Trends and Disparities in Amyloidosis and Cardiovascular Disease Mortality: A Population-Based Retrospective Study in the United States (1999–2020)

Trends and Disparities in Amyloidosis and Cardiovascular Disease Mortality: A Population-Based Retrospective Study in the United States (1999–2020) | 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 Trends and Disparities in Amyloidosis and Cardiovascular Disease Mortality: A Population-Based Retrospective Study in the United States (1999–2020) Faizan Ahmed, Tehmasp Rehman Mirza, Zoha Iftikhar, Saman Rauf, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7864719/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jan, 2026 Read the published version in BMC Cardiovascular Disorders → Version 1 posted 15 You are reading this latest preprint version Abstract Introduction : Cardiac amyloidosis (CA), most commonly caused by transthyretin (ATTR) or light chain (AL) deposition, is increasingly recognized as a contributor to heart failure, particularly in older adults and patients with heart failure with preserved ejection fraction (HFpEF). Despite advances in diagnostic imaging and disease-modifying therapies, CA remains underdiagnosed, and population-level data on its combined mortality burden with cardiovascular disease (CVD) are limited. Aims : This study aimed to analyze two decades of consecutive mortality data to investigate amyloidosis and cardiovascular disease (CVD) across the United States (US), identifying patterns and disparities in mortality rates. Methods : A retrospective analysis was conducted using mortality data from the CDC WONDER database spanning 1999–2020. Age-adjusted mortality rates (AAMRs) per 1,000,000 persons were calculated, and trends were assessed using Average Annual Percentage Change (AAPC) and Annual Percent Change (APC) using Joinpoint 5.0.2. Results : Between 1999 and 2020, 26,391 Amyloidosis and CVD-related deaths occurred among adults aged 25 and older in the US. The overall AAMR for Amyloidosis and CVD-related mortality increased from 4.40 in 1999 to 9.31 in 2020, with an AAPC of 3.49 (p < 0.001). Most striking was the recent steep rise in AAMRs from 2018 to 2020 with an APC of 13.60. Men exhibited higher AAMRs compared to women. Similar to the overall trend, AAMRs for both men and women had a steep incline in the last decade. African Americans or Blacks had the highest AAMRs (11.4) followed by White (5.11) and Hispanics (3.86). The highest mortality was in the Northeast region (AAMR: 6.71). Nonmetropolitan areas had higher AAMRs than metropolitan areas (5.73 vs 4.76), however, with a more remarkable increase in metropolitan areas. Conclusions : The prevalence of amyloidosis and cardiovascular disease-related deaths has risen markedly, especially between 2018 and 2020. Increased mortality rates were noted among men, African Americans, and individuals in the Northeast region. These patterns emphasize the necessity for focused public health initiatives. Amyloidosis Cardiovascular Disease Disparities Mortality Trends Epidemiology United States Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Extracellular deposits of misfolded proteins, especially transthyretin (ATTR) or immunoglobin light chains (AL), causing cardiac amyloidosis (CA) have shown to contribute heavily to heart failure, particularly among older individuals, and patients with heart failure with preserved ejection fraction (HFpEF) [ 1 ]. Although it was previously regarded as a rare condition, recent diagnostic procedures having high sensitivity and specificity such as cardiac MRI, bone scintigraphy and AI assisted imaging have led to a significant rise in its detection [ 2 , 3 ]. ATTRwt (wild type form of ATTR) is generally found in men with ages above 70, whereas ATTRv (hereditary ATTR) is caused by pathogenic gene mutations in the TTR gene which might present earlier [ 1 ]. Management is improving with recent therapeutic developments: a next-generation TTR stabilizer approved in 2024: acoramidis has reduced mortality and morbidity in ATTR cardiomyopathy (ATTR-CM) and RNA-silencing medicines, such as patisiran, have also shown to have a mortality and morbidity benefit in ATTR-CM [ 4 , 5 ]. These options are a shift towards disease-modifying treatment, unlike the previous palliative care approach. Despite these advances, CA is still vastly underdiagnosed, presenting with nonspecific symptoms or symptoms resembling other cardiac conditions. It has been speculated through autopsies and clinical studies that many older adults with HFpEF have amyloid deposits [ 6 ]. Untreated, CA leads to rapid clinical deterioration and poor survival rates particularly when comorbid with cardiovascular disease. Moreover, there is a racial and socioeconomic discrepancy. Black patients are affected more often with ATTRv because of the V122I mutation, and face higher in-hospital deaths, longer hospitalizations, and increased complications after being diagnosed [ 7 ]. Such disparities show systematic disparities in access to advanced diagnostics and treatment. The population-level data on mortality due to amyloidosis and CVD is scanty. Vast majority of studies investigate each of these diseases independently, overlooking the intersectional mortality burden which may compound health inequities. This study attempts to address this gap by using 20 years of U.S. national mortality data to evaluate trends and disparities in Amyloidosis and Cardiovascular Disease (CVD)-related deaths. By calculating age-adjusted mortality rates (AAMRs) and stratifying by sex, race/ethnicity, geography, and urbanization, we provide a comprehensive, demographic-driven epidemiologic profile of this emerging public health issue. METHODS Population and Study Setting This population-based analysis utilized publicly available mortality data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database, which compiles information from U.S. death certificates [ 8 ]. We examined all deaths attributed to amyloidosis ( International Classification of Diseases, 10th Revision [ICD-10] code E85 ) and cardiovascular diseases ( ICD-10 codes I00 to I99 ) occurring between 1999 and 2020 across all 50 states and the District of Columbia [ 9 ]. Adults aged 25 years and older at the time of death were included in the analysis. Because CDC WONDER provides deidentified, publicly available data, institutional review board approval was not required. