Heart Failure Attributable to Hemoglobinopathies and Hemolytic Anemia: A Three-Decade Cross-Sectional Assessment of the Global Burden

Heart Failure Attributable to Hemoglobinopathies and Hemolytic Anemia: A Three-Decade Cross-Sectional Assessment of the Global Burden | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Heart Failure Attributable to Hemoglobinopathies and Hemolytic Anemia: A Three-Decade Cross-Sectional Assessment of the Global Burden Xiaoqi Deng, Lei Yu, Jie He, Yufan Fu, Lan Jiao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4225579/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Complexity of anemia subtypes remains unresolved, and therapies targeting anemia have inconsistently improved heart failure (HF) outcomes. This study aims to assess the prevalence trend and contributing factors of HF impairment with hemoglobinopathies and hemolytic anemia at global, regional and national levels. Main body of the abstract: Utilizing Global Burden of Disease (GBD) data for HF and hemoglobinopathies inclusive of hemolytic anemia, we systematically gathered annual figures for prevalence and incidence. Estimated Annual Percentage Changes (EAPCs) were computed to assess temporal trends in these diseases. Estimates were subsequently disaggregated by sex, geographical regions, and national levels to present a concise yet detailed picture of the disease dynamics globally. During the past three decades, although the absolute caseloads of hemoglobinopathies and hemolytic anemias grew without altering their standardized prevalence (EAPC = 0.26), the rate of heart failure compounded by anemia sharply rose (EAPC = 0.49). Notably, in high Sociodemographic Index (SDI) regions, the HF-to-hematological disorder ratio ascended more rapidly, moving from 82.80 parts per million (ppm) in 1990 to 114.22 ppm in 2019, surpassing the worldwide average increment (40 ppm). Despite greater anemia-related burdens among females, male patients experienced a disproportionately higher frequency of heart failure. Short conclusion: Over the past three decades, there has been a steady rise in the prevalence of heart failure comorbid with hemoglobinopathies and hemolytic anemias, with a more pronounced disease burden observed among men and a discernible shift toward High SDI regions. GBD hemoglobinopathies hemolytic anemia heart failure Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Background Anemia is a prevalent comorbidity in heart failure (HF) patients, serving as an indicator of HF severity and a predictor of adverse outcomes.( 1 ) Both anemia and HF independently constitute significant global health burdens.( 2 , 3 ) Despite intensive evaluation over the past years, treatment with erythropoiesis-stimulating agent (ESA) for anemia in HF has not improved clinical outcomes but rather been linked to increased risks of adverse events,( 4 ) raising concerns about the role of anemia in HF progression and its therapeutic management. While previous reviews suggest that interventions aiming to elevate hemoglobin levels have shown no clear benefit, clinical evidence consistently indicates a correlation between anemia and HF.( 5 ) However, due to the multifactorial etiology of anemia, comprehensive and systematic screening for all subtypes remains challenging, and large-scale randomized controlled trials are difficult to conduct. In brief, anemia can be categorized into congenital and acquired forms, with hemoglobinopathies being genetic disorders characterized by quantitative or qualitative defects in hemoglobin molecules, exemplified by sickle cell disease and thalassemias.( 6 , 7 ) These hemoglobinopathies represent the most common monogenic diseases globally, historically confined to specific geographic regions but now more widely distributed due to population migration.( 8 ) More than 1% of couples worldwide carry a risk of having children affected by these conditions, with many affected children succumbing to early mortality.( 9 ) In recent years, hemoglobinopathies have become a focus of international public health concern,( 10 ) prompting global screening initiatives by organizations such as the World Health Organization (WHO).( 6 , 11 ) Hemolytic anemia(HA), another class of anemia, results from premature destruction or clearance of red blood cells and can be either inherited or acquired.( 12 ) Despite their significance, few studies have investigated the relationship between hemoglobinopathies, hemolytic anemia, and HF. Our study specifically focuses on the backdrop of the GBD project, concentrating on elucidating the intricate interplay between HF and concomitant anemia at a global level. Leveraging the GBD dataset, we aim to quantify the worldwide prevalence and implications of HF complicated by anemia, thereby delivering critical insights into the global health burden attributed to this comorbidity. The purpose of this endeavor is to inform future clinical practices and research strategies targeting the management and prevention of anemia among HF patients, ultimately leading to improved patient outcomes and alleviated global health consequences. 2. Construction and content 2.1 Study data The GBD project, initiated by the Institute for Health Metrics and Evaluation at the University of Washington, the Harvard School of Public Health, and several other organizations, provides a unified framework for tracking temporal trends in diseases, injuries, and risk factors across time and geography. Utilizing consistent or near-consistent data collection methods and tools, GBD covers health data from over 200 countries and territories between 1990 and 2019.