1992: 10.35 (7.94–12.43); 2021: 13.19 (9.51–15.60)] and ASDALYs [1992: 84.64 (65.06–101.29); 2021: 106.77 (77.07–126.03)]. Additionally, the ASDALYs for children aged 0–4 years [1992: 49.33 (28.87–68.82); 2021: 19.14 (14.66–24.22)] were significantly higher than those for individuals under 70 years old. From 1992 to 2021, the prevalence, mortality, and DALYs number showed an upward trend. However, the ASPR, ASDR, and ASDALYs exhibited a downward trend across most age subgroups, except for ASDR and ASDALYs, which showed some increase in the 90–94 and 95+ years age groups (Table S1).

SDI regions and 204 countries and territories

Across the five SDI regions, the prevalence and mortality number of PAH showed an upward trend, with the greatest increases observed in the middle and low-middle SDI regions (Figure S1). However, DALYs number increased only in high SDI regions, while decreasing in other regions. From 1992 to 2021, ASPR exhibited an upward trend in low-middle [EAPC 0.26 (0.23 to 0.29)], middle [EAPC 0.17 (0.10 to 0.23)], and high-middle SDI regions [EAPC 0.19 (0.10 to 0.28)], while showing a downward trend in low [EAPC −0.26 (−0.34 to −0.18)] and high SDI regions [EAPC −0.01 (−0.04 to 0.02)]. ASDR and ASDALYs showed a downward trend across all five SDI regions, with the most significant decrease observed in the high-middle SDI regions [ASDR EAPC −1.14 (−1.36 to −0.92); ASDALYs EAPC −2.28 (−2.44 to −2.11)] (Figures 1,2,3A; Tables S1-S3).

Figure 3 Annual change in PAH burden, 1992–2021. (A) The EAPCs for age-standardised rates (ASPR, ASDR, ASDALYs) by sex and SDI region. (B-D) Country‑level EAPC for age-standardised rates (ASPR, ASDR, ASDALYs), respectively. In the current legend, each interval is “closed” at its lower limit and “open” at its upper limit. ASDR, age-standardized death rate; ASDALYs, age-standardized rate of disability-adjusted life years; ASPR, age-standardized prevalence rate; EAPC, estimated annual percentage change; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

Among the 21 GBD regions, in 2021, the lowest ASPR were seen in South Asia [1.71 (1.38–2.09)]. Conversely, the highest ASPR was observed in Western Europe [3.56 (2.92–4.35)]. Meanwhile, the highest ASDR and ASDALYs were seen in North Africa and Middle East [ASDR: 0.44 (0.31 to 0.53); ASDALYs: 14.81 (10.76–17.96)], and the lowest ASDR and ASDALYs were observed in Central Latin America [ASDR: 0.08 (0.07 to 0.10); ASDALYs: 3.00 (2.63 to 3.51)]. From 1992 to 2021, the largest increase in ASPR was in Western Sub-Saharan Africa [EAPC 1.02 (0.80 to 1.23)]. Conversely, the largest decrease in ASPR wan in Eastern Sub-Saharan Africa [EAPC −0.84 (−0.97 to −0.7)]. Furthermore, Eastern Europe was the region with the greatest decrease in ASDR [EAPC −4.17 (−4.47 to −3.87)] and ASDALYs [EAPC −4.38 (−4.68 to −4.08)] (Figure S2; Tables S1-S3).

Of the 204 countries and territories, in 2021, the country with the lowest ASPR was Greenland [1.32 (1.06 to 1.62)], whereas the country with highest ASPR was Switzerland [7.09 (5.80 to 8.66)]. Additionally, the country with the lowest ASDR and ASDALYs were Republic of Moldova [ASDR: 0.01 (0.01 to 0.01); ASDALYs: 0.54 (0.44 to 0.68)], while the country with highest ASDR and ASDALYs were Mongolia [ASDR: 1.59 (0.91 to 2.05); ASDALYs: 43.92 (25.60 to 56.54)]. From 1992 to 2021, the largest increase in ASPR was in Nigeria [EAPC 3.66 (2.95 to 4.50)]. Conversely, the largest decrease in ASPR was in Egypt [EAPC −1.90 (−2.17 to −1.63)]. Furthermore, Puerto Rico [ASDR EAPC: −6.91 (−7.27 to −6.55); ASDALYs EAPC: −7.01 (−7.39 to −6.62)] was the region with the greatest decrease in ASDR and ASDALYs. On the contrary, Taiwan (Province of China) [EAPC 6.12 (4.62 to 7.63)] and Mauritius [EAPC 5.94 (5.01 to 6.88)] were the fastest growing regions for ASDR and ASDALYs, respectively (Figure 3B-3D; Figure S1; Tables S1-S3).

