Telomere Length Predictive of CHD Risk

January 12, 2007

January 12, 2007 (Leicester, UK) - The future risk of coronary heart disease events in middle-aged, high-risk men is correlated with the length of telomeres (the extreme ends of chromosomal DNA that shorten with age) in leukocytes, according to a new analysis of the West of Scotland Primary Prevention Study (WOSCOPS) [ 1]. The analysis, published in the January 13, 2007 issue of the Lancet, found that the risk of CHD events increased as telomeres shortened, but that this risk was substantially attenuated by pravastatin.

The authors, led by Dr Scott Brouilette (University of Leicester, UK), conclude that these findings could have important implications in helping to understand the pathophysiology of coronary heart disease and, in particular, the role of biological aging.

Senior author Prof Nilesh Samani (University of Leicester) told heartwire that this observation that shorter telomeres predict increased risk of CHD could be the factor that explains all the different causes of heart disease. "Many different things contribute toward heart disease. Several of these--genetics, oxidative stress (from smoking, obesity, lifestyle stress, etc), and rapid growth in early life--are all associated with shortening telomeres, and this could be the common link. Our findings support the hypothesis that differences in biological aging might contribute to the risk and variability in age of onset of coronary heart disease."

Could statins prevent aging?

As shortening telomeres are associated with aging of cells, the obvious implication is that this would affect many different aging processes. Samani commented to heartwire that it was not known if shortening of telomeres was involved in all diseases of aging, but that this was certainly a possibility. "There is more evidence in heart disease than any other condition at present, but the same mechanism could be taking place in many other aging processes."

The fact that pravastatin prevented the increased risk of heart disease in people with shorter telomeres in this study also raises the possibility that statins could prevent some aspects of aging. Samani explained to heartwire that statins have been shown to increase the production of a protein--telomere capping protein (TRF2)--that prevents telomeres from shortening, so it is possible that statins bring about some of their benefits by preventing telomeres from becoming shorter. This is still not proven and remains speculative, but several pieces of the puzzle are pointing to this possibility. If it is proven it could mean that statins could slow certain aging processes."

Coauthor of an accompanying editorial [ 2], Dr Ioakim Spyridopoulos (University of Frankfurt, Germany), who is also working in this field, agrees that statins could well have antiaging effects. "This study is very exciting," he told heart wire ."It is the first prospective study that shows that short telomere lengths are linked to a higher risk of cardiovascular events, and it also shows that statins do seem to be doing something to prevent this. We know that telomere shortening is connected to aging, cardiovascular disease, infectious disease, and death. Inflammation also appears to play a role in all these processes. We know also that statins reduce cardiovascular disease and inflammation, and we have shown that statins induce a protein that is capable of preventing the shortening of telomeres. It may be that all these things are linked. This is very early research but it does raise some very interesting possibilities."

Cellular aging could account for variation in CHD risk

In the paper, Brouilette et al point out that although several risk factors are known that explain most of the risk of coronary heart disease in a population, at an individual level there is wide variation in both the occurrence of coronary heart disease and age of manifestation, even in individuals with much the same risk-factor profiles, and the reasons for this wide variation in susceptibility are poorly understood.

They note that cellular senescence (cells showing advanced biological age) is a major feature of atherosclerotic plaques, and a hypothesis has thus emerged that biological aging may account for some of the interindividual variation in risk of CHD. They explain that telomeres progressively shorten with repeated cell division, and this telomere shortening has become regarded as a measure of biological age, with cell death often occurring when the mean telomere length reaches a critical value.


Previous cross-sectional studies have shown that mean telomere length in leukocytes is shorter in patients with heart disease than in those without, but because these studies were observational, it cannot be ruled out that the shorter telomere lengths might simply be a consequence of the development of coronary heart disease, rather than being a primary abnormality. To try to find out whether shorter telomeres are actually a predictive marker of CHD, a prospective study is needed, and this was achieved by using the DNA bank established as part of WOSCOPS.

