Trends and cross-country disparity in the burden of pulmonary arterial hypertension: results from Global Burden of Disease Study 2021

doi:10.21203/rs.3.rs-5175554/v1

Background

Pulmonary hypertension (PH) is a cardiopulmonary disease with complicated etiologies and classifications, gradually attracting extensive attention due to its ever-growing disease burden. Here, we aim to elucidate the PH burden and trends at global, regional and country levels over the past thirty-two years.

Methods

Data about PH prevalence, death and disability-adjusted life-years (DALYs) were obtained from Global Burden of Disease Study 2021. Moreover, the relationship between PH burden and social development index was explored. Eventually, the relevance of PH to four cardiopulmonary comorbidities were verified.

Results

From the global perspective, PH prevalence was annually rising from 1990 to 2021, primarily affecting females and young adults (age from 15 to 49). While PH death also elevated during the past 32 years and was the elder predomination. DALYs of PH presented a slightly overall decrease but surged in underdeveloped areas. Nevertheless, age-standardized death rate and DALYs exhibited significantly declines, especially in relatively developed regions with advanced healthcare resources. At meanwhile, correlation analysis demonstrated a certain negative association of SDI with age-standardized death rate or age-standardized DALYs either across 21 regions or 204 countries. Eventually, the prevalence of PH showed strongly positive associations with that of four cardiopulmonary disorders including chronic obstructive pulmonary disease, interstitial lung disease, ischemic heart disease and hypertensive heart disease.

Conclusion

The current report suggested an increasingly serious burden of PH, particularly in less developed regions. Comprehensive understanding of PH epidemiology and high-risk comorbidities can benefit those dedicated to PH prevention and control.

Pulmonary arterial hypertension

Global Burden of Disease Study 2021

Epidemiologic pattern

Concurrent cardiopulmonary disorders

Pulmonary hypertension (PH) is a progressive and debilitating cardiopulmonary disorder, evolving as a major global health challenge and affecting individuals of all ages [1]. PH refers to a mean pulmonary artery pressure ≥ 20 mmHg at rest, and characterized by pulmonary vascular remodeling, increased resistance to blood flow and eventually right heart failure and death [2]. According to the clinical and pathophysiological traits, PH is classified into five groups, including idiopathic PH, PH associated with left heart disease, PH related to lung disease or hypoxia, PH due to chronic thromboembolism, and PH with unclear mechanisms [3]. Generally, left heart disease presents the predominant cause of PH, followed by lung disease like chronic obstructive pulmonary disease (COPD) [4]. Considering the leading pathogenicity of cardiac and pulmonary diseases, individuals aged over 65 years present a higher prevalence of PH. Regardless of the underlying condition, developing PH is invariably relevant to deterioration of clinical symptoms and ever-growing mortality. [4] Comprehensive knowledge of PH epidemiology and the disease burden in the globe is quite necessary.

The epidemiological pattern and disease burden of PH vary greatly by countries and regions. Reported prevalence demonstrated 1.16 cases of 100,000 persons in Poland [5], while 9.3 cases of 100,000 persons in Utah, United States. [6] Annual incidence ranged from 0.008 cases per 100,000 individuals in Finland to 1.4 cases per 100,000 individuals in Utah, United States [6, 7]. Additionally, population ageing worldwide is contributing to a remarkable alteration in the phenotypes and distribution for PH patients. A large population-based study in Netherlands reported that 2.6% of the overall population might suffer PH suggested by echocardiographic signs, and a higher prevalence of 8.3% was observed in those aged above 85 years [8]. Noteworthy, different types of PH exhibited diverse susceptibility to individuals with different age or sex. Idiopathic PH was thought to predominantly affect younger females, especially heritable PH [9]. Moreover, geographical heterogeneity could inform the possible risk factors for PH. Altitude dwellers are at high risk of hypoxia-related PH [10], while residents in the developing regions are inclined to afflict with PH associated with infectious diseases like schistosomiasis and rheumatic heart disease [4, 11]. The complexity of PH pathogenesis and poor prognosis came across tremendous socioeconomic challenge around the world [12]. Therefore, increased efforts are needed to lighten PH burden.

Previous reviews have focused on prevalence and etiologies of PH in certain areas, lacking other epidemiological data like mortality [4, 13]. A recent review summarized the prevalence, incidence and 1-year survival for PH from different studies between 1980 and 2021 [14], which may help direct the evaluation of its burden. However, there remains to be expected for a report to systematically show the global and temporal trend of PH burden. The Global Burden of Disease (GBD) study is exactly a viable access. In this study, we evaluated the prevalence, death, disability-adjusted life years (DALYs) and their trend changes for PH across 204 countries, 21 geographic regions, 5 SDI regions and 4 health-system regions based on GBD 2021.

