Telomere length and cardiovascular risk in hypertensive ... - Nature

Journal of Human Hypertension (2011) 25, 711–718 & 2011 Macmillan Publishers Limited All rights reserved 0950-9240/11 www.nature.com/jhh

ORIGINAL ARTICLE

Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study F Fyhrquist1,2, K Silventoinen3, O Saijonmaa1,2, K Kontula2, RB Devereux4, U de Faire5, I Os6 and B Dahlo¨f7 1

Minerva Institute for Medical Research, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland; 3Department of Sociology, Population Research Unit, University of Helsinki, Helsinki, Finland; 4Weill Cornell Medical College, New York, NY, USA; 5Division of Cardiovascular Epidemiology, Karolinska Institute, Stockholm, Sweden; 6Department of Nephrology, Ullevaal University Hospital, Oslo, Norway and 7Sahlgrenska University Hospital/O¨stra, Gothenburg, Sweden

2

Short telomeres are associated with aging and agerelated diseases. Our aim was to determine whether short leukocyte telomere length is associated with risk factors and cardiovascular diseases in a high-risk hypertensive population. We measured leukocyte telomere lengths at recruitment in 1271 subjects with hypertension and left ventricular hypertrophy (LVH) participating in the Lifestyle Interventions and Independence for Elders (LIFE) study. At baseline, short mean telomere length was associated with coronary artery disease in males (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39–0.95), and transient ischemic attack in females (OR 0.62 95% CI 0.39–0.99). Proportion of short telomeres (shorter than 5 kb) was associated with Framingham risk score

(r ¼ 0.07, Po0.05), cerebrovascular disease (OR 1.18, 95% CI 1.01–1.15) and type 2 diabetes in men (OR 1.07, 95% CI 1.02–1.11). During follow-up, proportion of short telomeres was associated with combined cardiovascular mortality, stroke or angina pectoris (hazard ratio 1.04, 95% CI 1.01–1.07). Telomere length was not associated with smoking, body mass index, pulse pressure or selfreported use of alcohol. Our data suggest that reduced leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension and LVH. Journal of Human Hypertension (2011) 25, 711–718; doi:10.1038/jhh.2011.57; published online 23 June 2011

Keywords: telomeres; cardiovascular diseases; coronary artery disease; transient ischemic attack

Introduction Telomeres are located at the ends of chromosomal DNA. They are composed of thousands of tandem repeats of the TTAGGG sequence and associated protein.1,2 Telomeres participate in the maintenance of genomic and cellular stability and replication. Telomeres shorten with repeated cell division, and when a critical telomere length is reached the cell enters senescence followed by apoptosis. Therefore, telomeres are considered as a potential biological clock.3,4 Telomeres, mostly measured in the DNA of circulating leukocytes, shorten with age. In all populations studied telomeres were shorter in

Correspondence: Professor F Fyhrquist, Minerva Institute for Medical Research, Helsinki University Central Hospital, Biomedicum U2 Helsinki 00290, Helsinki, Finland. E-mail: [email protected] Received 7 February 2011; revised 4 May 2011; accepted 9 May 2011; published online 23 June 2011

age-matched males than in females, except in the very old.5 Shorter telomeres than in age- and sex-matched healthy control subjects have been reported in patients with inflammatory and cardiovascular diseases such as rheumatoid arthritis,6 coronary artery disease,7 stroke8 and hypertension.9 We recently observed that short leukocyte telomeres are predictive of progression of renal disease in patients with type 1 diabetes.10 Whether accelerated telomere shortening is a primary or secondary phenomenon in such diseases is not clear. In the LIFE study, patients with hypertension and left ventricular hypertrophy (LVH) by electrocardiography criteria were randomized in a double-blind study to treatment based on atenolol or losartan.11 The main results were 25% reductions in stroke and new-onset diabetes in the losartan-based treatment group compared with the atenolol-based group. In a post hoc substudy, we measured the leukocyte telomere length of 1271 patients from the LIFE

Telomere length in the LIFE study F Fyhrquist et al 712

study using the Southern blot method. We report associations of telomere length with cardiovascular disease and type 2 diabetes.