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational research [ 10 ]. The analytical framework was adapted from our previously published methodology on national cardiovascular mortality trends, with modifications to address amyloidosis-related outcomes [ 11 ]. Data Abstraction The dataset extracted from death certificates included information on year of death, place of occurrence, sex, age group, race and ethnicity, geographic region, state, and urban-rural classification. Deaths were categorized according to their location, which included hospitals, private residences, hospices, nursing homes, and long-term care facilities. Urbanization categories were based on the National Center for Health Statistics Urban-Rural Classification Scheme. Urban areas comprised large metropolitan regions with populations of one million or more, as well as medium or small metropolitan areas with populations between 50,000 and 999,999. Rural areas were defined as those with populations under 50,000, consistent with the 2013 U.S. Census definitions [ 12 ]. Geographical divisions followed the U.S. Census Bureau classification, which divides the country into four main regions namely the Northeast, Midwest, South and West. Statistical Analysis We calculated both crude and age-adjusted mortality rates (AAMRs) per 1,000,000 individuals for each calendar year, stratified by sex, race and ethnicity, state, and urban-rural status, with corresponding 95% confidence intervals (CIs). Crude mortality rates were derived by dividing the number of amyloidosis and CVD-related deaths by the corresponding U.S. population for each year. Age-adjusted mortality rates were calculated by standardizing amyloidosis and CVD-related deaths to the United States population in 2000. Temporal trends were analyzed using the Joinpoint Regression Program (Version 5.0.2, National Cancer Institute) to estimate the annual percent change (APC) and its 95% CI in AAMRs [ 13 ]. A two-tailed p-value of less than 0.05 was considered statistically significant. RESULTS From 1999 to 2020, Amyloidosis and CVD accounted for a total of 26,391 deaths in U.S adults aged ≥ 25 years (Supplementary Table 1). The age-adjusted mortality rate (AAMR) showed an upward trend, starting 4.4 per 1,000,000 (95% CI 4.09–4.71) in 1999 and peaking at 9.31 per 1,000,000 (95% CI 8.94–9.68) in 2020 (Supplementary Table 2). Annual Trends in AAMR From 1999 to 2020, the overall AAMR for Amyloidosis and CVD-related deaths in adults inclined from 4.4 to 9.31 (AAPC: 3.49, 95% CI: 3.15 to 3.78). A slight decrease occurred between 1999 and 2012 (APC: -0.54, 95% CI: -0.37 to 1.17), followed by a moderate increase from 2012 to 2018 (APC: 13.60, 95% CI: 8.57 to 16.77) and a significant increase until 2020 (APC: 13.60, 95% CI: 3.15 to 3.78). ( Fig. 1 A, Supplementary Table 3) . AAMR Stratified by Sex Between 1999 and 2020, Amyloidosis and CVD accounted for 15,745 deaths in men (59.7%) and 10,646 deaths in women (40.3%). Throughout this period, men had higher AAMRs than women (Overall AAMR: Men: 7.86, 95% CI: 7.73 to 7.98; Women: 3.92, 95% CI: 3.85 to 4) (Supplementary Table 2) . The overall Amyloidosis and CVD-related AAMR for both men and women increased from 1999 to 2020, with a greater decline in women (Men: AAPC: 4.41, 95% CI: 4.12 to 4.79, p < 0.001; Women: AAPC: 1.79, 95% CI: 1.04 to 2.57, p < 0.001). Specifically for men, increase occurred across the last decade [APC 2013–2018: 8.31, 95% CI: 5.37 to 9.96 (p < 0.001); APC 2018–2020: 15.32, 95% CI: 11.76 to 17.69 (p < 0.001)]. From 1999 to 2011, the AMR for women decreased (APC: -0.90, 95% CI: -4.80 to 0.66, p = 0.22), followed by a significant increase until 2020 (APC: 5.48, 95% CI: 3.52 to 11.25, p < 0.001). ( Fig. 1 B, Supplementary Table 3) . AAMR Stratified by Race/Ethnicity Significant variability in Amyloidosis and CVD-related deaths was observed among different racial/ethnic groups from 1999 to 2020. The highest number of deaths occurred in Whites (19,321, 73.2%), followed by Black or African Americans (4873, 18.5%), Hispanic or Latinos (1386, 5.3%), Asian or Pacific Islanders (678, 2.6%), and the lowest in American Indian or Alaska Natives (79, 0.3%). Overall, the Amyloidosis and CVD-related AAMRs were highest among Black or African Americans, followed by Whites and Hispanic or Latinos. (Overall AAMR: Black or African American: 11.4, 95% CI: 11.07 to 11.73; White: 5.11, 95% CI: 5.04 to 5.18; Hispanic or Latino: 3.86, 95% CI: 3.65 to 4.07). From 1999 to 2020, Amyloidosis and CVD-related AAMRs increased for Black or African Americans (AAPC: 4.36, 95% CI: 3.71 to 5.14, p < 0.001), Whites (AAPC: 3.15, 95% CI: 2.80 to 3.55, p < 0.001), and Hispanic or Latinos (AAPC: 3.32, 95% CI: 1.74 to 4.71, p < 0.001). ( Fig. 1 C, Supplementary Tables 3 and 4). AAMR Stratified by Geographical Regions From 1999 to 2020, the distribution of Amyloidosis and CVD -related deaths across the U.S. census regions showed 6231 (23.6%) deaths in the Northeast, 6309 (23.9%) in the Midwest, 7574 (28.7%) in the South, and 6277 (23.8%) in the West. On average, the highest Amyloidosis and CVD-associated mortality rates were observed in the Northeast (AAMR: 6.71, 95% CI: 6.54 to 6.88), followed by the West (AAMR: 6.18, 95% CI: 6.03 to 6.34), the Midwest (AAMR: 5.9, 95% CI: 5.76 to 6.05), and the South (AAMR: 4.34, 95% CI: 4.24 to 4.44). Overall, the AAMR associated with Amyloidosis and CVD increased in the all the regions from 1999 to 2020 [Northeast: AAPC: 4.39, 95% CI: 3.57 to 5.28 (p < 0.001); Midwest: AAPC: 3.41, 95% CI: 2.67 to 4.06 (p < 0.001); South: AAPC: 2.91, 95% CI: 2.25 to 3.61 (p < 0.001); West: AAPC: 3.31, 95% CI: 2.83 to 3.88 (p < 0.001)]. ( Fig. 1 D, Supplementary Tables 3 and 5). AAMR Stratified by Urbanization: Metropolitan areas consistently had higher AAMRs associated with amyloidosis and CVD compared to the nonmetropolitan areas from 1999 to 2020, with overall AAMRs of 5.73 (95% CI: 5.66 to 5.81) and 4.76 (95% CI: 4.61 to 4.91), respectively. Both nonmetropolitan and metropolitan areas exhibited an increase in Amyloidosis and CVD-related AAMRs from 1999 to 2020 [Nonmetropolitan: AAPC: 2.59, CI: 1.85 to 3.39 (p < 0.001); Metropolitan: AAPC: 3.53, CI: 3.18 to 3.83 (p < 0.001)]. ( Fig. 1 E, Supplementary Tables 3 and 6) . AAMR Stratified by State: Amyloidosis and CVD-related AAMRs varied significantly among U.S. states from 1999 to 2020, ranging from 2.4 (95% CI: 2.03 to 2.78) in Louisiana to 13.75 (95% CI: 11.21 to 16.29) in the District of Columbia. States in the top 90th percentile for AAMRs included Massachusetts, Rhode Island, Minnesota, Vermont, and District of Columbia, which had roughly four times the AAMRs of states in the lower 10th percentile - Kentucky, Mississippi, Alabama, Arkansas, and Louisiana. ( Fig. 2 , Supplementary Table 7) . AAMR Stratified by Place of Death: When stratified by the place of death, Amyloidosis-related deaths predominantly occurred in medical facilities (54.8%), followed by homes (26.0%), nursing homes/long-term care facilities (10.4%), hospice facilities (5.3%) and other/unknown locations (3.5%). (CENTRAL ILLUSTRATION [ Figure 3 ], Supplementary Table 8) DISCUSSION The current retrospective population-based analysis describes important trends and disparities in the mortality burden attributable to amyloidosis and cardiovascular disease (CVD) in the United States from the years 1999 to 2020. The multidirectional age-adjusted mortality