Rising Female Mortality in Combined Ischemic Heart Disease and Chronic Kidney Disease in the United States (1999–2023)

Rising Female Mortality in Combined Ischemic Heart Disease and Chronic Kidney Disease in the United States (1999–2023) | 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 Rising Female Mortality in Combined Ischemic Heart Disease and Chronic Kidney Disease in the United States (1999–2023) Hassaan Abid, Muhammad Vazaym, Muhammad Jawad, Gaaitri Lohano, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8993837/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Although age-adjusted mortality from ischemic heart disease (IHD) has declined in the United States over recent decades, the coexistence of chronic kidney disease (CKD) may be reshaping mortality patterns. Emerging data suggest that improvements in cardiovascular survival may not be uniform across sexes. Methods We conducted a retrospective population-based study using CDC WONDER multiple cause-of-death data from 1999–2023. Deaths mentioning IHD (ICD-10 codes I20–I25) and CKD (ICD-10 code N18) were identified. Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated using the 2000 U.S. standard population. Temporal trends were evaluated using Joinpoint Regression Program version 5.0 (National Cancer Institute) to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Results Between 1999 and 2023, 633,221 deaths involved both IHD and CKD. Overall AAMR declined modestly (AAPC − 1.13%; 95% CI − 2.46 to 0.21; p = 0.093). Male mortality declined significantly (APC − 1.12%; 95% CI − 2.19 to − 0.03; p = 0.044). In contrast, female mortality increased significantly from 2015 to 2023 (APC 3.25%; 95% CI 0.78 to 5.79; p = 0.013). Similar increases were observed among middle-aged adults. Persistent regional and racial disparities were noted. Conclusions Despite modest national declines in cardiorenal mortality, a sustained rise in female mortality since 2015 signals a concerning reversal of cardiovascular progress. Targeted sex-specific prevention strategies are urgently needed. Ischemic heart disease chronic kidney disease Mortality trends Sex differences CDC WONDER Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Ischemic heart disease (IHD) remains a significant public health concern and continues to be the leading cause of death in the United States, accounting for more than 300,000 deaths annually [ 1 ]. Although age-adjusted IHD mortality rates have declined over recent decades due to advances in preventive strategies, early diagnosis, pharmacologic therapy, and interventional cardiology [ 1 , 2 ], the absolute burden of disease remains substantial. Chronic kidney disease (CKD) represents another major and growing contributor to morbidity and mortality, affecting nearly 14% of U.S. adults [ 3 ]. From 1999 to 2020, CKD has been associated with approximately 1.94 million deaths nationwide [ 4 ]. CKD is widely recognized not only as a progressive renal condition but also as a powerful and independent risk factor for cardiovascular disease [ 3 , 5 ]. Individuals with CKD experience substantially higher rates of cardiovascular events and premature mortality compared with those without kidney dysfunction [ 5 ]. The pathophysiological relationship between CKD and IHD is multifactorial. Beyond shared risk factors such as hypertension, diabetes mellitus, and dyslipidemia, CKD accelerates atherosclerosis through chronic inflammation, endothelial dysfunction, oxidative stress, vascular calcification, and disordered mineral metabolism [ 6 , 7 ]. Consequently, cardiovascular disease, particularly IHD, remains the leading cause of death among patients with CKD [ 4 , 5 ]. Long-term analyses of mortality trends have demonstrated overall declines in cardiovascular mortality [ 3 ]. However, improvements are not uniform across demographic groups [ 5 ]. Mortality patterns may differ by sex, race, geography, and age, and multiple cause-of-death analyses allow more comprehensive assessment of CKD’s contributory role in cardiovascular mortality [ 3 , 5 ]. While overall IHD mortality has declined nationally [ 1 , 2 ], emerging evidence suggests that cardiovascular gains among women may be slowing or reversing. Sex differences in cardiovascular risk recognition and treatment remain well documented [ 22 , 23 ], and recent nephrology data indicate that CKD may confer greater excess cardiovascular risk in women compared with men [ 24 ]. Despite this, few studies have evaluated long-term sex-specific trends in combined IHD and CKD mortality. This study uses CDC WONDER data from 1999 to 2023 to evaluate national trends in IHD- and CKD-related mortality, with primary focus on emerging increases in female mortality and secondary examination of demographic and geographic disparities. Methods Study Design and Data Source We performed a retrospective, population-based study examining U.S. mortality trends from 1999 through 2023 using the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause-of-Death database. This publicly accessible dataset compiles information from national death certificates and allows identification of both underlying and contributing causes of death. Deaths were included if ischemic heart disease (IHD; ICD-10 codes I20–I25) and chronic kidney disease (CKD; ICD-10 code N18) were documented anywhere on the death certificate. Because the database contains de-identified, publicly available data, this study was exempt from Institutional Review Board oversight. The general analytic framework applied in this study has been described previously in similar CDC WONDER mortality analyses. [ 45 ] Variables and Definitions Mortality data were stratified by demographic and geographic characteristics, including sex, race/ethnicity, age group, U.S. Census region, state, urban–rural classification, and place of death. Race and ethnicity categories were defined according to CDC classifications as non-Hispanic (NH) White, NH Black or African American, Hispanic or Latino, NH American Indian or Alaska Native, and NH Asian or Pacific Islander. Age was categorized into three predefined groups: 25–44 years, 45–64 years, and ≥ 65 years. Geographic regions were classified according to U.S. Census Bureau definitions (Northeast, Midwest, South, and West). Urbanization status was determined using the 2013 National Center for Health Statistics Urban–Rural Classification Scheme for Counties. Place of death categories included inpatient medical facilities, outpatient or emergency departments, home, hospice, nursing home or long-term care facilities, and other specified locations. Statistical Analysis Crude mortality rates and age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated annually. Age adjustment was performed using the direct standardization method with the 2000 U.S. standard population as reference. Temporal trends in AAMRs were evaluated using the Joinpoint Regression Program (Version 