Methods Patients and study design

The LIFE study randomized 9193 patients aged 55– 80 years with hypertension and signs of LVH on electrocardiogram (according to Cornell voltage duration or Sokolow–Lyon voltage criteria) to losartan-based versus atenolol-based treatment after 1–2 weeks of placebo if they had sitting blood pressure of 160–200/95–115 mm Hg. Patient follow-up lasted for at least 4 years with regular visits. The main outcome and the study design, organization, clinical measures and endpoint definitions have been published.11 The primary end point was a composite of the first occurrence of cardiovascular death, stroke or myocardial infarction. Other pre-specified outcomes were total mortality, angina pectoris or heart failure requiring hospitalization, resuscitated cardiac arrest and new-onset diabetes. End points were adjudicated by an independent endpoint committee. Patients gave written informed consent, and the study protocol was approved by relevant ethics committees. An independent data and safety board monitored the study. Permission to use DNA samples from Finnish patients for scientific purposes was obtained by informed consent from patients under a protocol approved by the ethics committee of the Finnish National Institute of Health. The LIFE study is registered at http://www. clinicaltrials.org as NCT00338260.

Measurement of telomere length

Samples of peripheral venous EDTA blood for isolation of DNA were obtained at the start of the study and stored frozen until isolation of DNA at the Clinical Material Group, Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden. Extraction of DNA from EDTA blood was performed using PureGene KIT (Gentra Systems, Minneapolis, MS, USA). For this study, DNA samples of 1271 Finnish study participants (668 women and 603 men) were chosen as they represented a sufficiently large cohort from a population that was relatively homogenous genetically, socioeconomically and culturally. Telomere length was measured as described previously10 using TeloTAGGG Telomere length assay kits (Roche Molecular Biochemicals, Basel, Switzerland). In brief, an aliquot (1 mg) of DNA (sample or control DNA) was digested with HinfI and RsaI (20 U per mg DNA each; Roche Molecular Biochemicals) at 37 1C for 2 h. The separation of digested DNA was performed by 0.8% agarose gel Journal of Human Hypertension

electrophoresis at 5 V cm1 in 0.04 M Tris-acetate, 0.001 M EDTA, pH 8.0 buffer for 2–3 h. After electrophoresis, the DNA fragments were transferred by Southern blotting (by capillary transfer) to a positively charged nylon membrane (Hybond N þ , Amersham, Little Chalfont, UK) at room temperature using 3 M NaCl and 0.3 M sodium citrate, pH 7.0. The transferred DNA was then fixed on the blotting membrane by ultraviolet crosslinking (UV Stratalinker 1800, Stratagene, La Jolla, CA, USA). The blotted DNA fragments were hybridized to a digoxigenin-labeled probe specific for telomeric repeats in a hybridization oven (Techne, Burlington, NJ, USA) at 42 1C for 3 h. The membrane was incubated with a digoxigeninspecific antibody covalently coupled to alkaline phosphatase and then visualized by virtue of alkaline phosphatase-metabolizing CDP-Star (Roche Molecular Biochemicals), a highly sensitive chemiluminescence substrate. The membrane was then exposed to a hyperfilm ECL (Amersham). Films were analyzed using Adobe PhotoShop and Science Lab 99 Image gauge software (Fuji Photo Film Co, Ltd, Tokyo, Japan). Mean size of the telomere restriction fragment was estimated using the formula {sum}(ODibackground)/{sum}(ODibackground/Li), where ODi is the chemiluminescent signal and Li is the length of the telomere restriction fragment at position i. Interassay coefficient of variation was 3.70% when calculated from an internal control DNA sample in 96 assays. There is increasing evidence suggesting that regardless of mean telomere length, one critically short telomere may cause a cell to enter senescence.12,13 Therefore, using the same films as for mean telomere restriction fragment analysis, we also calculated the percentage of short telomeres (shorter than 5 kb) in each telomeric sample. This cutoff value was chosen as it identified the shortest 15% of telomeric DNA. Briefly, the total chemiluminescence intensity of each sample was measured and the signal intensity below molecular size marker 5 kb was quantified. Percentage of short telomeres ¼ (intensity of chemiluminescence signal below 5 kbbackground) 100/(total signal intensity background). Statistical methods and analysis

All analyses were conducted first separately in men and women and then in the pooled data. Disease prevalences at baseline were analyzed by computing odds ratios (ORs) using logistic regression models. Age and in the pooled analyses sex were adjusted for by including these variables as covariates in the models. Disease incidences were analyzed by computing hazard ratios using the Cox proportional hazard model. Subjects were followed up from baseline examination to event, death or other termination of the follow-up or the end of the


follow-up on 16 September 2001. Age was adjusted for by including it into the model as a covariate, and, additionally, sex was used in the pooled analyses as a strata variable allowing calculation of baseline hazards in men and women. Proportional hazard assumptions were tested for telomere log-length and proportion of short telomeres separately in men and women using Schoenfeld residuals and were found not to be violated for any disease outcome (P-values 0.28–0.97).