( 13 , 14 ) By aggregating information from publicly available sources such as measured data, literature reviews, surveillance reports, clinical datasets, and health insurance claims, the project employs Bayesian meta-regression tool DisMod-MR 2.1 to present a comprehensive quantification of health loss in terms of epidemiological metrics like prevalence, mortality rates, and disability-adjusted life years (DALYs), ensuring consistency across multiple data streams for a given disease.( 15 , 16 ) In this study, we extracted epidemiological data on hemoglobinopathies and hemolytic anemia prevalence from the GBD, stratified by sex and region. We further analyzed the temporal patterns of heart failure-related health burden globally, regionally, and nationally from 1990 to 2019. Access to these pertinent data is available via the Global Health Data Exchange website ( http://ghdx.healthdata.org/gbd-results-tool ). 2.2 Data collection In this section, we examined the global, regional, and national trends in the co-occurrence of heart failure with hemoglobinopathies and hemolytic anemia from 1990 to 2019, as well as the variations in associated indicators by sex and region. Specifically, we incorporated data across four dimensions of anemia: Hemoglobinopathies and HA, Thalassemia, Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency, and other HA, where the latter three are subsets within the broader category of HA. Heart failure was stratified into four severity groups: treated heart failure refers to patients diagnosed and actively managed with medications and lifestyle changes to maintain a good quality of life; mild heart failure includes those at risk or in the pre-heart failure stage without clinical symptoms; moderate heart failure denotes patients with evident clinical signs and symptoms; and severe heart failure pertains to individuals with significantly debilitating symptoms that severely impact their quality of life and functional status. These categories align with the clinical diagnostic criteria set forth by the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.( 17 ) The GBD project also computed the Sociodemographic Index (SDI) for each country, which is a composite metric reflecting social and economic conditions influencing health outcomes, incorporating total fertility rate among those under 25 years old, mean years of education for those aged 15 and above, and lag-distributed income per capita.( 14 , 18 ) The SDI is divided into five quintiles: low, low-middle, middle, high-middle, and high. Furthermore, we grouped countries and territories from over 200 nations based on their respective regions and national contexts. 2.3 Statistical analysis We employed Estimated Annual Percentage Changes (EAPC) as a quantifiable metric to assess prevalence trends over specific periods, which is independent of regional cultural backgrounds and socioeconomic conditions, thereby serving as an objective standard for measuring and comparing changes across different regions.( 19 , 20 ) If the EAPC value and its lower limit of the 95% Confidence Interval (95% CI) are less than 0, a declining trend is observed; conversely, an upward trend is indicated. These indicators were systematically compiled and tabulated according to sex, SDI level, and WHO regions. Statistical analyses, inclusive of determining statistical significance at p-values less than 0.05, were conducted using R Studio (Version 4.3.1). The data were synthesized into tables to present the comprehensive patterns of change. 3. Utility and discussion 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. 1 A 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. 1 C 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 S1 A). 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 S1 B). 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 S2 A, B). When HF severity was stratified (Figure S2 C, 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. 2 A). Sex-wise, the global HF-anemia burden was approximately balanced (Fig. 2 B), 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. 1 C), High SDI regions paradoxically exhibit the highest HF prevalence (Fig. 3 A) and proportion (Figure S3A). Conversely, Low-Middle SDI areas have the most anemia cases but record the lowest HF prevalence (Fig. 3 A) 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. 2 A), 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. 3 C, 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. 3 D). 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 S1 A), 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. 4 A-D), a noteworthy inversion emerges: the sex gap in HF prevalence is much smaller than that for anemia (Fig. 4 E), 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. 2 B). 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. 