Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity.
BACKGROUND
Shortening of mean telomere length (TL) in white blood cells is correlated with the development of coronary heart disease (CHD) and with increased mortality due to infectious disease. The goal of the present study was to investigate whether telomere shortening in CHD is restricted to specific peripheral blood lymphocyte and/or myeloid cell subpopulations. Results were correlated to TL in CD34+ hematopoietic peripheral blood stem cells and progenitor cells obtained from the same individual patients.


RESULTS
TL was measured by multicolor flow cytometry-fluorescent in situ hybridization in 12 leukocyte subpopulations after immunomagnetic bead sorting. We investigated TL in 14 young (mean age 25 years) and 13 older (mean age 65 years) healthy male volunteers and in 25 age-matched patients with CHD (mean age 65 years). We show that TL in granulocytes and monocytes mirrors TL of CD34+ peripheral blood stem cells and progenitor cells extremely well (r=0.95, P<0.0001) in patients and in healthy adults. TL was approximately 0.5 kilobases (kb) shorter in leukocytes from patients with CHD than in their age-matched control subjects. This difference was identical for CD34+ peripheral blood stem cells and progenitor cells, monocytes, granulocytes, B lymphocytes, and CD4+ T cells, including their memory and naïve subpopulations. Surprisingly, only in cytotoxic CD8+ T lymphocytes, we found a substantially increased TL deficit of 1.0 kb in CHD patients as opposed to control subjects. Further analysis revealed that TL shortening was particularly pronounced in CD8+CD28(-) T cells obtained from cytomegalovirus-seropositive CHD patients, whereas such a difference was not observed in healthy cytomegalovirus-positive as opposed to cytomegalovirus-negative control subjects. Finally, TL shortening of CD8+CD45(RA+) T cells was correlated with the decrease in left ventricular function in CHD patients (r=0.629, P=0.001).


CONCLUSIONS
Telomere shortening in patients with CHD could potentially be attributed to either inherited TL shortening or acquired accelerated telomere shortening restricted to the hematopoietic system, which affects the baseline TL of all peripheral blood cell populations, including peripheral blood stem cells and progenitor cells. In addition, cytomegalovirus-seropositive patients but not healthy control subjects exhibited further shortening of their cytotoxic T lymphocytes. Surprisingly, TL shortening of CD8+ T lymphocytes in CHD patients demonstrated a very strong correlation with cardiac dysfunction, which suggests a mechanistic link between CHD and immunosenescence.
Spyridopoulos
Ioakim
I
Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle Upon Tyne NE13BZ, United Kingdom. ioakim.spyridopoulos@newcastle.ac.uk
Hoffmann
Jedrzej
J
Aicher
Alexandra
A
Brümmendorf
Tim H
TH
Doerr
Hans W
HW
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003327:Coronary Disease / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000276:immunology; D005434:Flow Cytometry; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology; D012016:Reference Values; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000502:physiology* / Q000648:ultrastructure; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D019098:Telomerase