The primary data source was the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (CDC WONDER) mortality data, comprising of death certificate data for all US adults compiled by the National Center for Health Statistics (NCHS). Each death certificate includes a single underlying cause of death, up to 20 contributing causes of death, and demographic data. The underlying cause of death is determined based on World Health Organization criteria as the disease or condition that directly led to or initiated the sequence of events resulting in death, while contributing causes are defined as other conditions that played a role in the death, consistent with CDC classification and validation protocols. Causes of death in CDC WONDER are classified using the International Classification of Diseases, Tenth Revision (ICD-10), based on their appearance anywhere on the death certificate. CDC WONDER data have been well validated in analyses of cause-specific CVD mortality trends. ^, Data used for analysis is from the publicly available CDC WONDER database and only contains deidentified data, rendering the study exempt from institutional review board oversight.

An analysis of all available mortality data from 1999 to 2024 was conducted. Mortality data from individuals aged 15 to 44 years was included, as aligned with previous research. Deaths were included in the analysis if HHD was listed as an underlying cause or contributing of death (ICD‐10 codes I11.0, I11.9, and I11.x). Additional covariates abstracted from the death certificate included sex (male and female), race and ethnicity (non-Hispanic White; non-Hispanic Black; Hispanic/Latino; non-Hispanic Asian or Pacific Islander, and non-Hispanic American Indian or Alaska Native in accordance with NCHS classification), and 10-year standardized age categories (15–24, 25–34, and 35–44 years). ^, NCHS race and ethnicity classification is derived directly from death certificate data is reported by the funeral director as provided by an informant, often the surviving next of kin, or, in the absence of an informant, on the basis of observation, Information on place of residence, categorized by US Census region (Northeast, Midwest, South, and West), was also obtained. ^, CVD-related mortality was also included in the analysis to calculate overall and sex-stratified proportionate mortality percentages. CVD-related mortality was defined as any CVD (ICD-10 codes I00-I99) listed as either an underlying or contributing cause of death. ^,

HHD-related age-adjusted mortality rates (AAMR) for young adults were calculated per 100,000 population using annual population estimates standardized to the year 2000 US population. Proportionate mortality was then calculated to contextualize the burden of HHD-related deaths relative to all CVD deaths in the same age group. The proportion was derived by dividing the number of HHD-related deaths in individuals aged 15 to 44 by the total number of CVD-related deaths in the same age group each year, multiplied by 100 to obtain a percentage, enabling assessment of whether the share of CVD deaths attributable to HHD changed over time in young adults. Trends in AAMRs and proportionate mortality were analyzed using the Joinpoint Regression Program (Version 5.3.0, National Cancer Institute), to identify significant temporal changes by fitting connected linear segments on a log scale at points of temporal variation and calculating APCs with 95% confidence intervals using the Monte Carlo permutation test. A weighted average of these APCs was reported as the average annual percent change (AAPC) with corresponding 95% CIs, summarizing the overall trend across the study period. An APC was considered increasing or decreasing if its confidence interval did not include 0. Statistical significance was determined based on nonoverlapping confidence intervals. To further quantify changes in HHD-related mortality, we calculated percent change in AAMRs and proportionate mortality across four key reference years: 1999 (initial), 2019 (prepandemic), 2021 (peak pandemic), and 2024 (postpandemic). Percent changes were computed for 3 intervals: overall change since 1999, peak pandemic versus prepandemic, and postpandemic versus prepandemic. These were calculated by taking the difference between values at two time points, dividing by the earlier value, and multiplying by 100 to express the result as a percentage.

Between 1999 and 2024, a total of 119,264 HHD-related deaths occurred in young adults aged 15 to 44 ( Supplementary Table 1 ). Overall, HHD-related mortality increased from 1.3 deaths per 100,000 persons (95% CI: 1.23–1.36) in 1999 to 6.26 (95% CI: 6.12–6.40) in 2024 (AAPC: 6.2%, 95% CI: 5.96–6.47) ( Supplementary Table 2 ). The increase in HHD-related mortality was not uniform. Four inflection points were identified, occurring in 2001, 2006, 2018, and 2021. From 1999 to 2001, HHD-related mortality rates increased sharply (APC: 22.9%, 95% CI: 17.15–26.92) before slowing from 2001 to 2006 (APC: 6.9%, 95% CI: 5.45–8.37) and 2006 to 2018 (APC: 4.2%, 95% CI: 3.53–4.44). HHD-related mortality increased from 2018 to 2021 (APC 11.5%, 95% CI: 8.42–12.92) before leveling off from 2021 to 2024 (APC:–1.7%, 95% CI: −6.29 to 0.16). Overall HHD-related mortality rates are shown in ( Figure 1 ; Supplementary Table 3 ).

Overall and sex-stratified HHD-related age-adjusted mortality rates in the United States, 1999 to 2024. *Annual percentage change (APC) is significantly different from 0 at α = 0.05.