4. Conclusion Over the past three decades, while the global burden of hemoglobinopathies and hemolytic anemia has remained stable yet high, heart failure prevalence has been steadily increasing, particularly in High SDI regions and among men, underscoring the complex interplay of demographic characteristics, disease perceptions, genetic, and economic factors on disease progression. Our study provides a timely assessment of the overall disease burden and temporal trends regarding concurrent heart failure in patients with hemoglobinopathies and hemolytic anemia worldwide, further emphasizing the inherent connection between anemia and heart failure. These findings contribute valuable insights to inform appropriate policy responses to address this health issue effectively. List Of Abbreviations HF Heart failure GBD Global burden of disea EAPC Estimated Annual Percentage Changes ppm Parts per million ESA Erythropoiesis-stimulating agent WHO World Health Organization HA Hemolytic anemia DALYs Disability-adjusted life years G6PD Glucose-6-phosphate Dehydrogenase SDI Sociodemographic Index 95% CI 95% Confidence Interval SEV Summary exposure value Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The data are available from the Global Burden of Disease Results Tool of the Global Health Data Exchange (http://ghdx.healthdata.org/). Competing interests The authors declare that they have no competing interests. Funding This project has not received any form of funding. Authors' contributions All authors contributed to the study conception and design. X D: 'designed study', 'performed study', 'contributed important reagents', 'collected data', 'analyzed data' and 'wrote paper'; L Y: 'supervised the entire process', 'contributed important reagents' and 'offered sponsorship', J H, and Lan Jiao: 'performed study', 'analyzed data and 'wrote paper'; Y F: 'collected data', 'analyzed data' and 'wrote paper'. Acknowledgements We extend our heartfelt appreciation to the Global Burden of Disease Study group for their longstanding and outstanding contributions. References Magrì D, De Martino F, Moscucci F, Agostoni P, Sciomer S. Anemia and Iron Deficiency in Heart Failure: Clinical and Prognostic Role. Heart Fail Clin. 2019;15(3):359–69. Kassebaum NJ. The Global Burden of Anemia. Hematol Oncol Clin N Am. 2016;30(2):247–308. Metra M, Teerlink JR. Heart failure. Lancet (London England). 2017;390(10106):1981–95. Anand IS, Gupta P. 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Eur Heart J. 2016;37(14):1158–67. Aessopos A, Farmakis D, Trompoukis C, Tsironi M, Moyssakis I, Tsaftarides P, et al. Cardiac involvement in sickle beta-thalassemia. Ann Hematol. 2009;88(6):557–64. Sawicki KT, De Jesus A, Ardehali H. Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets. Circul Res. 2023;132(3):379–96. Triposkiadis F, Giamouzis G, Parissis J, Starling RC, Boudoulas H, Skoularigis J, et al. Reframing the association and significance of co-morbidities in heart failure. Eur J Heart Fail. 2016;18(7):744–58. Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002;106(20):2561–6. Aessopos A, Tsironi M, Vassiliadis I, Farmakis D, Fountos A, Voskaridou E, et al. Exercise-induced myocardial perfusion abnormalities in sickle beta-thalassemia: Tc-99m tetrofosmin gated SPECT imaging study. Am J Med. 2001;111(5):355–60. McMahon LP, Mason K, Skinner SL, Burge CM, Grigg LE, Becker GJ. Effects of haemoglobin normalization on quality of life and cardiovascular parameters in end-stage renal failure. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association -. Eur Ren Association. 2000;15(9):1425–30. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003;107(2):223–5. Kremastinos DT, Farmakis D, Aessopos A, Hahalis G, Hamodraka E, Tsiapras D, et al. Beta-thalassemia cardiomyopathy: history, present considerations, and future perspectives. Circulation Heart Fail. 2010;3(3):451–8. Modell B, Khan M, Darlison M, Westwood MA, Ingram D, Pennell DJ. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn resonance: official J Soc Cardiovasc Magn Reson. 2008;10(1):42. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of Sickle Cell Disease. Annu Rev Pathol. 2019;14:263–92. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350(9):886–95. Moussavi F, Ghasabeh MA, Roodpeyma S, Alavi S, Shakiba M, Gheiratmand R, et al. Optimal method for early detection of cardiac disorders in thalassemia major patients: magnetic resonance imaging or echocardiography? Blood Res. 2014;49(3):182–6. Hahalis G, Alexopoulos D, Kremastinos DT, Zoumbos NC. Heart failure in beta-thalassemia syndromes: a decade of progress. Am J Med. 2005;118(9):957–67. Tang H, Zhang N, Deng J, Zhou K. Changing trends in the prevalence of heart failure impairment with Thalassemias over three decades. Eur J Clin Invest. 2024;54(1):e14098. Reinius B, Saetre P, Leonard JA, Blekhman R, Merino-Martinez R, Gilad Y, et al. An evolutionarily conserved sexual signature in the primate brain. PLoS Genet. 2008;4(6):e1000100. Ober C, Loisel DA, Gilad Y. Sex-specific genetic architecture of human disease. Nat Rev Genet. 2008;9(12):911–22. Regitz-Zagrosek V, Kararigas G. Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiol Rev. 2017;97(1):1–37. Kloner RA, Carson C 3rd, Dobs A, Kopecky S, Mohler ER. 3rd. Testosterone and Cardiovascular Disease. J Am Coll Cardiol. 2016;67(5):545–57. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx TableS6.xlsx supplementarymaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4225579","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":288660267,"identity":"ad6c95dd-9de6-433d-ac0d-1fb13d997448","order_by":0,"name":"Xiaoqi Deng","email":"","orcid":"","institution":"The Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoqi","middleName":"","lastName":"Deng","suffix":""},{"id":288660268,"identity":"c5883c78-3a44-4799-83a5-1308b36a272b","order_by":1,"name":"Lei Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuElEQVRIiWNgGAWjYFAC5gaGhAoom4c4LYxALWdI1sLYRooWgxuJjQ8ezrOTXTsjgfHB2zYGeXMitDQbJG5LNt52I4HZcG4bg+HOBsJa2iQStx1IBGphk+ZtY0gwOEBYS/uPxDlgLey/idXSxpDYALGFmSgtkmceNkskHAP6BciQnHNOwnADIS18x5MPfvxRYye7Dcj48KbMRp6gLQpQBaDYaQDSEgTUA4F8A1zLKBgFo2AUjAIcAAAdakfFA4QvcAAAAABJRU5ErkJggg==","orcid":"","institution":"The Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lei","middleName":"","lastName":"Yu","suffix":""},{"id":288660269,"identity":"cd404d0f-4f25-4d63-b107-9b7b0a61ca25","order_by":2,"name":"Jie