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Telomere Length Linked to Risk of Coronary Heart Disease

By Judith Groch, Senior Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of
Medicine, University of California, San Francisco
January 12, 2007

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.

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=0·0006 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.

No financial disclosures were reported by Dr. Samani.

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.

Primary source: The Lancet
Source reference:
Brouilette SW, et al "Telomere length, risk of coronary heart disease,
and statin treatment in the West Scotland Primary Prevention Study: a
nested case-control study" Lancet 2007; 369: 107-114.

Additional source: The Lancet
Source reference:
Spyridopoulos, I, Dimmeler, S "Can telomere length predict
cardiovascular risk?" Lancet 2007; 369: 81-82.




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