Detection of sieric BAG3 in patients affected by cardiovascular diseases: State of art and perspectives.

BAG3 is highly expressed in the heart and its functions are essential in maintaining cardiac muscle cells homeostasis. In the past, BAG3 was detected in serum from advanced heart failure patients and its higher levels were correlated to an increased death risk. Moreover, it has also been reported that BAG3 levels in serum are increased in patients with hypertension, a known cardiovascular risk marker. Evidence from different laboratories suggested the possibility to use BAG3-based strategies to improve the clinical outcome of cardiovascular disease patients. This review aims to highlight the biological roles of intracellular or secreted BAG3 in myocardiocytes and propose additional new data on the levels of sieric BAG3 in patients with acute myocardial infarction (AMI), never assessed before. We evaluated BAG3 serum levels in relation to cardiovascular risk parameters in 64 AMI patients aged ≥18 years of either sex. We observed significant (p < .01) correlations of BAG3 positivity with dyslipidemic status and diabetic disease. We did not observe any significant correlations of BAG3 levels with smoking habit, hypertension or familiarity for AMI, although BAG3-positive seemed to be more numerous than BAG3-negative patients among hypertensives and among patients with familiarity for AMI. Furthermore, a significant (p < .001) correlation of BAG3 positivity with diuretics assumption was also noted. In conclusion, 32.8% of the patients were BAG3-positive and were characterized by some particular features as comorbidity presence or concomitant therapies. The significance of these observations needs to be verified by more extensive studies and could help in the validation of the use of BAG3 as a biomarker in heart attack risk stratification.

sRAGE and early signs of cardiac target organ damage in mild hypertensives.

BACKGROUND: Soluble Receptor for Advanced Glycation End Products (sRAGE) may be considered a marker inversely related to inflammation and its participation has been established in patients with advanced atherosclerotic vascular diseases. However, it is still unknown whether sRAGE reduction could be early metabolic change in the first stage of hypertension and initial hypertension-associated cardiac damage. We sought to determine the sRAGE values in otherwise healthy, untreated and recently diagnosed mild hypertensives and evaluate their association with blood pressure (BP) values, metabolic parameters, and with subclinical initial signs of cardiac target organ damage (TOD). METHODS: sRAGE were measured in 100 hypertensive and 100 normotensive subjects matched for age, gender and body mass index (BMI), submitted to a clinic visit and both ambulatory BP monitoring and echocardiography to determine the presence of initial cardiac TOD (presence of signs of left ventricular hypertrophy: left ventricular mass indexed for height2.7 (LVMi) > 48 g/m2.7 for men and > 44 g/m2.7 for women and/or increased left atrial volume 4-chamber indexed for body surface area (LAVi) > 34 ml/m2). RESULTS: sRAGE levels were similar between hypertensive and normotensive subjects and were not significantly correlated with office and 24-h BPs values. However, when subgrouping the hypertensive patients in Hyp-TOD and Hyp-withoutTOD, sRAGE was found to be different among the three groups (p = 0.030), being lower in the Hyp-TOD group than the values of both Hyp-withoutTOD (p = 0.038) and normotensives (p = 0.038). In hypertensive patients sRAGE was negatively related with both LVMi (r = - 0.239, p = 0.034) and LAVi (r = - 0.315, p = 0.005) and was independently related to cardiac TOD also in multivariable analysis. CONCLUSIONS: In this population of mild hypertensives, low circulating sRAGE may be a very early marker of initial TOD, suggesting the possible participation of oxidative stress in initial cardiac changes in human hypertension.

The Circulating Level of Soluble Receptor for Advanced Glycation End Products Displays Different Patterns in Ulcerative Colitis and Crohn's Disease: A Cross-Sectional Study.