The relationship between age-standardised rates and SDI was explored and summarized in Figure 4. It was shown that a significant correlation between SDI and age-standardised rates at both regional and national levels. At the regional level (Figure 4A), ASPR was positively correlated with SDI (R=0.52, P<0.001), indicating that higher-income populations are more susceptible to PAH. Conversely, ASDR (R=−0.20, P<0.001) and ASDALYs (R=−0.24, P<0.001) were negatively correlated with SDI, suggesting lower mortality and DALYs in higher-income populations, with a gender difference present only in males (ASDR: R=−0.07, P=0.02; ASDALYs: R=−0.15, P<0.001). At the national level (Figure 4B), Sweden and Switzerland exhibited higher ASPR levels than expected based on their SDI, while Mongolia showed higher ASDR and ASDALYs levels than expected based on its SDI.

Figure 4 Relationship between SDI and PAH burden. (A) Age‑standardised rates (ASPR, ASDR, ASDALYs) across 21 GBD regions, 1992–2021. (B) Age‑standardised rates (ASPR, ASDR, ASDALYs) for 204 countries and territories in 2021. ASDR, age-standardized death rate; ASDALYs, age-standardized rate of disability-adjusted life years; ASPR, age-standardized prevalence rate; GBD, global burden of disease; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

Temporal trend in PAH burden from 1992 to 2021

Joinpoint regression models was utilized to analyze the time trends in the burden of PAH-related age-standardised rates in global and SDI regions. The overall ASPR showed a decreasing trend [AAPC −0.03 (−0.05 to −0.02)], with a slight increase from 2000 to 2015, followed by a sharp decline from 2019 to 2021. Notably, the ASPR in males exhibited a marginally upward trend [AAPC 0.07 (0.05 to 0.09)], similar to the trends observed in low-middle [AAPC 0.24 (0.23 to 0.25)] and middle SDI regions [AAPC 0.19 (0.14 to 0.23)], while the low SDI regions [AAPC −0.28 (−0.30 to −0.26)] showed a more pronounced decline. The ASDR showed an overall decreasing trend [AAPC −0.84 (−0.98 to 0.69)], but experienced a slight increase from 2006 to 2010, followed by a significant decline from 2013 to 2018. The decline was more pronounced in males [AAPC −1.09 (−1.25 to −0.92)] compared to females [AAPC −0.64 (−0.77 to −0.51)], with both genders showing a significant increase in mortality rates during the 2006 to 2010 period. Among the five SDI regions, the high-middle SDI region showed a more noticeable decline in mortality rates [AAPC −1.34 (−1.61 to 1.07)]. ASDALYs also exhibited a decreasing trend [AAPC −1.57 (−1.68 to 1.46)], with a substantial decline from 2013 to 2021. Similarly, males [AAPC −1.29 (−1.40 to 1.18)] and the high-middle SDI region [AAPC −2.39 (−2.67 to 2.11)] showed more significant downward trends (Figure 5A-5C; Figure S3; Tables S4-S6).

Figure 5 Jionpoint regression analysis of global PAH burden, 1992–2021. (A-C) APC in age-standardised rates (ASPR, ASDR, ASDALYs) by sex. (D) Association between AAPC and SDI. *, P<0.05 for the correlation coefficient r. AAPC, average annual percent change; APC, average percent change; ASDR, age-standardized death rate; ASDALYs, age-standardized rate of disability-adjusted life years; ASPR, age-standardized prevalence rate; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

The relationship between AAPC and SDI was presented in Figure 5D. The results showed a significant correlation at the regional level from 1992 to 2021. The AAPC of prevalence (R=0.214, P=0.002) was positively correlated with regional income levels, while the AAPC of DALYs (R=−0.156, P=0.03) was negatively correlated. This indicates that higher regional income levels are associated with greater annual changes in prevalence rates and smaller annual changes in DALYs.

