Hee Tae Yu

Immunosenescent CD8 + T Cells and C-X-C Chemokine Receptor Type 3 Chemokines Are Increased in Human Hypertension

The pathogenic role of T cells in hypertension has been documented well in recent animal studies. However, the existence of T-cell–driven inflammation in human hypertension has not been confirmed. Therefore, we undertook immunologic characterization of T cells from patients with hypertension and measured circulating levels of C-X-C chemokine receptor type 3 chemokines, which are well-known tissue-homing chemokines for T cells. We analyzed immunologic markers on T cells from patients with hypertension by multicolor flow cytometry. We then measured circulating levels of the C-X-C chemokine receptor type 3 chemokines, monokine induced by &ggr; interferon (IFN), IFN &ggr;–induced protein 10, and IFN-inducible T-cell &agr; chemoattractant, in patients with hypertension and in age- and sex-matched control subjects by the cytometric bead array method. In addition, we examined histological features of IFN-inducible T-cell &agr; chemoattractant expression from renal biopsy specimens of patients with hypertensive nephrosclerosis and control subjects. The total T-cell population from patients with hypertension showed an increased fraction of immunosenescent, proinflammatory, cytotoxic CD8+ T cells. Circulating levels of C-X-C chemokine receptor type 3 chemokines were significantly higher in patients with hypertension than in control subjects. Furthermore, immunohistochemical staining revealed increased expression of the T-cell chemokine, IFN-inducible T-cell &agr; chemoattractant, in the proximal and distal tubules of patients with hypertensive nephrosclerosis. Immunosenescent CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension, suggesting a role for T-cell–driven inflammation in hypertension. A more detailed characterization of CD8+ T cells may offer new opportunities for the prevention and treatment of human hypertension.

Epicardial adipose tissue thickness is an indicator for coronary artery stenosis in asymptomatic type 2 diabetic patients: its assessment by cardiac magnetic resonance.

BackgroundWe used cardiovascular magnetic resonance (CMR) to investigate the association between epicardial adipose tissue (EAT) thickness and silent myocardial ischemia, as well as coronary artery stenosis, in asymptomatic type 2 diabetic patients.MethodsThe study included 100 type 2 diabetic subjects (51 male and 49 female; mean age: 56 ± 7 years). Silent myocardial ischemia, as determined by CMR, was defined as evidence of inducible ischemia or myocardial infarction. Signal reduction or stenosis of ≥ 50% in the vessel diameter was used as the criteria for significant coronary artery stenosis on coronary magnetic resonance (MR) angiography.ResultsEAT thickness was positively correlated with body mass index (BMI), waist-to-hip ratio, systolic blood pressure, postprandial glucose, fasting/postprandial triglyceride (TG), serum glycated hemoglobin (HbA1c) level, and homeostasis model assessment of insulin resistance (HOMA-IR) score. Significant coronary artery stenosis was found in 24 patients, while 14 patients had silent myocardial ischemia in CMR (1 with silent myocardial infarction, 11 with inducible ischemia, and 2 with both). EAT thickness was greater in patients who had coronary artery stenosis (13.0 ± 2.6 mm vs. 11.5 ± 2.1 mm, p = 0.01), but did not differ between the subjects with or without silent myocardial ischemia on CMR images (12.8 ± 2.1 vs. 11.7 ± 2.3 mm, p = 0.11). Multivariate logistic regression analysis indicated that EAT thickness was an independent indicator for significant coronary artery stenosis after adjusting for traditional risk factors (OR 1.403, p = 0.026).ConclusionsIncreased EAT thickness assessed by CMR is an independent risk factor for significant coronary artery stenosis in asymptomatic type 2 diabetes. However, EAT thickness was not associated with silent myocardial ischemia.

