Shorter mean leukocyte TL is a remarkable and consistent finding in subjects with ischemic heart disease, but the reason is not known. Nevertheless, short overall mean leukocyte telomere length has been viewed as a reflection of short telomere length in other cells, possibly of vascular progenitor cells, and thereby providing a link to an impaired vascular repair mechanism potentially causing ischemic heart disease. We indeed observed a good correlation between overall mean leukocyte telomere length and CD34+, MNCs and buccal cells in healthy subjects and also in their offspring. However, these high intra-individual correlations were lost in subjects with IHF and their offspring. The major difference in telomere length between IHF patients and controls was observed in the overall leukocyte pool, not specifically in CD34+, MNCs or buccal cells as a source of non-blood derived cells. We confirmed earlier findings, suggesting shorter leukocyte telomere length in offspring of patients with coronary artery disease versus offspring of healthy controls 
. Finally, we confirmed the strong associations between parent and offspring TL in all four cell types we examined.
The comparable TL of CD34+ cells in cases and controls and both offspring groups are consistent with earlier findings 
and strongly suggest that telomere shortening of CD34+ cells is not a major player in the pathophysiology of IHD. If there is any role of TL in this process – the consistent finding of shorter leukocyte TL in IHD patients does support this allegation – it would rather involve other leukocyte populations. It is known that leukocyte function changes with aging. In the elderly, specific immune responses might be diminished, but many other functions are unchanged or even augmented compared to young persons 
. A state of low-grade chronic inflammation has been recognized in elderly, which makes them prone to chronic inflammatory diseases, including atherosclerosis 
. Macrophages, and to a lesser extent other leukocytes, catalyse the process of atherosclerosis by eliciting an enhanced systemic inflammatory response, possibly through increased oxidative stress 
. Interestingly, it has been demonstrated that macrophages with short telomeres are more susceptible to damage from oxidative stress, and in addition have higher intracellular concentrations of oxidative stress molecules 
, which are suggested to be a driving force in the development and progression of atherosclerosis 
. These data strongly suggest that aging – chronologically or biologically – of leukocytes can possibly augment their unbeneficial contribution to IHD.
A secondary focus of our study was the heredity of TL traits among cell populations. Heritability of mean leukocyte telomere length has been demonstrated previously 
. We now add to this the heritability patterns in TL derived from different cell fractions. A tissue specific TL regulation has been suggested, since TLs differ between different types of tissue 
. In addition, external influences on TL are acknowledged. For instance, it has been shown that vascular endothelial cells that endure more hemodynamic sheer stress have shorter telomeres than endothelial cells in low pressure arteries 
. Also, oxidative stress is a well-known factor that causes telomere shortening 
. Our results indicate that despite external influences and tissue specific TL regulation, TL is a highly inheritable trait throughout different cell types.
Strengths and limitations
Our study is strengthened by the fact that we not only examined TL of IHF patients and controls, but also of their offspring. Our finding that TL in healthy offspring of IHF patients is shorter than in healthy offspring of controls supports the hypothesis that, next to the genetic predisposition to coronary artery disease deriving from specific genes, TL might also be a factor contributing to familial predisposition to IHD. Furthermore, we separated leukocyte cell fractions to determine differential expression of TL. This is significant, since knowledge on which specific cell types contribute to the shorter mean leukocyte TL is necessary in order to identify a potential mechanism underlying the association between TL and IHD. To our knowledge, our study is the first study that investigated both heritability features and differential expression of TL in leukocyte subpopulations. Also, our study was a prospective study, meaning all measures were taken in advance to preserve blood and tissue samples taken from participants, which contributed to high accuracy of experimental procedures and laboratory measurements.
We also have to acknowledge some limitations. The separation of white blood cells was limited to MNCs and CD34+. Because of potential functional relevance, our main interest was the CD34+ cell population. However, we demonstrated that the CD34+ cell population is not the cell population that drives the difference in leukocyte TL between IHF patients and controls. This difference must thus lie in other leukocyte cell populations that we did not separately analyse in this study.
In conclusion, we found that TL is shorter in leukocytes of IHF patients and their healthy offspring compared to healthy controls and their healthy offspring. This is supporting evidence for a causal role of TL in familial predisposition to ischemic heart disease. The fact that we did not find a difference in TL of CD34+ cells between IHF patients and healthy controls, suggests that these cells are not involved in the potential mechanism linking short TL and ischemic heart disease. Furthermore, we found good correlations between parent and offspring TL in all cell types we examined, indicating a strong inheritance pattern of TL. Evidence for a causal role of TL in ischemic heart disease will be helpful in finding new therapeutic targets.