Data acquisition

The data on PH was derived from the 2021 GBD study [15]. The related data of PH burden including prevalence, death, DALY, age-standardized rates (ASRs), and estimated annual percentage change (EAPC) could be accessed through the Global Health Data Exchange (https://ghdx.healthdata.org/gbd-2021/sources). The information about the distributions of sex and age, and related comorbidities including COPD, interstitial lung disease (ILD), ischemic heart disease (IHD) and hypertensive heart disease (HHD) was also acquired. The rates were standardized as per the GBD world population and presented per 100,000 person-years. In this study, the GBD Results Tool was employed to acquire the estimates and 95% uncertainty intervals (UIs) for prevalence, death, and DALYs as measures of PH burden from 1990 to 2021 by region and country. To learn the PH burden among various age groups, patients were divided into four groups, namely those aged under 15 years, from 15 to 49 years, from 50 to 69 years, and above 70 years. Social developmental index (SDI) was utilized to quantify a region’s sociodemographic progression, serving as a composite indicator of total fertility, per capita income, and the years of schooling. The 204 countries and territories were divided into 5 groups according to the SDI quintile, covering low-SDI, low-middle-SDI, middle-SDI, high-middle-SDI and high-SDI, and the association between PH burden and social development degree was furtherly explored. Meanwhile, health system was graded as advanced health system (ASH), basic health system (BSH), limited health system (LSH) and minimal health system (MSH) to determine the levels of PH burden by regions.

Statistical analysis

The prevalence, death and DALYs of PH and their corresponding ASRs were successively compared at the global, regional, and country levels. UIs were calculated from 1000 estimates for each parameter and 95% UIs were defined by the 25th and 975th values of the ordered 1000 estimates. 95% UI excluding 0 was considered statistically significant. Finally, the fit spline models were plotted to explore the associations of ASRs of PH with SDI, as well as associations between the prevalence of PH and COPD/ILD/IHD/HHD [16]. All statistical analyses were conducted using GraphPad Prism 8 software.

During the past thirty-two years, PH exhibited a sharp increase globally in prevalent cases and deaths (respectively from 105,700 (95%UI: 86,380 − 130,330) and 14,840 (95%UI: 12,370 − 17,480) in 1990 to 191,810 (95%UI: 155,360 − 235,790) and 22,020 (95%UI: 18,240 − 25,350) in 2021), while presented a certain decrease in DALYs (from 687,420 (95%UI: 535,240–813,090) in 1990 to 642,100 (95%UI: 552,270–728,990) in 2021) (Table 1–3 and Fig. 1). Of note, PH prevalence was female preference, especially in relatively developed areas. Across various SDI regions, consistent elevations in prevalent cases and deaths of PH could be observed (Fig. 1A-B). Interestingly, increased DALYs was in regions with high SDI or low SDI, whereas decreased DALYs were in other SDI regions (Fig. 1C). In addition, PH epidemiology was analyzed by different health system. In terms of prevalences and deaths, it showed ever-increasing changes in all regions (Figure S1A-B). As for DALYs, depressed trends could be seen in regions with advanced or basic health system and elevated trends were in LSH and MSH regions (Figure S1C).