Potential association between coronary artery disease and the inflammatory biomarker YKL-40 in asymptomatic patients with type 2 diabetes mellitus

BackgroundInflammation plays an important role in coronary artery disease from the initiation of endothelial dysfunction to plaque formation to final rupture of the plaque. In this study, we investigated the potential pathophysiological and clinical relevance of novel cytokines secreted from various cells including adipocytes, endothelial cells, and inflammatory cells, in predicting coronary artery disease (CAD) in asymptomatic subjects with type 2 diabetes mellitus.MethodsWe enrolled a total of 70 asymptomatic type 2 diabetic patients without a documented history of cardiovascular disease, and determined serum levels of chemerin, omentin-1, YKL-40, and sCD26. We performed coronary computed tomographic angiography (cCTA) in all subjects, and defined coronary artery stenosis ≥ 50 % as significant CAD in this study.ResultsSubjects were classified into two groups: patients with suspected coronary artery stenosis on cCTA (group I, n = 41) and patients without any evidence of stenosis on cCTA (group II, n = 29). Group I showed significantly higher YLK-40 levels and lower HDL-C levels than group II (p = 0.038, 0.036, respectively). Levels of chemerin, omentin-1, and sCD26 were not significantly different between the two groups. Serum YKL-40 levels were positively correlated with systolic/diastolic BP, fasting/postprandial triglyceride levels, and Framingham risk score. Furthermore, YKL-40 levels showed moderate correlation with the degree of coronary artery stenosis and the coronary artery calcium score determined from cCTA. In multivariate logistic analysis, after adjusting for age, gender, smoking history, hypertension, and LDL-cholesterol, YLK-40 levels showed only borderline significance.ConclusionsYKL-40, which is secreted primarily from inflammatory cells, was associated with several CVD risk factors and was elevated in type 2 diabetic patients with suspected coronary artery stensosis on cCTA. These results suggest the possibility that the inflammatory biomarker YKL-40 might be associated with coronary artery disease in asymptomatic patients with type 2 diabetes mellitus.

Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Although T cells are known to be involved in the pathogenesis of coronary artery disease, it is unclear which subpopulation of T cells contributes to pathogenesis in acute myocardial infarction (MI). We studied the immunological characteristics and clinical impact of CD8+CD57+ T cells in acute MI patients. The frequency of CD57+ cells among CD8+ T cells was examined in peripheral blood sampled the morning after acute MI events. Interestingly, the frequency of CD57+ cells in the CD8+ T-cell population correlated with cardiovascular mortality 6 months after acute MI. The immunological characteristics of CD8+CD57+ T cells were elucidated by surface immunophenotyping, intracellular cytokine staining and flow cytometry. Immunophenotyping revealed that the CD8+CD57+ T cells were activated, senescent T cells with pro-inflammatory and tissue homing properties. Because a high frequency of CD8+CD57+ T cells is associated with short-term cardiovascular mortality in acute MI patients, this specific subset of CD8+ T cells might contribute to acute coronary events via their pro-inflammatory and high cytotoxic capacities. Identification of a pathogenic CD8+ T-cell subset expressing CD57 may offer opportunities for the evaluation and management of acute MI.Cellular & Molecular Immunology advance online publication, 25 August 2014; doi:10.1038/cmi.2014.74

Gender-Based Differences in the Management and Prognosis of Acute Coronary Syndrome in Korea

Purpose Gender-based differences exist in the characteristics, management, and prognosis of acute coronary syndrome (ACS). However, their impact on prognosis remains unclear. We aimed to identify factors causing these differences in Koreans. Materials and Methods We examined 6,636 ACS patients (66.2% males) visiting 72 Korean hospitals between April-2007 and December-2008. Gender-based differences in clinical demographics, therapy, and outcomes were analyzed over 6 months. Results Women were older than men [mean (standard deviation, SD) age, 67.6 (9.8) vs. 60.6 (11.2) years; p<0.001]; had higher rates of hypertension, diabetes mellitus, and lack of exercise (p<0.001 for all); and lower rates of obesity, familial history of cardiovascular disease (CVD), and smoking (p<0.05 for all). Atypical symptoms were more common in women (20.5% vs. 15.1% in men, p<0.001), whereas myocardial infarction with ST-segment elevation was less common (17.1% vs. 27.8%, p<0.001). Mean (SD) time lapse from symptom onset to arrival at hospital was longer in women [11.44 (18.19) vs. 8.26 (14.89) hours in men, p<0.001], as was the duration of hospitalization [7.58 (7.61) vs. 7.04 (7.72) days, p=0.007]. Fewer women underwent revascularization procedures, including thrombolytic therapy, balloon angioplasty, stent implantation, and coronary artery bypass grafting (79.4% vs. 83.3% men, p<0.001). No significant differences were observed in CVD-related death, recurrent ACS, stroke, refractory angina, or rehospitalization for angina. Conclusion Female ACS patients were older than male subjects and had more atypical presentation. They arrived at the hospital later than men and had longer hospital stays, but less often required revascularization therapy. However, no gender-based differences were noted in ACS-related mortality and morbidity.