HHD-related mortality increased during the study period in both sexes, with males consistently exhibiting greater HHD-related mortality than females throughout the study period. Among males, mortality increased from 1.8 deaths per 100,000 persons (95% CI: 1.65–1.86) in 1999 to 9.1 deaths per 100,000 persons (95% CI: 9.32–9.81) in 2024, (AAPC: 6.5%, 95% CI: 6.13–6.72), while among females mortality increased from 0.8 (95% CI: 0.69–0.83) to 3.31 (95% CI: 3.34–3.64) deaths per 100,000 persons over the same period (AAPC: 5.8%, 95% CI: 5.26–6.17) as shown in Supplementary Table 3 . Notably, there was a statistically significant increase in APC for both sexes from 2018 to 2021, with females experiencing an increase of 11.3% (95% CI: 7.19–13.29) and males showing an increase of 11.1% (95% CI: 7.72–12.67). This was followed by a slight, nonsignificant decrease for both sexes through 2024. Overall HHD-related mortality rates stratified by sex are displayed in Figure 1 .

HHD-related mortality increased across all racial and ethnic groups over the study period, with each group showing a statistically significant rise in AAPC from 1999 to 2024. Throughout most of the study period, non-Hispanic Black population had the highest rates of HHD-related mortality, reaching 14.3 deaths per 100,000 persons in 2024 (95% CI: 13.76–14.93). However, AAMRs among non-Hispanic American Indian or Alaska Native populations rose sharply over time, surpassing those of non-Hispanic Black population after 2020 and reaching 16 per 100,000 in 2024 (95% CI: 13.36–18.54). The next highest rates were observed among non-Hispanic White (5.5; 95% CI: 5.34–5.69), Hispanic/Latino (4.4; 95% CI: 4.14–4.64), and non-Hispanic Asian American or Pacific Islander (2.2; 95% CI: 2.01–2.63) populations ( Supplementary Table 4 ). Among non-Hispanic Black adults, mortality rates did not increase uniformly over the duration of the study period. HHD-related mortality rose rapidly from 1999 to 2001 (APC 16.1%, 95% CI: 9.85–19.87), increased more gradually from 2001 to 2018 (APC 3.0%, 95% CI: 2.73–3.22), and increased further from 2018 to 2021 (APC 13.5%, 95% CI: 9.37–15.15), followed by a decline from 2021 to 2024 (APC: −3.6%, 95% CI: −9.38 to −1.23). Non-Hispanic White and Hispanic/Latino populations exhibited similar multisegmented time trends, with periods of both increase and decline similar to non-Hispanic Blacks. In contrast, non-Hispanic American Indian or Alaska Native and non-Hispanic Asian American or Pacific Islander populations experienced one continuous increase across the entire study period, with APCs of 11.2% (95% CI: 10.30–12.10) and 5.5% (95% CI: 4.83–6.21), respectively. HHD-related mortality rates stratified by race and ethnicity are displayed in Figure 2 .

HHD-related age-adjusted mortality rates stratified by race/ethnicity in the United States, 1999 to 2024. *Annual percent change (APC) is significantly different from 0 at α = 0.05. No AAMR values for non-Hispanic American Indian or Alaska Native population before 2002, since death counts were too low from HHD.

When stratified by age group, individuals aged 35 to 44 years had the highest crude mortality rates throughout the study period, followed by those aged 25 to 34 and 15 to 24 years ( Supplementary Table 5 ). For all age groups, the overall AAPC showed statistically significant increases during the study period. However, when examining specific time segments, both the 25 to 34 and 35 to 44 age groups experienced increases in HHD-related crude mortality rates through 2021, followed by a nonsignificant decline through 2024. In contrast, individuals aged 15 to 24 years experienced increasing HHD-related mortality until 2021, followed by a statistically significant decline between 2021 and 2024, with (APC: −13.9%, 95% CI: −29.81 to −4.86). HHD-related mortality rates stratified by age group are displayed in Figure 3 .

Trends in crude HHD‐related mortality rates among adults aged 15 to 44 years, stratified by 10-year age-groups in the United States, 1999 to 2024. *Annual percent change (APC) is significantly different from 0 at α = 0.05.

A total of 1,066,386 cases of CVD-related mortality were identified among adults aged 15 to 44 during the study period. Overall proportionate HHD-related mortality increased from 3.8% in 1999 to 16.8% in 2024 (AAPC: 5.63%, 95% CI: 5.26–6.03); however was not uniform, and inflection points were identified in 2001 and 2010. A rapid rise from 1999 to 2001 (APC, 24.4%; 95% CI: 15.29–31.07), followed by slower increases from 2001 to 2010 (APC, 6.3%; 95% CI: 5.24–7.37) and then another increase from 2010 to 2024 (APC, 2.8%; 95% CI: 2.17–3.22) was observed. Sex-stratified subgroup analyses were similar. Overall and sex-stratified annual CVD-related mortality frequency are summarized in Supplementary Table 7 , and overall and sex-stratified proportionate mortality trends are displayed in Figure 5 .

Overall and sex-stratified yearly trends in the proportionate mortality of HHD as a percentage of CVD deaths among adults aged 15 to 44, 1999 to 2024. *Annual percentage change (APC) is significantly different from 0 at α = 0.05.