Table 1

PH, pulmonary hypertension; SDI, social-demographic index; ASPR, age-standardized prevalent rate per 100 000 population; EAPC, annual percentage change.
Table 1. The prevalence of PH in 1990/2021 and temporal trends
Characteristics	1990		2021		1990–2021
Characteristics	prevalence No×10³(95% UI)	ASPR/10⁵ No. (95% UI)	prevalence No×10³ (95% UI)	ASPR/10⁵ No. (95% UI)	EAPC No. (95% UI)
Overall	105.7(86.38 ~ 130.33)	2.3(1.87 ~ 2.82)	191.81(155.36 ~ 235.79)	2.28(1.85 ~ 2.8)	-0.01(-0.02 ~ 0)
Sex
Male	39.42(32.16 ~ 48.68)	1.75(1.42 ~ 2.13)	73.13(58.94 ~ 89.63)	1.78(1.44 ~ 2.17)	0.02(0.01 ~ 0.03)
Female	66.28(54.06 ~ 81.49)	2.81(2.29 ~ 3.46)	118.68(95.92 ~ 146.29)	2.75(2.24 ~ 3.39)	-0.02(-0.03~-0.01)
Socio-demographic factor
High SDI	27.05(21.98 ~ 33.3)	2.67(2.17 ~ 3.27)	41.45(33.44 ~ 51.59)	2.64(2.15 ~ 3.23)	-0.01(-0.02 ~ 0)
High-middle SDI	27.44(22.3 ~ 33.8)	2.61(2.12 ~ 3.21)	42.64(34.24 ~ 52.93)	2.54(2.07 ~ 3.12)	-0.03(-0.04~-0.02)
Middle SDI	29.05(23.77 ~ 35.77)	2.07(1.68 ~ 2.54)	59.67(48.06 ~ 73.65)	2.21(1.8 ~ 2.71)	0.07(0.06 ~ 0.08)
Low-middle SDI	15.08(12.42 ~ 18.61)	1.77(1.43 ~ 2.15)	32.71(26.55 ~ 40.62)	1.9(1.53 ~ 2.33)	0.07(0.06 ~ 0.09)
Low SDI	6.97(5.74 ~ 8.61)	2.08(1.68 ~ 2.53)	15.18(12.47 ~ 18.75)	1.94(1.58 ~ 2.36)	-0.06(-0.08~-0.05)
Region
East Asia	22.87(18.51 ~ 28.35)	2.07(1.68 ~ 2.55)	42.49(33.93 ~ 53.04)	2.23(1.81 ~ 2.75)	0.08(0.06 ~ 0.09)
Southeast Asia	6.37(5.23 ~ 7.85)	1.77(1.43 ~ 2.17)	13.62(11.02 ~ 16.96)	1.9(1.54 ~ 2.32)	0.07(0.06 ~ 0.09)
Oceania	0.09(0.07 ~ 0.11)	1.98(1.6 ~ 2.4)	0.2(0.16 ~ 0.24)	1.8(1.45 ~ 2.17)	-0.09(-0.13~-0.06)
Central Asia	1.41(1.15 ~ 1.73)	2.46(2.01 ~ 3)	2.16(1.76 ~ 2.68)	2.33(1.9 ~ 2.85)	-0.05(-0.07~-0.03)
Central Europe	3.46(2.82 ~ 4.23)	2.52(2.08 ~ 3.05)	3.52(2.86 ~ 4.31)	2.3(1.89 ~ 2.79)	-0.09(-0.1~-0.07)
Eastern Europe	8.18(6.67 ~ 10.05)	3.21(2.65 ~ 3.91)	7.69(6.26 ~ 9.49)	2.83(2.32 ~ 3.43)	-0.12(-0.13~-0.1)
High-income Asia Pacific	6.37(5.21 ~ 7.81)	3.25(2.67 ~ 3.97)	9.17(7.43 ~ 11.36)	3.01(2.47 ~ 3.68)	-0.07(-0.09~-0.06)
Australasia	0.67(0.54 ~ 0.83)	2.99(2.44 ~ 3.7)	1.17(0.94 ~ 1.44)	2.83(2.29 ~ 3.44)	-0.05(-0.09~-0.01)
Western Europe	15.68(12.58 ~ 19.29)	3.22(2.62 ~ 3.95)	23.62(19.12 ~ 29.2)	3.56(2.92 ~ 4.35)	0.11(0.09 ~ 0.13)
Southern Latin America	1.28(1.04 ~ 1.57)	2.69(2.18 ~ 3.3)	2.23(1.8 ~ 2.76)	2.82(2.29 ~ 3.48)	0.05(0.01 ~ 0.08)
High-income North America	5.98(4.86 ~ 7.32)	1.87(1.53 ~ 2.29)	8.63(6.92 ~ 10.75)	1.73(1.4 ~ 2.12)	-0.08(-0.09~-0.06)
Caribbean	0.78(0.63 ~ 0.95)	2.56(2.08 ~ 3.13)	1.23(0.99 ~ 1.51)	2.39(1.93 ~ 2.93)	-0.07(-0.09~-0.04)
Andean Latin America	0.81(0.67 ~ 1)	2.91(2.35 ~ 3.58)	1.78(1.43 ~ 2.19)	2.77(2.24 ~ 3.4)	-0.05(-0.08~-0.02)
Central Latin America	3.26(2.68 ~ 3.99)	2.71(2.21 ~ 3.3)	8.42(6.86 ~ 10.38)	3.25(2.64 ~ 3.99)	0.2(0.17 ~ 0.22)
Tropical Latin America	2.89(2.36 ~ 3.54)	2.35(1.9 ~ 2.88)	6.24(5.02 ~ 7.68)	2.48(2 ~ 3.04)	0.06(0.04 ~ 0.07)
North Africa and Middle East	4.97(4.06 ~ 6.15)	2.02(1.64 ~ 2.49)	11.59(9.39 ~ 14.44)	2.03(1.64 ~ 2.49)	0(-0.02 ~ 0.02)
South Asia	12.9(10.58 ~ 15.99)	1.58(1.28 ~ 1.93)	29.56(23.84 ~ 36.93)	1.71(1.38 ~ 2.09)	0.08(0.06 ~ 0.09)
Central Sub-Saharan Africa	0.97(0.8 ~ 1.21)	2.79(2.26 ~ 3.44)	1.69(1.38 ~ 2.09)	1.86(1.49 ~ 2.24)	-0.34(-0.37~-0.3)
Eastern Sub-Saharan Africa	2.87(2.36 ~ 3.54)	2.4(1.94 ~ 2.92)	5.91(4.82 ~ 7.34)	2.09(1.7 ~ 2.53)	-0.13(-0.15~-0.12)
Southern Sub-Saharan Africa	0.8(0.66 ~ 0.97)	2.12(1.73 ~ 2.56)	1.6(1.29 ~ 1.94)	2.28(1.85 ~ 2.76)	0.08(0.05 ~ 0.1)
Western Sub-Saharan Africa	3.11(2.57 ~ 3.83)	2.42(1.96 ~ 2.97)	9.32(7.64 ~ 11.57)	2.97(2.4 ~ 3.63)	0.23(0.19 ~ 0.27)

