Evolving Mortality Burden of Valvular Heart Disease with Atrial Fibrillation Among U.S. Adults Aged 45 Years and Older: Trends (1999–2023) and Projections to 2035

Evolving Mortality Burden of Valvular Heart Disease with Atrial Fibrillation Among U.S. Adults Aged 45 Years and Older: Trends (1999–2023) and Projections to 2035 | 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 Evolving Mortality Burden of Valvular Heart Disease with Atrial Fibrillation Among U.S. Adults Aged 45 Years and Older: Trends (1999–2023) and Projections to 2035 Tehmasp Rehman Mirza, Faizan Ahmed, Fenilkumar Kotadiya, Saman Rauf, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7950876/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Valvular heart disease (VHD) and atrial fibrillation (AF) frequently coexist, presenting complex clinical challenges despite advances in diagnostics and therapeutics. Together, they contribute substantially to cardiovascular mortality. However, epidemiological patterns vary across demographics and regions Methods Mortality data from 1999–2023 were obtained from the CDC WONDER database. Deaths attributed to VHD (ICD-10: I30-I52) with co-diagnosed AF (ICD-10: I48) among adults ≥ 45 were included. Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated. Autoregressive integrated moving average (ARIMA) models were used to project mortality trends through 2035. Results From 1999 to 2023, there were 172,511 VHD and Afib-related deaths in adults ≥ 45. AAMRs increased until 2021, followed by a slight decline to 8.86. The overall AAPC for VHD with AF was 4.01%. AAMR increase was consistent across all age groups, highest seen in 65 + individuals. Males had consistently higher AAMRs than females. AAPC for males was 4.44% and for females 3.52%. Non- Hispanic White had the highest AAMR (10.56 in 2021), followed by Hispanics (4.19). Regionally, the West had the highest AAMR (11.27), followed by Mid-West (9.94). Non-metropolitan areas had higher AAMR 8.96 compared to metropolitan areas (AAMR: 7.59). Most VHD related deaths were reported in inpatient settings (n = 396,451) and 12% involved co-diagnosed AF. Conclusion Mortality associated with VHD and AF in the U.S population aged ≥ 45 has shown a concerning increase. Predictive models indicate this trend may persist, highlighting the need for early detection, equitable healthcare access and public health interventions tailored to high-risk populations. Valvular heart disease Atrial fibrillation Mortality trends Health disparities CDC WONDER Forecasting United States Epidemiology Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cardiac pathologies, specifically valvular heart disease (VHD) and atrial fibrillation (AF) are often coexisting conditions which despite improvements in diagnostic, pharmacologic and interventional approaches, remain a persistent clinical challenge and substantial public health burden in the United States, contributing markedly to both cardiovascular morbidity and mortality. Atrial fibrillation, the most common cardiac arrhythmia, often arises from gradual cardiac structural remodelling in VHD particularly rheumatic heart disease and mitral valve pathologies. Their coexistence also amplifies the risk of stroke, heart failure and death. The risk of valvular heart disease increases directly with age, which is more pronounced in elderly people, so multidisciplinary approaches and systemic evaluation have been advised for reducing complications and improving survival outcomes ( 1 ). A recent study found that the overall age adjusted mortality rates from 1999–2020 declined from 8.4 to 6.6 per 100,000 with men more inclined towards aortic pathologies and females with mitral valve pathologies ( 2 ). Over the past two decades, various trends in epidemiology of both the conditions have occurred, influenced by age, improved diagnostic strategies and recent advent of transcatheter valvular interventions. Globally, non-rheumatic valvular diseases have been rising in high-socio-demographic-index regions like North America. Between 1990 and 2019, the global incidence of NRVD showed gradual increase with an estimated annual percentage change of 0.39% ( 3 ). The prevalence and mortality also vary by geographical and socioeconomic stratifications, with rheumatic pathologies dominating in low- and middle-income countries while degenerative valvular states predominating in high income settings ( 4 ). Parallel to VHD, the prevalence of atrial fibrillation has also been rising. New diagnoses of atrial fibrillation have increased by about 30% between 2000 and 2020 owing to age, advancements in diagnostic strategies and rising risk factors ( 5 ). Some community-based studies show that while incidence rates stabilized over past decades, atrial fibrillation continues to predict short- and long-term mortality. In Olmsted County, over the last decade AF incidence and prevalence remained constant but a dramatic excess risk of death was observed in 90 days post diagnosis ( 6 ). Similarly, data from Framingham Heart Study confers that despite some gradual improvements, AF still confers a two-year loss of life expectancy ( 7 ). According to Centers for Disease Control and Prevention (CDC), atrial fibrillation/flutter related deaths rose until 2016 and plateaued afterwards when considered as underlying cause of death, when considered as a contributing factor, mortality rate continued rising through 2020 with the largest increase seen in Non-Hispanic Black males and residents of rural areas ( 8 ). Forecasting mortality patterns is essential for healthcare planning, resource utilization and preventive strategies. In this study, we evaluate the trends in mortality associated with valvular heart disease and atrial fibrillation from 1999 to 2023 stratified by age, gender, race, census, urbanization, census and place of death. Furthermore, we applied validated time series forecasting models to project mortality patterns through 2030. By providing a comprehensive view of past present and expected future mortality associated with these overlapping conditions, this study aims to guide health care providers of the evolving burden and targeted interventional strategies. Methods Mortality data from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging online Data for Epidemiologic Research) database was extracted and examined from 1999 to 2023 for Valvular heart disease (VHD) and atrial fibrillation AF related mortality in adults 45 + years age using codes from the International Statistical Classification of Diseases and Related Health Problems-10th Revision (ICD-10) as follows: MCD - ICD-10 Codes: I05.0 (Mitral stenosis); I05.1 (Rheumatic mitral insufficiency); I05.2 (Mitral stenosis with insufficiency); I05.8 (Other mitral valve diseases); I05.9 (Mitral valve disease, unspecified); I06.0 (Rheumatic aortic stenosis); I06.1; (Rheumatic aortic insufficiency); I06.2 (Rheumatic aortic stenosis with insufficiency); I06.8 (Other rheumatic aortic valve diseases); I06.9 (Rheumatic aortic valve disease, unspecified); I07.0 (Tricuspid stenosis); I07.1 (Tricuspid insufficiency); I07.2 (Tricuspid stenosis with insufficiency); I07.8 (Other tricuspid valve diseases); I07.9 (Tricuspid valve disease; unspecified); I08.0 (Disorders of both mitral and aortic valves); I08.1 (Disorders of both mitral and tricuspid valves); I08.2, (Disorders of both aortic and tricuspid valves); I08.3 (Combined disorders of mitral, aortic and tricuspid valves); I08.8 (Other multiple valve diseases); I08.9 (Multiple valve disease, unspecified); I34.0 (Mitral (valve) insufficiency); I34.1 (Mitral,(valve) prolapse); I34.2 (Nonrheumatic mitral (valve) stenosis); I34.8 (Other nonrheumatic mitral valve disorders); I34.9, (Nonrheumatic mitral valve disorder, unspecified); I35.0 (Aortic (valve) stenosis); I35.1 (Aortic (valve) insufficiency); I35.2, (Aortic (valve) stenosis with insufficiency); I35.8 (Other aortic valve disorders); I35.9 (Aortic valve disorder, unspecified); I36.0 (Nonrheumatic tricuspid (valve) stenosis); I36.1 (Nonrheumatic tricuspid (valve) insufficiency); I36.2 (Nonrheumatic, tricuspid (valve) stenosis with insufficiency); I36.8 (Other nonrheumatic tricuspid valve disorders); I36.9 (Nonrheumatic, tricuspid valve disorder, unspecified); I37.0 (Pulmonary valve stenosis); I37.1 (Pulmonary valve insufficiency); I37.2, (Pulmonary valve stenosis with insufficiency); I37.8 (Other pulmonary valve disorders); I37.9 (Pulmonary valve disorder, unspecified) and I48 for atrial fibrillation. The same ICD codes have been described previously to identify VHD and AF in administrative databases. This data set includes cause of death from death certificates for the 50 states and the District of Columbia and has been previously used in several studies to determine trends in mortality of cardiovascular diseases. The Multiple Cause-of-Death Public Use record death certificates were studied to select VHD and AF related deaths, which were identified as those with VHD and AF reported anywhere on the death certification either as a contributing