Results Table 1 shows mean telomere length, proportion of short telomeres (o5.0 kb) and baseline characteristics of the study population. Men had shorter mean telomere length (8.1±0.81 kb, mean±s.d.) and higher proportion of short telomeres (8.7±4.5%, mean±s.d.) compared with women (8.2±0.80 kb and 7.9±4.6%, respectively). Mean telomere length showed wide individual variation, and annual telomere shortening rate was similar in males and females (Figure 1). Because only one measurement was perfomed, the change in telomere length was calculated using age at the time of drawing the relevant blood sample. Mean telomere length was inversely correlated with proportion of short telomeres (Figure 2). Disease prevalence at baseline and disease incidence during follow-up are shown in Table 2. At baseline, proportion of short telomeres, but not mean telomere length, correlated with Framingham risk score and serum glucose (men only, Table 3). In this context, the problem of ‘mass significance’ should be considered, notably when significances

are modest or weak. Also at baseline, OR for disease prevalence versus mean telomere length was associated with angina pectoris and ischemic heart disease in males, and with transient ischemic attack in females (Table 4). Proportion of short telomeres (shorter than 5 kb) was associated with type 2 diabetes (not significant in females), cerebrovascular accidents and with any cardiovascular disease at baseline (Table 4). Surprisingly, mean telomere length was positively associated with myocardial infarction in females, but the number of cases was low (Table 2). Telomere length was not significantly associated with body mass index (BMI), systolic or diastolic blood pressure, pulse pressure, proteinuria (Table 3), smoking or self-reported use of alcohol (data not shown). Moreover, telomere length was not associated with electrocardiogram estimation of LVH by Cornell or Sokolow–Lyon criteria (data not shown). During follow-up, development of angina pectoris in men was associated with short mean telomere length (Table 5). Development of any cardiovascular disease during follow-up was associated with proportion of short telomeres in the whole study group. Outcomes of drug treatment based on either losartan or atenolol were not affected by telomere length at baseline.

Discussion Our observation of an association of short mean telomere length with previous transient ischemic attack (in women) has not been reported previously. Similar to our observation of an association of cerebrovascular accidents with proportion of short

Table 1 Means and s.d. of baseline study characteristics and statistical significance of the difference in mean values between men and women Men (N ¼ 603)

Age (years) Telomere length (kb) Proportion of short telomeres (%) Framingham risk score Serum creatinine (mmol l1) Serum glucose (mmol l1) Total cholesterol (mmol l1) HDL cholesterol (mmol l1) Height (cm) BMI (kg m2) Diastolic blood pressure (mm Hg) Systolic blood pressure (mm Hg) Pulse pressure (mm Hg) Pulse rate (beats min1) Proteinuria (mg mmol1 l1)b Serum uric acid (mmol l1)

P-valuea

Women (N ¼ 668)

Mean

s.d.

Mean

s.d.

63 8.1 8.7 24.5 87.9 5.93 5.7 1.42 174.4 27.5 99.8 171.1 71.3 69.9 3.8 370

5.7 0.81 4.46 7.37 13.18 1.76 0.97 0.37 5.97 3.48 7.61 14.28 14.74 10.31 21.97 71

65 8.2 7.9 14.6 75.6 5.54 6.3 1.72 160.4 28.5 98.4 174.4 76.0 73.1 3.4 310

6.6 0.80 4.59 5.51 17.21 1.33 1.02 0.43 5.64 4.45 7.88 13.98 14.42 10.57 21.46 64

o0.0001 o0.0001 0.0002 o0.0001 o0.0001 o0.0001 o0.0001 o0.0001 o0.0001 o0.0001 0.099 0.019 0.001 0.000 0.351 o0.0001

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein. a Adjusted for age. b Ratio of urine albumin to creatinine concentration. Journal of Human Hypertension

Telomere length in the LIFE study F Fyhrquist et al 714 Men

Women

mean telomere length (kb)

12.00

10.00

8.00

6.00

70

60

60

80

70

Age

80

Age

Figure 1 The mean telomere length and age in males and females. Slope of the solid line indicates the annual telomere-shortening rate in males (telomere log mean change 0.22, 95% CI 0.34, 0.11) and females (telomere log mean change 0.08, 95% CI 0.17, 0.01, per 10-year difference, not significant, P ¼ 0.06).