BACKGROUND: RAGE is a transmembrane receptor expressed on immune and endothelial cells, whose binding with its ligands, the S100 calgranulins, leads to chronic inflammation. Conversely, its soluble form (sRAGE) plays a protective role by acting as a decoy. We carried out a cross-sectional analysis of the sRAGE and S100A12 serum levels in patients with Crohn's disease (CD) and ulcerative colitis (UC) and searched for a correlation with clinical and biological markers of activity. METHODS: We enrolled 60 CD, 67 UC patients, and 66 controls (all adults). Disease activity was scored through the clinical, endoscopic, and histologic indexes of severity, whilst disease location and behaviour were assessed according to the Montreal classification. In all cases, the levels of serum sRAGE, S100A12, C-reactive protein, and faecal calprotectin were measured. RESULTS: sRAGE levels were significantly lower in UC, both active and inactive, than in controls and CD (817.35, range 437.3-1449; 1211, range 843.7-1618; 1207.5, range 743.15-1875.75; P < 0.05 for both), and inversely correlated with clinical and endoscopic indexes of activity in both IBD groups (P < 0.05 for all) and with the histologic score in the CD group. Moreover, those CD patients with a penetrating behaviour showed a significant reduction in both sRAGE (P = 0.006) and S100A12 (P = 0.034) as compared to those with an inflammatory/stricturing pattern. Although S100A12 levels were not found up-regulated, a negative correlation appeared evident with the clinical (r = -0.38) and endoscopic (r = -0.32) indexes of activity in UC and CD, respectively. CONCLUSION: These data suggest a different role for RAGE in CD and UC, and a potential use of sRAGE as a new biomarker.

Time-domain heart rate variability in coronary artery disease patients affected by thyroid dysfunction.

Subclinical hypothyroidism and hyperthyroidism have been recognized as clinical entities with negative effects on the cardiovascular system. Moreover, the effect of treated thyroid dysfunction on parameters associated with the cardiovascular control system has been poorly investigated. In the present study we analyzed time-domain heart rate variability in coronary artery disease (CAD) patients with known thyroid diseases. Twenty-four hour ECG monitoring was performed in 344 patients with coronary artery disease (174 with thyroid dysfunction and 170 without thyroid dysfunction used as a control group), using a 3-channel tape recorder. Time domain parameters of heart rate variability (HRV) were definitely lower both in patients with subclinical hypothyroidism and subclinical hyperthyroidism than in the control group, with statistically significant differences in SDNN, RMSSD, TINN, and mean RR for both subgroups. Furthermore, patients on L-thyroxine treatment and restored euthyroidism had generally higher HRV values than patients with subclinical hypothyroidism, nevertheless SDNN, RMSSD, SDNN index, TINN, and mean RR were significantly lower when compared to those of the control group. Significant differences in HRV were also found between hyperthyroid patients under treatment and control group subjects with respect to RMSSD, TINN, and mean RR values. In conclusion, patients with cardiac disease and known thyroid disease, even when the disease is in the subclinical range or despite treatment, should be regarded as patients at additional risk conveyed by thyroid hormone disturbances.

Therapeutic patient education and treatment intensification of diabetes and hypertension in subjects with newly diagnosed type 2 diabetes mellitus: a longitudinal study.

PURPOSE: The aim of this study is to prospectively evaluate whether individual and group Therapeutic Patient Education (TPE) can reduce the need to intensify treatment of diabetes and hypertension in newly diagnosed type 2 diabetic patients. METHODS: A total of 937 patients were recruited and followed-up for 42.7 ± 21.5 months. TPE was a structured comprehensive education delivered by trained nurses: 322 patients received individual TPE (ITPE), 291 underwent group TPE (GTPE), and 324 were in Usual Care (UC). The primary endpoints were intensification of diabetes treatment and intensification of hypertension treatment. RESULTS: The rate of diabetes treatment intensification was 40.1% in patients receiving ITPE, 47.8% in patients undergoing GTPE, and 64.2% in patients in UC (p < 0.001). The rate of hypertension treatment intensification was 24.2% in patients following ITPE, 31.3% in patients receiving GTPE, and 41.0% in patients in UC (p < 0.001). Multivariate analysis showed that both ITPE and GTPE were associated with reduced intensification of diabetes (ITPE: HR:0.51; 95% IC:0.40-0.64; p < 0.001 - GTPE: HR:0.46; 95% IC:0.44-0.70; p < 0.001) and hypertension medication (ITPE: HR:0.45; 95% IC:0.34-0.61; p < 0.001 - GTPE: HR:0.49; 95% IC:0.38-0.65; p < 0.001). The association was independent of age, sex, BMI, HbA1c, and presence of hypertension at baseline. CONCLUSIONS: TPE, delivered as both individual and group sessions, represents an effective tool to reduce the need to intensify treatment of both diabetes and hypertension. Therefore, it can ensure better control of diabetes and hypertension with fewer medications. This could reduce adverse effects and costs and improve quality of life and medication taking in patients with type 2 diabetes.

