Introduction
ST-segment elevation myocardial infarction (STEMI) is a life-threatening medical condition with a high incidence in Western societies [
1]. Timely reperfusion of the culprit artery by primary percutaneous coronary intervention (PCI) is the cornerstone of medical treatment to improve survival and reduce the risk of left ventricular (LV) dysfunction [
2]. Nevertheless, up to 30 % of patients develop systolic LV dysfunction after STEMI [
3], which is an important predictor for clinical outcome [
4]. However, the susceptibility to develop LV dysfunction among individuals suffering from STEMI remains partially unpredictable, even after considering factors as ischemic time and culprit lesion characteristics. Increasing our knowledge on these factors might provide novel avenues for risk stratification and future development of therapy.
We hypothesize that telomere length might be an important factor associated with the development of LV dysfunction after STEMI. In humans, telomeres are repetitive hexameric sequences (TTAGGG)
n
located at the terminal end of chromosomes, which protect genes from degradation during cell division due to the ‘end replication problem’ [
5,
6]. With each mitotic cell division, a terminal part of the telomere is lost since DNA polymerases fail to completely replicate the strand which begins at the 3′ chromosomal end [
7]. Aging is, therefore, associated with gradual loss of telomere length. If a critical telomere length is reached, cellular senescence or apoptosis is induced [
8]. Environmental stressors, for example oxidative stress [
9,
10], and inflammatory processes [
11], are associated with accelerated shortening of telomere length. Patients with cardiovascular diseases, like coronary artery disease [
12], myocardial infarction [
13], and heart failure [
14] are characterized by shorter telomeres compared to healthy controls [
6]. Telomere length has also been associated with LVEF in octogenarians in a non-STEMI setting [
15], nevertheless PCI treatment for STEMI has been proven safe and effective in this age group [
16,
17]. In addition, genetic variants implicated in LTL have also been associated with LVEF suggesting a potential causal relationship [
18].
We present a sub-study of the glycometabolic intervention as adjunct to primary coronary intervention in STEMI (GIPS-III) trial in which we measured leukocyte telomere length to investigate whether baseline leukocyte telomere length is associated with LVEF 4 months after STEMI.
Discussion
Leukocyte telomere length has been proposed as a marker of biological age and has been suggested to play an important role in cellular senescence or apoptosis [
8]. Previously, associations have been reported between LTL with coronary artery disease [
12], heart failure [
23], and LVEF [
15]. We hypothesized that LTL is associated with cardiac remodeling after STEMI as can be reflected by LVEF at 4 months. The main finding of the present study is that we could not find support for this hypothesis.
In our study, we did observe the well-established association of LTL with baseline characteristics such as the inverse association with age [
23,
24] and gender (females having longer LTL [
25]). The direction of smokers was opposite as frequently reported (active smokers in GIPS-III were found to have longer LTL) [
22,
26] but this could be completely explained by the large age difference between non-smokers and smokers. These associations suggest that our main finding is unlikely due to measurement error of LTL. A possible explanation for the absence of an association between LTL and LVEF in the GIPS-III trial might be the relatively well-preserved LVEF after STEMI. Considering the mean LVEF of approximately 54 % after STEMI, the variation of the primary endpoint might have been too small to establish an association with LTL. However, even in the absence of STEMI and the resulting cardiac remodeling, one could speculate on an association between LVEF and LTL. In a cohort of octogenarians (
N = 64; average age 85.2-year old) without evidence of previous myocardial infarction, LTL was strongly and independently associated with LVEF as determined by echocardiography [
15]. In this cohort, approximately 12 % of the observed variability in LVEF could be explained by LTL alone. In addition, an association between LTL and LVEF has been reported in subjects with hypertension (
N = 1106; average age 57.9-year old). A 1.5 fold larger LTL was associated with 0.6 % increase in absolute LVEF [
18]. On the other hand, there are also several studies reporting a lack of an association between LTL and LVEF in other settings. In a cohort with established heart failure patients (
N = 610; average age 66.2-year old), we did not observe an association with LVEF [
14]. In another cohort of patients with idiopathic cardiomyopathies (
N = 223; average age 51.1-year old), LTL was also not associated with LVEF as determined [
27]. Also in subjects derived from the general population, the absence of an association between LTL and LVEF has been reported. In the Malmö Preventive Project, a cross-sectional observational study including 1588 subjects (average age 67.7-year old), an association with LTL with LVEF was lacking [
28]. In an additional population-based cohort of Chinese Han people (
N = 139; average age 60.3-year old), there was also no association with LTL and LVEF [
29].
