Telomere biology in heart failure
Liza S.M. Wonga, Rudolf A. de Boera, Nilesh J. Samanib,
Dirk J. van Veldhuisena, Pim van der Harsta,⁎
aDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
bDepartment of Cardiovascular Sciences, Glenfield Hospital, University of Leicester, Leicester, United Kingdom
Received 8 December 2007; received in revised form 27 May 2008; accepted 14 August 2008
Available online 24 September 2008
The incidence and prevalence of cardiovascular disease increases progressively with advancing age. Cardiovascular disease is a major
cause of morbidity and mortality in Western Countries. In the near future, as the population ages, it is expected that the population prevalence
of cardiovascular disease will increase dramatically, imposing a major social and economical burden on society. Not only is age closely
related to the development and progression of cardiovascular disease, but genetic and environmental factors also play an important role.
Recently, a chromosomal mechanism, telomere shortening, has been considered a driving force by which genetic and environmental factors
jointly affect biological aging, and possibly the risk for developing age-associated diseases. Telomeres are the extreme ends of chromosomes
and shorten progressively during every cell cycle and therefore can be considered an indicator of biological age. In heart failure, telomere
length is severely reduced. In the current review, we will discuss the emerging role of telomere biology in the pathophysiology of heart
© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Telomeres; Telomerase; Heart failure; Atherosclerosis; Diabetes; Review
The incidence of cardiovascular disease, including
atherosclerosis and chronic heart failure, increases progres-
sively with advancing age . Cardiovascular disease
represents one of the major causes of morbidity and mortality
in Western Countries. In the near future, as the population
ages, it is expected that the prevalence of patients with
cardiovascular diseases will increase dramatically, imposing
a major social and economical burden on society. Although
medical and interventional therapies have greatly improved
event free survival, the prognosis of chronic heart failure
(CHF) remains poor [2–4] and the search to new strategies to
improve outcome continues . Many patients with
disorders associated with cardiovascular aging also have
concomitant chronic disorders of other organ systems,
including those of the kidneys and lungs.
Not only are age and concomitant diseases strongly
related to the development and progression of CHF, but
genetic and environmental factors also play important roles.
Only recently, have telomeres been considered as a driving
force by which genetic and environmental factors jointly
affect biological age and pace of aging, and consequently the
risk of developing disorders related to aging .
In vitro, most somatic cells can undergo only a finite
number of cell divisions before reaching senescence. This
phenomenon was discovered in the sixties by the famous
experiments of Leonard Hayflick . This so-called
“Hayflick limit” originates from progressive shortening of
telomeres during each cell division. Therefore, telomeres are
considered indicators or markers of biological age. The
potential role of telomeres and telomerase in the develop-
ment and progression of cardiovascular diseases is only just
beginning to be recognized .
European Journal of Heart Failure 10 (2008) 1049–1056
⁎Corresponding author. Tel.: +31 503612355; fax: +31 503614391.
E-mail address: email@example.com (P. van der Harst).
1388-9842/$ - see front matter © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
by guest on June 1, 2013
In the current review, we discuss the potential role of
telomeres and telomere maintenance in chronic heart failure
and risk factors.
2. Telomeres and telomerase
2.1. Structure and function
Chromosomal integrity is required for an organism to
function and survive . Several mechanisms contribute to
chromosomal integrity. One essential mechanism is chro-
mosomal capping by telomeres. However, the exact function
and regulation of chromosomal capping by telomeres are
only just beginning to be understood [9,10]. Telomeres are
specialized functional deoxyribonucleic acid (DNA)–protein
complexes which are located at both extreme ends of each
chromosome. Telomeres are arranged in such a way that they
can form loop structures (T- and D-loops), that act as a
protective chromosomal “cap”. (Fig. 1). The telomere
sequence varies among species. In humans telomeres are
composed of arrays of (TTAGGG)nup to 20 kilo-base pairs in
length, terminating in a 3' single stranded DNA overhang
consisting of 100–400 nucleotides [11,12].