Primary headache and silent myocardial ischemia in patients with coronary artery disease.

OBJECTIVE: The mechanisms by which migraine is linked to ischemic vascular disease remain uncertain and are likely to be complex. The aim of this study was to investigate the correlation between silent myocardial ischemia (SMI) and a history of documented primary headache in a large population of patients with exercise-induced myocardial ischemia. METHODS: The study involved 1,427 consecutive patients (918 symptomatic and 509 asymptomatic patients) with exercise-induced myocardial ischemia and documented coronary artery disease (CAD). RESULTS: Patients with anginal symptoms during exercise-induced myocardial ischemia had a significantly higher prevalence of primary headache than those without (41 vs. 30%, p < 0.001). Patients with angina pectoris in daily life also had greater prevalence of primary headache than those without anginal symptoms (37 vs. 20%; p < 0.0001). Symptomatic patients during percutaneous transluminal coronary angiography or myocardial infarction had a greater prevalence of primary headache than asymptomatic patients (p < 0.001 and p = 0.005, respectively). CONCLUSIONS: Our data suggest that a history of headache in CAD population is correlated to a high probability of anginal symptoms and a decreased probability of SMI. The anamnestic absence of headache requires a close monitoring for patients with risk factors for CAD, because this population seems to have a lower susceptibility to pain and the risk of developing SMI might be increased.

Soluble RAGE plasma levels in patients with coronary artery disease and peripheral artery disease.

The objective of the present study was define in a relatively large patient population with coronary artery disease (CAD) whether the concomitant presence of peripheral artery disease (PAD), which is known to convey additional cardiovascular risk, was associated with different circulating levels of sRAGE with respect to CAD alone and control subjects. Clinical and laboratory parameters including the ankle brachial index (ABI) and sRAGE (enzyme-linked immunosorbent assay kit) were investigated in 544 patients with angiographically documented CAD and 328 control subjects. 213/554 CAD patients (39%) showed an ABI <0.9 associated with typical symptoms (group CAD + PAD), whereas 331 patients were free from PAD. The concentration of plasma sRAGE was significantly lower (P < 0.0001) in CAD population, with and without PAD, than in control subjects. Among CAD patients, those with PAD showed lower levels of sRAGE. The distribution of the three groups (CAD, CAD + PAD, and controls) according to sRAGE tertiles showed that lower levels were more frequent in patients with CAD and CAD + PAD, whereas higher levels were more frequently found in controls. CAD patients presenting with PAD have lower sRAGE levels than CAD patients without peripheral atherosclerosis showing that stable atherosclerotic lesions in different vascular districts are inversely related to soluble decoy receptor sRAGE.

Possible role of -374T/A polymorphism of RAGE gene in longevity.

Demographic and social changes in the last decades have resulted in improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group. Environmental, genetic, and accidental factors have influenced the human life span. Researchers have gained substantial evidence that advanced glycation end products may play an important role in the processes of physiological aging. The aim of the present study was to investigate any differences in the frequencies of -374T/A polymorphism in subjects aged >90 years and in middle-aged individuals. We observed association between the A allele and genotype homozygous for this allele (AA) with a longer life expectancy in the male population. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in middle-aged subjects, indicating a possible protective role of the allele A to aging. In conclusion, our results support the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders.

Microalbuminuria and sRAGE in high-risk hypertensive patients treated with nifedipine/telmisartan combination treatment: a substudy of TALENT.

Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR) are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products). In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE) plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.

CR1 genotype and haplotype involvement in coronary artery disease: the pivotal role of hypertension and dyslipidemia.

Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and coronary syndromes. Atherosclerosis is a complex multifactorial disorder. Data indicate that the complement proteins play a crucial role in the link between inflammation and atherogenesis. Thus, there is evidence supporting the role of complement activation in atherogenesis. Complement receptor 1 (CR1) is a membrane protein found on different cells involved in various activities of the complement system. We demonstrated the possible involvement of CR1 in atherosclerosis studying the allele and genotype frequencies of the CR1 Pro1827Arg, CR1 His1208Arg exon 22 and int27 HindIII polymorphisms in a sample of patients with angiographically documented coronary artery disease (CAD) (n=550) and in healthy controls (n=380) matched for age, gender and ethnicity. Our data showed no significant deviations between the two groups with regard to either allele or genotype frequencies. After stratification according to risk factors, our analysis revealed a reduced frequency of the GG genotype of the Pro1827Arg polymorphism in patients with CAD and dyslipidemia vs the controls (p=0.031) and of the GG and LL genotypes in CAD patients with dyslipidemia vs CAD patients without dyslipidemia regarding the Pro1827Arg and CR1 HindIII intron 27 polymorphisms (GG, p=0.019; LL, p=0.184). We analyzed the haplotype frequencies of CR1. A decrease in CAD patients carrying the CAC haplotype compared to controls (p=0.043) and a decrease in the CAC haplotype in CAD patients with hypertension vs healthy controls (p=0.029) were demonstrated. Our data showed a possible involvement of CR1 gene polymorphisms in the predisposition to the development of this disease.

Functional polymorphisms of the receptor for the advanced glycation end product promoter gene in inflammatory bowel disease: a case-control study.

The receptor for the advanced glycation end products (RAGE) is a multiligand transmembrane receptor involved in chronic inflammation whose specific polymorphisms of the promoter gene were found to increase its transcriptional activity. We investigated the association of both allelic and genotypic -374T/A and -429T/C polymorphisms with inflammatory bowel disease. The STREGA guidelines were applied for planning and reporting. We enrolled 133 patients with Crohn's disease (CD), 149 with ulcerative colitis (UC), and 128 blood donors. Genomic DNA was extracted from peripheral blood leukocytes collected from each patient and control. RAGE polymorphisms were analyzed by PCR-restriction fragment length polymorphism assay. The Hardy-Weinberg equilibrium was first assessed, and then, the Kruskal-Wallis test and the Fisher exact test were used for etiologic group comparisons. Distribution of patients' characteristics across genotypes was evaluated by the Fisher exact test, while that across alleles was analyzed with a probit model. A 2-sided value of p < 0.05 was considered significant. Following the evidence of the Hardy-Weinberg equilibrium, we found a higher prevalence of the allele A of the -374T/A haplotype in UC (p = 0.043), and of the allele C of the -429T/C haplotype in CD (p < 0.001) with respect to the other groups. Moreover, the homozygous AA genotype of the -374T/A polymorphism resulted associated with late onset of CD, while its TT genotype with early onset (p = 0.049). The allele C of the 429T/C haplotype was associated with early onset of UC (p = 0.03), while a higher frequency of the heterozygous TC haplotype was found in those with pancolitis (p = 0.026). The differing distribution of these polymorphisms in healthy donors and CD/UC patients suggests a role in the development and outcome of these pathological conditions.

The -374T/A RAGE polymorphism protects against future cardiac events in nondiabetic patients with coronary artery disease.

BACKGROUND: The -374T/A polymorphism of the Receptor for Advanced Glycation End products (RAGE) may exert a protective effect toward the development of atherosclerosis. No data are currently available on the potential prognostic role of this polymorphism in patients with angiographically proven coronary artery disease (CAD). Hereto we sought to address this issue in a large consecutive cohort of patients undergoing coronary revascularization. METHODS: A total of 643 CAD patients who underwent myocardial revascularization were followed for 4.2 years (interquartile range: 2.2-8.1 years). The rates of major cardiac adverse events (death, nonfatal myocardial infarction, and unstable angina) were compared according to the -374T/A RAGE polymorphism. RESULTS: During a median follow-up period of 4.2 years, the study endpoint was reached by 126/643 patients (19.6%). We observed adverse cardiac events in 13.4% of patients with AA, 17.5% of those with AT, and 24.2% of those with TT genotype (p <0.05). In univariate Cox proportional hazard analysis, the AA genotype was significantly related to a better outcome in nondiabetic patients (hazard ratio: 0.47, 95% CI: 0.20-0.96; p <0.05). No association was found with adverse events in diabetic subjects. After allowance for potential confounders, the AA genotype remained a significant prognostic factor in the nondiabetic group (adjusted HR: 0.41, 95% CI: 0.17-0.94, p <0.05). CONCLUSIONS: The -374T/A RAGE polymorphism is an independent protective factor for cardiac events in nondiabetic patients with CAD. The effect of this genetic variant seems to be attenuated in diabetics, who have chronic RAGE upregulation.

