3.1 Global burden estimates of hemoglobinopathies and hemolytic anemia
Over the past three decades, global prevalence and trends of hemoglobinopathies and hemolytic anemia have been summarized by sex, SDI levels, and WHO regions in Table 1. While the absolute number of cases globally increased by 50% from 1990 (134,949,0276) to 2019 (211,467,0544), the standardized global prevalence showed a modest increase (EAPC = 0.26), transitioning from 25,093.8 per 100,000 in 1990 to 27,443.95 per 100,000 in 2019, which may could be attributed to population growth worldwide. However, there is a substantial disparity among countries. For instance, Australia had the lowest prevalence at 5,756.06 per 100,000 in 2019, while Burkina Faso recorded the highest at 51,401.63 per 100,000. Notably, all 14 countries with a prevalence exceeding 40,000 per 100,000 in 2019 were African, and out of the 34 nations with rates above 30,000 per 100,000, 25 were African, where the prevalence remained relatively stable between 1990 and 2019 (EAPC = 0.01), indicating a persistent high disease burden in this region (Table S1). From a perspective of change in prevalence, no region exhibited an EAPC greater than 1, with most countries showing declining trends. Malaysia experienced the most significant decline (EAPC=-1.81), with its net prevalence reducing from 29283.1 per 1,000,000 in 1990 to 17443.27 per 1,000,000 in 2019. Further analysis was conducted on the three subsets under hemoglobinopathies and hemolytic anemia category: thalassemia, G6PD deficiency, and other hemoglobinopathies and hemolytic anemias (Table S2-4). These analyses revealed similar findings, suggesting that despite global population growth, the prevalence of hemoglobinopathies and hemolytic anemia has generally stabilized across the world, accompanied by considerable regional disparities. It is important to note that in countries with low prevalence, the EAPC may not accurately reflect the situation. Guam, for example, displayed the largest relative change (EPAC = 4.51), yet its actual increase in prevalence was minimal, rising only from 0.1 per 100,000 to 0.32 per 100,000.
Notably, we observed that since 1990, the absolute number of cases and prevalence rates for hemoglobinopathies and hemolytic anemias have been consistently higher in women than men globally (Fig. 1A and B), with both sexes showing an annual increase. The trend lines for Middle SDI regions closely parallel those at the global level, yet the overall rise in global prevalence from 1990 to 2019 is largely attributed to increases in Low SDI (EAPC = 0.07) and Low-Middle SDI regions (EAPC = 0.22) (Fig. 1C and D). Although the global prevalence varied in its ascending or descending course across different SDI areas over this period, there was an upward trend in Low and Low-Middle SDI regions, particularly an exponential rise in the latter, suggesting significant influence of total fertility rate, education levels, and income status on disease burden. Upon further examination of sex disparities, we observed that the female-to-male prevalence ratio has remained constant between 1990 (ratio value = 1.92) and 2019 (ratio value = 1.94), indicating a persistent trend across all global regions where the prevalence of the disease is consistently higher among women than men (Figure S1A). Remarkably, in High SDI regions, this ratio steadily increased from 1990 until 2002, followed by an eight-year plateau and then a sharp decline beginning in 2010. Nonetheless, by 2019, High SDI regions still exhibited the highest woman-to-man ratio (ratio value = 2.55). In terms of prevalence in 2019, both man and woman patients showed the highest rates in African regions, followed by the South-East Asia Region (Figure S1B). These shifts indicate a gradually increasing imbalance in the disease burden of hemoglobinopathies and hemolytic anemias between sexes within various geographic regions.