5.0, National Cancer Institute). This approach applies segmented log-linear regression modeling to identify statistically significant changes in mortality trends over time. Annual percent change (APC) and average annual percent change (AAPC) were estimated with corresponding 95% confidence intervals (CIs). Statistical significance was assessed using permutation testing, and two-sided p-values < 0.05 were considered significant. A maximum of three joinpoints were permitted in model selection. Results Overall Between 1999 and 2023, a total of 633,221 deaths in the United States involved both ischemic heart disease (IHD) and chronic kidney disease (CKD). During this period, age-adjusted mortality rates (AAMRs) declined from 13.1 (95% CI 13.0–13.3) per 1,000,000 in 1999 to 9.1 (95% CI 9.0–9.2) in 2023. The highest AAMR was observed in 2012 at 18.5 (95% CI 18.4–18.7). Overall, the trend demonstrated a non-significant decline, with an average annual percent change (AAPC) of − 1.13% (95% CI − 2.46 to 0.21; p = 0.093) (Fig. 1 ). Gender Mortality rates were consistently higher among males than females throughout the study period. From 1999 to 2023, 375,585 deaths occurred among males and 257,636 among females. Among males, the AAMR peaked at 26.9 (95% CI 26.6–27.3) in 2012. Male mortality declined significantly over the study period (APC − 1.12%; 95% CI − 2.19 to − 0.03; p = 0.044). Among females, the highest AAMR was 12.8 (95% CI 12.6–13.0) in 2012. Female mortality declined significantly from 1999 to 2009 (APC − 2.75%; 95% CI − 3.93 to − 1.55; p < 0.001), followed by a non-significant increase from 2009 to 2012 (APC 17.57%; 95% CI − 0.23 to 38.62; p = 0.054). A significant decline was observed from 2012 to 2015 (APC − 24.27%; 95% CI − 40.13 to − 4.23; p = 0.024). However, from 2015 to 2023, mortality increased significantly (APC 3.25%; 95% CI 0.78 to 5.79; p = 0.013) (Fig. 1 ). Race and Ethnicity Mortality trends were stratified by race and ethnicity. From 1999 to 2023, AAMRs were highest among non-Hispanic (NH) White adults, followed by NH Black or African American, Hispanic or Latino, NH Asian or Pacific Islander, and NH American Indian or Alaska Native populations. Among NH White adults, mortality demonstrated a non-significant decline (APC − 0.59%; 95% CI − 1.88 to 0.72; p = 0.359). NH Black or African American adults experienced a significant decline (APC − 3.33%; 95% CI − 4.40 to − 2.24; p < 0.001). Hispanic or Latino individuals also demonstrated a significant decline (APC − 3.69%; 95% CI − 4.97 to − 2.39; p < 0.001). Among NH Asian or Pacific Islanders, mortality declined significantly from 1999 to 2009 (APC − 4.68%; 95% CI − 6.49 to − 2.83; p < 0.001), followed by a non-significant increase from 2009 to 2012 (APC 15.82%; 95% CI − 7.08 to 44.38; p = 0.175). A significant decline was observed from 2012 to 2015 (APC − 25.76%; 95% CI − 42.23 to − 4.60; p = 0.023), followed by a non-significant increase through 2023 (APC 1.63%; 95% CI − 0.48 to 3.78; p = 0.121). NH American Indian or Alaska Native individuals experienced a significant decline over the study period (APC − 3.19%; 95% CI − 4.44 to − 1.91; p < 0.001) (Fig. 2 ). Age Groups Mortality trends were analyzed across three age groups: 25–44 years, 45–64 years, and ≥ 65 years. Crude mortality rates were highest among adults aged ≥ 65 years. Among adults aged ≥ 65 years, mortality declined significantly from 1999 to 2023 (APC − 1.40%; 95% CI − 2.75 to − 0.04; p = 0.043). Among adults aged 45–64 years, mortality declined significantly from 1999 to 2009 (APC − 3.97%; 95% CI − 5.05 to − 2.88; p < 0.001), followed by a non-significant change through 2012 (APC 15.49%; 95% CI − 1.04 to 34.79; p = 0.065). A significant decline occurred from 2012 to 2015 (APC − 25.29%; 95% CI − 43.31 to − 1.54; p = 0.040). However, mortality increased significantly from 2015 to 2023 (APC 3.88%; 95% CI 1.15 to 6.69; p = 0.008). Among adults aged 25–44 years, mortality declined significantly over the entire study period (APC − 3.16%; 95% CI − 4.52 to − 1.79; p < 0.001). The AAPC was − 1.40% (95% CI − 2.75 to − 0.05; p = 0.043) for adults aged ≥ 65 years, − 2.24% (95% CI − 5.82 to 1.47; p = 0.234) for those aged 45–64 years, and − 3.16% (95% CI − 4.51 to − 1.79; p < 0.001) for those aged 25–44 years (Fig. 3 ). Geographic Region Mortality trends were evaluated across U.S. Census regions. From 1999 to 2023, 121,088 deaths occurred in the Northeast, 153,259 in the Midwest, 226,223 in the South, and 132,651 in the West. The West demonstrated a significant decline (AAPC − 1.59%; 95% CI − 2.94 to − 0.24; p = 0.023), as did the Northeast (AAPC − 2.22%; 95% CI − 3.16 to − 1.26; p < 0.001). Declines in the Midwest (AAPC − 1.04%; 95% CI − 2.22 to 0.16; p = 0.087) and South (AAPC − 1.12%; 95% CI − 2.37 to 0.15; p = 0.081) were not statistically significant (Fig. 4 ). State-level analysis (1999–2021) demonstrated the highest age-adjusted mortality rate in West Virginia (39.2 per 1,000,000) and the lowest in Nevada (17.8 per 1,000,000) (Fig. 5 ). Urbanization From 1999 to 2020, 449,095 deaths occurred in metropolitan areas and 103,076 in non-metropolitan areas. Both metropolitan (AAPC − 1.35%; 95% CI − 4.48 to 1.89; p = 0.410) and non-metropolitan areas (AAPC − 0.16%; 95% CI − 3.23 to 3.00; p = 0.918) demonstrated non-significant overall declines (Fig. 6 ). Urbanization data were only available through 2020. Place of Death From 1999 to 2023, most deaths occurred in medical facility inpatient settings (281,811), followed by decedents’ homes (133,292), nursing homes or long-term care facilities (122,525), medical facility outpatient or emergency departments (46,963), hospice facilities (24,483), other locations (19,251), medical facility deaths on arrival (3,236), place of death unknown (1,104), and medical facility status unknown (551). Discussion In this nationwide analysis of IHD- and CKD-related mortality from 1999 to 2023, we observed modest overall declines in age-adjusted mortality rates. However, this aggregate improvement concealed a critical and concerning finding: a statistically significant rise in female mortality during the 2015–2023 period, in contrast to continued improvement among males. This divergence suggests that prior gains in women’s cardiovascular survival may be eroding in the context of combined cardiorenal disease. The modest decline in overall IHD-CKD mortality likely reflects decades of progress in cardiovascular prevention and treatment, including widespread statin use, improved antihypertensive regimens, antiplatelet therapy, and advancements in revascularization strategies [ 8 , 9 ]. Similarly, improvements in CKD management—particularly renin-angiotensin system blockade, glycemic control, and earlier detection—have contributed to enhanced survival [ 10 , 11 ]. National surveillance has consistently documented declining IHD mortality during this period [ 16 , 17 ]. However, rising prevalence of