APC analysis

Net drift represents the overall annual percent-age change over the entire study period. Local drift represents the annual percentage change in mortality for each age group relative to net drift. Trends in net and local drift for globally and SDI regions were shown in Tables S7-S9. The Wald χ² test showed that the trends were almost statistically significant (Table S10). Estimates of age, period, and cohort effects on prevalence, mortality and DALYs from PAH were given in Figure S4. For the age effect, PAH patients exhibit extremely high mortality and DALYs before the age of 9 years, which sharply decline after 10 years old, then gradually increase with age. Similar mortality and DALYs trend models were found across different SDI regions, with most males having higher mortality and DALYs than females. Interestingly, in the high-middle and middle SDI regions, mortality and DALYs in females showed a sharp decline after the age of 94 years (Figure 6). For period and cohort effects, PAH mortality and DALYs in continuous period groups (reference 2002–2006) and birth cohort groups (reference 1947–1956) showed a downward trend. This trend was similar across different SDI regions, with significant improvements in high SDI regions, while other regions exhibited a fluctuating decline (Figure S5).

Figure 6 Longitudinal age curves of PAH absolute prevalence, mortality and DALYs (per 100,000 person-years) adjusted for period deviations. DALYs, disability-adjusted life years; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

Decomposition analysis of PAH burden

Our decomposition analysis provided insights into the relative contributions of aging, population, and demographically adjusted changes of epidemiology in PAH prevalence, mortality and DALYs. The past 30 years have seen a significant global increase in prevalence number, with the largest increase occurring in middle SDI regions. Aging and population growth accounted for 30.09% and 66.70%, of the worldwide increase in prevalence, respectively, with the most significant aging contribution occurring in the high-middle SDI quintile (52.78%), and the most significant population growth contributor in the low SDI region (110.21%). The effect of epidemiological change on prevalence growth was positive (3.21%) worldwide, while was negative in high (−3.81%), high-middle (−2.76%) and low SDI quintile (−12.71%). In terms of the GBD regions, the top 3 increases in ASPR were in East Asia, South Asia and Western Europe, and these were primarily due to population growth with 35.48%, 68.25% and 35.90%, respectively. Alternately, the decreases in ASPR was pronounced in Eastern Europe, with contributions of aging of −381.88% (Figure 7A; Table S11).

Figure 7 Decomposition of changes in PAH burden, 1992–2021. (A) Change in absolute prevalence; (B) change in absolute mortality; (C) change in absolute DALYs, each partitioned into contributions from population growth, population ageing, and epidemiological change. DALYs, disability-adjusted life years; GBD, Global Burden of Disease; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

Similarly, the effects of demography and epidemiology on mortality and DALYs number differed across countries and regions (Figure 7B,7C; Tables S12,S13). But it is worth noting that, the epidemiological alterations among world populations decreased the ASDR and ASDALYs by 36.37%and 91.77%, respectively, between 1992 and 2021, and trends were consistent across sex subgroups. The epidemiological change-based contribution to reduce ASDR and ASDALYs were relatively significant (−76.02% and −626.73%) in the high-middle SDI region, where the contribution was most pronounced among the aging population (119.56% and 401.68%).

Frontier analysis

In the comprehensive frontier analysis based on SDI and age-standardised rates spanning from 1992 to 2021 across 204 countries and territories, distinct trends emerged (Tables S14-S16). For prevalence, as the SDI value ascended from 0 to 1, there was an overall decline in ASPR, characterized by a progressive density shift from lighter to darker shades over the years, indicative of a general reduction in prevalence (Figure 8A). Similarly, the ASDR presented a downward trend with increasing SDI (Figure 8B), while the ASDALYs followed a similar pattern (Figure 8C), revealing that as developmental progress occurs, the PAH burden tends to diminish.

Figure 8 Frontier analysis based on SDI and age-standardised rates—ASPR (A,D), ASDR (B,E) and ASDALYs (C,F). The red dot indicates that the rate of 2021 is higher than that of 1992, the blue dot indicates that the rate of 2021 is lower than that of 1992, and the black dot indicates the 15 countries with the greatest distance between frontier and the true value. The red dot indicates the five countries with the largest distance between frontier and true value in the countries above the high SDI threshold, and the blue dot indicates the five countries with the smallest distance between frontier and true value in the countries below the low SDI threshold. ASDR, age-standardized death rate; ASDALYs, age-standardized rate of disability-adjusted life years; ASPR, age-standardized prevalence rate; PAH, pulmonary arterial hypertension; SDI, socio-demographic index.