3.2 The proportion of HF impairment with anemia worldwide
We further scrutinized the global burden of HF in conjunction with hemoglobinopathies and hemolytic anemias using GBD database. Globally, there was a significant increase in HF cases from 508,034.99 in 1990 to 8,477,358.8 in 2019, accompanied by a rising prevalence rate (EAPC = 0.49). The disease burden of HF combined with anemia displayed substantial regional disparities too (Table S5). In 2019, China had the highest number of HF cases (2,206,890), while Nuie recorded the fewest (0.01); Puerto Rico showed the largest EAPC (3.13), contrasting with Singapore's smallest (− 1.61), emphasizing that population size alone does not account for these variations. The proportionate contribution by subtype revealed that other hemoglobin diseases and hemolytic anemias exhibited the most considerable increase (Figure S2A, B). When HF severity was stratified (Figure S2C, D), treated HF contributed the most to the overall HF burden, with mild, moderate, and severe HF proportions remaining relatively stable, where treated HF accounted for the largest share and moderate HF for the least. By SDI quintiles (Figure S3A), the ratio of HF impairment to hemoglobinopathies and hemolytic anemias fluctuated around 40 parts per million (ppm) between 1990 and 2019. Low and Low-Middle SDI regions reported ratios lower than the global average and remained stable, whereas Middle-High SDI areas showed a marked annual increase from 48.78 ppm in 1990 to 62.04 ppm in 2019, exceeding the global mean level. Surprisingly, High SDI regions consistently registered higher increases, escalating from 82.80 ppm in 1990 to 114.22 ppm in 2019, well above the global average. On the other hand, the Western Pacific Region had the highest proportion of HF, with treated HF at 26.90 ppm and severe HF at 23.76 ppm in 2019, surpassing other regions (Fig. 2A). Sex-wise, the global HF-anemia burden was approximately balanced (Fig. 2B), yet given the woman preponderance in hemoglobinopathies and hemolytic anemias, this suggests potentially higher HF risk in man. In line with this, High SDI regions bore the heaviest burden, with both sexes showing the highest proportions, women exceeding men. However, when considering WHO regions, the Eastern Mediterranean Region uniquely demonstrated a sex reversal, with men HF proportions exceeding those of women. At the national level (Table S6), Japan had an exceptionally high percentage of HF impairment with hemoglobinopathies and hemolytic anemias (442.44 ppm in 2019), significantly higher than any other country. This was attributed to substantial increases across all HF severity categories: severe HF increased from 79.18 ppm in 1990 to 143.74 ppm in 2019; moderate HF from 29.74 ppm to 53.99 ppm; mild HF from 45.17 ppm to 82.03 ppm; and treated HF from 89.62 ppm to 162.67 ppm. Notably, India, which had the highest absolute number of cases of hemoglobinopathies and hemolytic anemias (549,607,496.9; 95% uncertainty intervals [UI]: 526,368,231.3–574,421,936.1), had a relatively low HF proportion of 6.23 ppm in 2019. Conversely, China, ranking third in case numbers (351,078,721.1; 95% UI: 35,324,615.8–371,551,646.8), had a notably higher HF proportion of 62.86 ppm in 2019, exceeding the global average (Table S6).
3.3 Prevalence trends of HF impairment with anemia
Since 1990, the global prevalence of anemia coexisting with HF has steadily risen, with a global EAPC value of 0.49 (Table S5). Despite the fewest anemia cases (Fig. 1C), High SDI regions paradoxically exhibit the highest HF prevalence (Fig. 3A) and proportion (Figure S3A). Conversely, Low-Middle SDI areas have the most anemia cases but record the lowest HF prevalence (Fig. 3A) and proportion (Figure S3A). Notably, we found that almost all WHO regions experience a persistent increase in the combined prevalence of anemia and HF, with the Western Pacific Region showing the largest increment (EAPC = 1.03) and concurrently the highest prevalence (Table 2). Of particular concern is the high proportion of severe HF cases in this region, which account for nearly one-third of all HF cases (Fig. 2A), potentially exacerbating future health disparities between regions. Among all WHO regions, only the Eastern Mediterranean Region showed a negative growth trend (EAPC=-0.06). At the national level, there is substantial variation in the combined prevalence of anemia and HF across countries, accompanied by differing proportions of HF subtypes. China alone surpasses the total number of HF cases in High SDI regions, with a relatively high annual growth rate (EAPC = 1.11). In contrast, countries with the highest EAPC—Puerto Rico (3.31), Guam (2.5), Trinidad and Tobago (2.38), and Northern Mariana Islands (2.23)—exhibit lower case numbers and prevalence rates (Table S5, Fig. 3C, D). Moreover, among nations with a prevalence greater than 1000 per 100,000, France (EAPC=-0.74), Canada (EAPC=-0.31), and the Democratic Republic of the Congo (EAPC=-0.1) are the only countries to show a decreasing trend in HF prevalence (Fig. 3D). When considering prevalence exceeding 5000 per 100,000, no country displayed a negative EAPC.
