Cardiovascular disease (CVD) is the leading cause of death in the United States, comprising 26.9% of annual mortality across all age groups (1). Sepsis contributes to at least 1.7 million hospitalizations of US adults each year, and conservative estimates place the cost of sepsis to the US healthcare system at $62 billion annually (2, 3). Concerningly, despite heightened attention to the mortality burden of sepsis, mortality rates in people aged 65 and over crept upwards from 277 per 100,000 in 2019 to 331 per 100,000 in 2021 (4, 5). Septic patients with cardiovascular dysfunction have been shown to have an increased mortality rate of 70%–90%, as opposed to 20% in those without cardiovascular impairment (6). Sepsis has also been shown to increase the likelihood of atherosclerotic and nonatherosclerotic cardiovascular events—both in-hospital and after hospital discharge—increasing the risk of mortality of sepsis patients (7–9). Though the precise pathophysiology of myocardial dysfunction in sepsis remains unclear, hemodynamic compromise and cytokine release are known to play a role in myocardial depression and ischemia (10–12).

With the COVID-19 pandemic came an acute rise in cardiovascular disease-related deaths, from 874,613 in 2019 to 928,741 in 2020 (13). The pandemic is thought to have increased CVD mortality due to the implications of viral infection and its effect on healthcare delivery as a whole. At the same time, sepsis-related deaths increased by nearly 36,000 beyond the expected rise in 2020 (14). Given the pathophysiological interplay between CVD and sepsis, it is crucial to determine the difference in the mortality rates for various demographic (i.e., racial and ethnic groups, gender, and age groups) and regional groups, long-term mortality trends, and how the recent COVID-19 pandemic has impacted these trends. Hence, to further understand these differences, we utilized the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) national database to analyze the death records of patients with both CVD and sepsis-related mortality in the United States from 1999 to 2022.

From 1999 to 2022, there were a total of 33,836,679 deaths related to CVD, 4,019,524 deaths related to sepsis, and 1,842,641 deaths with both cardiovascular disease and sepsis listed as a cause of death. Of these, 935,073 (50.74%) were men and 907,568 (49.25%) were women. 1,328,867 deaths (72.12%) were in Non-Hispanic (NH) White adults, 289,271 (15.70%) were NH Black adults, 151,793(8.24%) were Hispanic adults, and 11,873 (0.64%) were NH American Indian or Alaskan Native adults. 346,165 (18.79%) of the deaths were in middle-aged adults (45–64 years old) and 1,496,476 (81.21%) were in elderly adults (65+ years old).

Overall, there was a significant decline in mortality due to CVD from AAMR of 1,432.56 in 1999 to 1191.99 in 2022 (AAPC −0.58%, 95% CI: −0.87% to −0.34%). During this time, AAMR for CVD initially declined between 1999 and 2011 (APC −2.46*% 95% CI: −4.19% to −1.94%), then stayed stable from 2011 to 2019 (APC −0.09%, 95% CI: −1.97% to 1.57%) and finally increased from 2019 to 2022 (APC 4.36*%, 95% CI: 2.15%–8.32%) (Figure 1). Compared to that, the AAMR of Sepsis stayed stable from 136.54 in 1999 to 134.04 in 2019 and then significantly increased to 172.15 by 2021 (APC 4.85*%, 95% CI: 1.44% to 9.55%) (Figure 1).

Sepsis-related CVD mortality decreased between 1999 and 2013, from an AAMR of 65.71 in 1999 to 58.79 in 2013 (APC −1.02*%, 95% CI: −2.13% to −0.33%) (Figure 2). AAMR then rose to 74.33 in 2022 (APC 3.14*%, 95% CI: 2.01%–5.40%) (Figure 2).

Our analysis of 23 years of mortality data collected from the CDC demonstrates the increased AAMR from sepsis-associated cardiovascular disease following the COVID-19 pandemic. The study of mortality data concluded that males had a higher sepsis-associated CVD mortality than females. NH Black adults had the highest mortality rates throughout the study period as compared to all other races, and elderly adults over the age of 65 years had the highest mortality amongst all age groups. Out of the geographical regions, the Northeast was the only region to see a decline in mortality over the study period. Oklahoma was the state with the greatest increase in AAMR from 1999 to 2019, while Mississippi had the greatest increase in AAMR from 2019 to 2021.

