Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients.
BACKGROUND
There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals.


OBJECTIVE
The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients.


RESULTS
Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/μL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001).


CONCLUSIONS
Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Jedrzej
J
Hoffmann
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Evgeniya V
EV
Shmeleva
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Stephen E
SE
Boag
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Karel
K
Fiser
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Alan
A
Bagnall
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Santosh
S
Murali
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Ian
I
Dimmick
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Hanspeter
H
Pircher
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Carmen
C
Martin-Ruiz
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Mohaned
M
Egred
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Bernard
B
Keavney
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Thomas
T
von Zglinicki
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Rajiv
R
Das
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.).
Stephen
S
Todryk
From the Institute of Genetic Medicine (J.H., E.V.S., S.E.B., S.M., B.K., I.S.), Institute of Aging and Health (C.M.-R., T.v.Z.), and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., S.T.), Department of Cardiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (A.B., M.E., R.D., I.S.); Flow Cytometry Core Facility, International Center for Life, Newcastle upon Tyne, United Kingdom (I.D.); Department of Immunology, Institute of Medical Microbiology and Hygiene, Freiburg University, Germany (H.P.); CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic (K.F.); University Hospital Motol, Prague, Czech Republic (K.F.); Institute of Cardiovascular Sciences, The University of Manchester, United Kingdom (B.K.); and Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (S.M., S.T.). ioakim.spyridopoulos@newcastle.ac.uk.
Ioakim
I
Spyridopoulos
D000368:Aged; D016827:CD8 Antigens / Q000097:blood*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology*; D003430:Cross-Sectional Studies; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood* / Q000453:epidemiology / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000453:epidemiology / Q000821:virology; D015425:Myocardial Reperfusion / Q000379:methods*
D016827:CD8 Antigens
aging; cytotoxic T-lymphocytes; human cytomegalovirus; myocardial infarction; programmed cell death 1; reperfusion; telomere