Our findings further confirm that women bear a higher disease burden of anemia than men (Fig. 1 and Figure S1A), aligning with previous research.(21) Notably, in High SDI regions, despite a declining trend, the proportion of women affected by anemia remains significantly greater than men. In contrast, while HF prevalence is generally higher among women across most regions, with this disparity increasing over time (Fig. 4A-D), a noteworthy inversion emerges: the sex gap in HF prevalence is much smaller than that for anemia (Fig. 4E), and men exhibit a disproportionately higher rate of HF (Figure S3B), suggesting increased susceptibility to heart failure in men. Segmented by SDI quintiles, both men and women HF prevalence was highest in High SDI areas in 2019—interestingly, where hemoglobinopathies and hemolytic anemia rates are lowest across all SDI regions. This is largely due to the escalation in treated and severe heart failure cases (Fig. 2B). When categorized by WHO regions, the South-East Asia Region had the lowest HF prevalence for both sexes, with each class of HF being least prevalent within this region (Fig. 2).
3.4 Discussion
Anemia, due to its multifactorial etiology, has rarely been studied in depth concerning its specific subtypes and their relationship with heart failure. Our GBD study findings indicate that while the absolute number of cases for hemoglobinopathies and hemolytic anemias worldwide has increased annually, their standardized prevalence rates have remained stable over the past three decades. However, the prevalence of heart failure associated with anemia has significantly risen during this period (EAPC = 0.49), which demonstrating a marked regional specificity. There is an emerging tendency where disease burden shifts towards High SDI regions, potentially leading to a dichotomy where these areas may see the lowest numbers and rates of hemoglobinopathies and hemolytic anemias but the highest rates of heart failure exacerbated by anemia.
The relationship between anemia and heart failure has been subject to several decades of inquiry, with the exact inception point of focused research challenging to pinpoint due to the interplay of advancements across multiple disciplines.(22) Our findings indicate that in resource-poor regions, particularly those within sub-Saharan Africa, hemoglobinopathies and hemolytic anemias present with the highest absolute case numbers and prevalence rates, potentially exacerbated by a concentration of HB variants in specific populations.(23) A study involving 900 reproductive-age women and 395 children from anemia-endemic nations found that at least one genetic blood disorder was prevalent in 11% of women and 10% of children,(24) with malnutrition and food scarcity likely compounding this burden. High SDI areas, reflecting higher income, education, and fertility control,(14) generally provide better access to healthcare services including prenatal care, genetic counseling, and disease management. However, paradoxically, our data reveal a higher prevalence of heart failure associated with anemia-related damage in High SDI settings. In these contexts, while advanced medical resources can extend patient lifespans, prolonged disease presence may lead to complications, compounded by unhealthy lifestyle habits that elevate heart failure risk. On the other hand, iron overload increases heart failure risk,(25, 26) therefore the American College of Physicians recommends restrictive transfusion strategies (≤ 7–8 g/dl) for patients with heart failure who require transfusions.(27) Furthermore, the use of ESA to improve hemoglobin levels in heart failure patients is associated with increased risks of stroke and thrombotic events.(28) Concurrently, cardiovascular risk factor summary exposure value (SEV) is elevated in High SDI regions. Malekpour's report showed SEV for smoking ranging from 14.73 in High SDI to 10.80 in Low SDI areas.(29) Zhang attributed the largest increase in ischemic stroke incidence during 1990 to 2019 primarily to high alcohol consumption in High SDI regions.(30) The 2019 GBD data highlighted the highest incidence and prevalence of chronic kidney disease related to type 2 diabetes mellitus in High SDI regions.(31) Additionally, a global study on pediatric diabetes burden revealed a rate of 26.24 cases per 100,000 children in High SDI areas in 2019, significantly exceeding the global average and other SDI regions.(32) These findings suggest that in High SDI regions, cardiovascular diseases may be subject to heightened risk exposures influenced by a myriad of factors. It is also crucial not to overlook the potential underestimation of heart failure burden in Low SDI areas, where relative scarcity of healthcare resources could limit comprehensive disease detection and management.