From 1999 to 2013, AAMR declined at a relatively stable rate for both men and women, after which it began to rise slowly before drastically increasing in 2019 with the onset of the pandemic. The massive jump in AAMR at the onset of the pandemic can be attributed to the burden of the pandemic on CVD, sepsis, and limited healthcare system accessibility, which led to delays in diagnosis and treatment. Infection with SARS-CoV2 leads to an increase in myocardial injury, both in patients with and without pre-existing cardiovascular disease (15, 16). The SARS-CoV2 virus also increases proinflammatory cytokines and chemokines, unleashing a cytokine storm in the infected individual that can lead to multiple organ dysfunction (17, 18). Additionally, immunosuppression in the form of lymphopenia is implicated in severe COVID-19 and contributes to a dysregulated immune response and, ultimately, sepsis (19). Pathophysiology aside, the pandemic led to delays in outpatient healthcare access for patients with cardiovascular disease, increased rates of hospital avoidance, and fewer hospital admissions for those patients as resources were directed toward patients with acute infection (20–22).

With respect to gender, a similar pattern to overall mortality—a gentle decline in AAMR followed by a subsequent increase with the onset of the COVID-19 pandemic—is evident in both men and women during this period. Pandemic-era spikes are clearly present for both men and women, just as in the overall dataset. Male mortality remained consistently higher than female mortality throughout all the years encompassed in our analysis. Prior research indicates higher male sepsis-associated CVD mortality may be attributed to the higher risk of bloodstream infections in men, and to the higher rate of cardiovascular disease in men (23–25). In fact, it has been demonstrated that elevated mortality in men from bloodstream infections is at least partly mediated by cardiovascular risk factors (24).

We also identified racial disparities in AAMR, with non-Hispanic Black adults having the highest AAMR before and during the pandemic, as compared to NH White, Hispanic, and NH American Indian or Alaskan Native adults. In 1999, NH Black adults had an AAMR nearly twice as high as Hispanics and nearly triple that of White and American Indians or Alaskan Natives. In subsequent years, NH Black adults’ AAMR trended consistently downward until the beginning of the pandemic. These data trends align with those from prior studies of sepsis AAMR, which noted elevated mortality rates among Black adults but declining mortality in Black and Hispanic adults in the years before the COVID-19 pandemic (26). With the onset of the pandemic, AAMR in NH Black adults increased to a level such that the progress of decreasing AAMR over the previous 15 years was lost. The tangible impacts of the social determinants of health are evident in these disparities among Black adults. Higher incidence of comorbidities such as hypertension, diabetes, and asthma, and disparities in care access and outcomes, increase mortality related to CVD and sepsis in Black adults. Black adults were also found to be more likely to work high-risk frontline jobs during the pandemic that cannot be done remotely, and they are more likely to have limited access to healthcare and insurance (27).

The elderly population had a decreasing mortality trend compared to a stable trend for the middle-aged population before the COVID-19 pandemic. We found that the pandemic had a greater impact on the long-term trend for the elderly, with AAMR rising at double the rate of the middle-aged population during the pandemic years. Elderly adults have a greater susceptibility to infection by SARS-CoV2 due to their weaker immune defenses (28, 29). Elderly adults are also more likely to develop tissue damage from infection because of increased cytokine release due to COVID-19. When compared to middle-aged adults, elderly adults generally have more existing health conditions that increase the risk of CVD and sepsis-related mortality (29, 30).