or underlying cause of death ( 9 ). Older adults were defined as those who were aged 45 years or older at the time of death ( 10 ). Similar age cutoff has been used by previous studies to define older adults. The study was exempted from local institutional review board approval because it used deidentified government-issued public use data set and follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting ( 11 ). Data abstraction and variables Data for population size, year, location of death, demographics, urban-rural classification, region, and states were abstracted. Demographics included sex, age, and race/ethnicity, and location of death included medical facilities (outpatient, emergency room, inpatient, death on arrival, or status unknown), home, hospice, and nursing home/long-term care facility. Race/ethnicity was classified as non-Hispanic (NH) White, NH Black or African American, Hispanic or Latino, NH American Indian or Alaskan Native, and NH Asian or Pacific Islander. This information relies on reported data on death certificates and has been used in previous analyses of the WONDER database. The National Center for Health Statistics Urban-Rural Classification Scheme was used to assess the population by urban (large metropolitan area [population ≥ 1 million], medium/small metropolitan area [population 50,000-999,999]) and rural (population < 50,000) counties according to the 2013 U.S. census classification ( 12 ). Regions were classified into Northeast, Midwest, South, and West according to the U.S. Census Bureau definitions. Statistical analysis To examine national trends in VHD and AF related mortality, we calculated crude and age-adjusted mortality rates (AAMRs) per 10,000 population from 1999 to 2019 by year, sex, race/ethnicity, state, and urban-rural status with 95% CIs. Crude mortality rates were determined by dividing the number of VHD-related deaths by the corresponding U.S. population of that year. AAMRs were calculated by standardizing VHD AF-related deaths to the year 2000 U.S. population. To quantify national annual trends in VHD AF related mortality, the Joinpoint Regression Program (Joinpoint V 4.9.0.0, National Cancer Institute) was used to determine the annual percent change (APC) with 95% CI in AAMR. This method identifies significant changes in AAMR over time by fitting log-linear regression models where temporal variation occurred. APCs were considered increasing or decreasing if the slope describing the change in mortality was significantly different from zero using 2-tailed t-testing. A value of P < 0.05 was considered statistically significant. Future mortality AAMR were calculated till 2035 by doing projection analysis using ARIMA ( 13 ). Results Annual trends Valvular Heart Disease and Atrial Fibrillation caused a total of 172,511 deaths in the US from 1999 to 2023 ( Supplementary table 1 ). The age-adjusted mortality rates (AAMR) ranged between 3.64 (95% CI 3.52–3.76) in 1999 and 8.93 per million (95% CI 8.78–9.09) in 2023. The highest AAMR was reported in 2021 at 9.01 per million (Fig. 1 ). The rates had demonstrated two sets of upward slopes in these years with a significant incline in AAMR (APC: 2.12*, 95% CI: 0.90 to 2.93, p < 0.01) from 1999 to 2009 followed by steeper increase till 2023 with an APC of 5.39 (95% CI: 5.04 to 5.88, p < 0.01) ( Supplementary table 2 ). Gender Segregation of the database by gender revealed a similar burden for both groups initially, though trends diverged and males had a higher rise in AAMRs compared to the female population. Males had a total of 74,605 deaths and the females had a total of 97,906 deaths from 1999 to 2023, respectively (Fig. 3 , Supplementary table 1 ). The AAMR for females rose from 3.58 in 1999 to 7.90 per million in 2023 with an AAPC of 3.52 (95% CI 3.23 to 3.81, p < 0.001). Similarly, the AAMR for males rose from 3.83 in 1999 to 10.44 per million in 2023 with a steeper AAPC of 4.45 (95% CI 4.20 to 4.70, p < 0.001) (Fig. 2 A, Supplementary table 3 ). The greater rise in men is exemplified by the recent increase from 2018 to 2021 (APC: 9.73 95% CI 7.81 to 11.01) ( Supplementary table 2 ). Race Racial trends showed a drastically higher trend in Non-Hispanic (NH) White individuals compared to other races with an eventual AAMR of 10.46 per million in 2023. Though, initially unreliable NH American Indians had the highest peak of the other races with 6.69 AAMR in 2021; followed by Hispanics (4.19 in 2021), NH Asians (4.01 in 2023) and NH African Americans (3.89 in 2022) (Fig. 2 B, Supplementary table 4 ). Fascinatingly, rise in AAMR was steepest in NH Americans (AAPC: 4.49 95% CI 3.91 to 5.27, p < 0.001) owing to a period of sustained rise from 2009 to 2023 (APC: 7.20, p < 0.01). Unlike other races, which had an insignificant change in the initial decade of 2000s, burden in NH Whites kept rising in that period as well (APC 1999–2009: 2.30, p < 0.001) which was followed by the steeper rise (APC 2009–2023: 5.83, 95% CI 5.43 to 6.39, p < 0.001) ( Supplementary table 2 ). Age-specific Trends Age wise distribution was starkly skewed towards adults older than 65 years. Stratification revealed 6,722 deaths (4% of total deaths) in adults aged 45–64 years while 165,789 deaths occurred in adults aged above 65 ( Supplementary table 5 ). Regardless, 45–64 age groups have AAMR on a rising trend from 2011 onwards (APC: 7.94, 95% CI 6.53–10.42, p < 0.001). On the other hand, AAMR in adults aged above 65 rose from 9.66 in 1999 to 23.73 in 2023 (AAPC: 4.00, 95% CI 3.69 to 4.26, p < 0.001) ( Supplementary table 2 ). Geographic Trends The AAMR across the four census regions were generally similar with a slightly higher burden in West while South had a comparatively lower burden. Highest AAMR in West was 11.27 per million in 2021, followed by Midwest (9.94 in 2021), Northeast (9.17 in 2021), and South (7.18 in 2023) ( Supplementary table 6 ). The strongest rise in AAMR was in the Midwestern region (2010–2021 APC: 6.43, p < 0.001), closely followed by the Southern region (2012–2023 APC: 6.37, p < 0.001) (Fig. 2 C, Supplementary table 2 ). Stratification by urbanization up to 2020 revealed 81% of deaths occurred in metropolitan areas. The AAMR in both groups was relatively similar till 2011 (Metro AAMR: 4.94, Non-Metro AAMR: 4.98) after which rise in AAMR in non-metro areas occurred at a greater degree (Fig. 2 D, Supplementary table 7 ). The APC from 2011 to 2020 for non-metro areas was 6.32, p < 0.01 achieving a peak of 8.96 per million in 2020. Metropolitan areas peaked at 7.59 per million in 2020. State wise analysis occurred over two periods 1999 to 2020 and 2021 to 2023. Both periods yielded mostly similar results with Oregon, Vermont, Washington and New Hampshire being common in top 90th percentile. Georgia, Louisiana and Alabama were the states common in the bottom 10th percentile ( Supplementary table 8 ). The greatest rise in ranks was seen in Nevada which rose from the 7th to 42nd percentile while the highest drop was in Alaska going from 86th to 46th percentile. Inpatient Facility recorded the highest number of deaths at 60,952 (35%), followed by decedent's home (51,315; 30%), nursing homes (35402; 21%), hospice facilities (8877; 5%) and outpatient facilities (7628; 4%) ( Supplementary table 9 ). A central illustration provides an integrated overview of sex, race, age and region-stratified trends in valvular heart disease and atrial fibrillation-related mortality over the study period (Fig. 3 ). Forecasted Trends The forecasted rate for 2024 was 8.9 per 1,000,000 (95% CI: 3.7–14.2), with a projected increase to 12.6 per 1,000,000 (95% CI: -5.7–30.8) by 2035 with an APC of 3.15% (95% CI 3.13% to 3.17%). For female, the forecasted AAMR for 2024 was 7.4 (95% CI: 6.1–8.8), with a projected increase to 9.8 per 1,000,000 (95% CI: 5.5–14.2) by 2035 with an APC of 2.55% (95% CI 2.53% to 2.56%). For males, the forecasted rate for 2024 was 10.8 (95% CI: 3.2–18.3), with a projected increase to 15.9 per 1,000,000 (95% CI: -10.3–42.0) by 2035 with an APC of 3.56% (95% CI 3.53% to 3.58%) (Fig. 4 , Supplementary Table 10 ). Discussion This 24-year analysis of mortality data from the Centers for Disease Control and Prevention examined the trends in the mortality rate of patients with valvular heart disease and atrial fibrillation. This analysis showed that the overall AAMR nearly doubled from 3.6 per million in 1999 to 8.9 per million in 2023, with two distinct periods of rapid increase, particularly after 2009 ( 2 , 14 ). Males experienced a steeper rise in AAMR compared to females, and while non-Hispanic White individuals had the highest absolute mortality rates, non-Hispanic American Indians demonstrated the most rapid growth over time ( 15 ). Most of the deaths were in adults over 65 years, but adults aged 45 to 64 also showed a notable upward trend starting in 2011 ( 16 ). Geographically, the Western and Midwestern regions had higher AAMRs, with non-metropolitan areas experiencing sharper increases compared to metropolitan areas after 2011, and projections indicate