CHA2DS2-VASc Score for Identifying Truly Low-Risk Atrial Fibrillation for Stroke: A Korean Nationwide Cohort Study

Background and Purpose— As the threshold of stroke risk for initiating oral anticoagulants is lowered after the introduction of the nonvitamin K antagonist oral anticoagulants, the focus of stroke prevention in patients with nonvalvular atrial fibrillation has shifted away from predicting high-risk patients toward initially identifying patients with a truly low risk of ischemic stroke, who do not need antithrombotic therapy. We tested the predictive ability of the congestive heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack (doubled; CHADS2), congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65 to 74, female (CHA2DS2-VASc), and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk stratification schemes in oral anticoagulants naive patients with atrial fibrillation in a Korean nationwide sample cohort. Methods— From January 2002 to December 2008, a total of 5855 oral anticoagulant naive patients with nonvalvular atrial fibrillation aged ≥20 years were enrolled from Korea National Health Insurance Service-Sample Cohort database and were followed-up until December 2013. Results— At baseline, the proportions categorized as low risk using CHADS2, CHA2DS2-VASc, and ATRIA risk stratification schemes were 1049 (17.9%), 860 (14.7%), and 3280 (56.0%), respectively. During follow-up, the low-risk category using CHADS2, CHA2DS2-VASc, and ATRIA scores was retained in 811 (13.9%), 667 (11.4%), and 2729 (46.6%) patients, respectively. Rates of ischemic stroke (100 person-years) in the low risk categories of CHADS2, CHA2DS2-VASc, and ATRIA scores were 0.42, 0.26, and 1.43, respectively. CHA2DS2-VASc had the best sensitivity (98.8% versus 85.7% in CHADS2 and 74.8% in ATRIA) and negative predictive value (98.8% versus 95.3% for CHADS2 and 93.7% for ATRIA) for the prediction of stroke incidence and was best for the prediction of the absence of ischemic stroke during 5 years of follow-up (odds ratio, 16.4 [95% confidence interval, 8.8–30.8]). Conclusions— The CHA2DS2-VASc score shows good performance in defining truly low-risk Asian patients with atrial fibrillation for stroke compared with CHADS2 and ATRIA scores.

Advanced Left Atrial Remodeling and Appendage Contractile Dysfunction in Women Than in Men Among the Patients With Atrial Fibrillation: Potential Mechanism for Stroke

Background The risk of stroke imposed by atrial fibrillation (AF) is significantly greater in women than men; however, the mechanism remains elusive. We hypothesized that left atrial (LA) remodeling and poor contractile function of LA appendage (LAA) would be more predominant in women than men among AF patients. Methods and Results A total of 579 AF patients (216 women vs age‐, AF type–, and incidences of heart failure, hypertension, diabetes mellitus, stroke or transient ischemic attack, and vascular disease–matched 363 men, 61.3±10.2 years old, 70.1% paroxysmal AF) who underwent AF catheter ablation were included. Sex differences in LA volume index (LAVI) and LAA emptying flow velocity (FV) were analyzed in risk factor 0, 1, and ≥2 groups, according to their CHA 2 DS 2‐VASc scores beyond sex category. LAA‐FV was more significantly reduced in women with risk factor ≥2 than in men of the same risk group (P=0.022). Women showed greater LAVI than their male counterparts in the risk factor ≥2 group (P<0.001). The majority of female patients with a history of stroke had a large LAVI and low LAA‐FV (P<0.001); however, no such distribution was observed in men (P=0.596). LA volume index (odds ratio [OR], 1.038; 95% CI, 1.003–1.075, P=0.035) or LAA‐FV (OR, 0.976; 95% CI, 0.952–0.999; P=0.047) was significantly associated with a history of stroke in women. Conclusions More‐extensive LA remodeling and deterioration in LAA function were noted in women than in men with high calculated risk of stroke in AF.

