Lena Jonasson

Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque.

The cellular composition of human atherosclerotic plaques was analyzed by immunologic techniques. Plaques were removed from the internal carotid artery during surgery, and a panel of monoclonal antibodies was used to identify cell types. Macrophages stained by Anti-Leu-M3 were found throughout the plaque, particularly in the lipid core region, where 60% of the cells reacted with this antibody. T cells expressing the T3 antigen were most abundant in the fibrous cap, where they constituted 20% of the cell population. T cells were also isolated from the plaque and detected by a rosetting test; many of these T cells were activated, as indicated by the expression of HLA-DR. Other types of leukocytes were uncommon in the plaque. An antibody to the intermediate filament protein, desmin, was used as a marker for smooth muscle cells since some, but not all, vascular smooth muscle cells contain this protein. The desmin-positive cells were uncommon in the nonatherosclerotic intima but were more numerous in the plaque. In conclusion, atherosclerotic plaques are heterogeneous with respect to cellular composition. The smooth muscle cell dominates in the fibrous cap, which also contains many T cells; the lipid core is dominated by macrophages. We suggest that interactions between smooth muscle cells and blood-borne cells are important in the pathogenesis of atherosclerosis.

Inflammation and cortisol response in coronary artery disease

Atherosclerosis is characterized by chronic inflammation involving autoimmune components. The degree of inflammatory activity, as detectable both within the atherosclerotic plaque and in the circulation, is associated with plaque destabilization and atherothrombotic complications. Endogenous glucocorticoids are modulators of innate and acquired immune responses, and as such play a key role in the reciprocal interaction between neuroendocrine and immune systems. Abnormalities in hypothalamic-pituitary-adrenal axis (HPA) function have been described in several chronic inflammatory disorders, and evidence has emerged lately that HPA dysfunction may be implicated also in the pathogenesis of coronary artery disease. This review is an outline of knowledge gained so far by previous studies of glucocorticoids in coronary atherosclerosis and myocardial infarction. The results consistently point towards a dysregulated cortisol secretion that may involve a failure to contain inflammatory activity. A dysfunctional HPA axis and its possible implications for coronary artery disease progress, including the hypothetical link between stress and inflammation, are discussed.

Impaired cortisol response to acute stressors in patients with coronary disease. Implications for inflammatory activity

Objectives.  Inflammation is assumed to play a major role in the progress of atherosclerotic disease. We hypothesized that an altered hypothalamic‐pituitary adrenal (HPA) axis activity was linked to a disinhibited inflammatory activity in patients with coronary artery disease (CAD).

The Discovery of Cellular Immunity in the Atherosclerotic Plaque

It is now generally accepted that atherosclerosis is an inflammatory/immune disease triggered by LDL accumulation in the artery wall. When discovering T cells and the molecular components of a cellular immune response, we proposed that atherosclerosis is an inflammatory process with an autoimmune component. This notion was met with general skepticism but has gained support from experimental and clinical studies. Here we describe some of the early studies that helped developing this concept.

Cathepsin L is significantly associated with apoptosis and plaque destabilization in human atherosclerosis

OBJECTIVE Human atherosclerotic lesions overexpress elastolytic and collagenolytic cathepsins with unclear pathological implications. The aim of this study was to investigate the relationship among expression of cathepsin L, macrophage apoptosis in coronary artery disease (CAD) patients, clinical symptoms and plaque severity of human carotid atheroma. METHODS AND RESULTS Quantitative immunohistochemical analysis of human carotid atherosclerotic lesions (n=49) showed that expression of lysosomal cathepsin L was significantly increased in atherosclerotic plaques with formation of the necrotic core and rupture of the cap. In those plaques, cathepsin L was associated mainly with CD68-positive macrophages, whereas significant lower levels of smooth muscle cell actin were detected. The expression of cathepsin L in these plaques was also correlated with apoptosis and the stress protein ferritin. Plaques from symptomatic patients showed greater increased levels of cathepsin L than those from asymptomatic patients. Human monocyte-derived macrophages from CAD patients (n=7) showed significantly higher levels of cathepsin L, cellular lipids and apoptosis versus cells from matched healthy donors (n=7). 7Beta-hydroxycholesterol significantly enhanced cathepsin L in cells from healthy donors but not in cells from CAD patients. Moreover, macrophage apoptosis was significantly correlated with expression of cathepsin L in cell nuclei and membranes. CONCLUSION The results suggest that cathepsin L is involved in death of macrophages, necrotic core formation and development of atherosclerotic plaque instability. Macrophage lysosomal cathepsin L and related apoptosis may be potential targets for modulation or imaging of vulnerable plaques in human atherosclerosis.

