Telomeres, oxidative stress, and myocardial infarction

Telomeres are nucleotide sequences at the end of each eukaryotic chromosome, which confer a protective role during cell division. These segments are shortened with each cell division, unless replenished by the enzyme telomerase. When the length of telomeres shortens beyond a point, the cell becomes senescent and is no longer able to proliferate, ultimately undergoing apoptosis. Telomere length (TL) is determined by direct inheritance of telomeres through parental gametes, and genetic and non-genetic factors that affect the balance between telomere shortening and telomerase activity. As such, TL varies significantly in different populations, tissues, and cells. Immune cells, endothelial cells, and vascular smooth muscle cells (VSMCs) are all involved in the pathogenesis of atherosclerosis, and a short TL in these cell types has been associated with atherosclerosis. While short leucocyte TL (LTL) is correlated with increased mortality and risk of coronary atherosclerotic disease (CAD), it is unclear whether this increased risk is predominantly driven by genetic factors or non-genetic factors correlated with CAD which may also affect TL, such as increased oxidative stress and inflammation. In this issue of the journal, Margaritis et al. present exciting and thought-provoking results on the use of TL as a prognostic marker following acute myocardial infarction (AMI) as well as the interactions between oxidative stress and TL in whole blood vs. vascular tissue. In a first group of patients, TL was measured by quantitative PCR in whole blood samples (BTL) in patients post-AMI who were then followed for 1 year. Using a dichotomous cut-off based on receiver operating characteristic (ROC) analysis for predicting mortality, short BTL was a strong independent predictor of all-cause and cardiovascular mortality 1-year after AMI. The authors then used a second group of patients with ischaemic heart disease undergoing coronary artery bypass grafting to assess the relationship between oxidative stress and short TL. In this group, the authors used isolated peripheral blood mononuclear cells (PBMCs) to measure NADPH-stimulated superoxide (O2 ) production ex vivo, and show that PBMCs from patients with short BTL produced more O2 – upon stimulation. Single nucleotide polymorphisms (SNPs) of the CYBA gene encoding the p22 subunit of NADPH-oxidases (NOXs) was used to group the patients based on NOX activity. As expected, PBMCs with higher NOX activity produced more O2 – upon stimulation, but also had a shorter BTL. Saphenous venous graft (SV) and internal mammary artery (IMA) samples were also collected, and vascular tissue TL (VTL) and vascular O2 – production were measured. There was no significant correlation between BTL and VTL in this group. Furthermore, VTL (but not BTL) was inversely correlated with vascular O2 – production. Flow-mediated dilation (FMD) of the brachial artery was used as a measure of endothelial function, and again VTL from IMA samples correlated with FMD, but BTL showed no significant correlation. VSMCs were cultured from SV samples collected from patients with the lowest NOX activity SNPs (0 risk alleles) and the highest NOX activity SNPs (4 risk alleles), and angiotensin II (Ang II) was used to stimulate O2 – production. While VSMCs produced significantly higher levels of O2 – in response to Ang II stimulation as previously shown in cells with the highest NOX activity SNPs; this was not seen in cells with the lowest NOX activity SNPs. Moreover, TL showed significant shortening in the highest NOX activity cells along with evidence of increased DNA damage upon chronic exposure to Ang II, but not in the lowest NOX activity cells. The first important finding of this study is that patients with a short BTL had higher 1-year mortality rates following AMI, which has not been previously reported. This finding is concordant with previous reports that a short LTL is associated with increased mortality and risk of CAD. While further studies are needed to confirm the results in validation cohorts, the findings suggest that BTL may be useful as a prognostic factor in patients following AMI. Multiple methods for measuring TL have been developed, including but not limited to quantitative PCR assay of telomere repeats [in which TL is expressed as a ratio of telomeric repeat amplification to a known single-copy gene (T/S) as used in the current study], and terminal restriction