that this trend will continue, with the AAMR estimated to reach 12.6 per million by 2035, highlighting the continuous increase in the burden of disease ( 17 ). This study demonstrates an increase in the AAMR attributed to VHD and AF from 1999 to 2023, with a prominent increase noted after 2009. Although no prior studies have specifically addressed the mortality trends associated with the coexistence of atrial fibrillation and valvular heart disease, previous analyses that have independently assessed each condition have similarly reported an increase in mortality trends over the past few decades ( 2 , 14 , 15 ). This parallel rise is likely due to shared underlying factors. These include an aging population, a greater prevalence of comorbidities, and improvements in diagnostic tools that have enhanced detection and reporting of both conditions. Historically, the prevalence of atrial fibrillation was often underestimated because of the high number of clinically silent episodes and paroxysmal AF, which can be overlooked during a routine physical exam or with a standard 12-lead electrocardiogram. The development of wearable devices has provided clinicians with a more reliable method to identify previously undiagnosed atrial fibrillation, particularly in individuals at higher risk ( 16 – 18 ). At the same time, the burden of valvular heart disease may have increased because of the wider use of advanced imaging and echocardiographic screening, which enhances case detection. New interventional strategies have also improved survival rates among patients with heart failure but may put patients at risk for secondary (or functional) manifestation of diseases ( 19 , 20 ). The observed rise in mortality trends after 2009 could partly reflect these shifts in diagnostic and treatment practices, alongside the increasing survival of patients with complex multimorbidity, who remain at higher risk for adverse outcomes. Notably, we found that males experienced a steeper rise in AAMR compared to females over the study period. Several factors can contribute to this disparity. Firstly, male sex has classically been recognized as a major risk factor for certain structural heart diseases such as bicuspid aortic valve and degenerative calcific aortic stenosis which predispose them to the development of valvular heart disease and, subsequently, atrial fibrillation ( 21 ). Secondly, prior studies reported that women may derive greater benefit from anticoagulation compared to males, which could explain the steeper rise in mortality for males ( 22 ). Moreover, biological differences in atrial remodelling and thrombogenicity could contribute to more severe clinical manifestations or complications in men ( 23 , 24 ). Finally, it is possible that differences in healthcare-seeking behaviour, access to care, and adherence to treatment between men and women also play a role ( 12 ). This imbalance of sex ratios identified in the general population is important and could indicate a sex bias in referral patterns for diagnosis and treatment. The mechanisms for such an imbalance should be investigated prospectively. Cardiovascular mortality related to AF and VHD was higher in NHW compared to other racial groups. Given prior work documenting disproportionately higher burden of AF risk factors including obesity, hypertension and diabetes mellitus in Black adults ( 25 , 26 ). It is possible that our finding documenting lower mortality due to AF and VHD in Black adults may be due to disparities in diagnosis, awareness and treatment rather than an actual lower burden of disease ( 26 ). Under-recognition of AF in minority populations has been noted in previous studies ( 27 ). This may be due to differences in healthcare access, less frequent use of ambulatory monitoring, and structural inequalities in care delivery ( 28 ). These findings highlight the need to improve screening strategies and ensure equal access to diagnostic and therapeutic interventions for all racial and ethnic groups. Cardiovascular mortality linked to AF and VHD is rising more rapidly among younger adults (aged 35–64 years) than among older adults (aged 65–84 years).This change in young adults is alarming given the drop in life expectancy in the United States since 2014 which has been attributed to the increase in midlife cardiovascular mortality ( 29 ) 18 .Although our analysis of mortality trends cannot establish causation, both our study and prior research have suggested that the rising prevalence of cardiovascular risk factors among younger adults is possibly contributing to this observed increase in mortality in this age group ( 30 )19. Nevertheless, despite the steeper increase in AAMR among younger adults, the absolute number of deaths remains substantially higher in those over 65 years of age, highlighting the impact of an aging population on the overall burden of cardiovascular mortality in patients with coexisting VHD and AF. Together, these trends highlight an urgent need for early detection, risk factor modification, and age-specific prevention strategies to address the shifting and growing burden of AF and VHD-related mortality. Significant variations in mortality rates were observed geographically. While overall AAMRs were generally similar across regions, the West had a slightly higher burden, and the Midwest and South showed the steepest increases over time. Although most deaths occurred in metropolitan areas, non-metropolitan regions experienced a sharper rise in mortality after 2011. These geographical and regional disparities highlight the importance of local factors, access to healthcare, sociodemographic factors and resource distribution in influencing the mortality trends. This emphasizes the need for interventions and resource allocation tailored to specific regions to ensure the most effective and targeted approach to reducing disparities. Finally, our projections indicate that this rising trend will likely persist, with the AAMR estimated to reach 12.6 per million by 2035. This anticipated increase is largely driven by the aging U.S. population, as atrial fibrillation and valvular heart disease is predominantly a condition affecting older adults ( 5 ). Beyond demographic shifts, other important factors are likely contributing to the growing burden. The increasing prevalence of major risk factors including obesity, diabetes mellitus, and hypertension and improved detection of these through increased awareness and the widespread use of portable monitoring devices and advanced echocardiography has led to the identification of more cases that might previously have gone undiagnosed ( 31 – 33 ). Together, these trends suggest that without targeted prevention and management strategies, the burden of AF and valvular heart disease-related mortality will continue to escalate in the coming decade. This study has several strengths. It is, to our knowledge, the first comprehensive nationwide analysis examining long-term mortality trends specifically related to the coexistence of atrial fibrillation and valvular heart disease over a 24-year period. By using a large, population-based dataset from the CDC WONDER database, our analysis benefits from national coverage and the inclusion of diverse demographic, geographic, and clinical subgroups. The application of time series forecasting also offers valuable insight into future trends, which can inform healthcare planning and resource allocation. However, limitations must also be acknowledged. First, this study is observational and relies on death certificate data, which are subject to misclassification and underreporting, especially for conditions like paroxysmal or subclinical atrial fibrillation. Second, causality cannot be inferred from these mortality trends, and residual confounding by unmeasured factors, such as socioeconomic status, detailed comorbidity burden, and healthcare access, may influence the observed patterns. Third, changes in coding practices and increased use of diagnostic technologies over time may artificially inflate trends. Finally, the forecasting models are based on historical data and assume continuation of past patterns, which may not fully capture the impact of emerging treatments or policy changes. Future research should focus on understanding the causes of the rising mortality associated with coexisting atrial fibrillation and valvular heart disease. Greater emphasis should be given on evaluating the effectiveness of new screening tools like artificial intelligence algorithms to improve the early detection and lower mortality in this group. Additionally, studies should explore the impact of newer therapeutic strategies like transcatheter valve interventions, on long-term outcomes across diverse patient populations. Addressing disparities in diagnosis, treatment, and outcomes by sex, race, age, and geography should remain a priority. Finally, using predictive analytics in public health planning can help identify high-risk groups and support more customized prevention and management strategies. Conclusion Taken together, our