obesity, diabetes, and metabolic syndrome has counterbalanced these gains [ 12 – 15 ]. The growing cardiometabolic burden may be particularly relevant in patients with concurrent CKD, where cardiovascular risk is already amplified [ 18 – 21 ]. As a result, overall mortality trends appear flattened rather than dramatically improved. Importantly, these aggregate patterns obscure meaningful subgroup divergence—most notably by sex. The most consequential finding of this study is the sustained increase in female IHD-CKD mortality from 2015 to 2023. While women historically have lower absolute cardiovascular mortality compared with men [ 22 ], this survival advantage appears to be narrowing in the context of combined kidney and heart disease. Sex disparities in cardiovascular recognition and management are well documented. Women are more likely to present with atypical symptoms, experience delays in diagnosis, and receive fewer invasive procedures and guideline-directed medical therapies [ 23 ]. These disparities may become particularly consequential in high-risk populations such as those with CKD. Emerging nephrology literature further suggests that CKD may confer greater excess cardiovascular mortality risk in women than in men [ 24 ]. Potential mechanisms include sex-specific differences in vascular biology, inflammatory response, hormonal changes, and progression of kidney dysfunction. In post-menopausal women, accelerated metabolic dysregulation may further compound cardiovascular risk. The temporal pattern observed, early decline followed by post-2015 increase, raises concern that recent cardiometabolic trends may be disproportionately affecting women. Rising rates of obesity and diabetes [ 14 , 15 , 29 , 30 ], particularly in midlife women, may be contributing to the parallel increase observed in the 45–64 age group. If this trajectory continues, women with combined IHD and CKD may face increasing mortality risk over the next decade, potentially reversing decades of progress in cardiovascular survival. Although older adults bore the highest absolute mortality burden, middle-aged adults demonstrated a concerning post-2015 increase. Obesity, insulin resistance, and poorly controlled hypertension in midlife accelerate both CKD progression and atherosclerotic disease [ 29 , 30 ]. Given that women often experience delayed recognition of cardiovascular risk during midlife, this intersection may represent a critical window of vulnerability. These findings underscore the importance of early cardiovascular risk assessment and aggressive CKD management in middle-aged populations, particularly women. Consistent with prior literature, racial disparities persisted, with non-Hispanic White adults exhibiting the highest absolute mortality rates and minority populations demonstrating significant long-term declines [ 25 , 26 ]. Structural determinants of health, including socioeconomic status, healthcare access, and neighborhood disadvantage, continue to shape cardiovascular outcomes [ 27 , 28 ]. Regional variation was also evident, with the South experiencing the greatest mortality burden. Geographic differences in cardiometabolic risk factor prevalence, healthcare infrastructure, and specialty access likely contribute to these disparities [ 31 – 33 ]. Rural populations demonstrated slower improvement, consistent with limited access to cardiology and nephrology services [ 34 ]. Importantly, although these disparities remain substantial, most racial and regional groups demonstrated overall improvement rather than reversal. In contrast, the rise in female mortality represents a unique and emergent divergence. The interaction between CKD and IHD presents unique therapeutic challenges. CKD complicates cardiovascular management through altered pharmacokinetics, increased bleeding risk, and limitations in revascularization options [ 37 ]. As CKD prevalence continues to rise, cardiovascular mortality attributable to kidney dysfunction is projected to increase globally [ 38 ]. Given this landscape, sex-specific prevention strategies should include earlier cardiovascular risk screening in women with CKD, improved recognition of atypical ischemic symptoms, aggressive management of midlife cardiometabolic risk factors, integrated cardio-renal care pathways, and reduction of structural barriers to specialty care. Addressing inequities in cardio-renal care delivery remains essential [ 40 , 41 ]. A key strength of this study is the use of multiple cause-of-death methodology, which captures deaths in which CKD contributed even if not listed as the underlying cause [ 43 , 44 ]. This approach provides a more comprehensive estimate of cardiorenal mortality burden. However, limitations include reliance on death certificate data, potential misclassification, and lack of granular clinical detail regarding disease severity, treatment patterns, and risk factor control [ 39 ]. Conclusion Although overall IHD-CKD mortality declined modestly from 1999 to 2023, these aggregate trends conceal a concerning and statistically significant rise in female mortality since 2015. While racial and regional disparities persist, none demonstrated the sustained reversal observed among women. This emerging sex-specific divergence suggests that women with combined cardiovascular and renal disease may be entering a new phase of vulnerability. Without targeted prevention, earlier CKD detection, and improved cardiovascular risk recognition in women, prior survival gains may continue to erode. Abbreviations IHD: Ischemic heart disease CKD:Chronic kidney disease AAMR:Age-adjusted mortality rate APC:Annual percent change AAPC:Average annual percent change CDC:Centers for Disease Control and Prevention CI:Confidence interval Declarations Ethics approval and consent to participate This study used publicly available, de-identified data from the CDC WONDER database. Institutional Review Board approval and informed consent were not required. Consent for publication Not applicable. Availability of data and materials The datasets analyzed during the current study are publicly available in the CDC WONDER database (https://wonder.cdc.gov/). Competing interests The authors declare that they have no competing interests. Funding The authors received no specific funding for this work. Authors’ contributions HA conceptualized the study. 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Additional Declarations No competing interests reported. Supplementary Files Table1OverallandGender.xlsx Table2Race.xlsx Table3Regions.xlsx Table4AgeGroups.xlsx Table5States.xlsx Table6PlaceofDeath.xlsx Table7Urbanization.xlsx JPUrbanization.bmp JPAgeGroups.bmp JPRace.bmp JPRegion.bmp JPOverall.bmp Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 25 Mar, 2026 Editor assigned by journal 23 Mar, 2026 Editor invited by journal 04 Mar, 2026 Submission checks completed at journal 04 Mar, 2026 First submitted to journal 04 Mar, 2026 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. 