Cardiovascular characteristics of chronic fatigue syndrome.

Patients with chronic fatigue syndrome (CFS) commonly exhibit orthostatic intolerance. Abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli was previously described in numerous studies. The aim of the current study was to describe cardiological and clinical characteristics of Italian patients with CFS. All of the patients were of Caucasian ethnicity and had been referred to our center, the Cardiology Department of the University Hospital of Pavia (Pavia, Italy) with suspected CFS. A total of 44 patients with suspected CFS were included in the present study and the diagnosis was confirmed in 19 patients according to recent clinical guidelines. The characteristics at baseline of the population confirm findings from various previous reports regarding the prevalence in females with a female to male ratio of 4:1, the age of onset of the pathology and the presence of previous infection by the Epstein-Barr virus, cytomegalovirus and other human herpesviruses. Despite the current data indicating that the majority of the cardiological parameters investigated are not significantly different in patients with and without CFS, a significant association between the disease and low levels of blood pressure was identified. Other pilot studies revealed a higher prevalence of hypotension and orthostatic intolerance in patients with CFS. Furthermore, many of the CFS symptoms, including fatigue, vertigo, decreased concentration, tremors and nausea, may be explained by hypotension.

Current management and treatment of patients with stable coronary artery diseases presenting to cardiologists in different clinical contexts: A prospective, observational, nationwide study.

Background Stable coronary artery disease (CAD) is a leading cause of mortality worldwide. Few studies document the complete sequence of investigation of the overall stable CAD population during outpatient visits or hospitalisation. Aim To obtain accurate and up-to-date information on current management of patients with stable CAD. Methods START (STable coronary Artery diseases RegisTry) was a prospective, observational, nationwide study aimed at evaluating the presentation, management, treatment and quality of life of stable CAD patients presenting to cardiologists during outpatient visits or discharged from cardiology wards. Results Over a 3-month period, 5070 consecutive patients were enrolled in 183 participating centres: 72% managed by a cardiologist during outpatient or day hospital visits and 28% discharged from cardiology wards. The vast majority of patients (87%) received a coronary angiography (86% of patients managed during outpatient visits and 90% during hospitalisation; p < 0.0001). Outpatients more frequently received optimal medical therapy (OMT; i.e. aspirin or thienopyridine, ß-blockers and statins) compared to hospitalised patients (70.2% vs 67.1%; p = 0.03). A personalised diet was prescribed in 58% (60.5% in outpatients and 52.9% in those admitted to hospitals; p < 0.0001), physical activity programmes were suggested in 65% (69.4% and 54.3%; p < 0.0001) and smoking cessation was recommended in 71% of currently smoking patients (73.2% and 65.2%; p = 0.02). Conclusions In this large, contemporary registry, patients with stable CAD discharged from cardiology wards more commonly underwent diagnostic imaging procedures and less frequently received OMT or lifestyle modification programmes compared to patients manged by cardiologists during outpatient visits.

A W148R mutation in the human FOXD4 gene segregating with dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality.

The forkhead/winged helix box (FOX) gene family comprises at least 43 different genes encoding transcriptional factors with a highly conserved DNA-binding domain. To date, mutations in members of the FOX gene family have been causally linked to a variety of different human diseases. We describe a three-generation Albanian pedigree in which a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality is segregated with a missense mutation (W148R) in the human FOXD4 gene. This mutation disrupts an extremely highly conserved tryptophan residue in the forkhead domain of FOXD4, possibly resulting in reduced DNA binding capacity and altered transcriptional activity. Our present findings widen the spectrum of diseases associated with genetic aberrations in the forkhead gene family.

Rapid heart rate increase at onset of exercise predicts adverse cardiac events in patients with coronary artery disease.