results offer a comprehensive examination of the contemporary trend of death due to coexistence of AF and VHD in the recent era. The increasing burden is attributed to demographic aging, rising prevalence of cardiovascular risk factors, advances in diagnostic detection, and persistent disparities across sex, race, age, and geographic regions. These findings highlight the need for targeted public health interventions, early detection strategies, and equitable resource allocation to address the evolving epidemiology of AF and VHD-related mortality. Continued surveillance and prospective studies are essential to better understand underlying mechanisms and guide effective prevention and management strategies. Declarations Corresponding Author: Fenilkumar Kotadiya, [email protected] Data Availability Statement: All data used in this study are publicly available through the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database. The authors obtained access in accordance with the CDC’s data use guidelines. Funding Statement: This research did not receive any grants from funding agencies in the public, commercial or not-for-profit sectors. Conflict of Interest Disclosure: The authors declare no conflicts of interest related to this work. All authors have reviewed and approved the final manuscript. Ethics Approval Statement: This study used de-identified, publicly available mortality data from the CDC WONDER database and did not involve direct human participants or animal subjects. Institutional review board approval and informed consent were therefore not required. Patient Consent Statement: Informed consent was waived because the study used de-identified, publicly available data. Permission to Reproduce Material from Other Sources: Not applicable. No third-party material was reproduced. Clinical Trial Registration: Not applicable. References Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP, Gentile F, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. 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Supplementary Files VHDAfibsuppfiles.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 15 Dec, 2025 Reviews received at journal 03 Dec, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviews received at journal 23 Nov, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviewers invited by journal 21 Nov, 2025 Editor invited by journal 30 Oct, 2025 Editor assigned by journal 29 Oct, 2025 Submission checks completed at journal 29 Oct, 2025 First submitted to journal 26 Oct, 2025 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. 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1","display":"","copyAsset":false,"role":"figure","size":7351,"visible":true,"origin":"","legend":"\u003cp\u003eOverall VHD and AFib-related AAMRs per 1,000,000 in United States 1999-2023\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7950876/v1/6751264a8741b1aefe4fcddd.png"},{"id":96940602,"identity":"a7864d5a-b4e0-4394-9dc2-0f885e1f8627","added_by":"auto","created_at":"2025-11-27 17:44:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37818,"visible":true,"origin":"","legend":"\u003cp\u003eValvular Heart Disease and Atrial Fibrillation-related mortality trends in the United States, 1999 to 2023 with (A) sex-stratified VHD and AFib-related AAMR per million, (B) race/ethnicity Stratified VHD and AFib-related AAMR per million, (C) regionally stratified VHD and AFib-related AAMR per million, (D) urbanization stratified VHD and AFib-related AAMR per million.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7950876/v1/45b567e766aafe1c41b91efc.png"},{"id":97136461,"identity":"7841ec9d-47b6-487e-9ba7-6787b103046a","added_by":"auto","created_at":"2025-12-01 09:56:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":451549,"visible":true,"origin":"","legend":"\u003cp\u003eCentral Illustration: Demographic Profiles in VHD and AFib-related Mortality among adults 45+ In the United States, 1999 to 2023\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7950876/v1/dc8575057b9314ec3fdd4311.png"},{"id":96940604,"identity":"3d290f55-1197-423c-abf8-1b630419eb39","added_by":"auto","created_at":"2025-11-27 17:44:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":117167,"visible":true,"origin":"","legend":"\u003cp\u003eFuture Projections of VHD and AFib-related AAMRs stratified by sex from 1999 to 2035\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7950876/v1/3f0c9db4044640be4cd6efb6.png"},{"id":97144604,"identity":"9ce0ed26-5d29-4ebe-b932-f6efc7d17079","added_by":"auto","created_at":"2025-12-01 10:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1402471,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7950876/v1/22c2f9f7-7d92-47e5-97ee-304d69df049e.pdf"},{"id":97136618,"identity":"afd167df-2eeb-45b8-82d5-7683633ea645","added_by":"auto","created_at":"2025-12-01 09:56:49","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":57958,"visible":true,"origin":"","legend":"","description":"","filename":"VHDAfibsuppfiles.docx","url":"https://assets-eu.researchsquare.com/files/rs-7950876/v1/bf5f62e159390ee11af6eb6c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evolving Mortality Burden of Valvular Heart Disease with Atrial Fibrillation Among U.S. Adults Aged 45 Years and Older: Trends (1999–2023) and Projections to 2035","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiac pathologies, specifically valvular heart disease (VHD) and atrial fibrillation (AF) are often coexisting conditions which despite improvements in diagnostic, pharmacologic and interventional approaches, remain a persistent clinical challenge and substantial public health burden in the United States, contributing markedly to both cardiovascular morbidity and mortality. Atrial fibrillation, the most common cardiac arrhythmia, often arises from gradual cardiac structural remodelling in VHD particularly rheumatic heart disease and mitral valve pathologies. Their coexistence also amplifies the risk of stroke, heart failure and death.\u003c/p\u003e\u003cp\u003eThe risk of valvular heart disease increases directly with age, which is more pronounced in elderly people, so multidisciplinary approaches and systemic evaluation have been advised for reducing complications and improving survival outcomes (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). A recent study found that the overall age adjusted mortality rates from 1999\u0026ndash;2020 declined from 8.4 to 6.6 per 100,000 with men more inclined towards aortic pathologies and females with mitral valve pathologies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Over the past two decades, various trends in epidemiology of both the conditions have occurred, influenced by age, improved diagnostic strategies and recent advent of transcatheter valvular interventions. Globally, non-rheumatic valvular diseases have been rising in high-socio-demographic-index regions like North America. Between 1990 and 2019, the global incidence of NRVD showed gradual increase with an estimated annual percentage change of 0.39% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The prevalence and mortality also vary by geographical and socioeconomic stratifications, with rheumatic pathologies dominating in low- and middle-income countries while degenerative valvular states predominating in high income settings (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eParallel to VHD, the prevalence of atrial fibrillation has also been rising. New diagnoses of atrial fibrillation have increased by about 30% between 2000 and 2020 owing to age, advancements in diagnostic strategies and rising risk factors (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Some community-based studies show that while incidence rates stabilized over past decades, atrial fibrillation continues to predict short- and long-term mortality. In Olmsted County, over the last decade AF incidence and prevalence remained constant but a dramatic excess risk of death was observed in 90 days post diagnosis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Similarly, data from Framingham Heart Study confers that despite some gradual improvements, AF still confers a two-year loss of life expectancy (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). According to Centers for Disease Control and Prevention (CDC), atrial fibrillation/flutter related deaths rose until 2016 and plateaued afterwards when considered as underlying cause of death, when considered as a contributing factor, mortality rate continued rising through 2020 with the largest increase seen in Non-Hispanic Black males and residents of rural areas (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eForecasting mortality patterns is essential for healthcare planning, resource utilization and preventive strategies. In this study, we evaluate the trends in mortality associated with valvular heart disease and atrial fibrillation from 1999 to 2023 stratified by age, gender, race, census, urbanization, census and place of death. Furthermore, we applied validated time series forecasting models