Our investigation of state-level change in sepsis-associated CVD AAMR unearths the undeniable impact of the COVID-19 pandemic on mortality nationwide for patients with sepsis-associated cardiovascular disease. A moment's glance at the maps of AAMR from 1999 to 2019 and from 2019 to 2021 reveals the dramatic jump in mortality in all but three Northeastern states (Figures 6a,b). The near-even split from 1999 to 2019—with AAMR dropping in half of the states while rising in the other half—is disrupted during the three-year period encompassing the COVID-19 pandemic. Mapping and color-coding the AAMR data, as we have done, allows for further inspection of regional variation in AAMR change. Between 1999 and 2019, it appears that states with declining AAMRs are in the Northeast, Mid-Atlantic, and Southeast; all but five of these twenty-five states, as well as the District of Columbia (AAMR change of −84.61), are situated east of the Mississippi River. On this same map, the states with the most drastic sepsis-associated CVD AAMR increases are primarily clustered in the Midwest and Northwest. These geographic trends are upended in the map of AAMR change from 2019 to 2021, where all but three Northeastern states experienced a jump in AAMR. Seven of the ten states with the largest AAMR increases during this period—all but Wyoming (AAMR change of 39.99), California (27.42), and Delaware (24.57)—are located in the South Census Region (as classified by the CDC Wonder Multiple Cause of Death 1999–2020 dataset) (31). These findings align with prior research, which found that in the first full year of the pandemic, non-COVID-19 mortality in the Northeast increased less than would be expected given the concurrent COVID-19 mortality in those states (32). That same research, which also utilized the CDC WONDER database, found a greater-than-expected increase in non-COVID-19 mortality in the South census region.

Pandemic-era sepsis-associated CVD mortality varies clearly from state to state, likely due to varying levels of change in COVID-19 and non-COVID-19 mortality between states. Much media attention and scientific inquiry have been directed at state-level discrepancies in mortality during the pandemic. Research has linked statewide COVID-19 mortality rates with mean years of education, poverty rates, and healthcare access, factors which vary widely between US states (33). Links have also been drawn between COVID-19 mortality and levels of interpersonal trust, vaccination rates, vaccine allocation, and state-mandated lockdowns (33–36). Political partisanship (gauged by votes cast in the 2020 presidential election) and the urban-rural vaccination divide (although perhaps more applicable on a county level rather than a state level) are two additional factors which have been floated as underlying drivers of mortality discrepancies between states (33, 37, 38). Definitive conclusions will be challenging to draw. What appears certain is that the COVID-19 pandemic was accompanied by a substantial elevation in sepsis-associated CVD mortality in most states, even states that had seen declining mortality in the previous two decades.

This study provides valuable insight that can assist policy makers in improving healthcare interventions and shaping public health strategies. Identifying demographic disparities, such as the impact of race on sepsis-associated CVD mortality, highlights the importance of targeted interventions for vulnerable populations. Community health centers in underserved neighborhoods have been shown to increase access to healthcare and decrease poor heatlh outcomes (39, 40). By increasing funding for these centers, disadvantaged populations can have improved access to preventative healthcare, such as vaccinations, and more convienient access to treatment. Additionally, this disparities data can be used by policy makers to targeted regional improvements in healthcare equity. Expanding government insurance, such as Medicaid, as well as community-based efforts such as door-to-door vaccination education campaigns have the ability to increase coverage and health literacy across states with high mortality figures (33, 41). By integrating these findings into public health initiatives, policymakers can work to reduce health inequities, improve outcomes for patients with cardiovascular disease and sepsis, and build more resilient healthcare systems that are better equipped to manage future public health crises.

Sepsis-associated CVD mortality has seen an increase across the US over the past decade, with the COVID-19 pandemic further exacerbating this trend. Significant disparities in trends have persisted throughout, with the elderly, men, NH Black adults, and the Southern region being disproportionately affected by the pandemic. This increase in mortality rates from sepsis and cardiovascular diseases and the worsening of disparities highlight the gaps in the healthcare system and the demographic and regional differences in healthcare accessibility during periods of strain. These findings also demonstrate the interconnected nature of chronic health conditions, infectious diseases, and the social determinants of health. To improve outcomes in all population groups, healthcare strategies must be developed that increase health equity throughout the patient population, especially in the context of public health crises like the COVID-19 pandemic.