Turning attention to the frontier analysis results from 2021, the visual representations delineated clear distinctions among countries and territories. For ASPR, 15 countries such as Netherlands, Sweden, and Switzerland, among others, were observed to have significantly higher rates, placing them distant from the frontier. In contrast, countries like were closer to the frontier, suggesting optimal outcomes given their SDI (Figure 8D). When assessing the ASDR, nations like Mongolia, Georgia and Cyprus exhibited larger gaps from the frontier. Interestingly, high SDI countries such as Switzerland, Germany, Luxembourg, Japan and United States of America showed effective differences for their developmental stage (Figure 8E). Lastly, in the ASDALYs analysis, countries like Somalia, Niger, Mali, Benin and Ethiopia depicted rates closer to the aspirational benchmark set by the frontier (Figure 8F).

Projections of PAH burden to 2046

Finally, using BAPC modelling, we forcasted the global ASPR, ASDR, and ASDALYs from 2021 to 2046 (Figure 9; Tables S17-S19). ASPR showed an overall downward trend from 2022 to 2046, albeit with small fluctuations. Regarding gender differences, the ASPR and prevalence number in female were significantly higher than in male. Similarly, ASDR and ASDALYs are also predicted to continue declining globally. However, unlike ASPR, ASDR and ASDALYs were higher in males than in females before 2017. After 2010, the decline rate in males was higher than in females, and from 2022 onwards, ASDR and ASDALYs in males were predicted to be lower than those in females.

Figure 9 Predicted global PAH burden, 2022–2046. (A) Age‑standardised rates of prevalence, mortality, and DALYs; (B) corresponding absolute counts of cases, deaths, and DALYs. DALYs, disability-adjusted life years; PAH, pulmonary arterial hypertension.

Discussion

Using GBD 2021 data, our study extends previously published global estimates of PAH burden by integrating advanced trend-analysis and forecasting techniques. Consistent with the Lancet report (5), the age-standardised prevalence of PAH plateaued between 1992 and 2021, whereas both ASDR and DALYs declined, indicating improved outcomes despite stable rates. Our Joinpoint analysis refined these observations, revealing a modest rise in ASPR until the early 2000 s followed by a gradual decline, while mortality and DALY rates fell more uniformly—patterns that varied by sex and SDI region. Age-period-cohort modelling demonstrated a U-shaped mortality and DALY curve, with highest risks in early childhood and late adulthood; inter-regional contrasts were especially pronounced after age 60. Decomposition analysis showed that population ageing and growth were the dominant drivers of rising absolute case numbers, whereas epidemiological change had heterogeneous effects on DALYs across regions. Frontier analysis indicated that higher-SDI countries generally attain lower PAH burden yet still possess untapped efficiency potential. Projections to 2046 suggest continuing declines in both rates and absolute numbers for mortality and DALYs, alongside a modest contraction of the prevailing sex gap. These findings, supplementary to earlier GBD-based summaries, offer a more nuanced, policy-oriented picture of the evolving global PAH landscape.

The global trends in PAH from 1992 to 2021 exhibit a marginal increase in prevalence, accompanied by noteworthy reductions of mortality and DALYs. Advancements in medical technology and treatment options have significantly improved the management of PAH, leading to better patient outcomes and reduced mortality rates. For instance, the development of targeted therapies, such as prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, has been crucial in improving survival rates and quality of life for PAH patients (12). Improved diagnostic techniques and increased awareness of PAH among healthcare professionals have likely contributed to the higher prevalence. Enhanced screening and diagnostic practices facilitate earlier detection of PAH, which is critical for timely intervention and management (12). Moreover, demographic changes, such as population aging, have impacted the prevalence of PAH. As the global population ages, the prevalence of age-related diseases, including PAH, is expected to rise. Nevertheless, the overall decline in ASDR and ASDALYs suggests that despite the increasing prevalence, the burden of PAH in terms of mortality and disability has lessened, reflecting better disease management and healthcare delivery. Furthermore, socioeconomic considerations and healthcare access play a vital role in shaping these trends. Regions characterized by better healthcare infrastructure and elevated socioeconomic status tend to have lower PAH-related mortality and DALYs (13), highlighting the importance of equitable healthcare access and the need for targeted interventions in low- and middle-income countries to reduce the global burden of PAH.