to project mortality patterns through 2030. By providing a comprehensive view of past present and expected future mortality associated with these overlapping conditions, this study aims to guide health care providers of the evolving burden and targeted interventional strategies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eMortality data from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging online Data for Epidemiologic Research) database was extracted and examined from 1999 to 2023 for Valvular heart disease (VHD) and atrial fibrillation AF related mortality in adults 45\u0026thinsp;+\u0026thinsp;years age using codes from the International Statistical Classification of Diseases and Related Health Problems-10th Revision (ICD-10) as follows: MCD - ICD-10 Codes: I05.0 (Mitral stenosis); I05.1 (Rheumatic mitral insufficiency); I05.2 (Mitral stenosis with insufficiency); I05.8 (Other mitral valve diseases); I05.9 (Mitral valve disease, unspecified); I06.0 (Rheumatic aortic stenosis); I06.1; (Rheumatic aortic insufficiency); I06.2 (Rheumatic aortic stenosis with insufficiency); I06.8 (Other rheumatic aortic valve diseases); I06.9 (Rheumatic aortic valve disease, unspecified); I07.0 (Tricuspid stenosis); I07.1 (Tricuspid insufficiency); I07.2 (Tricuspid stenosis with insufficiency); I07.8 (Other tricuspid valve diseases); I07.9 (Tricuspid valve disease; unspecified); I08.0 (Disorders of both mitral and aortic valves); I08.1 (Disorders of both mitral and tricuspid valves); I08.2, (Disorders of both aortic and tricuspid valves); I08.3 (Combined disorders of mitral, aortic and tricuspid valves); I08.8 (Other multiple valve diseases); I08.9 (Multiple valve disease, unspecified); I34.0 (Mitral (valve) insufficiency); I34.1 (Mitral,(valve) prolapse); I34.2 (Nonrheumatic mitral (valve) stenosis); I34.8 (Other nonrheumatic mitral valve disorders); I34.9, (Nonrheumatic mitral valve disorder, unspecified); I35.0 (Aortic (valve) stenosis); I35.1 (Aortic (valve) insufficiency); I35.2, (Aortic (valve) stenosis with insufficiency); I35.8 (Other aortic valve disorders); I35.9 (Aortic valve disorder, unspecified); I36.0 (Nonrheumatic tricuspid (valve) stenosis); I36.1 (Nonrheumatic tricuspid (valve) insufficiency); I36.2 (Nonrheumatic, tricuspid (valve) stenosis with insufficiency); I36.8 (Other nonrheumatic tricuspid valve disorders); I36.9 (Nonrheumatic, tricuspid valve disorder, unspecified); I37.0 (Pulmonary valve stenosis); I37.1 (Pulmonary valve insufficiency); I37.2, (Pulmonary valve stenosis with insufficiency); I37.8 (Other pulmonary valve disorders); I37.9 (Pulmonary valve disorder, unspecified) and I48 for atrial fibrillation.\u003c/p\u003e\u003cp\u003eThe same ICD codes have been described previously to identify VHD and AF in administrative databases. This data set includes cause of death from death certificates for the 50 states and the District of Columbia and has been previously used in several studies to determine trends in mortality of cardiovascular diseases. The Multiple Cause-of-Death Public Use record death certificates were studied to select VHD and AF related deaths, which were identified as those with VHD and AF reported anywhere on the death certification either as a contributing or underlying cause of death (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Older adults were defined as those who were aged 45 years or older at the time of death (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Similar age cutoff has been used by previous studies to define older adults. The study was exempted from local institutional review board approval because it used deidentified government-issued public use data set and follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData abstraction and variables\u003c/h2\u003e\u003cp\u003eData for population size, year, location of death, demographics, urban-rural classification, region, and states were abstracted. Demographics included sex, age, and race/ethnicity, and location of death included medical facilities (outpatient, emergency room, inpatient, death on arrival, or status unknown), home, hospice, and nursing home/long-term care facility. Race/ethnicity was classified as non-Hispanic (NH) White, NH Black or African American, Hispanic or Latino, NH American Indian or Alaskan Native, and NH Asian or Pacific Islander. This information relies on reported data on death certificates and has been used in previous analyses of the WONDER database. The National Center for Health Statistics Urban-Rural Classification Scheme was used to assess the population by urban (large metropolitan area [population\u0026thinsp;\u0026ge;\u0026thinsp;1 million], medium/small metropolitan area [population 50,000-999,999]) and rural (population\u0026thinsp;\u0026lt;\u0026thinsp;50,000) counties according to the 2013 U.S. census classification (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Regions were classified into Northeast, Midwest, South, and West according to the U.S. Census Bureau definitions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eTo examine national trends in VHD and AF related mortality, we calculated crude and age-adjusted mortality rates (AAMRs) per 10,000 population from 1999 to 2019 by year, sex, race/ethnicity, state, and urban-rural status with 95% CIs. Crude mortality rates were determined by dividing the number of VHD-related deaths by the corresponding U.S. population of that year. AAMRs were calculated by standardizing VHD AF-related deaths to the year 2000 U.S. population. To quantify national annual trends in VHD AF related mortality, the Joinpoint Regression Program (Joinpoint V 4.9.0.0, National Cancer Institute) was used to determine the annual percent change (APC) with 95% CI in AAMR. This method identifies significant changes in AAMR over time by fitting log-linear regression models where temporal variation occurred. APCs were considered increasing or decreasing if the slope describing the change in mortality was significantly different from zero using 2-tailed t-testing. A value of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Future mortality AAMR were calculated till 2035 by doing projection analysis using ARIMA (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eAnnual trends\u003c/h2\u003e\u003cp\u003eValvular Heart Disease and Atrial Fibrillation caused a total of 172,511 deaths in the US from 1999 to 2023 (\u003cb\u003eSupplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/b\u003e). The age-adjusted mortality rates (AAMR) ranged between 3.64 (95% CI 3.52\u0026ndash;3.76) in 1999 and 8.93 per million (95% CI 8.78\u0026ndash;9.09) in 2023. The highest AAMR was reported in 2021 at 9.01 per million (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The rates had demonstrated two sets of upward slopes in these years with a significant incline in AAMR (APC: 2.12*, 95% CI: 0.90 to 2.93, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) from 1999 to 2009 followed by steeper increase till 2023 with an APC of 5.39 (95% CI: 5.04 to 5.88, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (\u003cb\u003eSupplementary table 2\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eGender\u003c/h3\u003e\n\u003cp\u003eSegregation of the database by gender revealed a similar burden for both groups initially, though trends diverged and males had a higher rise in AAMRs compared to the female population. Males had a total of 74,605 deaths and the females had a total of 97,906 deaths from 1999 to 2023, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The AAMR for females rose from 3.58 in 1999 to 7.90 per million in 2023 with an AAPC of 3.52 (95% CI 3.23 to 3.81, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, the AAMR for males rose from 3.83 in 1999 to 10.44 per million in 2023 with a steeper AAPC of 4.45 (95% CI 4.20 to 4.70, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, \u003cb\u003eSupplementary table 3\u003c/b\u003e). The greater rise in men is exemplified by the recent increase from 2018 to 2021 (APC: 9.73 95% CI 7.81 to 11.01) (\u003cb\u003eSupplementary table 2\u003c/b\u003e).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eRace\u003c/h2\u003e\u003cp\u003eRacial trends showed a drastically higher trend in Non-Hispanic (NH) White individuals compared to other races with an eventual AAMR of 10.46 per million in 2023. Though, initially unreliable NH American Indians had the highest peak of the other races with 6.69 AAMR in 2021; followed by Hispanics (4.19 in 2021), NH Asians (4.01 in 2023) and NH African Americans (3.89 in 2022) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, \u003cb\u003eSupplementary table 4\u003c/b\u003e). Fascinatingly, rise in AAMR was steepest in NH Americans (AAPC: 4.49 95% CI 3.91 to 5.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) owing to a period of sustained rise from 2009 to 2023 (APC: 7.