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Abid","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAl0lEQVRIiWNgGAWjYBACAwYehgM8FRIQNglazpCqhYG3jYEELebsZw8eeDvPIrGBvXmbBFFaLHvyEg7O3SaR2MBzrIw4LQYHcgwO84K0SOSYEanl/BugljlALfJviNVyA2RLA8gWHqK1vEs4OOeYhHEbT1qxBZEOyz384U1NnWw/++GNN4jSAgdspCkfBaNgFIyCUYAXAAChaS7yec6E1gAAAABJRU5ErkJggg==","orcid":"","institution":"Indiana University","correspondingAuthor":true,"prefix":"","firstName":"Hassaan","middleName":"","lastName":"Abid","suffix":""},{"id":612796363,"identity":"69640074-6f19-4ea1-b3fd-441bee7624fe","order_by":1,"name":"Muhammad Vazaym","email":"","orcid":"","institution":"Liaquat University of Medical \u0026 Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"","lastName":"Vazaym","suffix":""},{"id":612796367,"identity":"12438beb-7571-4580-b858-b0ffb66307f7","order_by":2,"name":"Muhammad Jawad","email":"","orcid":"","institution":"Liaquat University of Medical \u0026 Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"","lastName":"Jawad","suffix":""},{"id":612796376,"identity":"2cc2263d-6f0a-44e8-83f2-f79d06e09567","order_by":3,"name":"Gaaitri Lohano","email":"","orcid":"","institution":"Liaquat University of Medical \u0026 Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Gaaitri","middleName":"","lastName":"Lohano","suffix":""},{"id":612796393,"identity":"94e3e342-6787-4c3c-a83a-f7e49abb708b","order_by":4,"name":"Syed Mohamin Abbas Shah","email":"","orcid":"","institution":"King Edward Medical University","correspondingAuthor":false,"prefix":"","firstName":"Syed","middleName":"Mohamin Abbas","lastName":"Shah","suffix":""},{"id":612796403,"identity":"56c13f72-bac1-4c4b-a213-00d5a4fb2220","order_by":5,"name":"Naveed Ahmed Khan","email":"","orcid":"","institution":"Khyber Medical College","correspondingAuthor":false,"prefix":"","firstName":"Naveed","middleName":"Ahmed","lastName":"Khan","suffix":""}],"badges":[],"createdAt":"2026-02-28 09:24:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8993837/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8993837/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105599949,"identity":"6d246882-be7a-4983-9682-50920354b27c","added_by":"auto","created_at":"2026-03-27 19:27:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103580,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in age-adjusted mortality rates for combined ischemic heart disease and chronic kidney disease overall and stratified by sex, United States, 1999–2023.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/487fd22760d4250270ee73b9.png"},{"id":105728618,"identity":"fe5bb217-189f-427b-85e9-f9b25480804a","added_by":"auto","created_at":"2026-03-30 11:12:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":139877,"visible":true,"origin":"","legend":"\u003cp\u003eRace- and ethnicity-stratified age-adjusted mortality rates for IHD and CKD, 1999–2023.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/549644b9b9653a663ba19f93.png"},{"id":105728264,"identity":"67e897b6-c54b-46f6-90f0-bc95a3000058","added_by":"auto","created_at":"2026-03-30 11:11:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":87589,"visible":true,"origin":"","legend":"\u003cp\u003eAge group–stratified mortality trends, 1999–2023.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/9e4ade558582471461ec1880.png"},{"id":105728800,"identity":"a8359fd4-18bd-4131-9632-95377eb3c4df","added_by":"auto","created_at":"2026-03-30 11:12:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":113335,"visible":true,"origin":"","legend":"\u003cp\u003eRegional mortality trends by U.S. Census region.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/e6fc0803f7557e3abd095526.png"},{"id":105728806,"identity":"c055753e-692a-445d-b446-821068e8cec3","added_by":"auto","created_at":"2026-03-30 11:12:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":76942,"visible":true,"origin":"","legend":"\u003cp\u003eState-level age-adjusted mortality rates.\u003c/p\u003e","description":"","filename":"Figure53.png","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/d54d7c634c7284a9551a7fd4.png"},{"id":105728804,"identity":"c1db4ac4-ac55-41e4-ac71-91b607469834","added_by":"auto","created_at":"2026-03-30 11:12:45","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":90592,"visible":true,"origin":"","legend":"\u003cp\u003eUrban–rural stratified mortality trends.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/38c85df146ad8540d7f3ddc0.png"},{"id":105729996,"identity":"aa414069-8369-499d-ae38-3c1842e1d0cd","added_by":"auto","created_at":"2026-03-30 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19:27:14","extension":"bmp","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":2070566,"visible":true,"origin":"","legend":"","description":"","filename":"JPRace.bmp","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/ed0becf704c9910cb4d43f48.bmp"},{"id":105599964,"identity":"068d0d58-58a2-498b-91dc-c995f77efb02","added_by":"auto","created_at":"2026-03-27 19:27:14","extension":"bmp","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":2070566,"visible":true,"origin":"","legend":"","description":"","filename":"JPRegion.bmp","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/a49e8d2ada139d0b1dde302a.bmp"},{"id":105599963,"identity":"b4afd6f1-188a-4287-b7ab-4812c95d8acc","added_by":"auto","created_at":"2026-03-27 19:27:14","extension":"bmp","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":2070566,"visible":true,"origin":"","legend":"","description":"","filename":"JPOverall.bmp","url":"https://assets-eu.researchsquare.com/files/rs-8993837/v1/e4d6f814350e5ef6aa023aac.bmp"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rising Female Mortality in Combined Ischemic Heart Disease and Chronic Kidney Disease in the United States (1999–2023)","fulltext":[{"header":"Background","content":"\u003cp\u003eIschemic heart disease (IHD) remains a significant public health concern and continues to be the leading cause of death in the United States, accounting for more than 300,000 deaths annually [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although age-adjusted IHD mortality rates have declined over recent decades due to advances in preventive strategies, early diagnosis, pharmacologic therapy, and interventional cardiology [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], the absolute burden of disease remains substantial.