Furthermore, a detailed analysis was conducted on the variations across various SDI areas. High-income countries have had substantial reductions in mortality and DALYs, despite higher prevalence, due to advances in medical technology and increased health awareness (14,15). The optimal allocation of medical resources and early diagnosis measures in these countries have effectively improved patient outcomes. The prevalence of PAH has gradually increased in middle-income countries, indicating the impact of environmental contamination and lifestyle changes during industrialization and urbanization (3). The presence of genetic predispositions and a higher incidence of chronic conditions like connective tissue diseases in these populations also played a significant role in the increased prevalence of PAH (16). Despite improvements in health care in these countries, mortality remain high and the decline in DALYs has been limited attributed to unequal resource distribution and the heavy pressure on healthcare systems, highlighting challenges in disease management. The prevalence of PAH is relatively low in low-income countries, but the actual prevalence might be underestimated as a result of poor sanitation and inadequate health education (17). The gradual decrease in PAH mortality and DALYs in these countries reflects a deficiency in timely detection and effective treatment. Fluctuations in the global burden of PAH reflect a combination of economic, medical, environmental and social factors, underscoring differences in disease prevention strategies across economic regions.

The global burden of PAH showed pronounced sex differences—females comprised most incident cases, whereas males generally experienced poorer survival—but the mechanisms remained only partly understood. Experimental and clinical data suggested that oestrogen and its metabolites exert vasoprotective and right-ventricular-supporting effects, which might contribute to the female predominance, while sex-specific penetrance of pathogenic variants (e.g., BMPR2) could further modulate risk profiles (18). Conversely, androgen signalling, immune modulation, and differences in right-ventricular adaptation had been proposed to underlie the less favourable male prognosis, yet definitive causal pathways have not been established (19,20). Epidemiological factors, such as variation in symptom reporting, referral patterns, and access to specialist care, might also influence recorded prevalence and outcomes, but robust multinational evidence was still limited (21). Clarifying the relative contributions of these biological and health-system factors would require integrated mechanistic, genetic, and population-based studies, which were essential for developing effective, sex-specific prevention and management strategies for PAH.

It was observed that the prevalence of PAH was highest among those aged 75–79 years, while the ASDR and ASDALYs were highest in the age group above 95 years, which could be attributed to the following aspects. The reasons for the highest prevalence in the 75–79 years age group include increased damage to the pulmonary artery from cumulative cardiovascular risk factors (such as hypertension, diabetes, chronic obstructive pulmonary disease, etc.), reduced vascular elasticity and cardiopulmonary function due to physiological changes in older adults, and advances in medical technology have enabled more older adults to be diagnosed with PAH at this stage (22,23). The highest ASDR and ASDALYs in the age subgroup above 95 years old result from the aggravation of multiple complications (such as cardiovascular, chronic kidney and respiratory diseases) in the elderly population, the decreased physiological reserve capacity and lower tolerance to PAH and related surgery, and the complexity of medical resources and care increases the difficulty in treatment, leading to the deterioration of disease and the increased mortality (24,25). Another issue of concern was substantial increase in DALYs among children aged 0–4 years. PAH in children is often associated with congenital cardiac disease and genetic abnormalities that have significant and enduring health consequences for children (26). Moreover, during early childhood development, PAH would have a broad and far-reaching impact on their physical development and organ function, leading to higher morbidity and complications (27). Furthermore, the need for extended medical monitoring and complex treatment for children not only amplifies the economic burden on families and society, but also makes the overall health damage caused by disease to children more prominent (28).

The results of decomposition analysis indicate that aging contributes the most to the middle and high SDI regions, mainly because of the high level of medical care in these regions and the extension of population life span, resulting in an increase in the elderly population, thus increasing the prevalence of PAH and related disease burden (29). In contrast, population growth contributes the most to low-SDI regions, where high birth rates and rapid population growth result in more potential patients despite limited medical resources and diagnostic capacity. The impact of epidemiological changes on the growth of DALYs was negative globally, especially in high, middle-high, and middle SDI regions, reflecting significant progress in public health measures, disease prevention, and treatment in high- and middle-income regions, which has reduced PAH-related mortality and DALYs. From the perspective of GBD region, PAH ASPR increased the most in East Asia, South Asia and Western Europe, which may be related to the rapid economic development, urbanization process and environmental pollution increase in these regions, with South Asia showing the most significant increase, reaching 68.25%. On the other hand, ASPR decreased significantly in Eastern Europe, where the contribution of aging was −381.88%, indicating that the slowing of aging and improved public health in Eastern Europe effectively reduced the prevalence of PAH. Overall, global epidemiological changes reduced ASDR and ASDALYs of PAH by 36.37% and 91.77%, respectively, between 1992 and 2021, suggesting that public health measures and advances in medical technology have positively impacted global burden of PAH.