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Unlike other races, which had an insignificant change in the initial decade of 2000s, burden in NH Whites kept rising in that period as well (APC 1999\u0026ndash;2009: 2.30, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) which was followed by the steeper rise (APC 2009\u0026ndash;2023: 5.83, 95% CI 5.43 to 6.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cb\u003eSupplementary table 2\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAge-specific Trends\u003c/h3\u003e\n\u003cp\u003eAge wise distribution was starkly skewed towards adults older than 65 years. Stratification revealed 6,722 deaths (4% of total deaths) in adults aged 45\u0026ndash;64 years while 165,789 deaths occurred in adults aged above 65 (\u003cb\u003eSupplementary table 5\u003c/b\u003e). Regardless, 45\u0026ndash;64 age groups have AAMR on a rising trend from 2011 onwards (APC: 7.94, 95% CI 6.53\u0026ndash;10.42, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). On the other hand, AAMR in adults aged above 65 rose from 9.66 in 1999 to 23.73 in 2023 (AAPC: 4.00, 95% CI 3.69 to 4.26, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cb\u003eSupplementary table 2\u003c/b\u003e).\u003c/p\u003e\n\u003ch3\u003eGeographic Trends\u003c/h3\u003e\n\u003cp\u003eThe AAMR across the four census regions were generally similar with a slightly higher burden in West while South had a comparatively lower burden. Highest AAMR in West was 11.27 per million in 2021, followed by Midwest (9.94 in 2021), Northeast (9.17 in 2021), and South (7.18 in 2023) (\u003cb\u003eSupplementary table 6\u003c/b\u003e). The strongest rise in AAMR was in the Midwestern region (2010\u0026ndash;2021 APC: 6.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), closely followed by the Southern region (2012\u0026ndash;2023 APC: 6.37, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, \u003cb\u003eSupplementary table 2\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eStratification by urbanization up to 2020 revealed 81% of deaths occurred in metropolitan areas. The AAMR in both groups was relatively similar till 2011 (Metro AAMR: 4.94, Non-Metro AAMR: 4.98) after which rise in AAMR in non-metro areas occurred at a greater degree (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eD, \u003cb\u003eSupplementary table 7\u003c/b\u003e). The APC from 2011 to 2020 for non-metro areas was 6.32, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 achieving a peak of 8.96 per million in 2020. Metropolitan areas peaked at 7.59 per million in 2020.\u003c/p\u003e\u003cp\u003eState wise analysis occurred over two periods 1999 to 2020 and 2021 to 2023. Both periods yielded mostly similar results with Oregon, Vermont, Washington and New Hampshire being common in top 90th percentile. Georgia, Louisiana and Alabama were the states common in the bottom 10th percentile (\u003cb\u003eSupplementary table 8\u003c/b\u003e). The greatest rise in ranks was seen in Nevada which rose from the 7th to 42nd percentile while the highest drop was in Alaska going from 86th to 46th percentile.\u003c/p\u003e\u003cp\u003eInpatient Facility recorded the highest number of deaths at 60,952 (35%), followed by decedent's home (51,315; 30%), nursing homes (35402; 21%), hospice facilities (8877; 5%) and outpatient facilities (7628; 4%) (\u003cb\u003eSupplementary table 9\u003c/b\u003e). A central illustration provides an integrated overview of sex, race, age and region-stratified trends in valvular heart disease and atrial fibrillation-related mortality over the study period (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eForecasted Trends\u003c/h2\u003e\u003cp\u003eThe forecasted rate for 2024 was 8.9 per 1,000,000 (95% CI: 3.7\u0026ndash;14.2), with a projected increase to 12.6 per 1,000,000 (95% CI: -5.7\u0026ndash;30.8) by 2035 with an APC of 3.15% (95% CI 3.13% to 3.17%). For female, the forecasted AAMR for 2024 was 7.4 (95% CI: 6.1\u0026ndash;8.8), with a projected increase to 9.8 per 1,000,000 (95% CI: 5.5\u0026ndash;14.2) by 2035 with an APC of 2.55% (95% CI 2.53% to 2.56%). For males, the forecasted rate for 2024 was 10.8 (95% CI: 3.2\u0026ndash;18.3), with a projected increase to 15.9 per 1,000,000 (95% CI: -10.3\u0026ndash;42.0) by 2035 with an APC of 3.56% (95% CI 3.53% to 3.58%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cb\u003eSupplementary Table\u0026nbsp;10\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis 24-year analysis of mortality data from the Centers for Disease Control and Prevention examined the trends in the mortality rate of patients with valvular heart disease and atrial fibrillation. This analysis showed that the overall AAMR nearly doubled from 3.6 per million in 1999 to 8.9 per million in 2023, with two distinct periods of rapid increase, particularly after 2009 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Males experienced a steeper rise in AAMR compared to females, and while non-Hispanic White individuals had the highest absolute mortality rates, non-Hispanic American Indians demonstrated the most rapid growth over time (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Most of the deaths were in adults over 65 years, but adults aged 45 to 64 also showed a notable upward trend starting in 2011 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Geographically, the Western and Midwestern regions had higher AAMRs, with non-metropolitan areas experiencing sharper increases compared to metropolitan areas after 2011, and projections indicate that this trend will continue, with the AAMR estimated to reach 12.6 per million by 2035, highlighting the continuous increase in the burden of disease (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study demonstrates an increase in the AAMR attributed to VHD and AF from 1999 to 2023, with a prominent increase noted after 2009. Although no prior studies have specifically addressed the mortality trends associated with the coexistence of atrial fibrillation and valvular heart disease, previous analyses that have independently assessed each condition have similarly reported an increase in mortality trends over the past few decades (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This parallel rise is likely due to shared underlying factors. These include an aging population, a greater prevalence of comorbidities, and improvements in diagnostic tools that have enhanced detection and reporting of both conditions. Historically, the prevalence of atrial fibrillation was often underestimated because of the high number of clinically silent episodes and paroxysmal AF, which can be overlooked during a routine physical exam or with a standard 12-lead electrocardiogram. The development of wearable devices has provided clinicians with a more reliable method to identify previously undiagnosed atrial fibrillation, particularly in individuals at higher risk (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). At the same time, the burden of valvular heart disease may have increased because of the wider use of advanced imaging and echocardiographic screening, which enhances case detection. New interventional strategies have also improved survival rates among patients with heart failure but may put patients at risk for secondary (or functional) manifestation of diseases (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The observed rise in mortality trends after 2009 could partly reflect these shifts in diagnostic and treatment practices, alongside the increasing survival of patients with complex multimorbidity, who remain at higher risk for adverse outcomes.\u003c/p\u003e\u003cp\u003eNotably, we found that males experienced a steeper rise in AAMR compared to females over the study period. Several factors can contribute to this disparity. Firstly, male sex has classically been recognized as a major risk factor for certain structural heart diseases such as bicuspid aortic valve and degenerative calcific aortic stenosis which predispose them to the development of valvular heart disease and, subsequently, atrial fibrillation (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Secondly, prior studies reported that women may derive greater benefit from anticoagulation compared to males, which could explain the steeper rise in mortality for males (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Moreover, biological differences in atrial remodelling and thrombogenicity could contribute to more severe clinical manifestations or complications in men (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Finally, it is possible that differences in healthcare-seeking behaviour, access to care, and adherence to treatment between men and women also play a role (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This imbalance of sex ratios identified in the general population is important and could indicate a sex bias in referral patterns for diagnosis and treatment. The mechanisms for such an imbalance should be investigated prospectively.