Proportion of short telomers

Men

Women

30.00

20.00

10.00

0.00 6.00

8.00

10.00

mean telomer length (kb)

12.00

6.00

8.00

10.00

12.00

mean telomer length (kb)

Figure 2 Telomere length and proportion of short telomeres (shorter than 5 kb) in males and females.

telomeres (Table 4), it is in agreement with the reported association of telomere length with stroke.8 It also fits previous observations of an association between short telomeres and cardiovascular diseases such as carotid artery atherosclerosis,14 coronary artery disease7 and myocardial infarction.15 Our findings support the concept that short telomeres may represent premature vascular aging with increased risk of cardiovascular disease.3,4 Short telomere length was associated with ischemic heart disease in males only. This gender difference may be explained by differences by gender in clinical symptoms or by small patient numbers. The positive association of telomere length with prevalence of myocardial infarction at baseline observed in females, with OR 2.55 (not significant in males, Table 4), is surprising and may be a chance finding due to the low number of events. Proportion of short telomeres and risk factors

Interestingly, we noticed that proportion of short telomeres (shorter than 5 kb), but not mean telomere Journal of Human Hypertension

length, was associated with Framingham risk score (all subjects), cerebrovascular accidents, any cardiovascular disease, fasting blood glucose (men only) and type 2 diabetes. Proportion of short telomeres may more closely reflect cellular senescence of a subset of circulating leukocytes and vascular aging than mean telomere length, as has been suggested previously.12,13 Indeed, in a study concerning 274 Danish twin pairs, the proportion of shortest telomeres was a better predictor of mortality than mean telomere length.16 Accordingly, we recently reported that the proportion of shortest telomeres was a better predictor than mean telomere length of progression of renal disease in patients with type 1 diabetes.10 Telomere length and disease during follow-up

We noticed a negative association between mean telomere length and incidence of ischemic heart disease during follow-up in men and with any cardiovascular disease in the whole study group, which is in agreement with previous observations of


Table 2 Prevalence and incidence of cardiovascular disease and diabetes Disease prevalence

Men

Angina pectoris CVA Type 2 diabetes Ischemic heart disease MI Transient ischemic attack Any CVDa Disease incidence

Women

Number of cases

Cases per 100 participants

Number of cases

Cases per 100 participants

24 20 66 45 16 31 86

4.0 3.3 10.9 7.4 2.6 5.1 14.2

25 13 45 41 5 32 82

3.7 1.9 6.7 6.1 0.8 4.8 12.2

Number of cases

Cases per 1000 person years

Number of cases

Cases per 1000 person years

21 10 25 38 76 3709

9.4 4.4 11.2 17.0 33.3

27 14 18 31 58 4125

12.1 6.2 8.0 13.8 25.4

Total mortality Cardiovascular mortality Stroke Angina pectoris Any CVDb Number of person years

Abbreviations: CVA, cerebrovascular accident; CVD, cardiovascular disease; MI, myocardial infarction. a Angina pectoris or CVA or ischemic heart disease or MI or transient ischemic attack (TIA). b Cardiovascular mortality or stroke or angina pectoris.

Table 3 Age-adjusted correlations of telomere length and proportion of short telomeres (shorter than 5 kb) with metabolic and anthropometric factors Telomere lengtha Men

BMI Total cholesterol Framingham risk score Serum creatinine Diastolic blood pressure Serum glucose Total cholesterol HDL cholesterol Height Pulse rate Systolic blood pressure Pulse pressure Proteinuria Serum uric acid