He","email":"","orcid":"","institution":"The Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"He","suffix":""},{"id":288660270,"identity":"3a89cbff-d32f-4d93-ab32-b52d372cf9ca","order_by":3,"name":"Yufan Fu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yufan","middleName":"","lastName":"Fu","suffix":""},{"id":288660271,"identity":"15b241e9-b461-45d1-9c4f-12fed2a43431","order_by":4,"name":"Lan Jiao","email":"","orcid":"","institution":"The Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lan","middleName":"","lastName":"Jiao","suffix":""}],"badges":[],"createdAt":"2024-04-06 04:14:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4225579/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4225579/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54516279,"identity":"e8a9cbf0-08ed-48df-a603-3bebbafbed03","added_by":"auto","created_at":"2024-04-11 16:34:24","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":191524,"visible":true,"origin":"","legend":"\u003cp\u003eThe prevalence trend and gender differences of hemoglobinopathies and hemolytic anemia in different regions from 1990 to 2019. (A) The number of cases of hemoglobinopathies and hemolytic anemia by sex. (B) Prevalence rates of hemoglobinopathies and hemolytic anemia by sex. (C) The number of cases of hemoglobinopathies and hemolytic anemia by SDI regions. (D) Prevalence rates of hemoglobinopathies and hemolytic anemia by SDI regions\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/1237cd60aa7a99ec09231706.jpeg"},{"id":54516281,"identity":"1443f868-fa35-4bf5-9501-f1aabb257dae","added_by":"auto","created_at":"2024-04-11 16:34:24","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":257163,"visible":true,"origin":"","legend":"\u003cp\u003eRegional and sex differences in the severity of heart failure. (A) Regional differences in four degrees of heart failure; (B) Sex differences in 4 degrees of heart failure\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/544846f82856ee3ec6b43938.jpeg"},{"id":54516282,"identity":"171d112d-a5e1-4c32-b31b-64be8b0b2c18","added_by":"auto","created_at":"2024-04-11 16:34:25","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":305247,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Prevalence rates of HF impairment with anemia by countries and territories combined for both sexes. (B) The prevalence rates of HF impairment with anemia in 1990; (C) The prevalence rates of HF impairment with anemia in 2019; (D) The EAPC in the prevalence rate of HF from 1990 to 2019. EAPC, estimated annual percentage change\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/5075c98270df0f23654295f5.jpeg"},{"id":54516287,"identity":"a5530de8-8122-4a90-b13b-8a47737979bb","added_by":"auto","created_at":"2024-04-11 16:34:25","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":163532,"visible":true,"origin":"","legend":"\u003cp\u003eThe sex distribution and regional differences of HF impairment with anemia. (A) The distribution of HF impairment with anemia by sexes across SDI regions; (B) The distribution of HF impairment with anemia in males across SDI regions; (C) The distribution of HF impairment with anemia in females across SDI regions; (D) The distribution of the ratio of female to male of HF impairment with anemia across different SDI regions; (E) The distribution of HF impairment with anemia by sexes across different regions\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/a0e1e3624ccff0b9e045f8e9.jpeg"},{"id":58512822,"identity":"48f36a62-4088-4e9a-b075-18a50493dfef","added_by":"auto","created_at":"2024-06-17 16:10:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1366865,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/54e35966-6d4d-4750-9fcc-7aff788825a0.pdf"},{"id":54516280,"identity":"dcf39a50-0b65-41dc-a77c-7a93cd874338","added_by":"auto","created_at":"2024-04-11 16:34:24","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14412,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/e05d9ca8de857d75a8fe9595.xlsx"},{"id":54516284,"identity":"24f47351-209e-46c2-9e05-fa676576b31b","added_by":"auto","created_at":"2024-04-11 16:34:25","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10873,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/3f381661cf859c5bd0340796.xlsx"},{"id":54516286,"identity":"5970e8fc-e9c8-4084-a222-ab0356b4c492","added_by":"auto","created_at":"2024-04-11 16:34:25","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":137076,"visible":true,"origin":"","legend":"","description":"","filename":"TableS6.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/d30e9bc53ce63138863020a7.xlsx"},{"id":58511527,"identity":"3c2e23d3-6144-4b06-ac24-d26072f2718d","added_by":"auto","created_at":"2024-06-17 15:54:50","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":687964,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4225579/v1/bcf7ebca2e5cb4d2f04d9005.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Heart Failure Attributable to Hemoglobinopathies and Hemolytic Anemia: A Three-Decade Cross-Sectional Assessment of the Global Burden","fulltext":[{"header":"1. Background","content":"\u003cp\u003eAnemia is a prevalent comorbidity in heart failure (HF) patients, serving as an indicator of HF severity and a predictor of adverse outcomes.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Both anemia and HF independently constitute significant global health burdens.