Telomeres, composed of tandem repetitive DNA sequences at eukaryotic chromosome termini, are essential for maintaining genomic stability and integrity during cell division [1, 2]. Accumulating evidence suggests that telomere lengths act as a dependable biomarker of cellular aging, serving as a mitotic clock reflecting cell division history [3, 4, 5]. Telomere length is influenced by various factors, such as age, sex, diseases, genetic variation, physiological stress, and lifestyle [6, 7]. Notably, telomere length is inversely correlated with age, and its shortening can lead to chromosomal end instability and genetic information loss [8, 9, 10].

Despite continuous efforts, cardiovascular disease (CVD) remains a major cause of mortality globally, with it responsible for 32% of deaths worldwide in 2019 [11]. Inflammation and oxidative stress have been well demonstrated as primary contributors to CVD [12, 13, 14]. Telomere shortening may exacerbate oxidative stress, leading to DNA damage, inflammation, and cellular dysfunction [15, 16, 17].

In epidemiological studies, peripheral leukocyte DNA is widely used to measure telomere length owing to the simplicity of blood sample collections [4]. Emerging research indicates that reduced leukocyte telomere length (LTL) is significantly associated with elevated mortality risk in the general population [18, 19, 20]. A study examining the general U.S. population revealed an inverse relationship between LTL and the risk of CVD [21]. Moreover, a meta-analysis has drawn attention to the link between shortened LTL and increased all-cause mortality across a broader population [22]. Recently, Xiong et al. [23] reported increased rates of both all-cause and CVD-related death in metabolic syndrome patients who exhibited shorter LTLs. However, the relationship between the LTL and specific outcomes for CVD patients remains uncertain. Accordingly, we explore the association between LTL and both all-cause and CVD-specific death among CVD patients in this study.

Telomeres shorten with each cell division, eventually becoming critically short and fragile after numerous divisions [3, 38]. LTL serves as a biomarker, indicative of the overall telomere length in an organism. CVD encompasses a spectrum of heart and blood vessel disorders, including hypertension, atherosclerosis, myocardial infarction, and so forth [11], and it remains a major cause of mortality from non-communicable diseases [39].

In our investigation, which included 1599 CVD patients from the 1999 to 2002 NHANES, we examined the relationship between LTL and the prognosis of CVD. Notably, individuals in the low LTL group displayed an increased all-cause death than those in the high LTL group. Kaplan–Meier curve analyses revealed a marked difference in all-cause mortality across LTL tertiles (log-rank p 0.001). To delve deeper into the impact of LTL on all-cause mortality, we employed adjusted Cox regression to assess the association of LTL (as a continuous and categorical variable) with the risk of all-cause mortality. As a continuous variable, LTL was associated with an adjusted HR of 1.25 (95% CI, 1.05–1.48). The lowest LTL group (T1) had a significantly higher risk compared to the highest group (T3), with HR values of 1.29 (95% CI, 1.03–1.62). The RCS analysis indicated a linear dose-response relationship between LTL and all-cause mortality, with increased mortality risk accompanying decreasing LTL. While LTL showed no significant association with CVD-specific death in the competing risk model, it remained significantly associated with non-CVD death (adjusted HR: 1.24; 95% CI, 1.02–1.51).

Numerous studies have examined the length of telomere and survival outcomes [19, 20, 40]. A recent meta-analysis involving 121,749 individuals found a short LTL correlated with increased all-cause mortality in the general population [22]. Schneider et al. [10] observed a similar association between shortened LTL and all-cause, circulatory, and respiratory mortality based on 472,432 participants from UK Biobank. Recently, Xiong et al. [23] observed increased all-cause and CVD-specific mortality in patients with metabolic syndrome who had shorter LTL. However, the specific association between LTL and mortality in patients with CVD needs to be clarified.

Our study corroborates these findings and extends them to individuals with CVD, demonstrating that shorter LTL is associated with higher all-cause mortality, even considering multiple demographic and clinical factors. The long follow-up of our study highlights the important role of LTL as a prognostic biomarker in clinical practice, particularly for identifying high-risk groups among CVD patients.