Brouilette et al measured telomere length in leukocyte DNA of men aged 45 to 64 years already enrolled in WOSCOPS. They compared the telomere lengths of 484 men who went on to develop coronary heart disease with those of 1058 men who remained disease free.

They found that individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile.

Risk of developing CHD according to tertile of telomere length in entire study

Tertile of telomere length Odds ratio of CHD 95% CI
Highest 1
Middle 1.51 1.15–1.98
Lowest 1.44 1.10–1.90

In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile. By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated.

Risk of developing CHD according to tertile of telomere length in placebo patients

Tertile of telomere length Odds ratio of CHD 95% CI
Highest 1
Middle 1.93 1.33–2.80
Lowest 1.94 1.33–2.84

Risk of developing CHD according to tertile of telomere length in pravastatin patients

Tertile of telomere length Odds ratio of CHD 95% CI
Highest 1
Middle 1.12 0.75–1.69
Lowest 1.02 0.68–1.52

The authors note that the mechanism of this effect of the statin seems to be independent of its effects on lipid levels or markers of inflammation, since there was no difference in changes in plasma concentrations of LDL cholesterol, HDL cholesterol, triglycerides, CRP, or fibrinogen levels with statin treatment in people with different telomere lengths.

Risk correlates better than other risk factors?

They note that the risk of coronary heart disease associated with shorter telomeres is at least comparable to, if not greater than, more conventional risk factors. "On average, leukocyte telomere length at recruitment in individuals who developed coronary heart disease was comparable to control individuals chronologically six years older," they write. They point out that they did not see a progressive increase in risk with shorter telomeres, but that individuals in the lower and middle tertiles had much the same risk, suggesting that there could be a threshold beyond which further shortening of telomeres does not confer additional risk.

"Our findings indicate that the association of shorter telomeres with coronary heart disease is not a consequence of the disease. However, whether telomere length is simply another biomarker or whether the association has a functional basis remains to be determined," the researchers note. But they add: "The fact that cellular senescence is a major feature of atherosclerotic plaques and the finding that interference with telomere function in coronary endothelial cells in vitro causes expression of molecules implicated in atherogenesis suggest that shorter telomeres could conceivably contribute directly to the pathophysiology of atherosclerosis."

Can telomere length be used to assess CV risk?

Samani claims that telomere length could be used to identify individuals at high risk of heart disease who would benefit most from statin treatment. In their editorial, however, Spyridopoulos and his colleague Dr Stefanie Dimmeler caution that measuring telomeres in individual people may not be helpful in estimating their future risk of heart disease. Spyridopoulos explained to heart wire : "Length of telomeres is not like level of cholesterol-- there will not be one number that is deemed to be good or bad. Some people are born with longer telomeres than others, and it is probably how much they have shortened that is important, which is impossible to know from one measurement. You would have to have the birth measurement to compare it with to have an accurate idea of an individual's risk. Also, the critical length of a telomere that is associated with cell senescence and death may be different in different cells and individuals, so it is a highly complex area. In the current WOSCOPS analysis, the fact that telomere length was measured in a large group of people overcomes this issue somewhat, and it is possible to say that on a group level, mean telomere length is predictive of CHD risk, but there is still a lot of work to do transfer this finding to an individual's risk."

But Samani disagrees on this point. He told heartwire that he did not think telomere length was any different from any of the traditional risk factors in this regard. "If you have diabetes, you have an increased risk of heart disease but you are not definitely going to get heart disease. The same can be said for high cholesterol and for short telomeres. In general, longer telomeres are better than shorter telomeres for your risk of heart disease. The only reason why we have exact numbers for cholesterol that we say are good or bad is that we have been studying that field for many years. It may be that in future we will all have a number for our telomere length, which we will use to judge our cardiovascular risk."

  1. Brouilette SW, Moore JS, McMahon AD, et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 2007; 369: 107–114.

  2. Spyridopoulos I and Dimmeler S. Can telomere length predict cardiovascular risk? Lancet 2007; 369: 81-82.

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