\u003c/p\u003e \u003cp\u003eChronic kidney disease (CKD) represents another major and growing contributor to morbidity and mortality, affecting nearly 14% of U.S. adults [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. From 1999 to 2020, CKD has been associated with approximately 1.94\u0026nbsp;million deaths nationwide [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. CKD is widely recognized not only as a progressive renal condition but also as a powerful and independent risk factor for cardiovascular disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Individuals with CKD experience substantially higher rates of cardiovascular events and premature mortality compared with those without kidney dysfunction [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe pathophysiological relationship between CKD and IHD is multifactorial. Beyond shared risk factors such as hypertension, diabetes mellitus, and dyslipidemia, CKD accelerates atherosclerosis through chronic inflammation, endothelial dysfunction, oxidative stress, vascular calcification, and disordered mineral metabolism [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, cardiovascular disease, particularly IHD, remains the leading cause of death among patients with CKD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLong-term analyses of mortality trends have demonstrated overall declines in cardiovascular mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, improvements are not uniform across demographic groups [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Mortality patterns may differ by sex, race, geography, and age, and multiple cause-of-death analyses allow more comprehensive assessment of CKD\u0026rsquo;s contributory role in cardiovascular mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile overall IHD mortality has declined nationally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], emerging evidence suggests that cardiovascular gains among women may be slowing or reversing. Sex differences in cardiovascular risk recognition and treatment remain well documented [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and recent nephrology data indicate that CKD may confer greater excess cardiovascular risk in women compared with men [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Despite this, few studies have evaluated long-term sex-specific trends in combined IHD and CKD mortality.\u003c/p\u003e \u003cp\u003eThis study uses CDC WONDER data from 1999 to 2023 to evaluate national trends in IHD- and CKD-related mortality, with primary focus on emerging increases in female mortality and secondary examination of demographic and geographic disparities.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Data Source\u003c/h2\u003e \u003cp\u003eWe performed a retrospective, population-based study examining U.S. mortality trends from 1999 through 2023 using the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause-of-Death database. This publicly accessible dataset compiles information from national death certificates and allows identification of both underlying and contributing causes of death.\u003c/p\u003e \u003cp\u003eDeaths were included if ischemic heart disease (IHD; ICD-10 codes I20\u0026ndash;I25) and chronic kidney disease (CKD; ICD-10 code N18) were documented anywhere on the death certificate. Because the database contains de-identified, publicly available data, this study was exempt from Institutional Review Board oversight. The general analytic framework applied in this study has been described previously in similar CDC WONDER mortality analyses. [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eVariables and Definitions\u003c/h3\u003e\n\u003cp\u003eMortality data were stratified by demographic and geographic characteristics, including sex, race/ethnicity, age group, U.S. Census region, state, urban\u0026ndash;rural classification, and place of death.\u003c/p\u003e \u003cp\u003eRace and ethnicity categories were defined according to CDC classifications as non-Hispanic (NH) White, NH Black or African American, Hispanic or Latino, NH American Indian or Alaska Native, and NH Asian or Pacific Islander. Age was categorized into three predefined groups: 25\u0026ndash;44 years, 45\u0026ndash;64 years, and \u0026ge;\u0026thinsp;65 years.\u003c/p\u003e \u003cp\u003eGeographic regions were classified according to U.S. Census Bureau definitions (Northeast, Midwest, South, and West). Urbanization status was determined using the 2013 National Center for Health Statistics Urban\u0026ndash;Rural Classification Scheme for Counties. Place of death categories included inpatient medical facilities, outpatient or emergency departments, home, hospice, nursing home or long-term care facilities, and other specified locations.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCrude mortality rates and age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated annually. Age adjustment was performed using the direct standardization method with the 2000 U.S. standard population as reference.\u003c/p\u003e \u003cp\u003eTemporal trends in AAMRs were evaluated using the Joinpoint Regression Program (Version 5.0, National Cancer Institute). This approach applies segmented log-linear regression modeling to identify statistically significant changes in mortality trends over time. Annual percent change (APC) and average annual percent change (AAPC) were estimated with corresponding 95% confidence intervals (CIs). Statistical significance was assessed using permutation testing, and two-sided p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant. A maximum of three joinpoints were permitted in model selection.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOverall\u003c/h2\u003e \u003cp\u003eBetween 1999 and 2023, a total of 633,221 deaths in the United States involved both ischemic heart disease (IHD) and chronic kidney disease (CKD). During this period, age-adjusted mortality rates (AAMRs) declined from 13.1 (95% CI 13.0\u0026ndash;13.3) per 1,000,000 in 1999 to 9.1 (95% CI 9.0\u0026ndash;9.2) in 2023. The highest AAMR was observed in 2012 at 18.5 (95% CI 18.4\u0026ndash;18.7). Overall, the trend demonstrated a non-significant decline, with an average annual percent change (AAPC) of \u0026minus;\u0026thinsp;1.13% (95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.46 to 0.21; p\u0026thinsp;=\u0026thinsp;0.093) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGender\u003c/h2\u003e \u003cp\u003eMortality rates were consistently higher among males than females throughout the study period. From 1999 to 2023, 375,585 deaths occurred among males and 257,636 among females. Among males, the AAMR peaked at 26.9 (95% CI 26.6\u0026ndash;27.3) in 2012. Male mortality declined significantly over the study period (APC\u0026thinsp;\u0026minus;\u0026thinsp;1.12%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.19 to \u0026minus;\u0026thinsp;0.03; p\u0026thinsp;=\u0026thinsp;0.044). Among females, the highest AAMR was 12.8 (95% CI 12.6\u0026ndash;13.0) in 2012. Female mortality declined significantly from 1999 to 2009 (APC\u0026thinsp;\u0026minus;\u0026thinsp;2.75%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;3.93 to \u0026minus;\u0026thinsp;1.55; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), followed by a non-significant increase from 2009 to 2012 (APC 17.57%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.23 to 