CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
568
AFRICA
higher cellular turnover rates and consequently shorter telomere
length.
103
This variable telomere attrition rate indicates the
significant impact of environmental stress on telomere length.
Population studies have demonstrated a link between telomere
length and CAD.
104,105
In the pioneering study by Samani
et al.
of 10 cases and 20 control subjects, it was observed that mean
telomere length was significantly shorter in patients with severe
triple-vessel CAD compared with matched subjects who had
normal coronary angiograms.
106
A retrospective registry analysis of 383 patients (203 cases,
180
controls) showed that patients with premature myocardial
infarction had significantly shorter mean telomere lengths. In
this study the difference in telomere length between cases and
chronologically age-matched controls demonstrated a biological
age gap in excess of 11 years. Compared with subjects in the
highest quartile for telomere length, the risk of myocardial
infarction was increased between 2.8- and 3.2-fold in subjects
with shorter-than-average telomeres.
107
In another study of 143
normal blood donors over the age of 60 years, it was shown that
subjects with shorter telomeres had poorer survival, with a 3.18-
fold higher mortality rate from heart disease.
108
In a sub-study of the West of Scotland Primary Prevention
Study (WOSCOPS) that compared telomere lengths at
recruitment in 484 individuals who went on to develop coronary
heart disease events with those from 1 058 age-matched
controls who remained free of CAD, it was shown that subjects
with shorter telomere length at the time of recruitment had a
significantly higher risk of developing subsequent coronary
heart disease.
109
In a case-control sub-study of the Cardiovascular
Health Study that examined 419 older subjects, it was found that
individuals 73 years or younger had a threefold increased risk of
myocardial infarction and stroke for each one kilobase decrease
in telomere length.
110
Farzaneh-Far
et al
.
measured telomere length in 780 patients
with stable angina in a prospective cohort study. During a mean
follow up of 4.4 years, shorter telomere length was significantly
associated with all-cause mortality, independent of age, clinical
and echocardiographic variables.
111
Zee
et al
.
using samples
collected at baseline in the prospective Physician
′
s Health
Study from a cohort of 14 916 initially healthy men, of whom
337
went on to develop myocardial infarction, demonstrated
that participants with shorter telomere length at baseline had
a significantly increased risk of incident myocardial infarction
compared to age- and smoking-matched controls who remained
free of vascular disease over a mean follow up of 3.85 years.
112
Finally, in the prospective population-based Bruneck study,
baseline telomere length was a significant risk predictor for
subsequent myocardial infarction and stroke, independent of
standard risk factors. Of note in this study was that telomere
length was strongly associated with advanced pathology and
acute vascular syndromes but not early atherosclerosis.
7
Mechanisms to preserve telomere length
Telomerase has been shown to be activated by lifestyle choices
that include a healthy diet, stress relief through meditation,
chronic high-intensity aerobic physical exercise as well as by
pharmacological agents.
113,114
Exercise has been associated with improved cardiovascular
health and longevity. La Rocca
et al
.
in a recent study have
shown that maintaining high levels of aerobic fitness preserved
telomere length.
115
They examined young and old individuals
and compared sedentary subjects who exercised fewer than two
days per week for less than 30 min per day with active ones who
had exercised five days per week for more than 45 min per day
for five years. Telomere length was preserved in the older adults
who performed chronic, vigorous exercise and was positively
correlated with maximum aerobic capacity as assessed by higher
VO
2
max
levels.
The molecular mechanisms exploring the protective effects of
exercise on the heart has been studied in experimental animals.
Exercise has been shown to promote cell survival by increasing
the activity of telomerase and the expression of TRF2. The
up-regulation of telomerase was mediated via insulin-like growth
factor 2 and endothelial nitric oxide synthase. Exercise was also
shown to decrease levels of markers of cellular growth arrest and
apoptosis, such as p16, cell cycle-checkpoint kinase 2 and p53.
Molecules that enhance low residual telomerase activity
or re-express silenced telomerase may help preserve telomere
length. Natural products such as derivatives from the Chinese
Astragalus plant,
Ginko biloba
and resveratrol have been
shown to activate telomerase, the latter two via PI3k/Akt
signalling pathways. The anti-oxidants
N
-
acetylcysteine and
α
-
tocopherol enhance telomerase activity.
116,117
Farzaneh-Far
et
al
.
demonstrated in a prospective study of patients with stable
CAD, an inverse relationship between baseline blood levels of
marine omega-3 fatty acids and the rate of telomere shortening
over five years.
118
Aspirin, ACE inhibitors and particularly statin therapy have
been shown to positively impact on the vascular endothelium via
anti-senescence effects. Over and above its anti-thrombotic and
anti-inflammatory effects, aspirin has been shown to decrease
the formation of dimethylarginine, an endogenous inhibitor
of nitric oxide synthase, thereby reducing oxidative stress
and delaying endothelial cell senescence.
119
ACE inhibitors,
particularly those containing the sulfhydryl group, have been
shown to delay endothelial cell senescence by activating Akt
phosphorylation, increasing the expression of nitric oxide
synthase and up-regulating telomerase.
120
Several studies have suggested that the survival benefit
attributed to statin therapy may be linked to its effects on
telomere biology. Spyridopoulos
et al
.
have shown that statins
enhance the migratory capacity of endothelial progenitor
cells by up-regulation of TRF2, the telomere-binding protein
that stabilises telomere structure at the t-loop.
121
Satoh and
co-workers demonstrated that intensive statin therapy over 12
months, through its anti-oxidant effects, prevents endothelial
progenitor cell telomere erosion in patients with CAD.
122
A recent
publication by Saliques
et al
.
who studied patients presenting
with acute myocardial infarction, showed that prior statin therapy
was independently associated with significantly longer telomere
length in subjects below the age of 64 years.
123
Conclusion
Our interest in telomere biology stems from the high incidence
of both premature CAD and type 2 diabetes mellitus witnessed
in the population that we serve. Patients with CAD who have
diabetes have worse outcomes than those without diabetes.
This, coupled with the fact that the initial presentation in a