As demonstrated in Fig. 2A, PH prevalence predominantly affected young adults (age from 15 to 49 years). Of note, individuals aged from 50 to 69 years of both genders emerged as those with the highest PH prevalence in regions with high and high-middle SDI during the recent years. Moreover, advanced-age patients (aged above 70 years) dominated PH deaths almost in the globe, while males under 14 years and young-adult females had the highest PH deaths in low SDI regions (Fig. 2B). As for age distribution of DALYs (Fig. 2C), younger groups nearly presented remarkably decreased trends especially for those age under 14 years, while the older groups showed increased or no changes. Noteworthy, in relative higher SDI regions, PH DALYs presented rapid increases in those aged above 70 years.

Subsequently, age-standardized rates of prevalence, death and DALYs were successively evaluated. There’s no obvious change in ASPR in the globe, but significantly declined alterations in ASDR (from 0.35 per 100,000 populations (95%UI: 0.29–0.42) in 1990 to 0.27 per 100,000 populations (95%UI: 0.23–0.32) in 2021; EAPC = -0.22) and age-standardized DALYs (from 13.21 per 100,000 populations (95%UI: 10.78–15.36) in 1990 to 8.24 per 100,000 populations (95%UI: 7.14–9.39) in 2021; EAPC = -0.38), irrespective of genders (Table 1–3 and Fig. 3). Among 5 SDI regions, a slight increase or decrease in ASPR was realized (Fig. 3A), while markedly declined trends could be discerned in ASDR and age-standardized DALYs with most decrease in high-middle SDI regions (Fig. 3B-C and Table 2–3). Correlation analysis indicated a slightly positive association between ASPR and SDI across 21 regions and 204 territories (Figure S2A-B). Nevertheless, a subtly negative association could be discovered between ASDR or age-standardized DALYs and SDI (Figure S2C-F). Moreover, the similar changes of ASRs were appeared in regions with different health system to SDI regions ((Figure S3).