38.62; p\u0026thinsp;=\u0026thinsp;0.054). A significant decline was observed from 2012 to 2015 (APC\u0026thinsp;\u0026minus;\u0026thinsp;24.27%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;40.13 to \u0026minus;\u0026thinsp;4.23; p\u0026thinsp;=\u0026thinsp;0.024). However, from 2015 to 2023, mortality increased significantly (APC 3.25%; 95% CI 0.78 to 5.79; p\u0026thinsp;=\u0026thinsp;0.013) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRace and Ethnicity\u003c/h3\u003e\n\u003cp\u003eMortality trends were stratified by race and ethnicity. From 1999 to 2023, AAMRs were highest among non-Hispanic (NH) White adults, followed by NH Black or African American, Hispanic or Latino, NH Asian or Pacific Islander, and NH American Indian or Alaska Native populations. Among NH White adults, mortality demonstrated a non-significant decline (APC\u0026thinsp;\u0026minus;\u0026thinsp;0.59%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;1.88 to 0.72; p\u0026thinsp;=\u0026thinsp;0.359). NH Black or African American adults experienced a significant decline (APC\u0026thinsp;\u0026minus;\u0026thinsp;3.33%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.40 to \u0026minus;\u0026thinsp;2.24; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Hispanic or Latino individuals also demonstrated a significant decline (APC\u0026thinsp;\u0026minus;\u0026thinsp;3.69%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.97 to \u0026minus;\u0026thinsp;2.39; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Among NH Asian or Pacific Islanders, mortality declined significantly from 1999 to 2009 (APC\u0026thinsp;\u0026minus;\u0026thinsp;4.68%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;6.49 to \u0026minus;\u0026thinsp;2.83; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), followed by a non-significant increase from 2009 to 2012 (APC 15.82%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;7.08 to 44.38; p\u0026thinsp;=\u0026thinsp;0.175). A significant decline was observed from 2012 to 2015 (APC\u0026thinsp;\u0026minus;\u0026thinsp;25.76%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;42.23 to \u0026minus;\u0026thinsp;4.60; p\u0026thinsp;=\u0026thinsp;0.023), followed by a non-significant increase through 2023 (APC 1.63%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.48 to 3.78; p\u0026thinsp;=\u0026thinsp;0.121). NH American Indian or Alaska Native individuals experienced a significant decline over the study period (APC\u0026thinsp;\u0026minus;\u0026thinsp;3.19%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.44 to \u0026minus;\u0026thinsp;1.91; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eAge Groups\u003c/h3\u003e\n\u003cp\u003eMortality trends were analyzed across three age groups: 25\u0026ndash;44 years, 45\u0026ndash;64 years, and \u0026ge;\u0026thinsp;65 years. Crude mortality rates were highest among adults aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years. Among adults aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years, mortality declined significantly from 1999 to 2023 (APC\u0026thinsp;\u0026minus;\u0026thinsp;1.40%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.75 to \u0026minus;\u0026thinsp;0.04; p\u0026thinsp;=\u0026thinsp;0.043). Among adults aged 45\u0026ndash;64 years, mortality declined significantly from 1999 to 2009 (APC\u0026thinsp;\u0026minus;\u0026thinsp;3.97%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;5.05 to \u0026minus;\u0026thinsp;2.88; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), followed by a non-significant change through 2012 (APC 15.49%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;1.04 to 34.79; p\u0026thinsp;=\u0026thinsp;0.065). A significant decline occurred from 2012 to 2015 (APC\u0026thinsp;\u0026minus;\u0026thinsp;25.29%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;43.31 to \u0026minus;\u0026thinsp;1.54; p\u0026thinsp;=\u0026thinsp;0.040). However, mortality increased significantly from 2015 to 2023 (APC 3.88%; 95% CI 1.15 to 6.69; p\u0026thinsp;=\u0026thinsp;0.008). Among adults aged 25\u0026ndash;44 years, mortality declined significantly over the entire study period (APC\u0026thinsp;\u0026minus;\u0026thinsp;3.16%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.52 to \u0026minus;\u0026thinsp;1.79; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The AAPC was \u0026minus;\u0026thinsp;1.40% (95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.75 to \u0026minus;\u0026thinsp;0.05; p\u0026thinsp;=\u0026thinsp;0.043) for adults aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years, \u0026minus;\u0026thinsp;2.24% (95% CI\u0026thinsp;\u0026minus;\u0026thinsp;5.82 to 1.47; p\u0026thinsp;=\u0026thinsp;0.234) for those aged 45\u0026ndash;64 years, and \u0026minus;\u0026thinsp;3.16% (95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.51 to \u0026minus;\u0026thinsp;1.79; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) for those aged 25\u0026ndash;44 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eGeographic Region\u003c/h2\u003e \u003cp\u003eMortality trends were evaluated across U.S. Census regions. From 1999 to 2023, 121,088 deaths occurred in the Northeast, 153,259 in the Midwest, 226,223 in the South, and 132,651 in the West. The West demonstrated a significant decline (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;1.59%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.94 to \u0026minus;\u0026thinsp;0.24; p\u0026thinsp;=\u0026thinsp;0.023), as did the Northeast (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;2.22%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;3.16 to \u0026minus;\u0026thinsp;1.26; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Declines in the Midwest (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;1.04%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.22 to 0.16; p\u0026thinsp;=\u0026thinsp;0.087) and South (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;1.12%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.37 to 0.15; p\u0026thinsp;=\u0026thinsp;0.081) were not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). State-level analysis (1999\u0026ndash;2021) demonstrated the highest age-adjusted mortality rate in West Virginia (39.2 per 1,000,000) and the lowest in Nevada (17.8 per 1,000,000) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eUrbanization\u003c/h2\u003e \u003cp\u003eFrom 1999 to 2020, 449,095 deaths occurred in metropolitan areas and 103,076 in non-metropolitan areas. Both metropolitan (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;1.35%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.48 to 1.89; p\u0026thinsp;=\u0026thinsp;0.410) and non-metropolitan areas (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;0.16%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;3.23 to 3.00; p\u0026thinsp;=\u0026thinsp;0.918) demonstrated non-significant overall declines (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Urbanization data were only available through 2020.