Interestingly, our findings regarding CVD-specific mortality align with several previous studies [41, 42, 43] in demonstrating no significant association between LTL and cardiovascular mortality risk. Mons et al. [41] reported no correlation between telomere length and CVD-specific death in 12,199 participants from two population-based prospective cohort studies. In contrast, Xiong et al. [23] revealed that LTL was independently associated with CVD-specific mortality. This discrepancy between studies may stem from several factors. It should be noted that oxidative stress plays a critical role in telomere shortening and potentially impacts our findings. Oxidative stress leads to oxidative DNA damage, including telomere attrition, which is a key factor in aging and the pathogenesis of various diseases, including CVD [14, 44]. However, our research adjusted for multiple covariates that influence oxidative stress (e.g., age, sex, race, BMI, and lifestyle), although other potential covariates remain to be considered. Second, there is a discrepancy in the research population. Xiong et al. [23] focused on individuals with metabolic syndrome, whereas our study population comprised patients with CVD. Third, previous analysis employed the Cox regression model to examine cause-specific mortality, which may not adequately account for biases introduced by competing outcomes, potentially leading to overestimating the risk of CVD-specific death [23]. Our study utilized the competing risk regression, which sets non-cardiovascular death as a competing event, potentially providing a more accurate assessment of cardiovascular mortality risk. These findings indicate the complexity of telomere biology and its implications for disease. Therefore, additional research is necessary to clarify the relationship between LTL and cause-specific mortality. This could involve more extensive studies with diverse populations and methodologies, ensuring a comprehensive understanding of how LTL influences mortality risks in various contexts of cardiovascular health.

Moreover, our research found that LTL is inversely related to all-cause death in female patients with CVD, which was not observed in males. Males and females often experience varying aging rates, leading to differences in life expectancy between genders [45]. Females possess, on average, longer telomeres and a higher life expectancy than males of equivalent age [9, 45]. In humans, males live shorter lives and experience more rapid telomere shortening, leading to speculation in medical research that gender-specific telomere reduction might be a contributing factor to the differences in gender-specific death [45]. However, Xiong et al. [23] did not observe consistent results, and gender variables in subgroup analyses did not significantly alter the association between telomere length and risk of all-cause or CVD-specific death. Apart from the difference in the study population, their neglect of weighted study design is another possible cause, potentially leading to a conclusion containing selection bias.

Despite the novel perspectives on LTL and the prognosis of CVD, the limitations of this study should be mentioned. Firstly, while comprehensive, focusing on a nationally representative sample from the United States does not account for variations in physical activity, dietary, genetic factors, and other potential covariates. Moreover, the generalizability of our conclusion to populations in different regions, such as China and Europe, still needs to be determined due to the lack of representative data from these areas. These limitations suggest that more research should be performed to validate and expand our findings, ideally incorporating more diverse and global populations and a broader range of covariates.

Our study demonstrates that telomere length is inversely related to all-cause mortality in individuals with CVD. This finding reveals that shorter LTL correlates with an elevated mortality risk from all causes. However, this relationship does not relate to CVD-specific mortality. The significant link between reduced LTL and all-cause death underlines the importance of considering telomere length as a biomarker in managing CVD. By identifying patients with shorter LTLs, healthcare providers can potentially implement more targeted interventions and monitoring strategies, aiming to improve overall outcomes and reduce mortality risks in individuals with CVD.

All the data used in this study were acquired from the NHANES survey (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx).

JYS, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing — original draft, Writing — review & editing. QX, Formal analysis, Validation, Writing — review & editing. HS, Formal analysis, Methodology, Validation, Writing — original draft, Writing — review & editing. WH, Validation, Writing — review & editing. QQ, Methodology, Validation, Writing — original draft, Writing — review & editing. WS, Formal analysis, Investigation, Methodology, Project administration, Validation,Visualization, Supervision, Writing — original draft, Writing — review & editing. XQK, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Supervision, Writing — original draft, Writing — review & editing. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This research has been conducted using the National Health and Nutrition Examination Survey (https://www.cdc.gov/nchs/nhanes/index.htm). The ethical approval number is Protocol #98-12. This research was approved by the Ethics Review Committee of the National Center and was performed following the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants gave written informed consent.

We sincerely acknowledge the US National Center for Health Statistics for conducting the survey.

This work was supported by the National Key Research and Development Program of China (2019YFA0210104).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/j.rcm2509333.