rates (AAMRs) reflect an emerging clinical and epidemiologic challenge that relates to these fatal diseases. The increase in amyloidosis and CVD-related deaths from 4.4 per to 9.31 CVD-related deaths per 1,000,000 adults is consistent with the growing literature emphasizing the increasing clinical identification and diagnosis of amyloidosis, especially with the context of CVD regards to cardiac amyloidosis [ 14 ]. Current literature corroborates that increase, at least in part, with improved diagnostic experience, increased clinical identification, improving case work up, and perhaps, an increased true incidence of amyloidosis in relation to an aging population experiencing certain risk factors of hypertension, diabetes, and obesity [ 15 ]. Stratifying deaths by place of death showed that the majority of deaths were in medical venues, confirming past findings that noted the high levels of hospitalization and health care utilization of patients with amyloidosis—likely due to worsening cardiac dysfunction and intermittent acute decompensation [ 16 ]. Furthermore, the considerable percentage of home deaths suggests missed later gap opportunities associated with diagnosis, treatment, and palliation. Future studies should build on these findings by developing studies to consider addressing these late gaps and intervention methods based in the community and in outpatient settings that could assist with detection and chronic disease management. The sex-based stratification noted a persistent and increasing mortality gap between males and females; namely, men had consistently higher rates of mortality. This finding is similar to previous studies that have identified men as more likely to suffer from, and with more rapid disease progression from, cardiac amyloidosis. This difference may be related to biological differences, hormonal influences, and lifestyle risk factors likely influenced by the higher rates of tobacco use, and possibly higher rates of metabolic syndrome, among men [ 17 , 18 ]. For women overall, while the rates of mortality were much lower, the marked increase over the most recent decade highlights an emerging burden in the female population, which could be indicative of a need for targeted prevention strategies as well as further study of the underlying pathophysiological mechanisms that may differ based on sex [ 17 ]. There were significant differences noted in race/ethnic-based analyses, with indications that Black or African American patients had higher mortality rates than whites. This is in line with some literature that discusses racial disparities, particularly as they relate to genetic traits, social status, access of care, and possible differences regarding awareness of disease and management practices for individual races [ 19 , 20 ]. The increase in Hispanic or Latino patients also demonstrates changes in the epidemiology of this disorder, possibly due to demographic shifts, increased incidence of cardiometabolic risk factors, and changes in healthy behaviors within these populations. Geographically based stratification in mortality rates revealed significant regional differences since there were significantly higher mortality rates in the Northeast and West as compared to the Midwest and South. These differences are likely related to regional differences in healthcare capacity and access, diagnostic capabilities, and the availability of specialized treatment for amyloidosis [ 21 ]. A difference in access to centers with imaging capabilities with higher detection rates in more developed cities leading to higher rates of diagnosis. Other research has shown that there are regional differences in healthcare access and practice patterns with calls by others for use of a uniform, national guideline to ensure the same protocol and prevention is used regardless of race or geographic location of management and treatment of amyloidosis [ 22 ]. A difference in education level amongst states with people with higher education more likely to seek health care leading to higher rates of diagnosis. In the metropolitan versus nonmetropolitan areas, mortality was consistently higher in metropolitan areas, and both areas exhibited an increase in Amyloidosis and CVD-related AAMRs from 1999 to 2020 suggesting the potential presence of urban-rural effects stemming from differences in access to healthcare, diagnostic capabilities, specialized treatment options, and multiple other social determinants of health that may affect the ability to properly manage and outcome from disease [ 23 , 24 ]. Improving rural health disparities through telemedicine, and increasing access to specialized care through implementation of decentralized care models to help mitigate the mortality differences, may have a more significant impact than other interventions [ 25 ]. The marked difference in state-level mortality differences revealed substantial differences in mortality from the study with far higher rates in states such as Massachusetts, Rhode Island, and the District of Columbia, compared to many southern states. These reported mortality differences are likely a reflection of geographical diagnostic behaviors and access to specialized amyloidosis care centers being clustered in certain geographical areas [ 26 ]. This suggests by expanding the clinical expertise of care options, the diagnostic infrastructure, and establishing networks for specialty care in underserved areas, the mortality differences would likely diminish greatly [ 27 ]. LIMITATIONS There are a number of limitations in this study that need to be factored in. First, the use of death certificate data from the CDC WONDER database can lead to misclassification bias due to underreporting or incorrect coding of amyloidosis, especially when CVD is the main clinical concern at the time of death. Secondly, the ICD-10 E85 does not show distinction between the sub-types of amyloidosis (e.g. AL and ATTR) nor does it specify the presence of cardiac involvement, which limits the granularity of the analysis. Thirdly, the study uses aggregate data at the population level instead of clinical data at the patient level. This retrospective nature precludes causal inference. This does not allow adjustment for comorbidities, socioeconomic status, treatment regimens or diagnostic modalities, which influence mortality trends. Fourth, temporal changes in diagnostic capabilities, such as the increased use of cardiac MRI and bone scintigraphy in recent years, may have artificially inflated detection rates and associated mortality reporting in the latter part of the study period. And finally, geographical and racial variation seen in the analysis can be concealing system-wide inequity in health-care access, with underdiagnosis in underserved regions, as opposed to genuine biological differences. While age-adjusted rates mitigate some of these concerns, residual confounding cannot be ruled out. CONCLUSION