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Despite intensive evaluation over the past years, treatment with erythropoiesis-stimulating agent (ESA) for anemia in HF has not improved clinical outcomes but rather been linked to increased risks of adverse events,(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) raising concerns about the role of anemia in HF progression and its therapeutic management. While previous reviews suggest that interventions aiming to elevate hemoglobin levels have shown no clear benefit, clinical evidence consistently indicates a correlation between anemia and HF.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) However, due to the multifactorial etiology of anemia, comprehensive and systematic screening for all subtypes remains challenging, and large-scale randomized controlled trials are difficult to conduct.\u003c/p\u003e \u003cp\u003eIn brief, anemia can be categorized into congenital and acquired forms, with hemoglobinopathies being genetic disorders characterized by quantitative or qualitative defects in hemoglobin molecules, exemplified by sickle cell disease and thalassemias.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) These hemoglobinopathies represent the most common monogenic diseases globally, historically confined to specific geographic regions but now more widely distributed due to population migration.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) More than 1% of couples worldwide carry a risk of having children affected by these conditions, with many affected children succumbing to early mortality.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) In recent years, hemoglobinopathies have become a focus of international public health concern,(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) prompting global screening initiatives by organizations such as the World Health Organization (WHO).(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Hemolytic anemia(HA), another class of anemia, results from premature destruction or clearance of red blood cells and can be either inherited or acquired.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Despite their significance, few studies have investigated the relationship between hemoglobinopathies, hemolytic anemia, and HF.\u003c/p\u003e \u003cp\u003eOur study specifically focuses on the backdrop of the GBD project, concentrating on elucidating the intricate interplay between HF and concomitant anemia at a global level. Leveraging the GBD dataset, we aim to quantify the worldwide prevalence and implications of HF complicated by anemia, thereby delivering critical insights into the global health burden attributed to this comorbidity. The purpose of this endeavor is to inform future clinical practices and research strategies targeting the management and prevention of anemia among HF patients, ultimately leading to improved patient outcomes and alleviated global health consequences.\u003c/p\u003e"},{"header":"2. Construction and content","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study data\u003c/h2\u003e \u003cp\u003eThe GBD project, initiated by the Institute for Health Metrics and Evaluation at the University of Washington, the Harvard School of Public Health, and several other organizations, provides a unified framework for tracking temporal trends in diseases, injuries, and risk factors across time and geography. Utilizing consistent or near-consistent data collection methods and tools, GBD covers health data from over 200 countries and territories between 1990 and 2019.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) By aggregating information from publicly available sources such as measured data, literature reviews, surveillance reports, clinical datasets, and health insurance claims, the project employs Bayesian meta-regression tool DisMod-MR 2.1 to present a comprehensive quantification of health loss in terms of epidemiological metrics like prevalence, mortality rates, and disability-adjusted life years (DALYs), ensuring consistency across multiple data streams for a given disease.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn this study, we extracted epidemiological data on hemoglobinopathies and hemolytic anemia prevalence from the GBD, stratified by sex and region. We further analyzed the temporal patterns of heart failure-related health burden globally, regionally, and nationally from 1990 to 2019. Access to these pertinent data is available via the Global Health Data Exchange website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ghdx.healthdata.org/gbd-results-tool\u003c/span\u003e\u003cspan address=\"http://ghdx.healthdata.org/gbd-results-tool\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data collection\u003c/h2\u003e \u003cp\u003eIn this section, we examined the global, regional, and national trends in the co-occurrence of heart failure with hemoglobinopathies and hemolytic anemia from 1990 to 2019, as well as the variations in associated indicators by sex and region. Specifically, we incorporated data across four dimensions of anemia: Hemoglobinopathies and HA, Thalassemia, Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency, and other HA, where the latter three are subsets within the broader category of HA. Heart failure was stratified into four severity groups: treated heart failure refers to patients diagnosed and actively managed with medications and lifestyle changes to maintain a good quality of life; mild heart failure includes those at risk or in the pre-heart failure stage without clinical symptoms; moderate heart failure denotes patients with evident clinical signs and symptoms; and severe heart failure pertains to individuals with significantly debilitating symptoms that severely impact their quality of life and functional status. These categories align with the clinical diagnostic criteria set forth by the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) The GBD project also computed the Sociodemographic Index (SDI) for each country, which is a composite metric reflecting social and economic conditions influencing health outcomes, incorporating total fertility rate among those under 25 years old, mean years of education for those aged 15 and above, and lag-distributed income per capita.