Cardiovascular Death and Liver Disease: Mortality Trends and Disparities

• Cardiovascular
• Disparities
• Epidemiology
• Liver
• Mortality

Editor – Individuals with liver disease are at a higher risk of developing cardiovascular disease (CVD), leading to increased morbidity and mortality.¹ Many risk factors for liver disease and CVD are shared.¹ Furthermore, heart failure can heighten the risk of liver vascular congestion, liver fibrosis, and create a cycle of worsening cardiac preload and congestion due to liver fibrosis.¹ Despite this, there is currently limited information available regarding cardiovascular death trends and disparities in patients with liver disease. It remains unclear whether liver disease impacts cardiovascular health more severely in certain populations. Epidemiological insights from population-level data provide valuable information for developing targeted interventions and mitigating healthcare disparities. Therefore, this study aimed to explore trends in CVD-related mortality among individuals with liver disease.

All data were obtained from the Centers for Disease Control and Prevention’s (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database using death certificate information.² All CVD-related mortality (ICD10 codes: I00–I78) as the underlying cause of death with liver disease (ICD-10 codes displayed in Table 1) as the multiple causes of death were queried from 1999 to 2020.³ On death certificates, the underlying cause of death was defined as the disease process that directly led to death or initiated the sequence of events that led to death, and the multiple causes of death were defined as the diseases that contributed to death. All decedents that included both of these ICD-10 codes were included in our analysis. Decedents that included only one of these two ICD-10 codes were excluded. Age below 35 years were excluded given likelihood of congenital heart disease. Quantified measures included age-adjusted mortality rate (AAMR), average annual percentage change (AAPC), and 95% confidence intervals (CI). The AAMR was calculated by utilizing the direct method with the US population in the year 2000 set as the standard group. Subgroup analyses included gender, race, and geographic information. To analyze the trends in CVD-related mortality in individuals with liver disease, we utilized joinpoint regression (National Cancer Institute) to fit log-linear regression models to yearly AAMRs. We then used the Monte Carlo Permutation test to calculate weight averages of yearly average percentage changes, resulting in the AAPC. A two-tailed P value of <0.05 was considered statistically significant. Data analysis/visualization was completed using Stata software (Release 17.0). As the data used in this study are publicly available and deidentified, institutional review board approval was not required.

We observed a total of 201,015 deaths (Figure 1). AAMR increased from 1999 (5.62 [95% CI, 5.50 – 5.74]) to 2020 (6.29 [95% CI, 6.18 – 6.40]) with an AAPC of +0.5% (95% CI, 0.1 – 0.9; P = 0.027). AAMR in males (7.66 [95% CI, 7.61 – 7.70]) was higher compared to females (3.28 [95% CI, 3.25 – 3.30]) with a similar AAPC (Males: 0.3% [95% CI, −0.1 – 0.8]; P = 0.186 and Females: 0.1% [95% CI, −0.3 – 0.6]; P = 0.530).

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Figure 1.

Trends in AAMR, 1999 - 2020. (A) All (B) Gender (C) Hispanic/Non-Hispanic (D) Race (E) Urbanization (F) US Census Regions (Abbreviations: AAMR, age-adjusted mortality rates; US, United States).

Higher mortality rates were observed among Hispanic populations (6.22 [95% CI, 6.13 – 6.31]) compared to non-Hispanic populations (5.22 [95% CI, 5.19 – 5.24]); however, the AAPCs were similar (Hispanic: −0.7% [95% CI, −1.3 – −0.1]; P = 0.022 and non-Hispanic: 0.6% [95% CI, −0.1 – 1.3]; P = 0.106). American Indian/Alaska Native adults (7.82 [95% CI, 7.50 – 8.14]) had the highest AAMR, followed by Black adults (6.90 [95% CI, 6.81 – 6.98]), White adults (5.13 [95% CI, 5.11 – 5.16]), and Asian/Pacific Islander adults (3.61 [95% CI, 3.51 – 3.71]). AAPC accelerated between 1999 and 2020 among White (+0.6% [95% CI, 0.1 – 1.1]; P = 0.017) and American Indian/Alaska Native adults (+1.2% [95% CI, −0.5 – 3.0]; P = 0.174) and decelerated among Asian/Pacific Islander (−2.1% [95% CI, −3.1 – −1.2]; P < 0.001) and Black adults (−0.4% [95% CI, −1.2 – 0.4]; P = 0.352).

Non-metropolitan regions (5.45 [95% CI, 5.39 – 5.51]) had higher AAMR compared to metropolitan regions (5.25 [95% CI, 5.23 – 5.28]). A higher AAPC was seen in non-metropolitan regions (+1.5% [95% CI, 1.1 – 1.9]; P < 0.001) compared to metropolitan regions (0.2% [95% CI, −0.3 – 0.6]; P = 0.534). A higher AAMR was observed among Western regions (6.41 [95% CI, 6.36 – 6.47]) and Southern regions (5.31 [95% CI, 5.28 – 5.35]) compared to Midwest (4.66 [95% CI, 4.61 – 4.71]) and Northeast (4.63 [95% CI, 4.58 – 4.67]) regions. AAPC accelerated in Southern (+1.0% [95% CI, 0.5 – 1.6]; P < 0.001) and Midwestern (+0.8% [95% CI, −0.0 – 1.5]; P = 0.051) regions and decelerated in Western (−0.2% [95% CI, −0.6 – 0.2]; P = 0.391) and Northeastern (−1.0% [95% CI, −1.5 – −0.5]; P < 0.001) regions.

Our analysis found CVD-related mortality in the setting of liver disease has increased between 1999 and 2020, disproportionally affecting certain gender, racial, and geographic subgroups in the US. To our knowledge, we provide the first report of real-world data encompassing a comprehensive overview of mortality and disparities related to CVD-mortality in individuals with liver disease.

Despite the advancements in both cardiovascular and liver disease management, cardiovascular death remains a leading cause of mortality in patients with underlying liver disease. This is likely due to many shared risk factors, including hepatic necroinflammation, insulin resistance, and atherogenic dyslipidemia, all of which contribute to the progression of CVD.¹ Liver disease is also associated with impaired flow-mediated vasodilatation and an increase in intimal medial thickness, both of which are reliable markers for subclinical atherosclerosis.^4-7 There are also socioeconomic and cultural barriers that contribute to the racial heterogeneity in mortality rates.⁸ In addition, the higher mortality among male populations is likely attributable to the prevalence of sex-related susceptibilities and risk factors such as metabolic syndrome, alcohol use, and injection drug use.⁸ Finally, geographical disparities in mortality rates are a result of accessibility to treatment, health-literacy, and socio-economic factors.⁹

Limitations to our findings include the use of death certificates to identify causes of mortality, which subjects our study to misclassification. Given the use of ICD-10 codes to identify relevant deaths, there is a possibility of overestimating or missing CVD deaths related to liver diseases. Additionally, we are unable to adjust for co-variates other than age. Lastly, given the cross-sectional design of our analysis, we were unable to establish causality. Longitudinal studies are warranted to understand the unique factors contributing to CVD death disparities in populations with liver disease.

In conclusion, CVD remains a significant cause of mortality among patients with underlying liver disease. Our study identified notable differences in CVD-related mortality across various gender, racial, and geographic subpopulations with liver disease. These findings necessitate further investigation through prospective analyses to validate our results and identify the underlying contributors to these disparities. Additionally, efforts to develop targeted interventions are crucial to promote healthcare equity and reduce cardiovascular disease-related disparities.

• Received April 7, 2023.
• Revision received June 23, 2024.
• Accepted July 1, 2024.