Table 2

PH, pulmonary hypertension; SDI, social-demographic index; ASDR, age-standardized death rate per 100 000 population; EAPC, annual percentage change.
Table 2. The death of PH in 1990/2021 and temporal trends
Characteristics	1990		2021		1990–2021
Characteristics	Death No×10³ (95% UI)	ASDR/10⁵ No. (95% UI)	Death No×10³ (95% UI)	ASDR/10⁵ No. (95% UI)	EAPC No. (95% UI)
Overall	14.84(12.37 ~ 17.48)	0.35(0.29 ~ 0.42)	22.02(18.24 ~ 25.35)	0.27(0.23 ~ 0.32)	-0.22(-0.35~-0.08)
Sex
Male	7.33(5.92 ~ 8.71)	0.37(0.29 ~ 0.46)	9.58(7.52 ~ 11.7)	0.27(0.21 ~ 0.33)	-0.28(-0.43~-0.06)
Female	7.52(5.06 ~ 10.16)	0.34(0.23 ~ 0.45)	12.44(10 ~ 15.38)	0.28(0.22 ~ 0.34)	-0.17(-0.34 ~ 0.12)
Socio-demographic factor
High SDI	2.62(2.38 ~ 2.85)	0.26(0.24 ~ 0.28)	4.62(3.92 ~ 5.05)	0.22(0.19 ~ 0.23)	-0.17(-0.25~-0.08)
High-middle SDI	3.21(2.77 ~ 3.91)	0.35(0.31 ~ 0.43)	4.33(3.59 ~ 5.14)	0.24(0.2 ~ 0.29)	-0.32(-0.45~-0.14)
Middle SDI	4.73(3.77 ~ 5.85)	0.45(0.35 ~ 0.58)	7.55(5.14 ~ 9.03)	0.33(0.22 ~ 0.39)	-0.28(-0.5~-0.02)
Low-middle SDI	3.12(2.22 ~ 3.9)	0.35(0.22 ~ 0.47)	3.73(2.76 ~ 5.09)	0.26(0.18 ~ 0.38)	-0.25(-0.39~-0.08)
Low SDI	1.15(0.74 ~ 1.75)	0.32(0.15 ~ 0.51)	1.78(1.15 ~ 2.54)	0.27(0.15 ~ 0.4)	-0.16(-0.34 ~ 0.1)
Region
East Asia	3.51(2.37 ~ 4.92)	0.59(0.45 ~ 0.81)	7.49(4.99 ~ 9.27)	0.41(0.28 ~ 0.5)	-0.31(-0.55 ~ 0.01)
Southeast Asia	0.45(0.28 ~ 0.92)	0.15(0.09 ~ 0.43)	0.74(0.53 ~ 1.85)	0.12(0.08 ~ 0.32)	-0.21(-0.39 ~ 0.1)
Oceania	0.01(0.01 ~ 0.02)	0.28(0.18 ~ 0.53)	0.02(0.02 ~ 0.04)	0.24(0.16 ~ 0.48)	-0.14(-0.31 ~ 0.06)
Central Asia	0.21(0.16 ~ 0.24)	0.4(0.31 ~ 0.47)	0.32(0.26 ~ 0.38)	0.41(0.34 ~ 0.48)	0.04(-0.13 ~ 0.26)
Central Europe	0.35(0.31 ~ 0.39)	0.26(0.22 ~ 0.28)	0.44(0.4 ~ 0.48)	0.21(0.19 ~ 0.23)	-0.18(-0.28~-0.04)
Eastern Europe	0.56(0.51 ~ 0.65)	0.24(0.22 ~ 0.27)	0.28(0.26 ~ 0.3)	0.09(0.08 ~ 0.1)	-0.62(-0.67~-0.56)
High-income Asia Pacific	0.43(0.41 ~ 0.46)	0.26(0.24 ~ 0.27)	1.05(0.83 ~ 1.2)	0.23(0.2 ~ 0.26)	-0.1(-0.19~-0.02)
Australasia	0.05(0.04 ~ 0.06)	0.21(0.18 ~ 0.26)	0.06(0.05 ~ 0.06)	0.11(0.1 ~ 0.13)	-0.45(-0.58~-0.36)
Western Europe	1.23(1.09 ~ 1.38)	0.24(0.21 ~ 0.27)	1.79(1.53 ~ 1.94)	0.18(0.16 ~ 0.19)	-0.24(-0.34~-0.15)
Southern Latin America	0.17(0.15 ~ 0.19)	0.36(0.32 ~ 0.4)	0.15(0.14 ~ 0.16)	0.18(0.17 ~ 0.2)	-0.49(-0.56~-0.41)
High-income North America	1.06(0.95 ~ 1.17)	0.32(0.28 ~ 0.35)	1.88(1.62 ~ 2.04)	0.29(0.26 ~ 0.31)	-0.08(-0.16 ~ 0.01)
Caribbean	0.12(0.08 ~ 0.17)	0.38(0.28 ~ 0.49)	0.1(0.07 ~ 0.13)	0.2(0.13 ~ 0.29)	-0.47(-0.59~-0.32)
Andean Latin America	0.08(0.06 ~ 0.11)	0.28(0.21 ~ 0.35)	0.09(0.07 ~ 0.12)	0.16(0.12 ~ 0.2)	-0.45(-0.57~-0.26)
Central Latin America	0.18(0.16 ~ 0.21)	0.16(0.14 ~ 0.19)	0.2(0.18 ~ 0.23)	0.08(0.07 ~ 0.1)	-0.48(-0.57~-0.37)
Tropical Latin America	0.39(0.37 ~ 0.41)	0.37(0.35 ~ 0.39)	0.78(0.71 ~ 0.82)	0.32(0.29 ~ 0.34)	-0.14(-0.2~-0.08)
North Africa and Middle East	2.14(1.31 ~ 2.74)	0.77(0.56 ~ 1)	1.9(1.33 ~ 2.3)	0.44(0.31 ~ 0.53)	-0.42(-0.57~-0.2)
South Asia	2.39(1.5 ~ 3.42)	0.31(0.17 ~ 0.5)	3.55(2.32 ~ 5.53)	0.25(0.16 ~ 0.42)	-0.19(-0.38 ~ 0.04)
Central Sub-Saharan Africa	0.09(0.05 ~ 0.16)	0.24(0.11 ~ 0.47)	0.13(0.06 ~ 0.24)	0.19(0.08 ~ 0.37)	-0.21(-0.4 ~ 0.05)
Eastern Sub-Saharan Africa	0.37(0.22 ~ 0.69)	0.27(0.12 ~ 0.52)	0.47(0.22 ~ 0.88)	0.18(0.07 ~ 0.34)	-0.35(-0.46~-0.14)
Southern Sub-Saharan Africa	0.04(0.03 ~ 0.06)	0.12(0.08 ~ 0.17)	0.07(0.05 ~ 0.09)	0.11(0.08 ~ 0.13)	-0.07(-0.29 ~ 0.21)
Western Sub-Saharan Africa	0.33(0.19 ~ 0.62)	0.25(0.09 ~ 0.51)	0.52(0.31 ~ 0.77)	0.17(0.07 ~ 0.28)	-0.33(-0.52~-0.07)