Amyloidosis and cardiovascular disease (CVD) associated mortality in the United States has shown a significant rise in the last 20 years, with a particular steep rise in the last decade. The burden is disproportionate, being high among men, the African American communities and those living in the Northeast and metropolitan areas. These findings highlight an emerging, under-recognized overlap between two potentially fatal diseases that require immediate clinical and public health attention. Mortality patterns exhibit geographic and demographic variances that indicate possible inequities in diagnostic access, clinical suspicion, as well as therapeutic delivery. In light of the ongoing growth in awareness of cardiac amyloidosis, healthcare systems need to focus on an earlier diagnosis, particularly among those considered high-risk groups, and provide equal access to new diagnostic and treatment services. These population-based data are crucial to inform resource assignment, screening and future disease mechanism and disparity research. To better define disease dynamics and optimize outcomes in this vulnerable patient population, future investigations should include patient-level clinical variables and subtype-specific data. Declarations 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. 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Supplementary Files supplementarymaterialamyloidosiscdc.docx Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2026 Read the published version in BMC Cardiovascular Disorders → Version 1 posted Editorial decision: Revision requested 10 Dec, 2025 Reviews received at journal 02 Dec, 2025 Reviews received at journal 01 Dec, 2025 Reviewers agreed at journal 01 Dec, 2025 Reviews received at journal 26 Nov, 2025 Reviewers agreed at journal 26 Nov, 2025 Reviewers agreed at journal 22 Nov, 2025 Reviews received at journal 19 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers agreed at journal 13 Nov, 2025 Reviewers invited by journal 13 Nov, 2025 Editor assigned by journal 11 Nov, 2025 Editor invited by journal 18 Oct, 2025 Submission checks completed at journal 18 Oct, 2025 First submitted to journal 18 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. 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06:54:35","extension":"xml","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":89488,"visible":true,"origin":"","legend":"","description":"","filename":"013095133dae443c92271ca37513970b1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/5386107773ddc9429f16339a.xml"},{"id":96791078,"identity":"7838f2df-48d8-4219-8273-edd44e9e2ed4","added_by":"auto","created_at":"2025-11-26 06:54:41","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":100058,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/f3afa7f80e9719f44464f761.html"},{"id":96791086,"identity":"3f19dbea-83f2-4ce5-bf50-2c2863cc8014","added_by":"auto","created_at":"2025-11-26 06:54:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":641683,"visible":true,"origin":"","legend":"\u003cp\u003eCVD-related mortality trends in Amyloidosis in the United States, 1999 to 2020 with (A) overall CVD-related AAMR in Amyloidosis per million, (B) sex-stratified CVD-related AAMR in Amyloidosis per million, (C) race/ethnicity Stratified CVD-related AAMR in Amyloidosis per million, (D) regionally stratified CVD-related AAMR in Amyloidosis per million, (E) urbanization stratified CVD-related AAMR in Amyloidosis per million.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/ce7fbe5c76ec4aa3581d8e9c.png"},{"id":96791064,"identity":"1a34a013-2382-4f02-b845-de47d23d51d4","added_by":"auto","created_at":"2025-11-26 06:54:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":164924,"visible":true,"origin":"","legend":"\u003cp\u003eState-Stratified Amyloidosis and CVD-related AAMRs per 1,000,000 in United States 1999-2020\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/432c24b9de358e58f2631f49.png"},{"id":96790959,"identity":"eb1fb1b6-31eb-4640-9565-c44b8ac54683","added_by":"auto","created_at":"2025-11-26 06:54:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":691984,"visible":true,"origin":"","legend":"\u003cp\u003eCENTRAL ILLUSTRATION: Demographic Profiles in Amyloidosis and Cardiovascular Disease-related Mortality among adults 25 to 85+ in the United States, 1999 to 2020\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/5bab29117f01f05462611163.png"},{"id":101690806,"identity":"da9d5e66-07fb-4d37-9b94-fc70cffecc66","added_by":"auto","created_at":"2026-02-02 16:09:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2154853,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/17942dd2-bb08-4bdd-b569-c71af317e13c.pdf"},{"id":96791189,"identity":"4377e930-454b-44b9-a8d4-91b23e5a8582","added_by":"auto","created_at":"2025-11-26 06:54:54","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":44985,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterialamyloidosiscdc.docx","url":"https://assets-eu.researchsquare.com/files/rs-7864719/v1/b273953afdcecc5cf8c608a8.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Trends and Disparities in Amyloidosis and Cardiovascular Disease Mortality: A Population-Based Retrospective Study in the United States (1999–2020)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eExtracellular deposits of misfolded proteins, especially transthyretin (ATTR) or immunoglobin light chains (AL), causing cardiac amyloidosis (CA) have shown to contribute heavily to heart failure, particularly among older individuals, and patients with heart failure with preserved ejection fraction (HFpEF) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although it was previously regarded as a rare condition, recent diagnostic procedures having high sensitivity and specificity such as cardiac MRI, bone scintigraphy and AI assisted imaging have led to a significant rise in its detection [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. ATTRwt (wild type form of ATTR) is generally found in men with ages above 70, whereas ATTRv (hereditary ATTR) is caused by pathogenic gene mutations in the TTR gene which might present earlier [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eManagement is improving with recent therapeutic developments: a next-generation TTR stabilizer approved in 2024: acoramidis has reduced mortality and morbidity in ATTR cardiomyopathy (ATTR-CM) and RNA-silencing medicines, such as patisiran, have also shown to have a mortality and morbidity benefit in ATTR-CM [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These options are a shift towards disease-modifying treatment, unlike the previous palliative care approach.\u003c/p\u003e\u003cp\u003eDespite these advances, CA is still vastly underdiagnosed, presenting with nonspecific symptoms or symptoms resembling other cardiac conditions. It has been speculated through autopsies and clinical studies that many older adults with HFpEF have amyloid deposits [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Untreated, CA leads to rapid clinical deterioration and poor survival rates particularly when comorbid with cardiovascular disease.