In this large prospective study of patients with stable CAD, we found that leukocyte telomere length is associated with mortality independently of chronological age, clinical factors, CRP, and echocardiographic variables. Additionally, we found no significant interactions between the use of cardioprotective medications and leukocyte telomere length for adverse outcomes.
Cawthon et al measured leukocyte telomere length in 143 healthy blood donors age 60–97 years, and found poorer survival in those with shorter telomeres, largely attributable to increased deaths from infection and cardiovascular disease (16
). However, two subsequent studies found that leukocyte telomere length was not associated with morbidity and mortality in very elderly individuals when chronological age was taken into account (22
). Our results support an independent association between telomere shortening and all-cause mortality, and extend these findings for the first time to a prospectively-studied cohort of patients with stable CAD. These observations support the hypothesis that, in CAD, leukocyte telomere length reflects biological aging and may integrate multiple genetic and environmental factors as a final common pathway of cellular stress. Several factors important in the pathogenesis and progression of atherosclerosis are known to accelerate telomere attrition. These include inflammation, oxidative stress, and endocrine aberrations (24
). Further basic and epidemiologic studies are needed to elucidate the underlying mechanisms of telomere attrition in this patient population.
Our results differ from prior studies in individuals at risk of atherosclerosis in that we observed no relationship between telomere length and CRP (26
). One possible explanation is that in the preclinical phase of disease, systemic inflammation promotes both atherogenesis and leukocyte telomere attrition. However, once CAD is established other genetic and environmental factors have greater influence in determining the rate of telomere shortening. Whether leukocyte telomere shortening contributes directly to the progression of CAD at the cellular and molecular level cannot be determined from our results.
We also found a significant inverse association between telomere length and hospitalization for heart failure. This finding provides prospective validation of a recent study by van der Harst et al which demonstrated shorter telomeres in patients with CHF compared with age-balanced controls (27
). In that study, telomere length was incrementally shorter in the presence of advanced disease and an ischemic etiology. Further studies are warranted to investigate the interplay between systemic inflammation, atherogenesis, telomere shortening, and heart failure.
Brouillette et al used a nested case-control approach in the West of Scotland Primary Prevention Study to show that the risk of developing CAD was highest in individuals with short telomeres, and that this risk was substantially attenuated by treatment with pravastatin (28
). By contrast, in the present study, we found no interaction between statin use and telomere length, and no difference in mean telomere length between users and non-users of statins. Prior studies have also shown an association between telomere attrition and obesity (9
). In contrast, we found lower body mass index in patients with shorter telomeres. The explanation for this discrepancy is unclear but suggests an inverse U-shaped relationship between BMI and telomere length. Among our study population, lower body mass index (and shorter telomere length) may be a marker of greater cardiovascular disease severity.
Among the strengths of the present study is the \measurement of multiple potential confounding variables including inflammatory markers and echocardiographic parameters of systolic and diastolic function. The study design allowed us to prospectively investigate the prognostic value of leukocyte telomere length in a large cohort of comprehensively-phenotyped patients with CAD. However, several limitations should be considered in the interpretation of our results. First, telomere length in leukocytes derived from peripheral blood sampling does not necessarily reflect alterations in telomere length and function in the atherosclerotic plaque or myocardium (30
). There are limited data to suggest general correlation between telomere length in leukocytes and other tissues. Although no studies have directly compared leukocyte telomere length with endothelial cell telomere length, there is evidence that telomere shortening contributes to endothelial cell senescence, and may be accelerated by oxidative stress (32
). Second, our results are derived from a single measurement of telomere length at the outset of a prospective cohort study. As such, we are unable to determine the rate of change of telomere length which would likely provide further insights into the significance of telomere attrition in this population (34
). Furthermore, a single measurement of leukocyte telomere length cannot distinguish between chronic low-level stressors and a highly-stressful single prior event. Third, we did not evaluate the impact of telomere-associated proteins such as telomerase on the prognostic value of leukocyte telomere length. Fourth, we are unable to account for inherited differences in leukocyte telomere length between individuals. However, recent evidence suggests that early telomerase activity may “homogenize” telomere lengths such that longer telomeres shorten more quickly than short telomeres. (35
). Finally, the question of whether telomere shortening is merely an epiphenomenon, or whether it plays an active role in the progression of coronary atherosclerosis, cannot be answered on the basis of our results (37
In summary, we found that leukocyte telomere length in peripheral blood leukocytes is associated with mortality among ambulatory individuals with stable CAD. The prognostic value of leukocyte telomere length in this population is not fully captured by existing clinical, inflammatory, and echocardiographic markers of increased risk. Future studies should be aimed at investigating the mechanisms and significance of the association between telomere length and adverse outcomes in patients with stable CAD.