Table 3. The DALYs of PH in 1990/2021and temporal trends
Characteristics	1990		2021		1990–2021
Characteristics	DALYs No×10³ (95% UI)	Age standardized DALYs/10⁵ No. (95% UI)	DALYs No×10³ (95% UI)	Age standardized DALYs/10⁵ No. (95% UI)	EAPC No. (95% UI)
Overall	687.42(535.24 ~ 813.09)	13.21(10.78 ~ 15.36)	642.1(552.27 ~ 728.99)	8.24(7.14 ~ 9.39)	-0.38(-0.48~-0.25)
Sex
Male	369.69(316.03 ~ 424.98)	14.09(11.89 ~ 16.35)	299.64(246.73 ~ 348.33)	8.06(6.72 ~ 9.36)	-0.43(-0.51~-0.32)
Female	317.73(194.73 ~ 444.01)	12.32(7.78 ~ 16.8)	342.47(282.65 ~ 430.64)	8.39(6.92 ~ 10.53)	-0.32(-0.5~-0.02)
Socio-demographic factor
High SDI	81.79(77.18 ~ 88.11)	9.16(8.71 ~ 9.9)	93.18(84.87 ~ 99.19)	6.16(5.76 ~ 6.49)	-0.33(-0.4~-0.27)
High-middle SDI	127.64(106.71 ~ 154.44)	13.14(10.91 ~ 16.04)	99.45(85.76 ~ 117.64)	6.48(5.61 ~ 7.87)	-0.51(-0.62~-0.35)
Middle SDI	210.95(172.86 ~ 258.35)	14.29(11.66 ~ 17.69)	197.17(148.78 ~ 232.32)	8.23(6.26 ~ 9.7)	-0.42(-0.58~-0.25)
Low-middle SDI	195.28(117.19 ~ 245.59)	14.92(10.74 ~ 18.41)	156.4(122.43 ~ 194.17)	9.07(7.05 ~ 11.6)	-0.39(-0.51~-0.21)
Low SDI	71.12(48.63 ~ 111.61)	12.42(7.78 ~ 19.19)	95.34(67.47 ~ 133.05)	9.3(6.08 ~ 13.2)	-0.25(-0.43~-0.07)
Region
East Asia	151.6(117.39 ~ 205.77)	15.78(12.34 ~ 21.21)	154.74(102.94 ~ 190.4)	8.84(5.99 ~ 11.01)	-0.44(-0.65~-0.2)
Southeast Asia	27.79(18.24 ~ 51.94)	6.31(4.28 ~ 12.72)	31.11(22.91 ~ 58.71)	4.65(3.39 ~ 9.25)	-0.26(-0.43 ~ 0)
Oceania	0.7(0.45 ~ 1.09)	10.85(7.02 ~ 17.55)	1.45(0.99 ~ 2.41)	10.14(6.9 ~ 17.1)	-0.07(-0.27 ~ 0.2)
Central Asia	9.07(7.2 ~ 10.65)	14.14(11.27 ~ 16.45)	11.62(9.51 ~ 14.2)	12.91(10.61 ~ 15.6)	-0.09(-0.25 ~ 0.13)
Central Europe	11.03(9.78 ~ 12.15)	8.15(7.25 ~ 8.95)	10.42(9.51 ~ 11.46)	6.05(5.5 ~ 6.67)	-0.26(-0.35~-0.14)
Eastern Europe	20.63(18.78 ~ 23.86)	9.23(8.47 ~ 10.49)	8.36(7.76 ~ 9)	3.32(3.1 ~ 3.56)	-0.64(-0.69~-0.59)
High-income Asia Pacific	18.47(17.69 ~ 19.47)	12.03(11.43 ~ 12.79)	19.99(17.44 ~ 22)	8.31(7.74 ~ 8.87)	-0.31(-0.37~-0.25)
Australasia	1.51(1.34 ~ 1.86)	7.37(6.49 ~ 9.06)	1.43(1.31 ~ 1.56)	3.67(3.38 ~ 3.99)	-0.5(-0.61~-0.42)
Western Europe	34.6(31.74 ~ 38.28)	8.27(7.69 ~ 9.18)	34.04(31.02 ~ 36.44)	5.05(4.75 ~ 5.32)	-0.39(-0.46~-0.34)
Southern Latin America	7.98(7.18 ~ 8.8)	16.28(14.65 ~ 17.95)	4.74(4.44 ~ 5.09)	6.55(6.13 ~ 7.07)	-0.6(-0.65~-0.54)
High-income North America	30.59(28.11 ~ 33.06)	10.13(9.39 ~ 10.99)	38.37(35.06 ~ 40.84)	7.71(7.17 ~ 8.18)	-0.24(-0.31~-0.18)
Caribbean	7.4(4.17 ~ 11.15)	19.72(11.78 ~ 28.82)	5.07(2.99 ~ 7.88)	11.73(6.48 ~ 18.74)	-0.41(-0.56~-0.22)
Andean Latin America	5.05(2.98 ~ 7.42)	11.92(7.83 ~ 16.43)	3.54(2.8 ~ 4.49)	5.73(4.52 ~ 7.28)	-0.52(-0.65~-0.26)
Central Latin America	9.97(8.84 ~ 11.85)	6.12(5.4 ~ 7.16)	7.25(6.39 ~ 8.41)	3(2.63 ~ 3.51)	-0.51(-0.61~-0.41)
Tropical Latin America	19.06(17.86 ~ 20.36)	14.18(13.35 ~ 14.98)	24.23(23 ~ 25.4)	10.22(9.65 ~ 10.78)	-0.28(-0.34~-0.22)
North Africa and Midd le East	145.73(74.88 ~ 204.07)	35.84(21.25 ~ 46.14)	80.75(58.09 ~ 98.81)	14.81(10.76 ~ 17.96)	-0.59(-0.73~-0.4)
South Asia	136.09(77.81 ~ 184.38)	12.24(7.79 ~ 17.12)	136.56(97.81 ~ 189.35)	8.54(6.02 ~ 12.46)	-0.3(-0.44~-0.1)
Central Sub-Saharan Africa	5.37(3.26 ~ 10.52)	9.09(5.65 ~ 17.13)	6.52(3.59 ~ 11.03)	6.16(2.94 ~ 11.09)	-0.32(-0.55~-0.07)
Eastern Sub-Saharan Africa	23.15(14.69 ~ 45.77)	11.11(6.18 ~ 21.17)	26.6(14.27 ~ 49.62)	6.85(3.3 ~ 12.62)	-0.38(-0.53~-0.19)
Southern Sub-Saharan Africa	2.19(1.67 ~ 2.87)	4.7(3.65 ~ 6.37)	3.21(2.36 ~ 3.89)	4.33(3.21 ~ 5.2)	-0.08(-0.28 ~ 0.14)
Western Sub-Saharan Africa	19.83(13.55 ~ 38.85)	9.34(5.22 ~ 16.94)	32.07(22.08 ~ 47.22)	6.5(3.77 ~ 9.47)	-0.3(-0.48~-0.08)
Table 3. PH, pulmonary hypertension; SDI, social-demographic index; DALYs, disability-adjusted life years; EAPC, annual percentage change.