Our data contribute to the previous studies by investigating a specific population (STEMI) in which the role of LTL might be more prominent. However, our data demonstrate that even in the setting of STEMI and the subsequent remodeling process of the heart, LTL does not seem to be associated and, therefore, is unlikely to be involved. Biomarkers for predicting outcomes in coronary heart disease outcomes have been reported [
30], but the present study does not support the use of LTL as a biomarker in the setting of STEMI. The well-preserved LVEF 4 months after STEMI, which is the result of the high level of acute care in our STEMI network [
31], could have nullified the potential role of LTL in STEMI outcome prediction. Besides LVEF, we also took into account possible relationships between LTL and other outcome parameters. In our study, lower levels of NT proBNP, often elevated in heart failure, were associated with longer LTL only in the metformin group. Further studies are needed to clarify if this association can be attributed to the effect of metformin. Other studies report the predictive value of cardiopulmonary exercise testing in heart failure patients with previous myocardial infarction [
32]. In experimental mice model, physical activity prevented senescence of leukocytes and increased telomerase activity was seen in endurance athletes [
33]. In this study, physical activity was not measured; therefore, we cannot assess the effect of physical activity on LTL. Worsening renal function and acute kidney injury are associated with increased mortality in STEMI patients [
34]. In our study, serum creatinine was associated with shorter LTL; however, after adjusted for age and sex, this relationship did not remain significant.
The major limitation of our study that needs to be considered is that the cells we investigated are leukocytes. Therefore, we cannot exclude an important role of telomere length in other cell types, e.g., cardiomyocytes or endothelial cells [
35]. For practical (and ethical) reasons, it is not feasible to study cardiomyocytes of STEMI patients. Another limitation is that our analyses are based on a single LTL measurement. Therefore, we cannot exclude that LTL measurements in the stable setting or cross-sectionally at time of LVEF determination are associated with LVEF. This remains to be determined. In this study, PCR method was used for feasibility reasons; however, the gold standard for LTL assessment is FACS-FlowFISH which more specifically can differentiate between different cell subpopulations within the peripheral blood [
36]. Finally, telomere length is only one of the parameters of telomere biology related to apoptosis and senescence. Telomere biology is more complex than telomere length alone. It also involves many regulatory and stabilizing protein complexes (sheltering) interacting with the telomere DNA sequence to protect the DNA [
6,
37]. The exclusion of telomere length as a factor associated with LVEF does not exclude a role of telomere biology per se. The strengths of our study include that we have executed the current study within the framework of a clinical trial using the golden standard to determine LVEF.
In conclusion, LTL measured in the setting of STEMI is not associated with cardiac remodeling or LVEF as determined by MRI after 4 months. Our study does not lend support for a role of LTL as a causal factor in LV remodeling or for the use as a biomarker to predict clinical outcome in patients with acute myocardial infarction.
Acknowledgments
We thank J. Takens and M. M. Dokter for their excellent technical assistance during LTL measurements. The GIPS-III trial was supported by Grant 95103007 from ZonMw, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. The present analyses were supported by Grant 95103007 from ZonMw and the Innovational Research Incentives Scheme (NWO VENI, Grant Number 916.76.170 to PvdH) of the Netherlands Organization for Health Research and Development, The Hague, The Netherlands.