Telomere length and cardiovascular mortality: a multistate competing risk analysis

Background Cardiovascular disease (CVD) is the leading cause of mortality in the United States, with substantial economic and health impacts. While traditional risk factors are well studied, non-traditional factors like telomere length (TL), have garnered interest due to mixed findings on their association with CVD-specific mortality. This study investigates the association between TL and CVD-specific mortality, accounting for non-CVD-specific mortality as a competing risk, using a multistate framework.

We conducted a retrospective cohort study using data from the National Health and Nutrition Examination Survey 1999-2002 and 2019 Linked Mortality Files. This study included 6,516 non-institutionalized adults aged 25 years or older. TL was measured using quantitative PCR and analyzed continuously and categorically. We employed a multistate model to evaluate transitions from an event-free state to CVD-specific and non-CVD-specific mortality, estimating cause-specific hazard ratios (HRs) adjusted for sociodemographic and health risk factors.

The cumulative incidence function for CVD-specific mortality was significantly higher in the lowest TL quartile than in the highest quartile (Gray test, p < 0.01). Gray’s test was used to compare CIFs across quartiles without applying a Fine and Gray model. We found that a shorter TL was associated with a higher risk of CVD-specific mortality. In the adjusted model, each unit decrease in TL was associated with a 57% higher rate of CVD-specific mortality (HR: 1.57, 95% CI: 1.24-1.98). Adults in the shortest TL quartile had an 88% higher rate of CVD-specific mortality compared with those in the longest TL quartile (HR: 1.88, 95% CI: 1.29-2.72).

Our findings suggest a significant inverse association between TL and CVD-specific mortality, highlighting TL as a potential biomarker for CVD risk. The use of a multistate framework provides a comprehensive understanding of competing risks and enhances the robustness of our results. Further studies are needed to validate these findings and explore the underlying mechanisms. Competing Interest Statement The authors have declared no competing interest. Clinical Trial Not Applicable Funding Statement No funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study used publicly available, de-identified data from the National Health and Nutrition Examination Survey (NHANES); therefore, ethical approval was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability This study used publicly available de-identified data- National Health and Nutrition Examination Survey (NHANES), and 2019 Public-use Linked Mortality Files