The chromosomal caps formed by telomeres prevent the
loss of genetic information and prevent the chromosomes
from being recognized as double stranded DNA breaks by
DNA damage signalling mechanisms. Telomere cappingalso
prevents the detrimental end-to-end fusion and chromosomal
degradation, which leads to cellular senescence or even
Using quantitative fluorescence in situ hybridization
techniques, the length of telomeres on specific chromosomes
has been studied. In humans, women tend to have longer
telomeres than men. This difference has been attributed to
potential telomerase upregulation by oestrogens . For all
chromosomes there is a linear correlation between length and
age . It has been suggested that the telomere length of
chromosome 17p is shorter than the median telomere length
. However, 13p and 19p also have been identified as the
shortest telomere [14,16]. In women, accelerated shortening
of telomeres has been documented in the inactive X
chromosome . In males, there does not seem to be a
difference in attrition rate between the Yand X chromosomes
. Nevertheless, it remains to be determined whether low
average telomere length or specific chromosome arms are
responsible for inducing senescence.
the holoenzyme DNA polymerase aims to replicate telomeres,
just like any other chromosomal regions. The regular DNA
polymerases fail to completely replicate the human telomeric
DNA, a difficulty referred to as the “end-replication problem”.
Up to a few hundred base pairs of telomeric DNA are lost
during each mammalian mitosis. This erosion of telomere
lengthisa cumulative process andeventuallythe telomerewill
progress into a critical short, dysfunctional one, leading to
cellular senescence or even apoptosis [10,18–20]. Since
telomeres mark the number of cell divisions, they are regarded
as a biological counter, and as such a marker of biological age
many variables which determine the potential of telomeres to
form a protective structure .
In contrast to chronological age, defined by date of birth,
it may be possible to modify or influence biological aging.
Indeed, species as a whole are not aging leading to
extinction, but instead are reproducing for many millions
of years. Circumventing the Hayflick limit by maintaining
telomeric DNA length can be achieved by several mechan-
isms, including by the specialized ribonucleoprotein enzyme
telomerase, which can add the specific TTAGGG repeats to
the chromosomal ends . Under physiological conditions,
Fig. 1. Simplified depiction of a telomere folded in T-loop formation. Telomeres consist of specific nucleotide repeats (TTAGGG and AATCCC) at both ends of
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in humans, telomerase is only active in embryogenic stem
cells, germline cells and some epithelial and lymphoid
progenitor cells [26,27]. Human telomerase is composed of
Transcriptase (hTERT), and a RNA component, the human
Telomerase RNA Component (hTRC) . Increased activity
of telomerase has been linked to immortalization of cells,
uncontrollable growth and even malignancies . Decreased
linked to dyskeratosis congenita, a congenital, multi-system
disorder, phenotypically characterized by mucocutaneous
abnormalities, pulmonary aberrations, premature aging, and
X-linked and autosomal dominant form of dyskeratosis
congenita are associated with defects of telomerase and short
telomeres. This strongly suggests that telomerase activity is
required to maintain telomere length. In addition, short
telomeres and absence of telomerase have been shown to
result in premature aging in humans [29,30].
2.2. Telomere repeat binding factors and telomere function
Telomeres are unable to form the protective T- and D-
loops without the assistance of several essential proteins. The
single most important are the mammalian Telomere Repeat
binding Factors (TRF) 1 and TRF2. TRF1 and TRF2 can
bind directly to the telomeric DNA region and facilitate the
formation of the protective loops (Fig. 1). In the absence of
TRFs, telomeres lose these protective loop structures.
Telomere length itself is an important determinant of the
ability to form protective loops. However, in the presence of
sufficiently high levels of TRF2, even short telomeres can
form protective loop structures. . Nevertheless, an
abundance of TRF2 proteins has also been related to
increased telomere shortening in vitro [9,31]. Too much
TRF2 seems to lead to compromised repair of oxidative
telomeric damage, although it does not affect repair of
genomic DNA . A satisfactory explanation for these
apparently contrary effects of TRF2 has yet to be provided.
2.3. Oxidative stress and telomere length
In addition to telomerase dysfunction, several other
processes are associated with increased telomere attrition
rate and short telomeres. Oxidative stress, independent of its
origin, is considered the major cause of telomere erosion
. Cultured vascular smooth muscle cells and endothelial
cells exposed to oxidative stress, exhibit increased short-
ening of telomeres and accelerated cellular senescence .