Among 21 geographic regions, East Asia had the highest prevalences (42,490 (95%UI: 33,930 − 53,040)), deaths (7,490 (95%UI: 4,990-9,270)) and DALYs (154,740 (95%UI: 102,940 − 190,400)) in 2021 (Table 1–3). The highest ASPR was in West Europe in 2021 (3.56 per 100,000 populations (95%UI: 2.92–4.35)). ASDR and age-standardized DALYs were highest in North Africa and Middle East (0.44 per 100,000 populations (95%UI: 0.31–0.53) and 14.81 per 100,000 populations (95%UI: 10.76–17.96)).

At the national level, China presented the highest prevalences (41,135 (95%UI: 32,839 − 51,357)), deaths (7,318 (95%UI: 4,836-9,076)) and DALYs (150,941 (95%UI: 99,583 − 186,503)) in 2021 (Supplementary file 1). After age standardization, PH burden varied greatly in different countries (Fig. 4A-C). Switzerland had the biggest ASPR, while Mongolia held the highest ASDR and age-standardized DALYs in 2021 (Supplementary file 2). As for annual change of PH burden during the past thirty-two years, it increased most rapidly for ASPR in Nigeria, ASDR in Latvia and age-standardized DALYs in Mauritius, while it decreased most significantly for ASPR in Democratic Republic of the Congo, ASDR and age-standardized DALYs in Puerto Rico (Supplementary file 3 and Fig. 4D-F).

As reported, PH usually accompanied with multiple cardiopulmonary comorbidities, leading to the increase of difficulty in PH management [17]. Here, we assessed the relationship between PH prevalence and other common coincident disorders, containing COPD, ILD, IHD and HHD. As depicted in in Fig. 5, either in 21 regions or 204 countries, prevalence of PH all demonstrated strongly positive associations with that of COPD, ILD, IHD and HHD.

In the current study, we systematically summarized the global trend and cross-country disparity for PH burden from 1990 to 2021. In general, the prevalent cases and deaths of PH have surged during the past thirty-two years, even tripled in certain regions. Interestingly, PH prevalence preferred to affect young adult, whereas the death mainly attacked the advanced elders. Regional distributions of PH burden by SDI, health system, region and country, varied heterogeneously. After standardization by age, PH burden collectively presented declined trends, characterized by significant decreases in ASDR and age-standardized DALYs particularly in regions with more advanced SDI or health system. Eventually, we confirmed four coalescent cardiopulmonary diseases (COPD, ILD, IHD and HHD), intensively associated with PH prevalence. Collectively, this report provided a comprehensive understanding for epidemiological situation of PH, and a valuable reference for government or health-care workers in high-burden regions to combat this disease.

It’s not difficult to discern that compared with 1990, PH prevalence rose up to almost two times in 2021 by a large margin worldwide and cross various regions. On one hand, the significant increase in PH cases was primarily attributed to the rapid population growth, particularly in low-income areas [18]. On the other hand, constantly updated definition and classification of PH also enlarged the enrollment numbers of PH patients, such as the hemodynamic cutoff value altering from 25 mmHg to 20 mmHg [19, 20]. It can be easily imagined that there might be plenty of undiagnostic PH cases in 1990 owing to incomplete or unperfected standard of diagnosis. In addition, population ageing undoubtedly played an indispensable role in the climbing trend of PH prevalent cases [21], and ageing was reported to serve as a predictor of high mortality for PH patients [22]. As the society structure verges to demographic ageing, more elders have suffered from diversified cardiopulmonary diseases like COPD and heart failure, which increased the risk of class II and III PH [23, 24]. All factors above can likewise account for increased deaths of PH.