HHD-related mortality among US adults aged 15 to 44 years increased substantially from 1999 to 2024, rising by 385.3% over the 25-year period, Table 1 . The long-term rise was further amplified during the COVID-19 pandemic, with HHD-related mortality increasing by 30.7% between 2019 and 2021. HHD mortality in 2024 remained 24.7% higher than prepandemic levels. By sex, HHD mortality rates among men were 21.9% higher postpandemic than prepandemic, while HHD mortality rates were 27.8% greater postpandemic compared to prepandemic levels among women. Stratified by race and ethnicity, HHD mortality in non-Hispanic Whites increased 28.1% during the pandemic peak and remained 22.9% higher postpandemic relative to prepandemic levels. HHD mortality among Hispanic/Latinos rose 29.9% during the pandemic, and postpandemic mortality rates were 35.1% greater than prepandemic levels. Non-Hispanic American Indian or Alaska Native, non-Hispanic Black, and non-Hispanic Asian American or Pacific Islander populations experienced similar trends, though with smaller relative changes. Findings stratified by age group and US Census region are also displayed in Table 1 .

Table 1

Percent Changes in HHD-Related Mortality Among Adults Aged 15 to 44 Years in the United States, Comparing 1999 Baseline, Peak Pandemic, and Postpandemic Periods

	1999 (95% CI) AAMRs	2019 Prepandemic (95% CI) AAMRs	2021 Peak Pandemic (95% CI) AAMRs	2024 Postpandemic (95% CI) AAMRs	% Change Since 1999	% Change Peak Versus Prepandemic	% Change Post- Versus Prepandemic
Overall HHD	1.29 (1.23–1.36)	5.02 (4.89–5.15)	6.56 (6.42–6.71)	6.26 (6.12–6.40)	+385.27%	+30.68%	+24.70%
Sex
Female	0.76 (0.69–0.83)	2.59 (2.46–2.72)	3.49 (3.34–3.64)	3.31 (3.17–3.46)	+335.53%	+34.75%	+27.80%
Male	1.76 (1.65–1.86)	7.49 (7.27–7.71)	9.57 (9.32–9.81)	9.13 (8.89–9.37)	+418.75%	+27.77%	+21.88%
Race/ethnicity
Non-Hispanic White	0.83 (0.76–0.89)	4.49 (4.33–4.65)	5.75 (5.57–5.93)	5.52 (5.34–5.69)	+565.06%	+28.06%	+22.94%
Non-Hispanic Black	4.53 (4.19–4.86)	11.64 (11.11–12.17)	15.61 (14.99–16.22)	14.34 (13.76–14.93)	+216.78%	+34.11%	+23.20%
Non-Hispanic Asian or Pacific Islander	0.53 (0.35–0.78)	1.74 (1.47–2.02)	2.35 (2.04–2.67)	2.32 (2.01–2.63)	+337.74%	+35.06%	+33.33%
Non-Hispanic American Indian or Alaska Native	—	12.27 (10.08–14.46)	17.84 (15.08–20.60)	15.95 (13.36–18.54)	—	+45.40%	+29.99%
Hispanic or Latino	0.79 (0.64–0.94)	3.25 (3.03–3.48)	4.22 (3.97–4.47)	4.39 (4.14–4.64)	+455.70%	+29.85%	+35.08%
Age group
15–24 years	0.12 (0.09–0.16)	0.32 (0.26–0.37)	0.44 (0.38–0.51)	0.28 (0.23–0.33)	+133.33%	+37.50%	−12.50%
25–34 years	0.65 (0.57–0.73)	2.83 (2.68–2.99)	3.67 (3.49–3.84)	3.36 (3.20–3.53)	+416.92%	+29.68%	+18.72%
35–44 years	2.75 (2.60–2.90)	10.94 (10.62–11.26)	14.19 (13.83–14.54)	13.83 (13.48–14.17)	+403.27%	+29.72%	+26.39%
Census region
Northeast	1.12 (0.98–1.25)	4.49 (4.33–4.65)	5.75 (5.57–5.93)	5.12 (4.81–5.43)	+357.14%	+28.06%	+14.02%
Midwest	1.30 (1.17–1.43)	4.91 (4.68–5.14)	5.75 (5.57–5.93)	5.72 (5.42–6.02)	+340.00%	+17.10%	+16.50%
South	1.50 (1.39–1.62)	5.99 (5.76–6.22)	8.77 (8.50–9.04)	7.72 (7.47–7.97)	+414.67%	+46.42%	+28.79%
West	0.94 (0.82–1.05)	3.63 (3.41–3.85)	5.01 (4.76–5.26)	5.26 (5.00–5.51)	+459.57%	+38.01%	+44.90%
Proportionate HHD deaths versus CVD (%)	3.77%	12.27%	16.37%	16.78%	+345.35%	+33.47%	+36.73%
Proportionate HHD deaths versus CVD (%)—Female	3.08%	9.25%	11.94%	12.44%	+303.90%	+29.19%	+34.51%
Proportionate HHD deaths versus CVD (%)—Male	4.17%	13.55%	18.04%	19.12%	+358.75%	+33.10%	+41.12%

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