BACKGROUND: We previously demonstrated that reduced vagal activity and/or increased sympathetic activity identify post-myocardial infarction patients at high risk for cardiac mortality. Simple and inexpensive autonomic markers are necessary to perform autonomic screening in large populations. We tested our hypothesis that abnormally elevated heart rate (HR) responses at the onset of an exercise stress test, which imply rapid vagal withdrawal immediately preceding sympathetic activation, might predict adverse cardiac events in patients with documented coronary artery disease. METHODS AND RESULTS: The HR increase during the first minute (DeltaHR1 minute) of a symptom-limited exercise stress test was quantified in 458 patients with documented coronary artery disease. During a 6-year (interquartile range 3.7 to 9.0 years) follow-up, 71 patients experienced adverse cardiac events (21 cardiac deaths, 56 nonfatal myocardial infarctions). In univariate analysis, DeltaHR1 minute > or =12 bpm (above the median value of its distribution) predicted both adverse outcome and cardiac death with a hazard ratio of 5.0 (95% CI 2.7 to 9.1; P<0.0001) and of 15.6 (95% CI 2.0 to 118.7; P<0.001), respectively. After adjustment for potential confounders, DeltaHR1 minute remained predictive for both combined end points and for cardiac death. CONCLUSIONS: A marked HR increase at the onset of a standard exercise stress test is a novel and easily available parameter that could be clinically useful as an independent predictor of adverse cardiac events, including death, among patients with documented coronary artery disease.

Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target.

The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimer's disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimer's disease.

Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease.

Eotaxin (CCL11) is an eosinophil-specific chemoattractant which has been found to be highly expressed at sites of vascular pathology. In the present study, we aimed to evaluate the association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease (CAD). Three hundred and fifty six consecutive patients attending for elective coronary angiography were investigated. Compared with 111 patients without CAD, 245 with CAD showed higher eotaxin concentrations [median (interquartile range): 76.0 (56.3-103.0)pg/ml versus 116.0 (80.5-162.0)pg/ml, respectively; P<0.001]. Importantly, a significant Spearman correlation was found between eotaxin levels and the extent score of coronary artery stenosis (r=0.449, P<0.001). A stepwise increase in plasma levels of eotaxin was also found depending on the number of >50% coronary stenosis: median value 76.0 pg/ml in CAD(-) subjects, 96.0 pg/ml in 1-vessel disease, 128.0 pg/ml in 2-vessel disease, and 129.0 pg/ml in 3-vessel disease (P<0.001 for trend). After confounding variables were controlled for, multiple stepwise regression analysis demonstrated that plasma eotaxin was an independent predictor of angiographic extent of CAD (beta=0.426, P<0.001). Our data suggest that increased eotaxin levels are associated with the presence of CAD and that circulating levels of this chemokine may reflect the extent of coronary atherosclerosis.

Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder.

The zinc metalloenzyme glyoxalase I (GLO1) is thought to play a role in anxiety disorders because a reduced brain expression of GLO1 has been associated with increased anxiety-behaviours in mice. Recently, a functional Ala111Glu polymorphism in GLO1 has been shown to result in a reduced enzyme activity. The present study tested the hypothesis that this common genetic variant could confer susceptibility to panic disorder using an Italian population sample of 162 panic disorder patients and 288 matched controls. Statistical analysis failed to show association with the overall diagnosis of the disease. However, a weak but significant association was demonstrated between this polymorphism and panic disorder without agoraphobia. While our data suggest that this polymorphism is unlikely to have a major function in the pathogenesis of panic disorder, it could play a role in the subgroup of patients without agoraphobic avoidance.

Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men.

OBJECTIVE: The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose signaling pathway has been implicated in atherogenesis. RAGE has an endogenous secretory receptor form, called soluble RAGE (sRAGE), that could exert antiatherogenic effects by acting as a decoy. We sought to determine whether a decreased plasma level of sRAGE could be independently associated with the prevalence of coronary artery disease (CAD) in nondiabetic men. METHODS AND RESULTS: Plasma levels of sRAGE were determined in 328 nondiabetic male patients with angiographically proved CAD and in 328 age-matched healthy controls. The concentration of sRAGE in plasma was significantly lower (P<0.0001) in CAD cases [median (interquartile range): 966 (658-1372) pg/mL] than in control subjects [1335 (936-1954) pg/mL]. In logistic regression analysis, the multivariate-adjusted odds ratio for the presence of CAD was 6.719 (95% confidence interval, 3.773 to 11.964; P<0.0001) when the lowest quartile of the sRAGE level was compared with the highest quartile. CONCLUSIONS: Our findings indicate that low levels of sRAGE in plasma are independently associated with the presence of CAD in nondiabetic men and suggest that sRAGE is one of the clinically important molecules associated with atherosclerosis.