\u003c/p\u003e\u003cp\u003eMoreover, there is a racial and socioeconomic discrepancy. Black patients are affected more often with ATTRv because of the V122I mutation, and face higher in-hospital deaths, longer hospitalizations, and increased complications after being diagnosed [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Such disparities show systematic disparities in access to advanced diagnostics and treatment.\u003c/p\u003e\u003cp\u003eThe population-level data on mortality due to amyloidosis and CVD is scanty. Vast majority of studies investigate each of these diseases independently, overlooking the intersectional mortality burden which may compound health inequities. This study attempts to address this gap by using 20 years of U.S. national mortality data to evaluate trends and disparities in Amyloidosis and Cardiovascular Disease (CVD)-related deaths. By calculating age-adjusted mortality rates (AAMRs) and stratifying by sex, race/ethnicity, geography, and urbanization, we provide a comprehensive, demographic-driven epidemiologic profile of this emerging public health issue.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePopulation and Study Setting\u003c/h2\u003e\u003cp\u003eThis population-based analysis utilized publicly available mortality data from the \u003cem\u003eCenters for Disease Control and Prevention\u0026rsquo;s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER)\u003c/em\u003e database, which compiles information from U.S. death certificates [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We examined all deaths attributed to amyloidosis (\u003cem\u003eInternational Classification of Diseases, 10th Revision [ICD-10] code E85\u003c/em\u003e) and cardiovascular diseases (\u003cem\u003eICD-10 codes I00 to I99\u003c/em\u003e) occurring between 1999 and 2020 across all 50 states and the District of Columbia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Adults aged 25 years and older at the time of death were included in the analysis. Because CDC WONDER provides deidentified, publicly available data, institutional review board approval was not required. The study adhered to the \u003cem\u003eStrengthening the Reporting of Observational Studies in Epidemiology (STROBE)\u003c/em\u003e guidelines for observational research [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The analytical framework was adapted from our previously published methodology on national cardiovascular mortality trends, with modifications to address amyloidosis-related outcomes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData Abstraction\u003c/h3\u003e\n\u003cp\u003eThe dataset extracted from death certificates included information on year of death, place of occurrence, sex, age group, race and ethnicity, geographic region, state, and urban-rural classification. Deaths were categorized according to their location, which included hospitals, private residences, hospices, nursing homes, and long-term care facilities. Urbanization categories were based on the National Center for Health Statistics Urban-Rural Classification Scheme. Urban areas comprised large metropolitan regions with populations of one million or more, as well as medium or small metropolitan areas with populations between 50,000 and 999,999. Rural areas were defined as those with populations under 50,000, consistent with the 2013 U.S. Census definitions [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Geographical divisions followed the U.S. Census Bureau classification, which divides the country into four main regions namely the Northeast, Midwest, South and West.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eWe calculated both crude and age-adjusted mortality rates (AAMRs) per 1,000,000 individuals for each calendar year, stratified by sex, race and ethnicity, state, and urban-rural status, with corresponding 95% confidence intervals (CIs). Crude mortality rates were derived by dividing the number of amyloidosis and CVD-related deaths by the corresponding U.S. population for each year. Age-adjusted mortality rates were calculated by standardizing amyloidosis and CVD-related deaths to the United States population in 2000. Temporal trends were analyzed using the \u003cem\u003eJoinpoint Regression Program (Version 5.0.2, National Cancer Institute)\u003c/em\u003e to estimate the annual percent change (APC) and its 95% CI in AAMRs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A two-tailed p-value of less than 0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eFrom 1999 to 2020, Amyloidosis and CVD accounted for a total of 26,391 deaths in U.S adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years \u003cb\u003e(Supplementary Table\u0026nbsp;1).\u003c/b\u003e The age-adjusted mortality rate (AAMR) showed an upward trend, starting 4.4 per 1,000,000 (95% CI 4.09\u0026ndash;4.71) in 1999 and peaking at 9.31 per 1,000,000 (95% CI 8.94\u0026ndash;9.68) in 2020 \u003cb\u003e(Supplementary Table\u0026nbsp;2).\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003eAnnual Trends in AAMR\u003c/h3\u003e\n\u003cp\u003eFrom 1999 to 2020, the overall AAMR for Amyloidosis and CVD-related deaths in adults inclined from 4.4 to 9.31 (AAPC: 3.49, 95% CI: 3.15 to 3.78). A slight decrease occurred between 1999 and 2012 (APC: -0.54, 95% CI: -0.37 to 1.17), followed by a moderate increase from 2012 to 2018 (APC: 13.60, 95% CI: 8.57 to 16.77) and a significant increase until 2020 (APC: 13.60, 95% CI: 3.15 to 3.78). \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, \u003cb\u003eSupplementary Table\u0026nbsp;3)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eAAMR Stratified by Sex\u003c/h2\u003e\u003cp\u003eBetween 1999 and 2020, Amyloidosis and CVD accounted for 15,745 deaths in men (59.7%) and 10,646 deaths in women (40.3%). Throughout this period, men had higher AAMRs than women (Overall AAMR: Men: 7.86, 95% CI: 7.73 to 7.98; Women: 3.92, 95% CI: 3.85 to 4) \u003cb\u003e(Supplementary Table\u0026nbsp;2)\u003c/b\u003e. The overall Amyloidosis and CVD-related AAMR for both men and women increased from 1999 to 2020, with a greater decline in women (Men: AAPC: 4.41, 95% CI: 4.12 to 4.79, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Women: AAPC: 1.79, 95% CI: 1.04 to 2.57, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Specifically for men, increase occurred across the last decade [APC 2013\u0026ndash;2018: 8.31, 95% CI: 5.37 to 9.96 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); APC 2018\u0026ndash;2020: 15.32, 95% CI: 11.76 to 17.69 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)]. From 1999 to 2011, the AMR for women decreased (APC: -0.90, 95% CI: -4.80 to 0.66, p\u0026thinsp;=\u0026thinsp;0.22), followed by a significant increase until 2020 (APC: 5.48, 95% CI: 3.52 to 11.