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePlace of Death\u003c/h2\u003e \u003cp\u003eFrom 1999 to 2023, most deaths occurred in medical facility inpatient settings (281,811), followed by decedents\u0026rsquo; homes (133,292), nursing homes or long-term care facilities (122,525), medical facility outpatient or emergency departments (46,963), hospice facilities (24,483), other locations (19,251), medical facility deaths on arrival (3,236), place of death unknown (1,104), and medical facility status unknown (551).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this nationwide analysis of IHD- and CKD-related mortality from 1999 to 2023, we observed modest overall declines in age-adjusted mortality rates. However, this aggregate improvement concealed a critical and concerning finding: a statistically significant rise in female mortality during the 2015\u0026ndash;2023 period, in contrast to continued improvement among males. This divergence suggests that prior gains in women\u0026rsquo;s cardiovascular survival may be eroding in the context of combined cardiorenal disease.\u003c/p\u003e \u003cp\u003eThe modest decline in overall IHD-CKD mortality likely reflects decades of progress in cardiovascular prevention and treatment, including widespread statin use, improved antihypertensive regimens, antiplatelet therapy, and advancements in revascularization strategies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Similarly, improvements in CKD management\u0026mdash;particularly renin-angiotensin system blockade, glycemic control, and earlier detection\u0026mdash;have contributed to enhanced survival [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. National surveillance has consistently documented declining IHD mortality during this period [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, rising prevalence of obesity, diabetes, and metabolic syndrome has counterbalanced these gains [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The growing cardiometabolic burden may be particularly relevant in patients with concurrent CKD, where cardiovascular risk is already amplified [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. As a result, overall mortality trends appear flattened rather than dramatically improved. Importantly, these aggregate patterns obscure meaningful subgroup divergence\u0026mdash;most notably by sex.\u003c/p\u003e \u003cp\u003eThe most consequential finding of this study is the sustained increase in female IHD-CKD mortality from 2015 to 2023. While women historically have lower absolute cardiovascular mortality compared with men [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], this survival advantage appears to be narrowing in the context of combined kidney and heart disease. Sex disparities in cardiovascular recognition and management are well documented. Women are more likely to present with atypical symptoms, experience delays in diagnosis, and receive fewer invasive procedures and guideline-directed medical therapies [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. These disparities may become particularly consequential in high-risk populations such as those with CKD. Emerging nephrology literature further suggests that CKD may confer greater excess cardiovascular mortality risk in women than in men [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Potential mechanisms include sex-specific differences in vascular biology, inflammatory response, hormonal changes, and progression of kidney dysfunction. In post-menopausal women, accelerated metabolic dysregulation may further compound cardiovascular risk. The temporal pattern observed, early decline followed by post-2015 increase, raises concern that recent cardiometabolic trends may be disproportionately affecting women. Rising rates of obesity and diabetes [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], particularly in midlife women, may be contributing to the parallel increase observed in the 45\u0026ndash;64 age group. If this trajectory continues, women with combined IHD and CKD may face increasing mortality risk over the next decade, potentially reversing decades of progress in cardiovascular survival.\u003c/p\u003e \u003cp\u003eAlthough older adults bore the highest absolute mortality burden, middle-aged adults demonstrated a concerning post-2015 increase. Obesity, insulin resistance, and poorly controlled hypertension in midlife accelerate both CKD progression and atherosclerotic disease [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Given that women often experience delayed recognition of cardiovascular risk during midlife, this intersection may represent a critical window of vulnerability. These findings underscore the importance of early cardiovascular risk assessment and aggressive CKD management in middle-aged populations, particularly women.\u003c/p\u003e \u003cp\u003eConsistent with prior literature, racial disparities persisted, with non-Hispanic White adults exhibiting the highest absolute mortality rates and minority populations demonstrating significant long-term declines [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Structural determinants of health, including socioeconomic status, healthcare access, and neighborhood disadvantage, continue to shape cardiovascular outcomes [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Regional variation was also evident, with the South experiencing the greatest mortality burden. Geographic differences in cardiometabolic risk factor prevalence, healthcare infrastructure, and specialty access likely contribute to these disparities [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Rural populations demonstrated slower improvement, consistent with limited access to cardiology and nephrology services [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Importantly, although these disparities remain substantial, most racial and regional groups demonstrated overall improvement rather than reversal. In contrast, the rise in female mortality represents a unique and emergent divergence.