\u003c/p\u003e\u003cp\u003eCardiovascular mortality related to AF and VHD was higher in NHW compared to other racial groups. Given prior work documenting disproportionately higher burden of AF risk factors including obesity, hypertension and diabetes mellitus in Black adults (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). It is possible that our finding documenting lower mortality due to AF and VHD in Black adults may be due to disparities in diagnosis, awareness and treatment rather than an actual lower burden of disease (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Under-recognition of AF in minority populations has been noted in previous studies (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). This may be due to differences in healthcare access, less frequent use of ambulatory monitoring, and structural inequalities in care delivery (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). These findings highlight the need to improve screening strategies and ensure equal access to diagnostic and therapeutic interventions for all racial and ethnic groups.\u003c/p\u003e\u003cp\u003eCardiovascular mortality linked to AF and VHD is rising more rapidly among younger adults (aged 35\u0026ndash;64 years) than among older adults (aged 65\u0026ndash;84 years).This change in young adults is alarming given the drop in life expectancy in the United States since 2014 which has been attributed to the increase in midlife cardiovascular mortality (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) 18 .Although our analysis of mortality trends cannot establish causation, both our study and prior research have suggested that the rising prevalence of cardiovascular risk factors among younger adults is possibly contributing to this observed increase in mortality in this age group (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)19. Nevertheless, despite the steeper increase in AAMR among younger adults, the absolute number of deaths remains substantially higher in those over 65 years of age, highlighting the impact of an aging population on the overall burden of cardiovascular mortality in patients with coexisting VHD and AF. Together, these trends highlight an urgent need for early detection, risk factor modification, and age-specific prevention strategies to address the shifting and growing burden of AF and VHD-related mortality.\u003c/p\u003e\u003cp\u003eSignificant variations in mortality rates were observed geographically. While overall AAMRs were generally similar across regions, the West had a slightly higher burden, and the Midwest and South showed the steepest increases over time. Although most deaths occurred in metropolitan areas, non-metropolitan regions experienced a sharper rise in mortality after 2011. These geographical and regional disparities highlight the importance of local factors, access to healthcare, sociodemographic factors and resource distribution in influencing the mortality trends. This emphasizes the need for interventions and resource allocation tailored to specific regions to ensure the most effective and targeted approach to reducing disparities.\u003c/p\u003e\u003cp\u003eFinally, our projections indicate that this rising trend will likely persist, with the AAMR estimated to reach 12.6 per million by 2035. This anticipated increase is largely driven by the aging U.S. population, as atrial fibrillation and valvular heart disease is predominantly a condition affecting older adults (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Beyond demographic shifts, other important factors are likely contributing to the growing burden. The increasing prevalence of major risk factors including obesity, diabetes mellitus, and hypertension and improved detection of these through increased awareness and the widespread use of portable monitoring devices and advanced echocardiography has led to the identification of more cases that might previously have gone undiagnosed (\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Together, these trends suggest that without targeted prevention and management strategies, the burden of AF and valvular heart disease-related mortality will continue to escalate in the coming decade.\u003c/p\u003e\u003cp\u003eThis study has several strengths. It is, to our knowledge, the first comprehensive nationwide analysis examining long-term mortality trends specifically related to the coexistence of atrial fibrillation and valvular heart disease over a 24-year period. By using a large, population-based dataset from the CDC WONDER database, our analysis benefits from national coverage and the inclusion of diverse demographic, geographic, and clinical subgroups. The application of time series forecasting also offers valuable insight into future trends, which can inform healthcare planning and resource allocation.\u003c/p\u003e\u003cp\u003eHowever, limitations must also be acknowledged. First, this study is observational and relies on death certificate data, which are subject to misclassification and underreporting, especially for conditions like paroxysmal or subclinical atrial fibrillation. Second, causality cannot be inferred from these mortality trends, and residual confounding by unmeasured factors, such as socioeconomic status, detailed comorbidity burden, and healthcare access, may influence the observed patterns. Third, changes in coding practices and increased use of diagnostic technologies over time may artificially inflate trends. Finally, the forecasting models are based on historical data and assume continuation of past patterns, which may not fully capture the impact of emerging treatments or policy changes.\u003c/p\u003e\u003cp\u003eFuture research should focus on understanding the causes of the rising mortality associated with coexisting atrial fibrillation and valvular heart disease. Greater emphasis should be given on evaluating the effectiveness of new screening tools like artificial intelligence algorithms to improve the early detection and lower mortality in this group. Additionally, studies should explore the impact of newer therapeutic strategies like transcatheter valve interventions, on long-term outcomes across diverse patient populations. Addressing disparities in diagnosis, treatment, and outcomes by sex, race, age, and geography should remain a priority. Finally, using predictive analytics in public health planning can help identify high-risk groups and support more customized prevention and management strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTaken together, our results offer a comprehensive examination of the contemporary trend of death due to coexistence of AF and VHD in the recent era. The increasing burden is attributed to demographic aging, rising prevalence of cardiovascular risk factors, advances in diagnostic detection, and persistent disparities across sex, race, age, and geographic regions. These findings highlight the need for targeted public health interventions, early detection strategies, and equitable resource allocation to address the evolving epidemiology of AF and VHD-related mortality. Continued surveillance and prospective studies are essential to better understand underlying mechanisms and guide effective prevention and management strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCorresponding Author:\u0026nbsp;\u003c/strong\u003eFenilkumar Kotadiya, [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eAll data used in this study are publicly available through the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database. The authors obtained access in accordance with the CDC\u0026rsquo;s data use guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement:\u0026nbsp;\u003c/strong\u003eThis research did not receive any grants from funding agencies in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosure:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest related to this work. All authors have reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval Statement:\u0026nbsp;\u003c/strong\u003eThis study used de-identified, publicly available mortality data from the CDC WONDER database and did not involve direct human participants or animal subjects. Institutional review board approval and informed consent were therefore not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Consent Statement:\u0026nbsp;\u003c/strong\u003eInformed consent was waived because the study used de-identified, publicly available data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermission to Reproduce Material from Other Sources:\u0026nbsp;\u003c/strong\u003eNot applicable. No third-party material was reproduced.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOtto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP, Gentile F, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. 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Circulation [Internet]. 2017 Mar 28 [cited 2025 Aug 9];135(13):1227\u0026ndash;39. Available from: https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.116.022388?download=true\u003c/li\u003e\n\u003cli\u003eWang YC, Xu X, Hajra A, Apple S, Kharawala A, Duarte G, et al. Current Advancement in Diagnosing Atrial Fibrillation by Utilizing Wearable Devices and Artificial Intelligence: A Review Study. Diagnostics [Internet]. 