One noticeable feature for PH is female preponderance [25, 26], which was totally echoed by our result. The disparities in the incidence, progression and prognosis for PH patients with different sexes covered multiple mechanisms, taking sex hormones, metabolites, genetic and sociocultural factors for instance, which probably exert a complicated effect in disease expression [27]. Moreover, group I PH including idiopathic PH, heritable PH, congenital heart disease related-PH and connective tissue disease related-PH, often affects women of childbearing age [28]. Therefore, a better knowledge of PH preference in females may conduce to a decreased disease burden and an improved quality of life [29].

In this report, PH prevalence exhibited young adult predomination, closely followed by populations age from 50 to 69 years. Discrepantly, more researches suggested advanced elders (> 65 years) were inclined to suffer from PH and showed worse clinical manifestations [30, 31], which can be attributed to elders accompanied by more chronic conditions. In addition, the age distribution of PH prevalence by SDI regions indicated that PH majorly affected the elders (> 50 years) in high SDI regions, whereas affects the young in low SDI regions probably owing to shorter life span for residents inhabited in those relatively poor regions [32]. According to a summary report of rare diseases in China, approximately 52% of rare diseases including PH spread in adults age from 25 to 64 years, similar to our result [33].

In areas with higher SDI, PH deaths and DALYs were primarily distributed in advanced-age elders, which could be ascribed to that advanced medical equipment and technology can manage the younger PH patients whereas cannot deal with older patients because of their complicated physical condition. In areas with lower SDI, the main deaths and DALYs were among children under 14 years, which might be related to poorer medical conditions and lower immunity with susceptibility to infection-related deaths [34]. Intriguingly, after age standardization, ASDR and age-standardized DALYs presented distinctive decreases globally and slightly negative association with SDI across different regions or countries. The self-evident reason is certainly due to the milder disease severity and easier management for most young PH patients, especially in developed districts with advanced medical resources.

As reported, PH exhibited intimate association with chronic respiratory disease, particularly with COPD and ILD [35], which was furtherly verified by our study. From the pathogenesis, in patients suffered from COPD or ILD, the number of blood vessels notably diminished and impaired gas reflux or exchange, consequently leading to elevated pressure of pulmonary vasculature [36]. Additionally, long-term exposure to hypoxia facilitates the generation of various vasoconstrictive agents like endothelin and serotonin, resulting in proliferations of multiple cells like pulmonary artery smooth muscle cells [37], which can lead to intimal hyperplasia and medial hypertrophy, finally contributing to PH incidence. Of note, the causal relationship between PH and chronic respiratory disorders might be of bidirection with complex and multifactorial mechanisms, potentially attributable to the interaction between genetic and environmental insults [38]. In addition, we confirmed two cardiac disorders closely associated with PH prevalence, namely IHD and HHD, which could eventually progress to heart failure, a known cause of PH [39]. Nevertheless, the development and severity of PH with cardiac diseases are highly variable, and contributing factors remain under investigation.

Several limitations have been acknowledged in this study. Firstly, the robustness and reliability of these results primarily rely on the quality and availability of each country’s vital registration system. Moreover, there’s no available data on PH burden by different classifications, which leads to a certain difficulty in comprehensive analysis for PH burden. Eventually, more interconnected disorders with PH deserve further explorations, like connective tissue disease and infectious diseases.

In conclusion, the global burden of PH is tremendous and female predomination, and varied greatly among different regions and countries. PH primarily affects the elders in relatively advanced regions, while affects the youngers in low-income areas. As society and medical system progresses, age-standardized rates of PH deaths and DALYs both exhibited alleviations. Furthermore, PH prevalence presented strong associations with multiple cardiopulmonary disorders. Therefore, we highlight that this report may assist policy-makers and healthcare workers to acquaint the global and regional burden of PH, and develop cost-effective strategies to further lower its burden.

Acknowledgments

We are grateful to all staffs of the Global Burden of Disease Study for their work.

Conflict of Interest

The authors declare no conflicts of interest.

Author Contributions

ZLZ and YZ had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final manuscript. Concept and design: ZLZ and YZ. Acquisition, analysis and interpretation of data: HLC, LYP, QHL, QW, SC and QYC. Drafting of the manuscript: ZLZ, RNY and YZ. Revision of the manuscript: LYP and JQH. Statistical analysis: RNY and LYP; Supervision: ZLZ and YZ.

Funding

This work was funded by National Natural Science Foundation of China (No. 81800041 and 82000078).

Data Availability Statement

The datasets used in the present study are available in GBD 2021.

Ethics approval and consent to participate

N/A.

Consent for publication

N/A

Competing interests

All authors declare no conflict of interest.

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No competing interests reported.

Trends and cross-country disparity in the burden of pulmonary arterial hypertension: results from Global Burden of Disease Study 2021

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