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European Journal of Heart Failure 2008 10(11):1049-1056; doi:10.1016/j.ejheart.2008.08.007
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© 2008 European Society of Cardiology

Telomere biology in heart failure

Liza S.M. Wonga, Rudolf A. de Boera, Nilesh J. Samanib, Dirk J. van Veldhuisena and Pim van der Harsta,*

a Department of Cardiology, University Medical Center Groningen, University of Groningen Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
b Department of Cardiovascular Sciences, Glenfield Hospital, University of Leicester Leicester, United Kingdom

* Corresponding author. Tel.: +31 503612355; fax: +31 503614391. E-mail address: p.van.der.harst{at}thorax.umcg.nl (P. van der Harst)


   Abstract
Top
 Abstract
1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
 References
 
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 failure.

Key Words: Telomeres • Telomerase • Heart failure • Atherosclerosis • Diabetes • Review

Received December 8, 2007; Revised May 27, 2008; Accepted August 14, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
 References
 
The incidence of cardiovascular disease, including atherosclerosis and chronic heart failure, increases progressively with advancing age [1]. 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 [5]. 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 [6].

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 [7]. 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 development and progression of cardiovascular diseases is only just beginning to be recognized [6].

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
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
 References
 
2.1. Structure and function
Chromosomal integrity is required for an organism to function and survive [8]. Several mechanisms contribute to chromosomal integrity. One essential mechanism is chromosomal 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)n up to 20 kilo-base pairs in length, terminating in a 3' single stranded DNA overhang consisting of 100-400 nucleotides [11,12].


Figure 01
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  		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 each chromosome.

 
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 capping also prevents the detrimental end-to-end fusion and chromosomal degradation, which leads to cellular senescence or even apoptosis [9,10].

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 [13]. For all chromosomes there is a linear correlation between length and age [14]. It has been suggested that the telomere length of chromosome 17p is shorter than the median telomere length [15]. 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 [17]. In males, there does not seem to be a difference in attrition rate between the Y and X chromosomes [14]. Nevertheless, it remains to be determined whether low average telomere length or specific chromosome arms are responsible for inducing senescence.

Unfortunately, telomeres are unstable structures. In each cell 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 length is a cumulative process and eventually the telomere will 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 [18,21-24]. However, telomere length per se is only one of the many variables which determine the potential of telomeres to form a protective structure [8].

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 mechanisms, including by the specialized ribonucleoprotein enzyme telomerase, which can add the specific TTAGGG repeats to the chromosomal ends [25]. Under physiological conditions, 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 two essential protein components, human TElomerase Reverse Transcriptase (hTERT), and a RNA component, the human Telomerase RNA Component (hTRC) [28]. Increased activity of telomerase has been linked to immortalization of cells, uncontrollable growth and even malignancies [18]. Decreased activity of telomerase and extremely short telomeres have been linked to dyskeratosis congenita, a congenital, multi-system disorder, phenotypically characterized by mucocutaneous abnormalities, pulmonary aberrations, premature aging, and early death due to bone marrow insufficiency [29,30]. Both the 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. [9]. 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 [31]. 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 [32]. Cultured vascular smooth muscle cells and endothelial cells exposed to oxidative stress, exhibit increased shortening of telomeres and accelerated cellular senescence [33]. 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 [34]. Smoking and obesity are well-known factors causing in vivo oxidative stress, and are both linked to decreased telomere length [35]. 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 activity [36,37].


   3. Telomeres, telomerase and factors leading to chronic heart failure
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
 References
 
CHF is a complex, multi-causal, polygenic disorder of different aetiologies which is becoming increasingly prevalent 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.


Figure 02
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  		Fig. 2 Relationships between telomeres and cellular processes, cardiovascular disease, and kidney disease. Dashed arrow: associative relationship. Continuous arrows: potential causal relationships.

 
3.1. Hypertension
Hypertension, leading to left ventricular hypertrophy and diastolic dysfunction, is an important early factor involved in the development of CHF. In addition to diastolic dysfunction, it leads to systolic dysfunction and ventricular dilatation [40,41].

Hypertension has been shown to be associated with reduced 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 [43]. 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 [44]. Pulse pressure, the difference between diastolic and systolic blood pressure, which is known to increase with age, is regarded as an indicator of biological aging of central arteries [45], and predicts cardiovascular mortality [46]. 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 [47]. Interestingly, in the Framingham Heart Study, shorter telomere length was also related to higher renin-to-aldosterone ratio, especially in participants with hypertension [48]. Interestingly, telomerase knockout mice with reduced telomere length also suffer from hypertension due to an increased expression of the endothelin-converting enzyme and consequently increased serum levels of the vasoconstrictor peptide endothelin-1 [49].

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 [50]. 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 pathways, hyperinsulinaemia can induce cardiac hypertrophy [51]. Furthermore, hyperglycaemia in diabetes results in increased production of deleterious advanced glycation end products (AGEs), which negatively affect cardiac contractility and ventricular filling pressures [51].