In addition, telomerase activity decreases in response to
oxidative stress, which is thought to be a direct consequence
of oxidative stress, rather than the result of premature
senescence . Smoking and obesity are well-known
factors causing in vivo oxidative stress, and are both linked
to decreased telomere length . Alternatively, strategies to
reduce oxidative stress (e.g. in a state of hypoxia or by over-
expression of anti-oxidant enzymes) can maintain telomere
length and have been associated with increased telomerase
3. Telomeres, telomerase and factors leading to chronic
CHF is a complex, multi-causal, polygenic disorder of
different aetiologies which is becoming increasingly pre-
valent as the population ages [38,39]. Hypertension,
diabetes, and smoking are well-known risk factors for the
progression of coronary artery disease and the development
of CHF (Fig. 2), but have also been related to reduced
telomere length. We will discuss risk factors for CHF and
their relationship with telomere dynamics below.
Hypertension, leading to left ventricular hypertrophy and
diastolic dysfunction, is an important early factor involved in
the development of CHF. In addition to diastolic dysfunc-
tion, it leads to systolic dysfunction and ventricular dilatation
telomere length in several, but not all, studies [42–44].
In hypertensive men, white blood cell (WBC) telomere length
has been shown to be shorter compared to normotensive men,
even after adjustment for chronological age . In patients
with type 1 diabetes, hypertensive subjects had shorter
telomeres than non-hypertensive, but this difference failed
to reach significance after additional adjustment for age .
Pulse pressure, the difference between diastolic and systolic
Fig. 2. Relationships between telomeres and cellular processes, cardiovascular disease, and kidney disease. Dashed arrow: associative relationship. Continuous
arrows: potential causal relationships.
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blood pressure, which is known to increase with age, is
regarded as an indicator of biological aging of central arteries
, and predicts cardiovascular mortality . In men,
telomere length in white blood cells (WBCs) negatively
correlates with pulse pressure, independently from age
[21,45]. The relationship between telomere length and pulse
pressure in women is inconsistent [45,21]. The renin–
angiotensin system is associated with outcome in patients
with coronary heart disease . Interestingly, in the
Framingham Heart Study, shorter telomere length was also
related to higher renin-to-aldosterone ratio, especially in
participants with hypertension . Interestingly, telomerase
knockout mice with reduced telomere length also suffer from
converting enzyme and consequently increased serum levels
of the vasoconstrictor peptide endothelin-1 .
3.2. Diabetes mellitus
Diabetes mellitus is another important risk factor for the
development of atherosclerosis and CHF. Diabetes can lead
to cardiac dysfunction through several complementary
mechanisms. Increased levels of non-esterified fatty acids
in diabetes alter the activity of K-channels at the myocyte
membrane, leading to decreased cardiac contractility . In
addition, the heart is less affected by insulin resistance
compared to other organs. As insulin acts as a growth factor,
stimulating cell growth through nuclear transcription path-
ways, hyperinsulinaemia can induce cardiac hypertrophy
. Furthermore, hyperglycaemia in diabetes results in
increased production of deleterious advanced glycation end
products (AGEs), which negatively affect cardiac contrac-
tility and ventricular filling pressures .
Diabetes is also associated with reduced telomere length.
Type 1 diabetes mellitus patients have shorter telomeres in
WBCs compared to non-diabetic controls . Potential
confounders such as age, duration of diabetes, or albumi-
nuria showed no independent correlation with telomere
length. Type 2 diabetes mellitus has also been associated
with shorter telomeres compared to healthy age- and sex-
matched controls . There may also be a difference
between monocyte and lymphocyte telomere length. Mono-
cyte telomere length has been demonstrated to be signifi-
cantly shorter in type 2 diabetic patients, but no difference
was observed for lymphocyte telomere length . The
reason for the differential expression of telomere length
among subpopulations of peripheral WBCs is unclear.
Interestingly, insulin resistance has also been reported to be
associated with reduced telomere length [54,43].