T cell immunosenescence, hypertension, and arterial stiffness

Immunosenescence is a concept used to describe the age-associated deterioration of immune function, characterized by functional and phenotypic changes on both cellular and systemic levels [1,2]. Immunosenescence in elderly people is associated with an increased susceptibility to infectious diseases, impaired response to vaccinations, and increased incidence of cancer and autoimmunity [3-5]. During immune aging, senescent T cells accumulate in the peripheral T cell pool [2,6,7]. By repetitive antigenic stimulation of T cells, their telomeres are shortened [8] and the expression of CD28, a co-stimulatory molecule, is lost [9]. In humans, cytomegalovirus (CMV) is known to be one of the most important antigens that cause repetitive T cell stimulation [10,11]. As a result of such repetitive stimulation, CD28null T cells accumulate during the immune aging process [12]. Similarly, the expression of CD57 antigen on T cells is currently considered to be another surrogate marker of the replicative senescence of T cells [13]. CD57 is a terminally sulfated glycan carbohydrate epitope, and CD57+T cells showed an inability to proliferate after antigenic stimulation in vitro and a high susceptibility to activation-induced apoptosis [14,15] (Figure 1). Compared to CD28+CD57-T cells, CD57+ T cells produce more proinflammatory cytokines and exert greater cytotoxicity [16]. These senescent CD57+ T cells are known to be associated with a number of inflammatory diseases in humans [17-19].

Soluble CD93 Levels in Patients with Acute Myocardial Infarction and Its Implication on Clinical Outcome

Background Inflammation plays a key role in the pathogenesis of acute myocardial infarction (MI). However, it is unclear whether marker of immune activation will provide prognostic information in these patients. We hypothesized that circulating levels of soluble CD93 (sCD93), a soluble form of transmembrane glycoprotein CD93, is increased in acute MI patients and its level would be associated with clinical outcomes in patients with acute MI. Methods We measured circulating levels of sCD93 in 120 patients with acute MI (63±13 yrs, M∶F = 85∶35) and in 120 age, sex-matched control subjects. In patients with acute MI, clinical characteristics, echocardiographic and laboratory findings were assessed at the time of initial enrollment. The primary outcome was defined as all-cause and cardiovascular death. Results Circulating sCD93 levels were significantly higher in patients with acute MI than in control subjects (552.1±293.7 vs. 429.8±114.2 ng/mL, p<0.0001). Upon in vitro inflammatory stimulation, increased CD93 shedding was demonstrated in acute MI patients but not in control subjects. During follow up period (median 208 days, 3-1058 days), the primary outcome occurred in 18 (15%) patients (9 cardiovascular deaths). Circulating levels of sCD93 were associated with all cause (p<0.0001) and cardiovascular (p<0.0001) mortality in patients with acute MI. Multivariate Cox regression analysis revealed that initial sCD93 level was found to be an independent predictor of all cause (p = 0.002) and cardiovascular mortality (p = 0.033) when controlled for age and left ventricular ejection fraction. Conclusions Circulating levels of sCD93 are elevated in patients with acute MI and their levels were associated with adverse clinical outcomes.

Pulmonary Hypertension Associated with Use of Phentermine

Weight-control drugs (known as anorexigens) such as fenfluramine have been linked with pulmonary hypertension in previous reports. In our case, a 29 year old woman was admitted for shortness of breath and was diagnosed with pulmonary hypertension. Three months ago, she had been taking phentermine for five weeks. Other factors that might have contributed to the development of pulmonary hypertension were excluded. With treatment, her symptoms improved. This is the first case that can suggest a possible connection between phenermine single medication with pulmonary hypertension. Phentermine has been considered a relatively safe drug to treat obesity, and further investigation is needed to decide the safety and dosage of phentermine.