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) The SDI is divided into five quintiles: low, low-middle, middle, high-middle, and high. Furthermore, we grouped countries and territories from over 200 nations based on their respective regions and national contexts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eWe employed Estimated Annual Percentage Changes (EAPC) as a quantifiable metric to assess prevalence trends over specific periods, which is independent of regional cultural backgrounds and socioeconomic conditions, thereby serving as an objective standard for measuring and comparing changes across different regions.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) If the EAPC value and its lower limit of the 95% Confidence Interval (95% CI) are less than 0, a declining trend is observed; conversely, an upward trend is indicated. These indicators were systematically compiled and tabulated according to sex, SDI level, and WHO regions. Statistical analyses, inclusive of determining statistical significance at p-values less than 0.05, were conducted using R Studio (Version 4.3.1). The data were synthesized into tables to present the comprehensive patterns of change.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Utility and discussion","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Global burden estimates of hemoglobinopathies and hemolytic anemia\u003c/h2\u003e \u003cp\u003eOver 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\u0026nbsp;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\u0026thinsp;=\u0026thinsp;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\u0026thinsp;=\u0026thinsp;0.01), indicating a persistent high disease burden in this region (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). 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 \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e-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\u0026thinsp;=\u0026thinsp;4.51), yet its actual increase in prevalence was minimal, rising only from 0.1 per 100,000 to 0.32 per 100,000.\u003c/p\u003e \u003cp\u003eNotably, 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA 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\u0026thinsp;=\u0026thinsp;0.07) and Low-Middle SDI regions (EAPC\u0026thinsp;=\u0026thinsp;0.22) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC 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\u0026thinsp;=\u0026thinsp;1.92) and 2019 (ratio value\u0026thinsp;=\u0026thinsp;1.94), indicating a persistent trend across all global regions where the prevalence of the disease is consistently higher among women than men (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA). 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\u0026thinsp;=\u0026thinsp;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 \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eB). These shifts indicate a gradually increasing imbalance in the disease burden of hemoglobinopathies and hemolytic anemias between sexes within various geographic regions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 The proportion of HF impairment with anemia worldwide\u003c/h2\u003e \u003cp\u003eWe 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\u0026thinsp;=\u0026thinsp;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 (\u0026minus;\u0026thinsp;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 \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003eA, B). When HF severity was stratified (Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003eC, 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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Sex-wise, the global HF-anemia burden was approximately balanced (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), 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\u0026ndash;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\u0026ndash;371,551,646.8), had a notably higher HF proportion of 62.86 ppm in 2019, exceeding the global average (Table S6).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Prevalence trends of HF impairment with anemia\u003c/h2\u003e \u003cp\u003eSince 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC), High SDI regions paradoxically exhibit the highest HF prevalence (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) and proportion (Figure S3A). Conversely, Low-Middle SDI areas have the most anemia cases but record the lowest HF prevalence (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) 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\u0026thinsp;=\u0026thinsp;1.03) and concurrently the highest prevalence (Table\u0026nbsp;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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), 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\u0026thinsp;=\u0026thinsp;1.11). In contrast, countries with the highest EAPC\u0026mdash;Puerto Rico (3.31), Guam (2.5), Trinidad and Tobago (2.38), and Northern Mariana Islands (2.23)\u0026mdash;exhibit lower case numbers and prevalence rates (Table S5, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC, 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.