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB, \u003cb\u003eSupplementary Table\u0026nbsp;3)\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAAMR Stratified by Race/Ethnicity\u003c/h3\u003e\n\u003cp\u003eSignificant variability in Amyloidosis and CVD-related deaths was observed among different racial/ethnic groups from 1999 to 2020. The highest number of deaths occurred in Whites (19,321, 73.2%), followed by Black or African Americans (4873, 18.5%), Hispanic or Latinos (1386, 5.3%), Asian or Pacific Islanders (678, 2.6%), and the lowest in American Indian or Alaska Natives (79, 0.3%). Overall, the Amyloidosis and CVD-related AAMRs were highest among Black or African Americans, followed by Whites and Hispanic or Latinos. (Overall AAMR: Black or African American: 11.4, 95% CI: 11.07 to 11.73; White: 5.11, 95% CI: 5.04 to 5.18; Hispanic or Latino: 3.86, 95% CI: 3.65 to 4.07). From 1999 to 2020, Amyloidosis and CVD-related AAMRs increased for Black or African Americans (AAPC: 4.36, 95% CI: 3.71 to 5.14, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Whites (AAPC: 3.15, 95% CI: 2.80 to 3.55, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and Hispanic or Latinos (AAPC: 3.32, 95% CI: 1.74 to 4.71, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC, \u003cb\u003eSupplementary Tables\u0026nbsp;3 and 4).\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003eAAMR Stratified by Geographical Regions\u003c/h3\u003e\n\u003cp\u003eFrom 1999 to 2020, the distribution of Amyloidosis and CVD -related deaths across the U.S. census regions showed 6231 (23.6%) deaths in the Northeast, 6309 (23.9%) in the Midwest, 7574 (28.7%) in the South, and 6277 (23.8%) in the West. On average, the highest Amyloidosis and CVD-associated mortality rates were observed in the Northeast (AAMR: 6.71, 95% CI: 6.54 to 6.88), followed by the West (AAMR: 6.18, 95% CI: 6.03 to 6.34), the Midwest (AAMR: 5.9, 95% CI: 5.76 to 6.05), and the South (AAMR: 4.34, 95% CI: 4.24 to 4.44). Overall, the AAMR associated with Amyloidosis and CVD increased in the all the regions from 1999 to 2020 [Northeast: AAPC: 4.39, 95% CI: 3.57 to 5.28 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); Midwest: AAPC: 3.41, 95% CI: 2.67 to 4.06 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); South: AAPC: 2.91, 95% CI: 2.25 to 3.61 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); West: AAPC: 3.31, 95% CI: 2.83 to 3.88 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)]. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD, \u003cb\u003eSupplementary Tables\u0026nbsp;3 and 5).\u003c/b\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eAAMR Stratified by Urbanization:\u003c/h2\u003e\u003cp\u003eMetropolitan areas consistently had higher AAMRs associated with amyloidosis and CVD compared to the nonmetropolitan areas from 1999 to 2020, with overall AAMRs of 5.73 (95% CI: 5.66 to 5.81) and 4.76 (95% CI: 4.61 to 4.91), respectively. Both nonmetropolitan and metropolitan areas exhibited an increase in Amyloidosis and CVD-related AAMRs from 1999 to 2020 [Nonmetropolitan: AAPC: 2.59, CI: 1.85 to 3.39 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); Metropolitan: AAPC: 3.53, CI: 3.18 to 3.83 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)]. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, \u003cb\u003eSupplementary Tables\u0026nbsp;3 and 6)\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eAAMR Stratified by State:\u003c/h2\u003e\u003cp\u003eAmyloidosis and CVD-related AAMRs varied significantly among U.S. states from 1999 to 2020, ranging from 2.4 (95% CI: 2.03 to 2.78) in Louisiana to 13.75 (95% CI: 11.21 to 16.29) in the District of Columbia. States in the top 90th percentile for AAMRs included Massachusetts, Rhode Island, Minnesota, Vermont, and District of Columbia, which had roughly four times the AAMRs of states in the lower 10th percentile - Kentucky, Mississippi, Alabama, Arkansas, and Louisiana. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eSupplementary Table\u0026nbsp;7)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eAAMR Stratified by Place of Death:\u003c/h2\u003e\u003cp\u003eWhen stratified by the place of death, Amyloidosis-related deaths predominantly occurred in medical facilities (54.8%), followed by homes (26.0%), nursing homes/long-term care facilities (10.4%), hospice facilities (5.3%) and other/unknown locations (3.5%). \u003cb\u003e(CENTRAL ILLUSTRATION [\u003c/b\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e], Supplementary Table\u0026nbsp;8)\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe current retrospective population-based analysis describes important trends and disparities in the mortality burden attributable to amyloidosis and cardiovascular disease (CVD) in the United States from the years 1999 to 2020. The multidirectional age-adjusted mortality rates (AAMRs) reflect an emerging clinical and epidemiologic challenge that relates to these fatal diseases.\u003c/p\u003e\u003cp\u003eThe increase in amyloidosis and CVD-related deaths from 4.4 per to 9.31 CVD-related deaths per 1,000,000 adults is consistent with the growing literature emphasizing the increasing clinical identification and diagnosis of amyloidosis, especially with the context of CVD regards to cardiac amyloidosis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Current literature corroborates that increase, at least in part, with improved diagnostic experience, increased clinical identification, improving case work up, and perhaps, an increased true incidence of amyloidosis in relation to an aging population experiencing certain risk factors of hypertension, diabetes, and obesity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eStratifying deaths by place of death showed that the majority of deaths were in medical venues, confirming past findings that noted the high levels of hospitalization and health care utilization of patients with amyloidosis\u0026mdash;likely due to worsening cardiac dysfunction and intermittent acute decompensation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Furthermore, the considerable percentage of home deaths suggests missed later gap opportunities associated with diagnosis, treatment, and palliation. Future studies should build on these findings by developing studies to consider addressing these late gaps and intervention methods based in the community and in outpatient settings that could assist with detection and chronic disease management.