Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Whether suPAR level predicts the presence and the severity of coronary artery disease (CAD), and of incident death and myocardial infarction (MI) in subjects with suspected CAD, is unknown. METHODS AND RESULTS: We measured plasma suPAR levels in 3367 subjects (67% with CAD) recruited in the Emory Cardiovascular Biobank and followed them for adverse cardiovascular (CV) outcomes of death and MI over a mean 2.1±1.1 years. Presence of angiographic CAD (≥50% stenosis in ≥1 coronary artery) and its severity were quantitated using the Gensini score. Cox's proportional hazard survival and discrimination analyses were performed with models adjusted for established CV risk factors and C-reactive protein levels. Elevated suPAR levels were independently associated with the presence of CAD (P<0.0001) and its severity (P<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youden's index) predicted future risk of MI (hazard ratio [HR]=3.2; P<0.0001), cardiac death (HR=2.62; P<0.0001), and the combined endpoint of death and MI (HR=1.9; P<0.0001), even after adjustment of covariates. The C-statistic for a model based on traditional risk factors was improved from 0.72 to 0.74 (P=0.008) with the addition of suPAR. CONCLUSION: Elevated levels of plasma suPAR are associated with the presence and severity of CAD and are independent predictors of death and MI in patients with suspected or known CAD.

Coronary artery ectasia and inflammatory cytokines: link with a predominant Th-2 immune response?

OBJECTIVE: The role of inflammation in coronary artery ectasia (CAE) remains controversial. We evaluated the hypothesis that CAE might be associated with a specific pattern of T helper (Th) lymphocyte activation by measuring the Th-1 cytokine, interleukin-2 (IL-2) and the Th-2 cytokines, interleukin-4 (IL-4) and interleukin-6 (IL-6) in patients with CAE, obstructive coronary artery disease (CAD) and controls. METHODS: Serum levels of IL-2, IL-4 and IL-6 were measured in 74 patients undergoing an elective cardiac catheterization due to angina pectoris and positive or equivocal non-invasive screening for cardiac ischaemia: 34 had CAE and non-obstructive CAD (Group A), 22 had obstructive CAD (Group B) and 18 had normal coronaries (Group C). RESULTS: Group A had significantly higher IL-4 than Group B and Group C (p<0.001 and p=0.006, respectively). In contrast, Group A had markedly lower IL-2 than Group B and Group C (p<0.001 for both comparisons). Group C had higher IL-4 and lower IL-2 than Group B (p<0.001 for both comparisons). Interleukin-6 was significantly higher in Groups A and B compared to Group C (p<0.001 for both comparisons), whilst it was comparable between Group A and Group B. Multivariate logistic regression analysis showed that higher levels of IL-4 and lower levels of IL-2 were the strongest independent predictors associated with CAE (OR: 3.846, CI: 1.677-8.822, p=0.001 and OR: 0.567, CI: 0.387-0.831, p=0.004, respectively). CONCLUSIONS: Our data demonstrates that Th-2 immune response, exhibited through increased IL-4 and low IL-2, constitutes a fundamental feature of CAE.

Clinical and neurohormonal correlates and prognostic value of serum prolactin levels in patients with chronic heart failure.

AIMS: Hypothalamic axis deregulation is associated with clinical severity and depression in chronic heart failure (CHF). We investigated the relationship of serum prolactin, an indicator of hypothalamic axis function, to neurohomonal/immune activation and depressive symptoms in CHF as well as its prognostic value. METHODS AND RESULTS: Serum prolactin was determined in 180 patients with advanced CHF (aged 65 ± 12 years, mean LVEF 27 ± 7%) along with natriuretic peptides (BNP), inflammatory cytokines, endothelial adhesion molecules, 6 min walk test (6MWT), and the Zung self-rating depression scale (SDS). Patients were followed for all-cause death or hospitalization for cardiovascular reasons for up to 8 months. Prolactin levels were significantly correlated with NYHA class (r = 0.394, P < 0.001), LVEF (r = -0.314, P < 0.001), 6MWT (r = -0.353, P < 0.001), BNP (r = 0.374, P < 0.001), Zung SDS (r = 0.544, P < 0.001), interleukin-6 (IL-6) (r = 0.451, P < 0.001), IL-10 (r = -0.426, P < 0.001), tumour necrosis factor (TNF)-α (r = 0.310, P = 0.001), soluble Fas (r = 0.333, P < 0.001), soluble Fas-ligand (r = 0.517, P < 0.001), soluble intercellular adhesion molecule-1 (ICAM-1) (r = 0.409, P < 0.001), and soluble vascular cell adhesion molecule-1 (VCAM-1) (r = 0.480, P < 0.001). During follow-up, 119 patients (66%) died or were hospitalized for cardiovascular events after a median time of 72 days (range 5-220 days); these patients had higher baseline prolactin levels (10.2 ± 5.7 vs. 6.7 ± 4.3 ng/mL, P < 0.001), and a prolactin value ≥4.5 ng/mL was associated with a higher rate of death or hospitalization (116 ± 7 vs. 181 ± 11 days, P = 0.0001). In multivariate analysis, prolactin levels remained an independent predictor of death or hospitalization (<4.5 vs. ≥4.5 ng/mL; odds ratio, 0.368; 95% confidence interval 0.148-0.913; P = 0.031), along with BNP (P < 0.001) and 6MWT (P = 0.020). CONCLUSIONS: Serum prolactin is associated with neurohormonal/immune activation and depressive symptoms and is an independent predictor of prognosis in advanced CHF.