Diabetes is also associated with reduced telomere length. Type 1 diabetes mellitus patients have shorter telomeres in WBCs compared to non-diabetic controls [44]. Potential confounders such as age, duration of diabetes, or albuminuria 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 [52]. There may also be a difference between monocyte and lymphocyte telomere length. Monocyte telomere length has been demonstrated to be significantly shorter in type 2 diabetic patients, but no difference was observed for lymphocyte telomere length [53]. 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) [55] and consequently the development of CHF. Smoking predisposes to several other atherosclerotic syndromes, including intermittent claudication, cerebrovascular disease, and glomerular sclerosis. Smoking decreases nitric oxide bioavailability and subsequently vasomotor function, and increases inflammation, leukocyte adhesion, and platelet activation [55]. Smoking slightly increases the number of circulating leukocytes, thereby possibly promoting systemic inflammation.

Smoking has also repeatedly been associated with reduced telomere length. In women, the mean telomere length of WBCs is shorter in smokers than in non-smokers in a dose-dependent manner [35]. Furthermore, a dose-dependent negative relationship between pack years and telomere length in peripheral lymphocytes was found in both patients with chronic obstructive pulmonary disease and controls with normal lung function [56]. Also, among bladder cancer patients and controls, telomere length of WBCs was gradually decreased with increasing number of pack years smoked [57]. However, not all studies have consistently observed a negative relationship between smoking and telomere length, possibly due to confounding factors [23,58].

3.4. Atherosclerosis
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 [23]. 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 [60].

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 [23]. 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 [63]. In addition, the absolute benefit of pravastatin treatment was greatest in patients with the shortest telomeres [63].

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 hypertrophy and eventually dilatation and compromised cardiac pump function. Aortic valve abnormalities can be congenital or degenerative, and age-related [64]. 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 associated with aging [64].

3.6. Iatrogenic
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 [65]. 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
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
 References
 
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 ventricular failure and pathological cardiac remodelling, mimicking the end stage dilated cardiomyopathy of humans, develops in these mice with critically short telomeres [69]. 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 [67]. 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 [67].

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 [71]. The old, senescent, poorly contracting myocytes were found to have severely shortened telomeres, while the young and more efficient cells had longer telomeres [71]. 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 [72], and can migrate to damaged regions of the myocardium and generate young myocytes [73]. 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 dysfunctional, 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 [70]. Myocytes with forced TERT- expression also exhibit increased incorporation of mitosis markers compared to control in the first weeks after birth. This suggests a delay of cell cycle exit, and thus replicative abilities of myocytes, under the influence of telomerase activity [70].

Another histological hallmark of heart failure is a decreased capillary density [74]. Endothelial progenitor cells are an important source of vascular repair and maintenance [75]. Short telomeres significantly reduce the angiogenic potential of progenitor cells [76]. Over-expression of TERT, resulting in an increase of telomerase activity and maintenance of telomere length, prolongs the life span and proliferation potential of cultured vascular smooth muscle cells [36].

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-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 senescence, and cell death [66]. Using confocal microscopy, a 39% reduction in average telomere length in CHF patients compared to healthy controls was observed [66]. These preliminary findings were recently substantiated in a large cohort of 620 CHF patients compared to 183 age- and sex-matched controls.(Fig. 3) [62]. 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 associated with shorter telomeres in patients with CHF. Even the number of atherosclerotic manifestations was associated with shorter telomeres [62] (Table 1). In patients with CHF, telomere length was shorter in those with renal dysfunction than in those without [77]. There are suggestions that telomere length is associated with reduced ejection fraction in the elderly [78] (Table 1).


Figure 03
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  		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 [62].

 


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  		Table 1 Literature overview of the relationship between telomeres and heart failure

 
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 researchers 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
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
6. Conclusions and perspectives
 Acknowledgments
 References
 
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 preventive treatment strategies [23,42,63]. For example, TRF2 in endothelial progenitor cells can be increased by statin therapy in vitro [79]. These statin treated EPCs also have lower levels of Chk2 [79]. Telomere modifying strategies might be useful in stem cell transplantation or for intracoronary infusion 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 [70]. 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 between therapeutic benefit and harmful side effects must be found.

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
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
Acknowledgments
 References
 
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 epidemiological 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.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
References
 
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 Interuniversitair Cardiologisch Instituut Nederland (ICIN). N.J. Samani holds a British Heart Foundation Chair. R.A. de Boer is a research fellow of the Netherlands Heart Foundation (grant 2004T004). D.J. van Veldhuisen is an Established Investigator of the Netherlands Heart Foundation (grant D97-017).


   References
Top
 Abstract
 1. Introduction
 2. Telomeres and telomerase
 3. Telomeres, telomerase and...
 4. Telomeres, telomerase, and...
 5. Therapeutic opportunities
 6. Conclusions and perspectives
 Acknowledgments
 References
 

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