\u003c/p\u003e\u003cp\u003eThe sex-based stratification noted a persistent and increasing mortality gap between males and females; namely, men had consistently higher rates of mortality. This finding is similar to previous studies that have identified men as more likely to suffer from, and with more rapid disease progression from, cardiac amyloidosis. This difference may be related to biological differences, hormonal influences, and lifestyle risk factors likely influenced by the higher rates of tobacco use, and possibly higher rates of metabolic syndrome, among men [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For women overall, while the rates of mortality were much lower, the marked increase over the most recent decade highlights an emerging burden in the female population, which could be indicative of a need for targeted prevention strategies as well as further study of the underlying pathophysiological mechanisms that may differ based on sex [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThere were significant differences noted in race/ethnic-based analyses, with indications that Black or African American patients had higher mortality rates than whites. This is in line with some literature that discusses racial disparities, particularly as they relate to genetic traits, social status, access of care, and possible differences regarding awareness of disease and management practices for individual races [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The increase in Hispanic or Latino patients also demonstrates changes in the epidemiology of this disorder, possibly due to demographic shifts, increased incidence of cardiometabolic risk factors, and changes in healthy behaviors within these populations.\u003c/p\u003e\u003cp\u003eGeographically based stratification in mortality rates revealed significant regional differences since there were significantly higher mortality rates in the Northeast and West as compared to the Midwest and South. These differences are likely related to regional differences in healthcare capacity and access, diagnostic capabilities, and the availability of specialized treatment for amyloidosis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A difference in access to centers with imaging capabilities with higher detection rates in more developed cities leading to higher rates of diagnosis. Other research has shown that there are regional differences in healthcare access and practice patterns with calls by others for use of a uniform, national guideline to ensure the same protocol and prevention is used regardless of race or geographic location of management and treatment of amyloidosis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A difference in education level amongst states with people with higher education more likely to seek health care leading to higher rates of diagnosis.\u003c/p\u003e\u003cp\u003eIn the metropolitan versus nonmetropolitan areas, mortality was consistently higher in metropolitan areas, and both areas exhibited an increase in Amyloidosis and CVD-related AAMRs from 1999 to 2020 suggesting the potential presence of urban-rural effects stemming from differences in access to healthcare, diagnostic capabilities, specialized treatment options, and multiple other social determinants of health that may affect the ability to properly manage and outcome from disease [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Improving rural health disparities through telemedicine, and increasing access to specialized care through implementation of decentralized care models to help mitigate the mortality differences, may have a more significant impact than other interventions [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe marked difference in state-level mortality differences revealed substantial differences in mortality from the study with far higher rates in states such as Massachusetts, Rhode Island, and the District of Columbia, compared to many southern states. These reported mortality differences are likely a reflection of geographical diagnostic behaviors and access to specialized amyloidosis care centers being clustered in certain geographical areas [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This suggests by expanding the clinical expertise of care options, the diagnostic infrastructure, and establishing networks for specialty care in underserved areas, the mortality differences would likely diminish greatly [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eLIMITATIONS\u003c/h2\u003e\u003cp\u003eThere are a number of limitations in this study that need to be factored in. First, the use of death certificate data from the CDC WONDER database can lead to misclassification bias due to underreporting or incorrect coding of amyloidosis, especially when CVD is the main clinical concern at the time of death. Secondly, the ICD-10 E85 does not show distinction between the sub-types of amyloidosis (e.g. AL and ATTR) nor does it specify the presence of cardiac involvement, which limits the granularity of the analysis.\u003c/p\u003e\u003cp\u003eThirdly, the study uses aggregate data at the population level instead of clinical data at the patient level. This retrospective nature precludes causal inference. This does not allow adjustment for comorbidities, socioeconomic status, treatment regimens or diagnostic modalities, which influence mortality trends. Fourth, temporal changes in diagnostic capabilities, such as the increased use of cardiac MRI and bone scintigraphy in recent years, may have artificially inflated detection rates and associated mortality reporting in the latter part of the study period. And finally, geographical and racial variation seen in the analysis can be concealing system-wide inequity in health-care access, with underdiagnosis in underserved regions, as opposed to genuine biological differences. While age-adjusted rates mitigate some of these concerns, residual confounding cannot be ruled out.\u003c/p\u003e\u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eAmyloidosis and cardiovascular disease (CVD) associated mortality in the United States has shown a significant rise in the last 20 years, with a particular steep rise in the last decade. The burden is disproportionate, being high among men, the African American communities and those living in the Northeast and metropolitan areas. These findings highlight an emerging, under-recognized overlap between two potentially fatal diseases that require immediate clinical and public health attention.\u003c/p\u003e\u003cp\u003eMortality patterns exhibit geographic and demographic variances that indicate possible inequities in diagnostic access, clinical suspicion, as well as therapeutic delivery. In light of the ongoing growth in awareness of cardiac amyloidosis, healthcare systems need to focus on an earlier diagnosis, particularly among those considered high-risk groups, and provide equal access to new diagnostic and treatment services.\u003c/p\u003e\u003cp\u003eThese population-based data are crucial to inform resource assignment, screening and future disease mechanism and disparity research. To better define disease dynamics and optimize outcomes in this vulnerable patient population, future investigations should include patient-level clinical variables and subtype-specific data.