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FASEB J ; 35(5): e21604, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33913566


Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes. We retrospectively analyzed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical, and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand, circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (P < .05) and correlated inversely with left ventricular function (r = 0.41, P = .04). The early fall in NC monocytes post-reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury. In conclusion, rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.

Traumatismos Cardíacos/sangue , Traumatismos Cardíacos/patologia , Monócitos/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Animais , Feminino , Traumatismos Cardíacos/etiologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos
Antioxid Redox Signal ; 26(12): 660-675, 2017 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-28006953


SIGNIFICANCE: Myocardial ischemia/reperfusion (I/R) is an important complication of reperfusion therapy for myocardial infarction (MI). It is a complex process involving metabolic and immunological factors. To date, no effective treatment has been identified. Recent Advances: Previous research has focused on the role of innate immune cells in I/R injury. In recent years, increasing evidence has accumulated for an important role for adaptive immune cells, particularly T lymphocytes. Data from ST elevation MI patients have identified prognostic significance for lymphocyte counts, particularly postreperfusion lymphopenia. Dynamic changes in circulating CD4+ T cell subsets occurring early after reperfusion are associated with development of I/R injury in the form of microvascular obstruction. Transcoronary gradients in cell counts suggest sequestration of these cells into the reperfused myocardium. These findings support existing data from mouse models indicating a role for CD4+ T cells in I/R injury. It is clear, however, the effects of lymphocytes in the ischemic myocardium are time and subset specific, with some having protective effects, while others are pathogenic. CRITICAL ISSUES: An understanding of the cellular events that lead to accumulation of lymphocytes in the myocardium, and their actions once there, is key to manipulating this process. Chemokines produced in response to ischemia and cellular injury have an important role, while lymphocyte-derived cytokines are critical in the balance between inflammation and healing. FUTURE DIRECTIONS: Further research into the involvement of lymphocytes in myocardial I/R injury may allow development of targeted therapies, opening a new avenue of considerable therapeutic potential. Antioxid. Redox Signal. 26, 660-675.

Imunidade Adaptativa , Linfócitos T CD4-Positivos/imunologia , Infarto do Miocárdio/imunologia , Traumatismo por Reperfusão Miocárdica/imunologia , Animais , Comunicação Celular/imunologia , Humanos , Camundongos , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/patologia
J Clin Invest ; 125(8): 3063-76, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26168217


BACKGROUND: Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury. METHODS: Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI. RESULTS: In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8+ T cells decreased more than CD4+ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir. CONCLUSIONS: Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells. TRIAL REGISTRATION: Not applicable. FUNDING: British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.

Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CX3CL1/sangue , Linfopenia , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Linfopenia/sangue , Linfopenia/etiologia , Linfopenia/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida
Immun Inflamm Dis ; 3(2): 56-70, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26029366


CMV infection is responsible for acceleration of immune senescence and linked to systemic pathologies, including cardiovascular diseases. In this study, we investigated differences in the immune response between CMV-seropositive and seronegative patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (MI). Peripheral blood samples were taken at six different time points: pre-, 15, 30, 90 min, 24 h after PPCI and at 3 months after MI. Absolute counts of lymphocyte subpopulations, immune response to specific and nonspecific stimulation, serum cytokines and levels of CMV-IgG, cardiolipin-IgG, and anti-endothelial cell antibodies were assessed. CMV-seropositive patients with MI showed a twofold higher IFN-γ production to PHA-stimulation, up to 2.5-fold higher levels of IP-10 in serum and up to 30% lower serum levels of IL-16 compared to CMV-seronegative individuals. CMV-seropositive patients could be divided into two subgroups with high (IL-10Hi) and low (IL-10Lo) IL-10 serum levels during the acute stage of MI. The IL-10Hi CMV-seropositive subgroup showed an increased exit of late-differentiated T lymphocytes, NK and NKT-like cells from the circulation, which may potentially enhance cytotoxic damage in the ischemic myocardium. Finally, we did not observe an acceleration of autoimmunity by MI in CMV-seropositive individuals. The immune response during acute MI showed characteristic differences between CMV seronegative and seropositive patients, with a stronger pro-inflammatory response in seropositive patients. The effects of IP-10, IL-16, and IL-10 on characteristics of acute immune responses and formation of different immune profiles in CMV-seropositive individuals require further investigation.

Circ Res ; 116(1): 87-98, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25385851


RATIONALE: 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. METHODS AND 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.

Antígenos CD8/sangue , Senescência Celular/fisiologia , Citomegalovirus/metabolismo , Síndromes de Imunodeficiência/sangue , Isquemia Miocárdica/sangue , Reperfusão Miocárdica/métodos , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos Transversais , Citomegalovirus/imunologia , Feminino , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/virologia