3.3. Cigarette smoking
Cigarette smoking is widely known to be related to the
development of coronary heart disease (CHD)  and
consequently the development of CHF. Smoking predisposes
to several other atherosclerotic syndromes, including inter-
mittent claudication, cerebrovascular disease, and glomerular
sclerosis. Smoking decreases nitric oxide bioavailability and
leukocyte adhesion, and platelet activation . Smoking
slightly increases the number of circulating leukocytes,
thereby possibly promoting systemic inflammation.
telomere length. In women, the mean telomere length of
WBCs is shorter in smokers than in non-smokers in a dose-
dependent manner . Furthermore, a dose-dependent
in peripheral lymphocytes was found in both patients with
chronic obstructive pulmonary disease and controls with
normal lung function . Also, among bladder cancer
patients and controls, telomere length of WBCs was
gradually decreased with increasing number of pack years
smoked . However, not all studies have consistently
observed a negative relationship between smoking and
telomere length, possibly due to confounding factors [23,58].
In addition to the association between telomeres and the
risk factors for atherosclerosis, a relationship between
telomeres and atherosclerotic disease itself has also been
observed [23,59–62]. WBC telomere length in patients who
had a myocardial infarction before the age of 50 years was
shorter than in healthy controls, independently from other
atherosclerotic risk factors . These findings have been
confirmed in other cohorts of patients with coronary disease
[59,62]. Not only are WBC telomeres shorter, but telomeres
of coronary artery endothelial cells of atherosclerotic plaques
are also shorter compared to non-atherosclerotic segments
and healthy controls .
Telomere length also predicts future coronary heart
disease. In a study, involving 383 subjects, shorter WBC
telomere length was associated with an approximately three
times higher risk of myocardial infarction . This finding
was recently confirmed in a larger study involving 1542
subjects, which demonstrated that subjects with a WBC
telomere length of the lowest or middle tertile were at
increased risk of developing CHD compared to individuals
with the longest telomeres . In addition, the absolute
benefit of pravastatin treatment was greatest in patients with
the shortest telomeres .
Whether short telomeres are causally involved in the
pathogenesis of hypertension, diabetes, or atherosclerosis
requires further evaluation. The alternative explanation, that
telomere length marks the cumulative life burden of
leukocyte turnover or inflammation, cannot be denied.
3.5. Valvular heart disease
Valvular heart diseases, such as aortic valve stenosis, can
also lead to the development of CHF due to prolonged
increased cardiac strain, which causes left ventricle
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hypertrophy and eventually dilatation and compromised
cardiac pump function. Aortic valve abnormalities can be
congenital or degenerative, and age-related . Recently,
degenerative aortic stenosis has also been associated with
decreased leukocyte telomere length independently from
possible confounding factors. This may be due to a
telomere-dependent decrease in regenerative capacity asso-
ciated with aging .
Many anti-cancer drugs cause cardiotoxicity or introduce
a risk of delayed cardiovascular events. Although direct
effects on cardiomyocytes are likely, chemotherapy also
induces permanent telomere shortening in blood and bone
marrow and possibly in other cells . Currently, several
new strategies in the oncology field are aimed at inhibiting
telomerase to slowdown cell proliferation. Monitoring of the
patients included in studies of these new strategies for
cardiovascular side effects, is therefore important.
4. Telomeres, telomerase, and chronic heart failure
CHF is characterised by increased myocyte apoptosis
[66,67]. Several studies in animal models have provided
important pathophysiological insights into the role of
telomeres and telomerase in cardiac failure and myocyte
apoptosis [67,68–70]. Later generations of telomerase
knockout (Terc−/−) mice show progressively shortened
telomeres. Telomere shortening in these mice is associated
with attenuated myocyte proliferation, increased apoptosis
and cardiac myocyte hypertrophy. Eventually, left ventricu-
lar failure and pathological cardiac remodelling, mimicking
the end stage dilated cardiomyopathy of humans, develops in
these mice with critically short telomeres . In vitro
experiments with cultured rat myocytes have demonstrated
that downregulation of TRF2 leads to telomere attrition,
activation of the pro-apoptotic protein Chk2, and eventually
apoptosis. Conversely, upregulation of TRF2 can protect
myocytes from premature apoptosis . Mechanical
myocyte stress, comparable to cardiac strain in hypertension,
also shortens telomeres and induces Chk2 related apoptosis.
In this in vitro model, forced hTERT expression could
reverse telomere attrition and related apoptosis .
Recently, it has been suggested that cardiac cells are not
simply a homogenous population of post-mitotic cells.
