Can telomere length be used as a biomarker for cardiovascular diseases? Insights from a large clinical study

Cardiovascular diseases (CVDs) remain among the leading causes of death worldwide. An accurate identification of individuals who are at risk of a cardiovascular event plays a critical role in successful preventative intervention. Traditionally, risk prediction has relied on the assessment of factors such as age, sex, hypertension, hyperlipidaemia, diabetes mellitus and smoking history. However, these traditional risk factors do not identify everyone at risk of a cardiovascular event. Thus, there is a need for new ways to improve cardiovascular risk stratification. Vascular stiffness, a common consequence of elastin degradation in artery walls, is a hallmark of vascular ageing and is commonly used as an age-related index of cardiovascular health. Increased vascular stiffness has been found to positively associate with many CVD risk factors, such as arterial cholesterol and high glucose levels, and has been suggested to be the primary cause of several CVD events including stroke and myocardial infarction. Clinical assessment of vascular stiffness is made possible by determining aortic pulse wave velocity (aPWV), which represents the rate of pulse waves travelling down the aorta. A low aPWV is typically associated with reduced CVD risk, whereas a high aPWV is associated with increased CVD risk (Safar et al. 2003). Over the past decade, the potential use of new biomarkers with traditional cardiovascular risk factors has emerged. Chief among these is the measure of telomere length (TL) in leukocytes. Telomeres are protein-complexed tandem DNA repeat sequences that reside at the ends of each chromosome to provide genetic stability. Progressive shortening of telomeres over time is known to be a consequence of DNA replication in cell division, and the change in their length has been used as a common indicator for cellular senescence and ageing (Blasco, 2005). Interestingly, mounting evidence in the literature suggests TL may be associated with CVD and its risk factors; however, characterization of this link remains obscure. Thus, expanding our knowledge about the potential biomarker and clinical value of TL in CVDs will provide significant insights into risk prediction and prevention of CVDs. In a recent article by McDonnell et al. (2017) in The Journal of Physiology, a cross-sectional clinical study was conducted to investigate the association between vascular stiffness and telomere length (TL) by using aPWV as an indicator for measuring vascular health, which is a gold-standard measure of arterial stiffness (Laurent et al. 2006). This study was designed in part to address the unclear cumulative results of several previously published studies. While Wang et al. (2011) found an inverse correlation between the length of DNA telomeres and the degree of vascular stiffness, Bekaert et al. (2007) found no significant associations between TL and CVD risk factors in middle-aged adults. To account for this discrepancy, McDonnell and his colleagues took an approach of examining TL and vascular stiffness among a thousand healthy participants free of any existing CVDs, selected from two age extreme (younger, <30 years, and older, >50 years) and aPWV extreme (upper or lower 15%) categories of the Anglo-Cardiff Collaborative Trial. Participants from each of these groups were assessed for leukocyte TL, as well as confounding physiological factors (i.e. sex, BMI and blood pressure). The key finding of this work is that ageing is a critical factor that modifies the association between TL and vascular stiffness. According to the data, TL is inversely correlated with aPWV in younger individuals, suggesting that shortening of DNA telomeres is associated with increased vascular stiffness. However, the opposite result is observed in older individuals. This is the first direct evidence to suggest that the association between TL and vascular stiffness is age group dependent. The work presented by McDonnell and colleagues is informative and prompts studies to take account of the complexity of cellular and vascular ageing interaction over the whole life course. It complements the works of Benetos et al. (2001), who also previously demonstrated the complex cellular and vascular ageing interaction but between sexes instead of age groups. They showed that TL was inversely correlated with age in both sexes, but TL significantly contributed to aPWV only in males. In contrast to this finding, Raymond et al. (2015) demonstrated that TL does not differ by sex. They showed that TL was inversely correlated with age in both males and females, and in both premenopausal and postmenopausal females. Therefore, due to the discrepancy found in these studies, it would be interesting to study the association of TL and CVDs between age, sex and other cardiovascular risk factors using different means of vascular health measurement. As an example, flow-mediated dilatation (FMD) assessed by ultrasound is a clinically non-invasive method to examine vascular endothelial function (Inaba et al. 2010). It is measured by brachial artery diameter changes after increase in shear stress induced by reactive hyperaemia. Impairment of brachial FMD is significantly associated with future cardiovascular events (Ras et al. 2013) and a strong correlation has been found between aPWV and FMD (Jadhav & Kadam, 2005). Therefore, replicating results demonstrating the association of vascular function and leukocyte TL by using FMD as an indicator for measuring vascular health would further support the usage of TL as a potential biomarker for CVDs. Furthermore, while the authors were successful in correlating telomere length to aPWV in each age group, they acknowledged that the cross-sectional and retrospective nature of this study prevented them from quantifying telomerase activity in the participants. Such data would provide a clearer picture of how dynamic telomere regulation plays into the observed correlations, particularly in the younger age group where age-associated and environmental factors may be assumed to have a lower contribution. In lieu of a telomerase assay, an alternative approach might be to screen for genetic mutations or allelic variation in the telomerase genes. Dai et al. (2015) screened for mutations in both telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) in patients with idiopathic pulmonary fibrosis, which is known to arise from extensive telomere loss. Six novel mutations were identified and patients with these exhibited shorter telomeres relative to the non-mutant patients. Using DNA samples from the present study, it would be insightful to determine whether there is a higher incidence of TERT and/or TERC mutations in young participants with high aPWV relative to those with low aPWV. In order to quantify telomere length, McDonnell and his colleagues performed qPCR on DNA extracted from participant leukocytes and calculated the ratio of telomere signal to the signal obtained from a single-copy standard gene. As the authors themselves pointed out, it remains unclear from previous studies whether leukocyte telomere length tends to correlate with that of aortic tissue. It would thus be of particular value to perform a similar comparison between aPWV and aortic telomere length, while taking advantage of the relatively large sample size and confounding factor data from this study. In conclusion, McDonnell et al. (2017) have provided a novel hypothesis that cardiovascular health may be evaluated by an age group-dependent association between TL and aPWV. Such age group dependency reveals the complexity of cellular and vascular ageing interaction, which raises the big question of whether TL is a suitable biomarker for CVDs. The direct measurement of TL and aPWV in a large population is a definite strength. However, in order to increase knowledge about the biomarker value of TL in CVDs in all age groups, these novel findings need to be substantiated with further studies. As discussed, these may assess the association between mutations in telomerase genes and aPWV or consider other means of vascular stiffness measurement. Ultimately, further characterization and consideration of patient age as a factor in how TL and CVDs are associated will prove useful in assessing the strength of TL as a biomarker for CVDs. None declared. The authors contributed equally to the article. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. SH.L. is supported by a SickKids Hospital Research Training Competition (Restracomp) Award and a University of Toronto Open Fellowship Award from the Department of Molecular Genetics. N.G. is supported by a Canada Graduate Scholarships-Canadian Institutes of Health Research Master's Award.

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