2022 Mar 1 [cited 2025 Aug 9];12(3). Available from: https://pubmed.ncbi.nlm.nih.gov/35328243/\u003c/li\u003e\n\u003cli\u003eKirchhof P. The future of atrial fibrillation management: integrated care and stratified therapy. The Lancet [Internet]. 2017 Oct 21 [cited 2025 Aug 9];390(10105):1873\u0026ndash;87. Available from: https://pubmed.ncbi.nlm.nih.gov/28460828/\u003c/li\u003e\n\u003cli\u003eSchnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, et al. Fifty-Year Trends in Atrial Fibrillation Prevalence, Incidence, Risk Factors, and Mortality in the Community. Lancet [Internet]. 2015 Jul 11 [cited 2025 Aug 9];386(9989):154. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4553037/\u003c/li\u003e\n\u003cli\u003ePraz F, Beyersdorf F, Haugaa K, Prendergast B. Valvular heart disease: from mechanisms to management. The Lancet [Internet]. 2024 Apr 20 [cited 2025 Aug 9];403(10436):1576\u0026ndash;89. Available from: https://pubmed.ncbi.nlm.nih.gov/38554728/\u003c/li\u003e\n\u003cli\u003eWang Y, Cao T, Liu X, He S, Ran Z, Du C, et al. A New Benchmark for Modern Management of Valvular Heart Disease: The Whole-Life Cycle Management System. JACC Asia [Internet]. 2025 May 1 [cited 2025 Aug 9];5(5):609. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12081237/\u003c/li\u003e\n\u003cli\u003eDesjardin JT, Chikwe J, Hahn RT, Hung JW, Delling FN. Sex Differences and Similarities in Valvular Heart Disease. Circ Res [Internet]. 2022 Feb 18 [cited 2025 Aug 9];130(4):455\u0026ndash;73. Available from: https://pubmed.ncbi.nlm.nih.gov/35175844/\u003c/li\u003e\n\u003cli\u003eMichelena HI, Powell BD, Brady PA, Friedman PA, Ezekowitz MD. Gender in atrial fibrillation: Ten years later. Gend Med [Internet]. 2010 [cited 2025 Aug 9];7(3):206\u0026ndash;17. Available from: https://pubmed.ncbi.nlm.nih.gov/20638626/\u003c/li\u003e\n\u003cli\u003eWesterman S, Wenger N. Gender Differences in Atrial Fibrillation: A Review of Epidemiology, Management, and Outcomes. Curr Cardiol Rev [Internet]. 2018 Dec 5 [cited 2025 Aug 9];15(2):136\u0026ndash;44. Available from: https://pubmed.ncbi.nlm.nih.gov/30516110/\u003c/li\u003e\n\u003cli\u003eHahn RT, Clavel MA, Mascherbauer J, Mick SL, Asgar AW, Douglas PS. Sex-Related Factors in Valvular Heart Disease: JACC Focus Seminar 5/7. J Am Coll Cardiol [Internet]. 2022 Apr 19 [cited 2025 Aug 9];79(15):1506\u0026ndash;18. Available from: https://pubmed.ncbi.nlm.nih.gov/35422247/\u003c/li\u003e\n\u003cli\u003eVelarde G, Bravo-Jaimes K, Brandt EJ, Wang D, Douglass P, Castellanos LR, et al. Locking the Revolving Door: Racial Disparities in Cardiovascular Disease. J Am Heart Assoc [Internet]. 2023 Apr 18 [cited 2025 Aug 9];12(8). Available from: https://pubmed.ncbi.nlm.nih.gov/36942617/\u003c/li\u003e\n\u003cli\u003eNorby FL, Benjamin EJ, Alonso A, Chugh SS. Racial and Ethnic Considerations in Patients With Atrial Fibrillation: JACC Focus Seminar 5/9. J Am Coll Cardiol [Internet]. 2021 Dec 21 [cited 2025 Aug 9];78(25):2563\u0026ndash;72. Available from: https://pubmed.ncbi.nlm.nih.gov/34887142/\u003c/li\u003e\n\u003cli\u003eMacias-Konstantopoulos WL, Collins KA, Diaz R, Duber HC, Edwards CD, Hsu AP, et al. Race, Healthcare, and Health Disparities: A Critical Review and Recommendations for Advancing Health Equity. Western Journal of Emergency Medicine [Internet]. 2023 Sep 1 [cited 2025 Aug 9];24(5):906\u0026ndash;18. Available from: https://pubmed.ncbi.nlm.nih.gov/37788031/\u003c/li\u003e\n\u003cli\u003eUnderstanding and addressing racial disparities in health care - PubMed [Internet]. [cited 2025 Aug 11]. Available from: https://pubmed.ncbi.nlm.nih.gov/11481746/\u003c/li\u003e\n\u003cli\u003eMehta NK, Abrams LR, Myrskyl\u0026auml; M. US life expectancy stalls due to cardiovascular disease, not drug deaths. Proc Natl Acad Sci U S A [Internet]. 2020 Mar 31 [cited 2025 Aug 11];117(13):6998\u0026ndash;7000. Available from: /doi/pdf/10.1073/pnas.1920391117?download=true\u003c/li\u003e\n\u003cli\u003eOgden CL, Carroll MD, Lawman HG, Fryar CD, Kruszon-Moran D, Kit BK, et al. Trends in obesity prevalence among children and adolescents in the United States, 1988-1994 through 2013-2014. JAMA - Journal of the American Medical Association [Internet]. 2016 Jun 7 [cited 2025 Aug 11];315(21):2292\u0026ndash;9. Available from: https://pubmed.ncbi.nlm.nih.gov/27272581/\u003c/li\u003e\n\u003cli\u003ePham HN, Ibrahim R, Truong HH, Sainbayar E, Tran VN, Abdelnabi M, et al. Advances in Atrial Fibrillation Management: A Guide for General Internists. Journal of Clinical Medicine 2024, Vol 13, Page 7846 [Internet]. 2024 Dec 23 [cited 2025 Aug 11];13(24):7846. Available from: https://www.mdpi.com/2077-0383/13/24/7846/htm\u003c/li\u003e\n\u003cli\u003eSengupta PP, Kluin J, Lee SP, Oh JK, Smits AIPM. The future of valvular heart disease assessment and therapy. The Lancet [Internet]. 2024 Apr 20 [cited 2025 Aug 11];403(10436):1590\u0026ndash;602. Available from: https://pubmed.ncbi.nlm.nih.gov/38554727/\u003c/li\u003e\n\u003cli\u003eSingh A, Bruemmer D. Cardiometabolic Risk: Shifting the Paradigm Toward Comprehensive Assessment. 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Available from: https://pubmed.ncbi.nlm.nih.gov/38939673/\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Valvular heart disease, Atrial fibrillation, Mortality trends, Health disparities, CDC WONDER, Forecasting, United States, Epidemiology","lastPublishedDoi":"10.21203/rs.3.rs-7950876/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7950876/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eValvular heart disease (VHD) and atrial fibrillation (AF) frequently coexist, presenting complex clinical challenges despite advances in diagnostics and therapeutics. Together, they contribute substantially to cardiovascular mortality. However, epidemiological patterns vary across demographics and regions\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eMortality data from 1999\u0026ndash;2023 were obtained from the CDC WONDER database. Deaths attributed to VHD (ICD-10: I30-I52) with co-diagnosed AF (ICD-10: I48) among adults\u0026thinsp;\u0026ge;\u0026thinsp;45 were included. Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated. Autoregressive integrated moving average (ARIMA) models were used to project mortality trends through 2035.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom 1999 to 2023, there were 172,511 VHD and Afib-related deaths in adults\u0026thinsp;\u0026ge;\u0026thinsp;45. AAMRs increased until 2021, followed by a slight decline to 8.86. The overall AAPC for VHD with AF was 4.01%. AAMR increase was consistent across all age groups, highest seen in 65\u0026thinsp;+\u0026thinsp;individuals. Males had consistently higher AAMRs than females. AAPC for males was 4.44% and for females 3.52%. Non- Hispanic White had the highest AAMR (10.56 in 2021), followed by Hispanics (4.19). Regionally, the West had the highest AAMR (11.27), followed by Mid-West (9.94). Non-metropolitan areas had higher AAMR 8.96 compared to metropolitan areas (AAMR: 7.59). Most VHD related deaths were reported in inpatient settings (n\u0026thinsp;=\u0026thinsp;396,451) and 12% involved co-diagnosed AF.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eMortality associated with VHD and AF in the U.S population aged\u0026thinsp;\u0026ge;\u0026thinsp;45 has shown a concerning increase. Predictive models indicate this trend may persist, highlighting the need for early detection, equitable healthcare access and public health interventions tailored to high-risk populations.\u003c/p\u003e","manuscriptTitle":"Evolving Mortality Burden of Valvular Heart Disease with Atrial Fibrillation Among U.S. Adults Aged 45 Years and Older: Trends (1999–2023) and Projections to 2035","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-27 17:44:16","doi":"10.21203/rs.3.rs-7950876/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-15T13:34:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-04T03:05:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78545199253128441117545955430695128741","date":"2025-11-24T00:22:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-23T22:01:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299545382478626986125570485611931948705","date":"2025-11-23T21:45:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-21T08:13:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-30T15:58:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-29T11:00:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-29T11:00:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-10-26T13:55:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9b79bcf6-4a24-441d-b71f-f3fdc7672d2b","owner":[],"postedDate":"November 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-21T07:39:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-27 17:44:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7950876","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7950876","identity":"rs-7950876","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}