Instead, the myocardium consists of a heterogeneous
population of myocytes from different biological age-
categories, myocytes appear to age prematurely under
pathophysiological conditions. Experiments in mice have
demonstrated that the heart is constantly repopulating the
myocyte compartment to replace old, functionally impaired
myocytes with younger ones . The old, senescent, poorly
contracting myocytes were found to have severely shortened
telomeres, while the young and more efficient cells had
longer telomeres . A possible source of myocytes for
repopulation of the myocardium could be the pool of cardiac
progenitor cells (CPCs). It has been reported that CPCs have
stem cell like potential, increase in number after myocardial
infarction , and can migrate to damaged regions of the
myocardium and generate young myocytes . In human
failing hearts, telomeres are shorter compared to healthy,
age-matched controls. This suggests that telomere shortening
in the heart does not necessarily accompany normal aging. A
possible explanation for the increased number of dysfunc-
tional, prematurely aged myocytes could be the shortened
telomeres observed in failing hearts.
In animals with forced TERT expression, telomerase
activity is increased. This prevents telomere erosion and
results in increased myocyte density, either by hyperplasia or
decreased apoptosis . Myocytes with forced TERT-
expression also exhibit increased incorporation of mitosis
markers comparedtocontrolinthe firstweeks after birth.This
suggestsa delayofcellcycle exit,andthusreplicative abilities
of myocytes, under the influence of telomerase activity .
capillary density . Endothelial progenitor cells are an
important source of vascular repair and maintenance .
Short telomeres significantly reduce the angiogenic potential
length, prolongs the life span and proliferation potential of
cultured vascular smooth muscle cells .
As mentioned previously, atherosclerosis — a risk factor
for heart failure — is associated with shorter telomeres.
However, recent studies in humans have also suggested an
important role for telomeres in the pathophysiology of non-
Fig. 3. Telomere length of 620 CHF patients compared to 183 age- and sex-
matched controls. Patients with CHF have decreased telomere length
compared with healthy controls. CHF patients with concomitant CHD have
further decreased telomere length. Reprinted from van der Harst P, van der
Steege G, de Boer RA, et al. Telomere length of circulating leukocytes is
decreased in patients with chronic heart failure J Am Coll Cardiol 2007;
49:1459–64, with permission from Elsevier .
1053L.S.M. Wong et al. / European Journal of Heart Failure 10 (2008) 1049–1056
by guest on June 1, 2013
ischaemic CHF. Endomyocardial biopsies from 19 elderly
patients with dilated cardiomyopathy were compared with
biopsies from 7 subjects of comparable age but without
cardiomyopathy. Myocytes from the aged diseased hearts
showed significant telomeric shortening, cellular senes-
cence, and cell death . Using confocal microscopy, a
39% reduction in average telomere length in CHF patients
compared to healthy controls was observed . These
preliminary findings were recently substantiated in a large
cohort of 620 CHF patients compared to 183 age- and sex-
matched controls.(Fig. 3) . Telomeres were shown to be
related to the severity of heart failure as they were shorter in
patients with higher New York Heart Association (NYHA)
class. Ischaemic aetiology was an additional factor asso-
ciated with shorter telomeres in patients with CHF. Even the
number of atherosclerotic manifestations was associated
with shorter telomeres  (Table 1). In patients with CHF,
telomere length was shorter in those with renal dysfunction
than in those without . There are suggestions that
telomere length is associated with reduced ejection fraction
in the elderly  (Table 1).
Notwithstanding all these promising associations, we
have to be careful when drawing conclusions regarding
cause or effect. The exact mechanism explaining the
relationship between reduced telomere length and CHF
remains to be elucidated. Although data from experimental
models strongly suggests a causal role, evidence beyond
associations in humans is now required. The major limitation
of almost all human data is its cross-sectional nature, or the
lack of telomere length follow-up.
Interestingly, not much is known about telomere length in
specific subpopulations of circulating WBCs. Most research-
ers have determined telomere length in easily accessible
circulating WBCs. However, these might not be the most
relevant cells to consider in CHF.