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). When considering prevalence exceeding 5000 per 100,000, no country displayed a negative EAPC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur findings further confirm that women bear a higher disease burden of anemia than men (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA), aligning with previous research.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) 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.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-D), a noteworthy inversion emerges: the sex gap in HF prevalence is much smaller than that for anemia (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE), 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\u0026mdash;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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). 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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Discussion\u003c/h2\u003e \u003cp\u003eAnemia, 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\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eThe 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.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) 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.(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) 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,(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) with malnutrition and food scarcity likely compounding this burden. High SDI areas, reflecting higher income, education, and fertility control,(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) 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,(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) therefore the American College of Physicians recommends restrictive transfusion strategies (\u0026le;\u0026thinsp;7\u0026ndash;8 g/dl) for patients with heart failure who require transfusions.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Furthermore, the use of ESA to improve hemoglobin levels in heart failure patients is associated with increased risks of stroke and thrombotic events.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) 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.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Zhang attributed the largest increase in ischemic stroke incidence during 1990 to 2019 primarily to high alcohol consumption in High SDI regions.(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) The 2019 GBD data highlighted the highest incidence and prevalence of chronic kidney disease related to type 2 diabetes mellitus in High SDI regions.(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) 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.(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) 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.\u003c/p\u003e \u003cp\u003eProlonged anemia directly yields elevated cardiac output and cardiac iron accumulation.(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) A multitude of reports attest that iron excess potentiates the generation of reactive oxygen species(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and fosters oxidative reactions, culminating in endothelial injury, atherosclerotic progression, and hence myocardial and vascular pathologies, amplifying the vulnerability to heart failure.(\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) Furthermore, augmented hemoglobin levels resulting from transfusions raise systemic vascular resistance and increase left ventricular workload.(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) Notably, there exists a temporal correlation between rising hemoglobin concentrations and diminishing left ventricular ejection fraction.(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) Genetically, heart disease assumes a central role in morbidity and mortality within the context of β-thalassemia,(\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e) being the predominant cause of death, and similarly represents a critical etiological factor and key prognosticator in the course of sickle cell anemia.(\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOver 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.(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e) 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.(\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e) 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.(\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e) Potential mechanisms may involve differential gene regulation in men and women, particularly in sex steroid-responsive genes,(\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e) 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.(\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e) Beyond these factors, environmental conditions, lifestyle habits such as smoking and alcohol consumption, and dietary practices may collectively heighten cardiovascular risks for men.\u003c/p\u003e \u003cp\u003eOur 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.