Prolonged anemia directly yields elevated cardiac output and cardiac iron accumulation.(33, 34) A multitude of reports attest that iron excess potentiates the generation of reactive oxygen species(35) and fosters oxidative reactions, culminating in endothelial injury, atherosclerotic progression, and hence myocardial and vascular pathologies, amplifying the vulnerability to heart failure.(36–38) Furthermore, augmented hemoglobin levels resulting from transfusions raise systemic vascular resistance and increase left ventricular workload.(39) Notably, there exists a temporal correlation between rising hemoglobin concentrations and diminishing left ventricular ejection fraction.(40) Genetically, heart disease assumes a central role in morbidity and mortality within the context of β-thalassemia,(41, 42) being the predominant cause of death, and similarly represents a critical etiological factor and key prognosticator in the course of sickle cell anemia.(43, 44)
Over the past three decades, the proportion of cases where anemia coexists with heart failure has been approximately twice as high in men compared to women (Figure S3B). Research on hemoglobinopathies suggests that among male and female patients with similar serum ferritin levels and equivalent numbers of blood transfusions, men tend to experience more left ventricular systolic dysfunction.(45, 46) A study on the disease burden of thalassemia concurrent with heart failure also underscores that men are at greater risk for heart failure within the anemic population.(47) Two plausible reasons for these differences are genetic predispositions and sex-specific hormonal influences. While autosomal DNA sequences, gene structure, and allele frequencies do not differ between sexes, regulatory genomic elements can exhibit sexual dimorphism.(48) Potential mechanisms may involve differential gene regulation in men and women, particularly in sex steroid-responsive genes,(49) where potential sex differences in oxidative stress response pathways could differently affect susceptibility to cardiovascular diseases in both sexes. Additionally, hormonal profiles contribute further to cardiovascular disparities.(50, 51) Beyond these factors, environmental conditions, lifestyle habits such as smoking and alcohol consumption, and dietary practices may collectively heighten cardiovascular risks for men.
Our study is fundamentally constrained by its reliance on secondary data sources, a dependency that inherently introduces potential biases due to limitations in measurement accuracy, variations in case definitions over time, and heterogeneity in study designs. This constellation of factors can lead to systematic deviations in the statistical outcomes we derive. Meanwhile, it centers on disease analysis within the context of big data and stands in contrast to traditional analyses in its lack of consideration for potential confounding variables, thereby predisposing it to bias. Future research endeavors should actively contemplate incorporating additional variables with latent explanatory power, such as the application of iron chelation therapy. The exploration of these elements could significantly bolster the robustness and reliability of the derived results. Simultaneously, the GBD project has been evolving and maturing, enhancing the precision and credibility of its estimation techniques. As opposed to standalone studies reliant on primary data alone, GBD's aggregated estimates furnish a more comprehensive and consistent epidemiological panorama of disease prevalence worldwide. Ultimately, overcoming these limitations constitutes a critical endeavor aimed at providing rigorous guidance for decision-making in clinical care and public health policy formulation. By refining our understanding through improved methodologies, we aspire to inform the optimization of healthcare strategies and public health interventions, thus steering policy decisions towards greater effectiveness and relevance.