Telomere Length Linked to Risk of Coronary Heart Disease

LEICESTER, England, Jan. 12 -- One of the apparently myriad benefits of statins in coronary artery disease may be to retard the shortening of telomeres, the bits of DNA that cap the ends of chromosomes.

So it would appear from a study here of biological aging at the cellular level. It revealed that men with short telomeres seem to have a higher risk of developing coronary artery disease than men with long telomeres and that statins keep telomeres from shortening too much.

In the study of 484 middle-age, high-risk men, those with shorter leukocyte-derived telomeres at the outset had a 50% greater risk of coronary heart disease than those with longer telomeres, according to a report in the Jan. 13 issue of The Lancet.

Individual differences in biological aging, as shown by shortening of telomere length, could affect susceptibility to coronary heart disease and might serve as a predictor of the disease, said Nilesh Samani, M.D., of the University of Leicester here, and colleagues. Short-telomere individuals might benefit most from statin treatment.

The findings came from a comparison of telomere lengths at recruitment in 484 individuals who later developed coronary heart disease events with telomere lengths of 1,058 matched controls. Subjects were enrolled in the West of Scotland Primary Prevention Study.

Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; P=0.001) in controls, with much the same trend seen in cases (-5.9% per decade, -3.1 to 14.1; P=0.1902), they reported.

However, individuals in the middle and lowest telomere tertile length had an approximately 44% to 50% increased risk of developing a coronary heart disease event compared with those in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, CI 1.15-1.98; P=0.0029 in the middle tertile; 1.44, 1.10-1.90, P=0.0090 in the lowest).

Further calculation and use of age-regression length in leukocytes at recruitment found that mean telomere length in individuals who developed coronary heart disease was comparable to control individuals chronologically six years older.

"The risk of coronary heart disease associated with shorter telomere was at least comparable to, if not greater than, more conventional risk factors," the researchers said.

In a further nested placebo-controlled comparison of patients treated with Pravachol (pravastatin), the researchers reported that among the placebo-treated patients, the risk of coronary heart disease was almost double for those in the lower two tertiles of telomere length compared with those in the highest tertile (OR 1.93, 1.33-2.80, P=0.0005 in the middle tertile and OR 1.94, 1.33-2.84, P=00006 in the lowest).

By contrast, they reported, among patients treated with Pravachol, the increased risk with shorter telomeres was substantially attenuated (OR 1.12, 0.75-1.69, P=0.5755 in the middle tertile; OR 1.02, 0.68-1.52, P=0.9380 in the lowest). The interaction between telomere shortening ratio and treatment on coronary heart disease risk was significant (P= 0.0422).

Shorter leukocyte telomeres in people prone to coronary heart disease could indicate the cumulative effect of other cardiovascular risk factors on telomere length, the investigators said. If coronary heart disease is a chronic inflammatory process, the shorter telomere length in high-risk individuals could simply indicate a greater white-blood-cell turnover. Oxidative stress is also a possible contributor, they said.

Another, though not mutually exclusive possibility, is that the association of shorter telomeres with increased risk of coronary heart disease has a genetic basis, as suggested in several studies. Any genetic susceptibility could be exacerbated or retarded by postnatal effects on telomere length.

Finding an interaction between mean telomere length and statin treatment on the risk of coronary heart disease "is intriguing," the authors said. Nevertheless, despite several possible explanations, they concluded that "either telomere-dependent or telomere-independent processes" could explain the interaction.

The study had an important limitation, the researchers said. Although leucocytes provide an easily accessible source for DNA analysis, the relevance of telomere measurement in these circulating cells remains to be established. There is evidence that telomere length attrition is accelerated in vascular sites prone to atherogenesis. Further study of other cell types is required, especially in vascular tissue, they said.

In summary, Dr. Samani's team said, "We have shown that leukocyte telomere length is associated with future coronary heart disease events in middle-aged, high-risk men, and that it could identify those individuals who would benefit most from statin treatment."

These findings, they said, "lend support to the hypothesis that biological aging might contribute to the risk -- and variability in age onset -- of coronary heart disease." The results could have important implications for the understanding of the pathophysiology of coronary heart disease and, in particular, the role of biological aging, they concluded.

In an accompanying commentary, Ioakim Spyridopoulos, M.D., and Stefanie Dimmeler, Ph.D., of the University of Frankfurt in Germany wrote that to discuss the value of telomere length as an individual prognostic marker might be of interest. The study could give the impression that telomere length can be used to identify individual patients at risk for coronary events. However, this is not the case, they said.

The high genetic variability of telomere length between individuals at birth prevents judgment on individual telomere length. As a result, they said, large cohorts would be needed to identify significant differences in telomere length between groups.

Despite the study's impressive size, shortening of telomere length in cases compared with controls was only just statistically significant (P=0.045). "Although the study showed convincingly that biological ageing-as indicated by telomere shortening-could contribute to the risk of coronary artery disease, we do not know what the individual telomere means," they wrote.

By contrast, biomarkers -- such as high-sensitivity C-reactive protein -- have distinct cutoff values. "These findings," they concluded, "should provide further motivation to identify a marker for individual telomere shortening, a marker for which absolute numbers predict absolute risk."

Commenting on the value of statins in treating telomere-attributed risk, they said the reduction of inflammation associated with oxidative stress could have contributed to the effect, or statins may have protected telomeres from stress-induced damage and telomere shortening or erosion. However, they said, the study could not explain the mechanisms by which statins could affect telomere length in actual patients.

Dr. Spyridopoulos reported receiving grants from Novartis and Amersham. He has been a speaker for Novartis and Sanofi-Aventis, and has been a scientific adviser for Novartis and is supported by grants of the Deutsche Forschungsgesellschaft. Dr. Dimmeler reported being a scientific adviser for Pfizer.