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eOver the past three decades, while the global burden of hemoglobinopathies and hemolytic anemia has remained stable yet high, heart failure prevalence has been steadily increasing, particularly in High SDI regions and among men, underscoring the complex interplay of demographic characteristics, disease perceptions, genetic, and economic factors on disease progression. Our study provides a timely assessment of the overall disease burden and temporal trends regarding concurrent heart failure in patients with hemoglobinopathies and hemolytic anemia worldwide, further emphasizing the inherent connection between anemia and heart failure. These findings contribute valuable insights to inform appropriate policy responses to address this health issue effectively.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003eHF Heart failure\u003c/p\u003e \u003cp\u003eGBD Global burden of disea\u003c/p\u003e \u003cp\u003eEAPC Estimated Annual Percentage Changes\u003c/p\u003e \u003cp\u003eppm Parts per million\u003c/p\u003e \u003cp\u003eESA Erythropoiesis-stimulating agent\u003c/p\u003e \u003cp\u003eWHO World Health Organization\u003c/p\u003e \u003cp\u003eHA Hemolytic anemia\u003c/p\u003e \u003cp\u003eDALYs Disability-adjusted life years\u003c/p\u003e \u003cp\u003eG6PD Glucose-6-phosphate Dehydrogenase\u003c/p\u003e \u003cp\u003eSDI Sociodemographic Index\u003c/p\u003e \u003cp\u003e95% CI 95% Confidence Interval\u003c/p\u003e \u003cp\u003eSEV Summary exposure value\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are available from the Global Burden of Disease Results Tool of the Global Health Data Exchange (http://ghdx.healthdata.org/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project has not received any form of funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. X D: \u0026apos;designed study\u0026apos;, \u0026apos;performed study\u0026apos;, \u0026apos;contributed important reagents\u0026apos;, \u0026apos;collected data\u0026apos;, \u0026apos;analyzed data\u0026apos; and \u0026apos;wrote paper\u0026apos;; L Y: \u0026apos;supervised the entire process\u0026apos;, \u0026apos;contributed important reagents\u0026apos; and \u0026apos;offered sponsorship\u0026apos;, J H, and Lan Jiao: \u0026apos;performed study\u0026apos;, \u0026apos;analyzed data and \u0026apos;wrote paper\u0026apos;; Y F: \u0026apos;collected data\u0026apos;, \u0026apos;analyzed data\u0026apos; and \u0026apos;wrote paper\u0026apos;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extend our heartfelt appreciation to the Global Burden of Disease Study group for their longstanding and outstanding contributions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMagr\u0026igrave; D, De Martino F, Moscucci F, Agostoni P, Sciomer S. 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J Am Coll Cardiol. 2016;67(5):545\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"GBD, hemoglobinopathies, hemolytic anemia, heart failure","lastPublishedDoi":"10.21203/rs.3.rs-4225579/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4225579/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eComplexity of anemia subtypes remains unresolved, and therapies targeting anemia have inconsistently improved heart failure (HF) outcomes. This study aims to assess the prevalence trend and contributing factors of HF impairment with hemoglobinopathies and hemolytic anemia at global, regional and national levels.\u003c/p\u003e\u003ch2\u003eMain body of the abstract:\u003c/h2\u003e \u003cp\u003eUtilizing Global Burden of Disease (GBD) data for HF and hemoglobinopathies inclusive of hemolytic anemia, we systematically gathered annual figures for prevalence and incidence. Estimated Annual Percentage Changes (EAPCs) were computed to assess temporal trends in these diseases. Estimates were subsequently disaggregated by sex, geographical regions, and national levels to present a concise yet detailed picture of the disease dynamics globally. During the past three decades, although the absolute caseloads of hemoglobinopathies and hemolytic anemias grew without altering their standardized prevalence (EAPC\u0026thinsp;=\u0026thinsp;0.26), the rate of heart failure compounded by anemia sharply rose (EAPC\u0026thinsp;=\u0026thinsp;0.49). Notably, in high Sociodemographic Index (SDI) regions, the HF-to-hematological disorder ratio ascended more rapidly, moving from 82.80 parts per million (ppm) in 1990 to 114.22 ppm in 2019, surpassing the worldwide average increment (40 ppm). Despite greater anemia-related burdens among females, male patients experienced a disproportionately higher frequency of heart failure.\u003c/p\u003e\u003ch2\u003eShort conclusion:\u003c/h2\u003e \u003cp\u003eOver the past three decades, there has been a steady rise in the prevalence of heart failure comorbid with hemoglobinopathies and hemolytic anemias, with a more pronounced disease burden observed among men and a discernible shift toward High SDI regions.\u003c/p\u003e","manuscriptTitle":"Heart Failure Attributable to Hemoglobinopathies and Hemolytic Anemia: A Three-Decade Cross-Sectional Assessment of the Global Burden","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-11 16:34:20","doi":"10.21203/rs.3.rs-4225579/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec2e5fc9-c083-4ff6-b5e8-b2d285eb3614","owner":[],"postedDate":"April 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-22T06:52:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-11 16:34:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4225579","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4225579","identity":"rs-4225579","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}