Proportion of short telomeres Allb

Women

Men

Allb

Women

r

P-value

r

P-value

r

P-value

r

P-value

r

P-value

r

P-value

0.01 0.00 0.03 0.00 0.03 0.06 0.00 0.01 0.05 0.02 0.03 0.04 0.00 0.02

0.65 0.87 0.47 0.85 0.50 0.19 0.87 0.83 0.24 0.59 0.59 0.36 0.94 0.64

0.01 0.03 0.03 0.07 0.03 0.01 0.03 0.03 0.05 0.02 0.01 0.02 0.01 0.07

0.99 0.45 0.55 0.09 0.59 0.78 0.45 0.47 0.35 0.33 0.39 0.25 0.81 0.11

0.01 0.02 0.04 0.04 0.00 0.03 0.02 0.01 0.00 0.02 0.01 0.01 0.00 0.01

0.77 0.59 0.24 0.15 0.91 0.29 0.59 0.76 0.79 0.34 0.87 0.92 0.89 0.56

0.05 0.03 0.07 0.06 0.08 0.12 0.03 0.05 0.02 0.03 0.01 0.04 0.02 0.06

0.17 0.60 0.11 0.15 0.06 0.01 0.60 0.30 0.68 0.73 0.80 0.45 0.58 0.10

0.02 0.01 0.07 0.04 0.01 0.02 0.01 0.06 0.02 0.05 0.01 0.00 0.01 0.05

0.69 0.72 0.10 0.32 0.99 0.57 0.72 0.14 0.65 0.38 0.77 0.77 0.73 0.19

0.03 0.02 0.07 0.05 0.03 0.07 0.02 0.06 0.00 0.01 0.00 0.02 0.00 0.06

0.24 0.53 0.02 0.10 0.21 0.01 0.53 0.07 0.98 0.70 0.70 0.76 0.09 0.05

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein. Logarithmic transformation was used. b Additionally adjusted for sex. Numbers in bold denote significance. a

associations of short telomeres with coronary artery disease17 and premature myocardial infarction.15 Shorter telomeres in cardiovascular diseases may reflect the cumulative burden of inflammatory mechanisms and oxidative stress,18 associated with atherosclerosis and vascular aging. Telomere length, BMI, smoking and blood pressure

We were unable to demonstrate significant correlations between telomere length or proportion of short

telomeres, and BMI, smoking, systolic blood pressure or pressure. In contrast with our observations, two studies on healthy female twins aged 18–75 years, from the St Thomas’ (Twins UK) Twin Registry, showed that short telomeres were associated with BMI and smoking.19,20 Similar observations were recently made in young (mean age 31.4–37.4 years) whites and African Americans participating in the Bogalusa Heart Study.21 Associations between BMI, smoking and telomere length may be obscured by several factors known to affect telomere length, Journal of Human Hypertension


Table 4 Age-adjusted odds ratios with 95% confidence intervals of telomere length and proportion of short telomeres for disease prevalence at baseline Men

Alla

Women

OR

95% CI

OR

95% CI

OR

95% CI

Telomere lengthb Angina pectoris CVA Type 2 diabetes Ischemic heart disease MI Transient ischemic attack Any CVDc

0.49 0.94 0.82 0.61 0.90 1.21 0.91

0.27–0.91 0.53–1.66 0.58–1.15 0.39–0.95 0.47–1.73 0.79–1.87 0.69–1.21

1.09 0.89 0.71 1.08 2.55 0.62 0.91

0.66–1.78 0.43–1.82 0.48–1.05 0.73–1.61 1.03–6.31 0.39–0.99 0.64–1.19

0.79 0.92 0.77 0.84 1.19 0.87 0.91

0.54–1.14 0.59–1.44 0.60–1.00 0.63–1.11 0.71–2.00 0.63–1.21 0.75–1.11

Proportion of short telomeres Angina pectoris CVA Type 2 diabetes Ischemic heart disease MI Transient ischemic attack Any CVDc

1.04 1.09 1.07 1.05 1.01 1.01 1.03

0.95–1.14 0.99–1.19 1.01–1.14 0.98–1.12 0.90–1.13 0.93–1.10 0.99–1.08

1.01 1.07 1.06 1.03 1.00 1.07 1.04

0.92–1.10 0.97–1.18 0.99–1.12 0.96–1.10 0.82–1.21 0.99–1.14 0.99–1.09

1.02 1.15 1.07 1.04 1.01 1.04 1.04

0.96–1.09 1.01–1.18 1.02–1.11 0.99–1.09 0.92–1.11 0.99–1.10 1.01–1.08

Abbreviations: CVA, cerebrovascular accident; CVD, cardiovascular disease; MI, myocardial infarction. a Additionally adjusted for sex. b Logarithmic transformation was used. c Angina pectoris or CVA or ischemic heart disease or MI or transient ischemic attack (TIA).