The anticipated global disease burden for PAH demonstrated a consistent decline in ASPR, ASDR, and ASDALYs from 2022 to 2046. The downward trend in ASPR, while less fluctuating, showed an overall improvement, with females in particular having significantly higher prevalence cases, which might be related to their longer life expectancy and specific biological factors (17). ASDR and ASDALYs were also expected to continue to decline, reflecting advancements in public health measures and medical technology worldwide. However, there were significant changes in terms of gender differences. Before 2017, males had higher ASDR and ASDALYs compared to females, but since 2010, the decline rate had been higher for males, and by 2022, it was projected that males would have lower ASDR and ASDALYs than females. Specific reasons for this change in trend might include a gradual decline in males engaging in high-risk health behaviors such as smoking and alcohol abuse, together with advancements in health service utilization and health management (30). The slower decrease in ASDR and ASDALYs in females, despite the higher overall burden, might be related to the multiple health issues females encounter as they age and long-term chronic diseases management (31). Taken together, the projected PAH global burden suggests that the prevalence, mortality and DALYs would continue to improve in coming decades as medical and public health measures are further strengthened, but gender and regional differences still require special attention to ensure that all populations benefit from health advances.

Previous assessments of the PAH burden have largely been restricted to single countries or specialised cohorts. For instance, data from the Swedish PAH & CTEPH Registry (SPAHR) yielded detailed information on demographics, disease severity and treatment patterns but offers limited global generalizability (24). Socio-economic disparities have likewise been documented: semi-structured interviews at Pulmonary Hypertension Comprehensive Care Centres (PHCCCs) revealed substantial barriers to timely diagnosis and optimal therapy among patients with lower socio-economic status (32). Nonetheless, cohort-based studies lack the breadth required to delineate worldwide temporal trends and to separate the impacts of population ageing, growth and epidemiological change. By contrast, the GBD 2021 study synthesises standardised data from vital-registration systems, household surveys and other sources across 195 countries and territories—explicitly distinguishing Group 1 PAH from other forms of pulmonary hypertension (Groups 2–5). This enables calculation of ASPR, ASDR and DALYs for PAH over three decades. Although a portion of the age-related signal could stem from misclassification of Group 2 or Group 3 pulmonary hypertension as PAH, the magnitude of this effect is unlikely to explain the consistent global decline in age-standardised PAH rates. The extensive geographic and temporal coverage of GBD data therefore provides a robust platform for analysing socio-demographic patterns, forecasting future burden and informing evidence-based allocation of health resources.

This study provides a comprehensive assessment of PAH burden based on GBD 2021 data, stratified by year, age, sex, region, country, and socioeconomic status from 1992 to 2021, offering evidence to inform public health policy. While there have been significant improvements in data collection and modeling in GBD 2021, the inherent limitations of GBD study should not be overlooked. Firstly, data loss and quality inconsistencies across countries, particularly in underdeveloped regions, lead to underestimation and misdiagnosis. Secondly, the GBD data lag and reliance on modeling and predictive covariates, as well as inconsistencies in data collection, also affect accuracy. Thirdly, the macro-level focus fails to capture micro-level trends, and its decomposition analysis may overlook other modulators. These factors emphasize the need for enhanced data quality, comprehensive data collection, and considering additional factors to increase the accuracy and reliability of future analyses.

Conclusions

This study offered a pioneering global assessment of PAH burden, using GBD 2021 data to estimate prevalence, mortality, and DALYs, with predictions for future trends. The study highlighted a relatively stable PAH prevalence from 1992 to 2021, despite decreasing mortality and DALYs, indicating improved health outcomes. Higher development levels correlated with lower PAH burden, but disparities persisted. Projections suggested ongoing declines in PAH burden globally, with expected reductions in gender differences. These findings hold considerable importance in enhancing our understanding of the epidemiology, development trends, appropriate allocation of medical resources, and formulation of relevant health policies of PAH.

Acknowledgments

This study draws exclusively on publicly available data from the Global Burden of Disease (GBD) 2021 database. We gratefully acknowledge the GBD Collaborators and their funding partners for providing open access to these high-quality data. The GBD investigators did not review or approve this manuscript; all analyses, interpretations, and conclusions are solely those of the authors and do not necessarily reflect the views of the GBD Collaboration or its member institutions.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-305/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-305/prf

Funding: This study was supported by Scientific research funding for the introduction of talents by The First Affiliated Hospital of Fujian Medical University (No. YJRC4183), National Natural Science Foundation of China under Grant (No. 82370351) and Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2020Y9108).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-305/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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