\u003c/p\u003e \u003cp\u003eThe interaction between CKD and IHD presents unique therapeutic challenges. CKD complicates cardiovascular management through altered pharmacokinetics, increased bleeding risk, and limitations in revascularization options [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. As CKD prevalence continues to rise, cardiovascular mortality attributable to kidney dysfunction is projected to increase globally [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven this landscape, sex-specific prevention strategies should include earlier cardiovascular risk screening in women with CKD, improved recognition of atypical ischemic symptoms, aggressive management of midlife cardiometabolic risk factors, integrated cardio-renal care pathways, and reduction of structural barriers to specialty care. Addressing inequities in cardio-renal care delivery remains essential [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA key strength of this study is the use of multiple cause-of-death methodology, which captures deaths in which CKD contributed even if not listed as the underlying cause [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. This approach provides a more comprehensive estimate of cardiorenal mortality burden. However, limitations include reliance on death certificate data, potential misclassification, and lack of granular clinical detail regarding disease severity, treatment patterns, and risk factor control [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough overall IHD-CKD mortality declined modestly from 1999 to 2023, these aggregate trends conceal a concerning and statistically significant rise in female mortality since 2015. While racial and regional disparities persist, none demonstrated the sustained reversal observed among women.\u003c/p\u003e \u003cp\u003eThis emerging sex-specific divergence suggests that women with combined cardiovascular and renal disease may be entering a new phase of vulnerability. Without targeted prevention, earlier CKD detection, and improved cardiovascular risk recognition in women, prior survival gains may continue to erode.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIHD: Ischemic heart disease\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCKD:Chronic kidney disease\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAAMR:Age-adjusted mortality rate\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAPC:Annual percent change\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAAPC:Average annual percent change\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCDC:Centers for Disease Control and Prevention\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCI:Confidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eThis study used publicly available, de-identified data from the CDC WONDER database. Institutional Review Board approval and informed consent were not required.\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eAvailability of data and materials\u003c/h3\u003e\n\u003cp\u003eThe datasets analyzed during the current study are publicly available in the CDC WONDER database (https://wonder.cdc.gov/).\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u003c/h3\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\n\u003ch3\u003eAuthors\u0026rsquo; contributions\u003c/h3\u003e\n\u003cp\u003eHA conceptualized the study. HA and MV performed data extraction and statistical analyses. MJ and GL contributed to interpretation of results. SMAS and NAK drafted and critically revised the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNowbar AN, Gitto M, Howard JP, Francis DP, Al-Lamee R. Mortality From Ischemic Heart Disease: Analysis of Data From the World Health Organization and Coronary Artery Disease Risk Factors From NCD Risk Factor Collaboration. Circ: Cardiovascular Quality and Outcomes. 2019;12(6):e005375.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKing SJ, Wangdak Yuthok TY, Bacong AM, Khandelwal A, Kazi DS, Mussolino ME, et al. Heart Disease Mortality in the United States, 1970 to 2022. JAHA. 2025;14(13):e038644.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmad E, Ahmad S, Naeem A, Ahmed S, Shehzad M, Akram U, et al. 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Diabetes Epidemiol Manag. 2026;21:100300. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.deman.2026.100300\u003c/span\u003e\u003cspan address=\"10.1016/j.deman.2026.100300\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 7 are available in the Supplementary Files section.\u003c/p\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-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ischemic heart disease, chronic kidney disease, Mortality trends, Sex differences, CDC WONDER","lastPublishedDoi":"10.21203/rs.3.rs-8993837/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8993837/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough age-adjusted mortality from ischemic heart disease (IHD) has declined in the United States over recent decades, the coexistence of chronic kidney disease (CKD) may be reshaping mortality patterns. Emerging data suggest that improvements in cardiovascular survival may not be uniform across sexes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective population-based study using CDC WONDER multiple cause-of-death data from 1999\u0026ndash;2023. Deaths mentioning IHD (ICD-10 codes I20\u0026ndash;I25) and CKD (ICD-10 code N18) were identified. Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated using the 2000 U.S. standard population. Temporal trends were evaluated using Joinpoint Regression Program version 5.0 (National Cancer Institute) to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween 1999 and 2023, 633,221 deaths involved both IHD and CKD. Overall AAMR declined modestly (AAPC\u0026thinsp;\u0026minus;\u0026thinsp;1.13%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.46 to 0.21; p\u0026thinsp;=\u0026thinsp;0.093). Male mortality declined significantly (APC\u0026thinsp;\u0026minus;\u0026thinsp;1.12%; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;2.19 to \u0026minus;\u0026thinsp;0.03; p\u0026thinsp;=\u0026thinsp;0.044). In contrast, female mortality increased significantly from 2015 to 2023 (APC 3.25%; 95% CI 0.78 to 5.79; p\u0026thinsp;=\u0026thinsp;0.013). Similar increases were observed among middle-aged adults. Persistent regional and racial disparities were noted.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDespite modest national declines in cardiorenal mortality, a sustained rise in female mortality since 2015 signals a concerning reversal of cardiovascular progress. Targeted sex-specific prevention strategies are urgently needed.\u003c/p\u003e","manuscriptTitle":"Rising Female Mortality in Combined Ischemic Heart Disease and Chronic Kidney Disease in the United States (1999–2023)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-27 19:27:09","doi":"10.21203/rs.3.rs-8993837/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-03-25T12:25:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-23T10:50:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-04T11:17:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-04T09:46:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2026-03-04T07:30:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"14c07df1-6688-44a6-bd8c-8a1fd0e0ebc9","owner":[],"postedDate":"March 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-27T19:27:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-27 19:27:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8993837","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8993837","identity":"rs-8993837","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}