Table 5 Age-adjusted HRs with 95% CIs of telomere length and proportion of short telomeres for mortality and disease incidence during follow-up Men

Alla

Women

HR

95% CI

HR

95% CI

HR

95% CI

Telomere lengthb Total mortality Cardiovascular mortality Myocardial infarction Stroke Angina pectoris Any CVDc

0.94 0.92 1.02 1.00 0.51 0.91

0.53–1.64 0.41–2.04 0.65–1.58 0.61–1.65 0.26–0.99 0.69–1.21

0.97 0.70 1.24 0.99 1.28 0.91

0.60–1.58 0.35–1.39 0.81–2.22 0.56–1.75 0.66–2.49 0.69–1.19

0.95 0.79 1.14 1.00 0.79 0.91

0.66–1.38 0.46–1.34 0.82–1.58 0.69–1.45 0.50–1.27 0.75–1.11

Proportion of short telomeres Total mortality Cardiovascular mortality Myocardial infarction Stroke Angina pectoris Any CVDc

1.02 1.03 1.01 1.03 1.05 1.03

0.93–1.13 0.90–1.19 0.93–1.09 0.94–1.12 0.96–1.16 0.99–1.08

1.03 1.06 0.99 1.02 0.98 1.04

0.95–1.12 0.95–1.17 0.90–1.09 0.92–1.14 0.87–1.12 1.00–1.09

1.03 1.05 1.00 1.02 1.03 1.04

0.96–1.09 0.96–1.14 0.94–1.07 0.96–1.10 0.95–1.11 1.01–1.07

Abbreviations: CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio. a Additionally adjusted for sex. b Logarithmic transformation was used. c CV mortality or stroke or angina pectoris.

including gender, age and cardiovascular disease. Thus, the subjects studied by us were elderly (mean age 67, range 55–80 years) and had two or more cardiovascular risk factors, including LVH and hypertension. Consistent with our findings, other investigators have also failed to demonstrate a significant association between telomere attrition and BMI,3,8,22 smoking22,23 or pulse Journal of Human Hypertension

pressure.23 Several explanations for such apparent lack of consensus may be offered.24 For instance, telomere length varies individually and is under genetic control.25 Further, variability of telomere length may be caused by influences of diet and physical activity,26 psychological stress27 and various diseases.5–8,15,16,22–24 Importantly, a recent report stated that in 850 Framingham Heart


Study participants, leukocyte telomere length was positively associated with left ventricular mass and wall thickness, especially in participants with hypertension.28 If applicable to the LIFE study participants, this observation may partly explain some of the above-mentioned discrepancies, as all of our patients had both hypertension and LVH. However, we failed to show associations of either Cornell product or Sokolow–Lyon voltage index with telomere length (unpublished observation). This may be due to the well-known weakness of these criteria to reliably assess the degree of LVH.

What is known about this topic K Mean leukocyte telomere length is associated with cardiovascular disease and risk factors. K Leukocyte telomeres are shorter in age-matched males than in females. K Telomeres are considered the biological clock of the cell. What this study adds K This is the only study in hypertensive patients with left ventricular hypertension. K Transient ischemic attack is associated with short telomere. K Proportion of short telomeres may offer additional information on cardiovascular risk compared with mean telomere length.

Telomere length and prediction of cardiovascular events

Telomere length was predictive of new angina pectoris and any cardiovascular disease taken together, but not of cardiovascular or total mortality, myocardial infarction or stroke as individual outcomes. This may be partly explained by the low numbers of cardiovascular death and stroke during follow-up in this study population. Moreover, antihypertensive treatment might have modified the predictive power of telomere length at baseline. In fact, we noticed in hypertensive patients with type 1 diabetes that those treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker had longer telomeres than patients receiving either a b blocker or a calcium channel blocker.10 Strengths and limitations of this study

The strengths of this study were the following: first, the relatively large number of participants; second, all subjects were carefully examined and findings prospectively recorded; third, end points were adjudicated by an endpoint committee; and fourth, the use of a reliable Southern blot10,22 method for the measurement of telomere length. An additional strength was that all subjects belonged to an ethnically homogenous Finnish population. The limitations of this study were its character of a cross-sectional post hoc study, and the lack of an age-matched control group.

Conclusions We have shown in a high-risk middle aged to elderly hypertensive population with LVH that leukocyte telomere length was associated with ischemic heart disease in men and transient ischemic attack in women, and that a high proportion of short telomeres was related to increased cardiovascular risk and type 2 diabetes. Short telomere length was predictive of the combination of any cardiovascular disease during follow-up. The association of telomere length with cardiovascular risk and diabetes supports the concept that short telomeres are markers of cardiovascular aging and risk.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements This work was supported by grants from the Wilhelm and Else Stockmann Foundation, the Sigrid Juse´lius Foundation and the Liv och Ha¨lsa Foundation, Helsinki, Finland. The LIFE study was sponsored by Merck & Co, Inc.

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Journal of Human Hypertension

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