5. Therapeutic opportunities
If short telomeres and decreased telomerase activity indeed
play a role in pathogenesis of cardiovascular disease, this
provides opportunities for intervention. Telomere length in
easily obtainable WBCs might provide an early marker of
increased cardiovascular risk and could therefore be used to
identify patients who would benefit most from early primary
in endothelial progenitor cells can be increased by statin
levels of Chk2 . Telomere modifying strategies might be
of cells after myocardial infarction. Gene therapy is another
conceivable approach. For example, specific over-expression
of telomerase or TRF2 could contribute to the stability of
telomeres, which in turn could contribute to better function of
cells directly involved in angiogenesis. Forced hTERT
expression in mice has been shown to lead to ventricular
hypertrophy without compromising ventricular function and
increased tolerance to ischaemia . However, as we
discussed earlier, increased telomerase activity can also lead
to immortalization of cells, which could possibly result in the
growth of malignancies. As with all treatments, the balance
Literature overview of the relationship between telomeres and heart failure
Study subjectsMain findingsRef.
Suggestive for causal relationship between telomeres and heart failure
DogsTERT upregulation, indicating increased telomerase activity, was found shortly after induced heart failure. Possibly,
telomerase activity increases in newly developed heart failure to preserve telomere length and rescue cellular function,
and declines as heart failure progresses.
Mice and mouse myocytes Counteracting telomere shortening by TERT over-expression has beneficial effects on cardiac morphology,
decreases infarct size in vivo, and rescues myocytes from apoptosis after hypoxia in vivo and in vitro.
MiceAblation of telomerase, and subsequently short telomeres, lead to myocyte apoptosis, decreased cardiomyocyte number,
abnormal myocardial fibre morphology, decreased cardiac myocyte proliferation, myocyte hypertrophy, decreased +dP/dt,
decreased −dP/dt, decreased LV developed pressure, elevated LVend-diastolic pressure, development dilated cardiomyopathy,
left ventricular failure, and death due to heart failure.
Mice Cardiac strain induces telomere shortening and myocyte apoptosis in the myocardium. Over-expression of TERT
has cardioprotective effects.
RatsFunctionally competent cardiac progenitor cells, which are thought to be able to regenerate damaged or aged myocardium,
had longer telomeres than the aged cardiac progenitor cells.
Associative relationship between telomeres and heart failure
Human, myocardium Shorter telomere length was measured in myocardium of hearts with dilated cardiomyopathy, compared to healthy controls.
Human, myocardium Myocytes from hearts diseased from aging cardiomyopathy had approximately 40% shorter telomeres compared to aged
Human, myocardium In chronic ischemic heart failure myocardial telomerase activity was increased compared to normal hearts, but less increased
than in hearts with acute myocardial infarction. In chronic ischemic heart failure more cardiac progenitor cells with short
telomere length were found compared to acute myocardial infarction.
Human, leukocytesSeverity of heart failure, expressed in NYHA class, is correlated to shorter telomere length. Telomere length was shorter
in case of ischaemic aetiology of heart failure.
Human, mononuclear cells Ventricular ejection fraction was correlated to shorter telomere length in a population of age above 85 years.
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between therapeutic benefit and harmful side effects must be
Besides pharmacological and gene therapy, behavioural
changes could also reduce telomere attrition rate. Smoking
cessation and increased physical activity also have potential
as effective interventions, and may be exceptionally effective
in patients with short telomeres.
6. Conclusions and perspectives
Telomere and telomerase have recently been shown to be
associated with cardiovascular disease and its risk factors.
Critically short telomeres, changes in telomere-binding
proteins, and decreased telomerase activity have all been
implicated in the activation of cellular damage pathways, and
eventually cellular dysfunction, senescence and apoptosis. It
remains to be elucidated whether WBC telomere shortening,
which is frequently observed in CHD and CHF is a cause or a
consequence of the disease. Future experimental and epide-
miological studies to determine telomere length in relation to
cardiac function will contribute to our understanding of the
role of telomeres in cardiovascular disease and might open up
new avenues for risk stratification and interventions.
This work was supported by the Innovational Research
Incentives Scheme program of the Netherlands Organisation
for Scientific Research (NWO VENI, grant 916.76.170 to P.
van der Harst). P. van der Harst is a research fellow of the
Netherlands Heart Foundation (grant 2006T003) and the
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