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\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’s data use guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\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\u003e\u003c/p\u003e\n\u003cp\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\u003e\u003c/p\u003e\n\u003cp\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\u003cli\u003e\u003cspan\u003eTon VK, Mukherjee M, Judge DP. Transthyretin cardiac amyloidosis: pathogenesis, treatments, and emerging role in heart failure with preserved ejection fraction. Clin Med Insights Cardiol. 2015;8(Suppl 1):39\u0026ndash;44. 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Role of Telemedicine in Improving Access to Specialized Care in Rural Health Systems and Its Future in Health Care Delivery. J Health Stat Rep 2022, 1\u0026ndash;3, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.47363/JHSR/2022(1)118\u003c/span\u003e\u003cspan address=\"10.47363/JHSR/2022(1)118\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAggarwal V, Mohanty A, Seltzer R, Ghannam H, Dev S. Abstract 12799: Geographic Variation in Cardiac Amyloidosis in U.S. Veterans From 2012 to 2021. Circulation. 2023;148. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/circ.148.suppl_1.12799\u003c/span\u003e\u003cspan address=\"10.1161/circ.148.suppl_1.12799\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNativi-Nicolau J, Sarswat N, Fajardo J, Finkel M, Abdulsattar Y, Casta\u0026ntilde;o A, Klein L, Haddad-Angulo A. Best Practices in Specialized Amyloidosis Centers in the United States: A Survey of Cardiologists, Nurses, Patients, and Patient Advocates. Clin Med Insights Cardiol. 2021;15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/11795468211015230\u003c/span\u003e\u003cspan address=\"10.1177/11795468211015230\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Amyloidosis, Cardiovascular Disease, Disparities, Mortality, Trends, Epidemiology, United States","lastPublishedDoi":"10.21203/rs.3.rs-7864719/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7864719/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eIntroduction\u003c/b\u003e: Cardiac amyloidosis (CA), most commonly caused by transthyretin (ATTR) or light chain (AL) deposition, is increasingly recognized as a contributor to heart failure, particularly in older adults and patients with heart failure with preserved ejection fraction (HFpEF). Despite advances in diagnostic imaging and disease-modifying therapies, CA remains underdiagnosed, and population-level data on its combined mortality burden with cardiovascular disease (CVD) are limited.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAims\u003c/b\u003e: This study aimed to analyze two decades of consecutive mortality data to investigate amyloidosis and cardiovascular disease (CVD) across the United States (US), identifying patterns and disparities in mortality rates.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e: A retrospective analysis was conducted using mortality data from the CDC WONDER database spanning 1999\u0026ndash;2020. Age-adjusted mortality rates (AAMRs) per 1,000,000 persons were calculated, and trends were assessed using Average Annual Percentage Change (AAPC) and Annual Percent Change (APC) using Joinpoint 5.0.2.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e: Between 1999 and 2020, 26,391 Amyloidosis and CVD-related deaths occurred among adults aged 25 and older in the US. The overall AAMR for Amyloidosis and CVD-related mortality increased from 4.40 in 1999 to 9.31 in 2020, with an AAPC of 3.49 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Most striking was the recent steep rise in AAMRs from 2018 to 2020 with an APC of 13.60. Men exhibited higher AAMRs compared to women. Similar to the overall trend, AAMRs for both men and women had a steep incline in the last decade. African Americans or Blacks had the highest AAMRs (11.4) followed by White (5.11) and Hispanics (3.86). The highest mortality was in the Northeast region (AAMR: 6.71). Nonmetropolitan areas had higher AAMRs than metropolitan areas (5.73 vs 4.76), however, with a more remarkable increase in metropolitan areas.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe prevalence of amyloidosis and cardiovascular disease-related deaths has risen markedly, especially between 2018 and 2020. Increased mortality rates were noted among men, African Americans, and individuals in the Northeast region. These patterns emphasize the necessity for focused public health initiatives.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e","manuscriptTitle":"Trends and Disparities in Amyloidosis and Cardiovascular Disease Mortality: A Population-Based Retrospective Study in the United States (1999–2020)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 06:53:40","doi":"10.21203/rs.3.rs-7864719/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-10T06:12:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-02T20:29:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-01T16:19:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187511658378028259796802069342481322477","date":"2025-12-01T14:47:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-26T11:30:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161581805436050932431722549491673826816","date":"2025-11-26T10:07:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"133367374634370398608775083723427073001","date":"2025-11-22T07:35:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-19T09:41:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323158912240696108715975155770164085483","date":"2025-11-15T16:49:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"191832042829744766252752721496290114203","date":"2025-11-13T15:49:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-13T15:20:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-11T06:52:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-18T09:15:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-18T08:40:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-10-18T08:37:18+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 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:05:49+00:00","versionOfRecord":{"articleIdentity":"rs-7864719","link":"https://doi.org/10.1186/s12872-026-05510-8","journal":{"identity":"bmc-cardiovascular-disorders","isVorOnly":false,"title":"BMC Cardiovascular Disorders"},"publishedOn":"2026-01-30 15:59:29","publishedOnDateReadable":"January 30th, 2026"},"versionCreatedAt":"2025-11-26 06:53:40","video":"","vorDoi":"10.1186/s12872-026-05510-8","vorDoiUrl":"https://doi.org/10.1186/s12872-026-05510-8","workflowStages":[]},"version":"v1","identity":"rs-7864719","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7864719","identity":"rs-7864719","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}