Source of inflammatory markers in patients with atrial fibrillation

AIMS Elevated levels of C-reactive protein and other inflammatory markers have been reported in some patients with atrial fibrillation (AF). Whether this finding is related to AF per se or to other conditions remains unclear. In addition, the source of inflammatory markers is unknown. Therefore, in the present study, we sought to assess the extent and the source of inflammation in patients with AF and no other concomitant heart or inflammatory conditions. METHODS AND RESULTS The study group consisted of 29 patients referred for radiofrequency catheter ablation: 10 patients with paroxysmal AF, 8 patients with permanent AF, and 10 control patients with Wolf-Parkinson-White (WPW) syndrome and no evidence of AF (mean age 54 +/- 11 vs. 57 +/- 13 vs. 43 +/- 16). No patient had structural heart diseases or inflammatory conditions. High-sensitive C-reactive protein, interleukin-6 (IL-6), and interleukin-8 (IL-8) were assessed in blood samples from the femoral vein, right atrium, coronary sinus, and the left and right upper pulmonary veins. All samples were collected before ablation. Compared with controls and patients with paroxysmal AF, patients with permanent AF had higher plasma levels of IL-8 in the samples from the femoral vein, right atrium, and coronary sinus, but not in the samples from the pulmonary veins (median values in the femoral vein: 2.58 vs. 2.97 vs. 4.66 pg/mL, P = 0.003; right atrium: 2.30 vs. 3.06 vs. 3.93 pg/mL, P = 0.013; coronary sinus: 2.85 vs. 3.15 vs. 4.07, P = 0.016). A high-degree correlation existed between the IL-8 levels in these samples (correlation coefficient between 0.929 and 0.976, P < 0.05). No differences in the C-reactive protein and IL-6 levels were noted between the three groups of patients. CONCLUSION The normal levels of C-reactive protein and IL-6, along with the elevated levels of IL-8 in patients with permanent AF but not in those with paroxysmal AF, suggest a link between a low-grade inflammatory reaction and long-lasting AF. The elevated IL-8 levels in the peripheral blood, right atrium, and coronary sinus but not in the pulmonary veins suggest a possible source of inflammation in the systemic circulation.

Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population

Background Elevated levels of circulating matrix metalloproteinase-9 (MMP-9) have been demonstrated in patients with established coronary artery disease (CAD). The aim of this study was to analyse levels of MMP-9 in a population free from symptomatic CAD and investigate their associations with cardiovascular (CV) risk factors, including C-reactive protein (CRP). Methods A cross-sectional study was performed in a population based random sample aged 45–69 (n = 345, 50% women). MMP-9 levels were measured in EDTA-plasma using an ELISA-method. CV risk factors were measured using questionnaires and standard laboratory methods. Results Plasma MMP-9 was detectable in all participants, mean 38.9 ng/mL (SD 22.1 ng/mL). Among individuals without reported symptomatic CAD a positive association (p<0.001) was seen, for both men and women, of MMP-9 levels regarding total risk load of eight CV risk factors i.e. blood pressure, dyslipidemia, diabetes, obesity, smoking, alcohol intake, physical activity and fruit and vegetable intake. The association was significant also after adjustment for CRP, and was not driven by a single risk factor alone. In regression models adjusted for age, sex, smoking, alcohol intake and CRP, elevated MMP-9 levels were independently positively associated with systolic blood pressure (p = 0.037), smoking (p<0.001), alcohol intake (p = 0.003) and CRP (p<0.001). The correlation coefficient between MMP-9 and CRP was r = 0.24 (p<0.001). Conclusions In a population without reported symptomatic CAD, MMP-9 levels were associated with total CV risk load as well as with single risk factors. This was found also after adjustment for CRP.

Expansion of peripheral CD8+ T cells in patients with coronary artery disease : Relation to cytomegalovirus infection

Abstract. Jonasson L, Tompa A, Wikby A (Heart Center, University Hospital, Linköping; Ryhov Hospital, Jönköping; and School of Health Sciences, Jönköping University, Jönköping; Sweden). Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection. J Intern Med 2003; 254: 472–478.

Early measurements of plasma matrix metalloproteinase-2 predict infarct size and ventricular dysfunction in ST-elevation myocardial infarction

Background Immediate reopening of the acutely occluded infarct-related artery via primary PCI is the preferred treatment in ST-elevation myocardial infarction (STEMI). However, the sudden reinitiation of blood flow can lead to a local acute inflammatory response with further endothelial and myocardial damage, so-called reperfusion injury. The activation of matrix metalloproteinases (MMPs) is suggested to be a key event in this process. Objectives To investigate circulating MMPs, tissue inhibitors of metalloproteinases (TIMPs) and myeloperoxidase (MPO) in relation to infarct size, left ventricular dysfunction and remodelling in a STEMI population undergoing PCI. Methods 58 Patients with STEMI undergoing primary PCI were included. Blood samples were collected at baseline before PCI and at 12, 24 and 48 h for later analysis of MMPs, TIMPs and MPO by ELISA. Infarct size, left ventricular (LV) dysfunction and remodelling were assessed by cardiac MRI at 5 days and 4 month after STEMI. Results Plasma MMP-2 at 0 and 12 h showed a consistent and significant correlation with infarct size and LV dysfunction measured both at 5 days and at 4 months and correlated well with troponin I measurements. For TIMP-1 and TIMP-2 some support was found for associations with infarct size and LV dysfunction, but these were not as consistent as for MMP-2. MMP-8, MMP-9 and MPO did not overall correlate with measures of infarct size, LV dysfunction or remodelling. Conclusions In patients with STEMI, circulating levels of MMP-2, measured early and even before reperfusion therapy, are strongly associated with infarct size and LV dysfunction. This provides further evidence for the role of MMP-2 in ischaemia-reperfusion injury.

Active cytomegalovirus replication in patients with coronary disease

Objectives. To study the prevalence of active cytomegalovirus (CMV) infection in patients with stable and unstable conditions of coronary artery disease (CAD). Design. Forty patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 clinically healthy controls were included. Monocytes were isolated from peripheral blood and CMV-RNA expression was determined by a nested RT-PCR assay. CMV IgM and IgG antibodies, interleukin-(IL)-6, IL-10 and CRP were measured in serum. Results. The prevalence of active CMV infection was significantly higher in patients with ACS (15%) and in patients with SA (10%) compared with controls (2%) (p<0.001). The presence of an active CMV infection was associated with increased serum concentrations of IL-6. Conclusions. Active CMV infection was found to a larger extent in CAD patients than in healthy controls. The data indicate that CAD patients are more susceptible to reactivation of CMV and put new focus on the role of CMV in atherosclerosis.