Revealing infective endocarditis complications by echocardiography: the value of real-time 3D transesophageal echocardiography.

A 72-year-old patient was admitted to the Department of Cardiology of Emory University Hospital with the diagnosis of infective endocarditis. Two-dimensional transesophageal echocardiography (TEE) showed a vegetation attached to the posterior mitral valve leaflet that led to severe mitral regurgitation. Real-time 3-dimensional TEE clearly identified the large posterior leaflet vegetation but additionally showed the perforated posterior mitral valve leaflet. Real time 3D TEE, and especially the large sector-focused data, allow for detailed identification of the mitral valve leaflets from both the atrial and the ventricular side. Those characteristics of real-time 3D TEE confer incremental value in assessing infective endocarditis lesions and complications.

Effective sleep apnoea treatment improves cardiac function in patients with chronic heart failure.

BACKGROUND: Sleep disordered breathing (SDB) is highly prevalent in patients with chronic heart failure (CHF) and is associated with adverse effects on cardiac geometry and function. Continuous positive airway pressure (CPAP) has been proved an effective treatment modality for obstructive sleep apnoea (OSA), whereas adaptive servoventilation (ASV) is more effective in patients with central sleep apnoea (CSA). The impact of selection of therapy and effective apnoea alleviation on cardiac performance and reverse left ventricular remodelling (r-LVR) has not yet been evaluated. METHODS: Eighty five patients with stable CHF were screened for SDB and underwent polysomnography and treatment according to the type of SDB. Clinical evaluation and a comprehensive echocardiographic study was performed before initiation of therapy and after six months of effective treatment (ventilator use >5h/day with AHI <5 events/h). RESULTS: Seventeen compliant patients under effective treatment were included in the analysis (8 OSA under Autoset CPAP and 9 CSA under ASV). In both groups, a significant improvement in all measured, conventional and TDI LV systolic indexes was recorded, including LVEF (32% ± 6% vs. 27% ± 6%, p<0.001). A decrease in LV end-systolic volume (189 ± 94 ml vs. 211 ± 88 ml, p=0.015, difference >10%) was indicative of r-LVR. Furthermore, RV systolic parameters were also increased (TAPSE, p<0.001; systolic TDI wave from lateral tricuspid annular aspect, p=0.001), whereas right heart dimensions and areas were diminished, indicating better pulmonary haemodynamics. Moreover, a significant improvement in patients' clinical status, as evaluated by New York Heart Association Class was also documented at the end of six months follow-up. CONCLUSIONS: Effective alleviation of SDB in CHF patients is associated with significant improvements in LV and RV systolic function and r-LVR. Longitudinal studies are needed to evaluate effects on morbidity and mortality.

Arterial stiffness is associated with increased monocyte expression of adiponectin receptor mRNA and protein in patients with coronary artery disease.

BACKGROUND: Arterial stiffness and carotid intima-media thickness (IMT) constitute validated cardiovascular prognostic markers. Adiponectin and its receptors 1 (AdipoR1) and 2 (AdipoR2) are involved in coronary artery disease (CAD). We investigated whether AdipoR1 and R2 mRNA and protein expression are associated with arterial stiffness, IMT and extent of coronary atherosclerosis. METHODS: We studied 71 patients (61 men, 10 women) with angiographically proven CAD. We measured: (i) monocyte expression of AdipoR1 and AdipoR2 mRNA (quantitative real-time PCR) and protein expression (flow cytometry) (iii) adiponectin, metalloproteinase-9 (MMP-9) and C-reactive protein (CRP) blood levels, (iv) carotid-femoral artery pulse wave velocity (PWV) and carotid IMT. RESULTS: Patients with multi-vessel CAD had higher AdipoR1 and AdipoR2 mRNA than those with single-vessel (P < 0.05). PWV was associated with AdipoR1 mRNA (r = 0.474), AdipoR1 protein (r = 0.228), AdipoR2 mRNA (r = 0.716), AdipoR2-protein (r = 0.261), adiponectin (r = 0.236), and MMP-9 (r = 0.350) (P < 0.05, for all correlations). After adjustment for age, sex, waist-hip ratio, and mean blood pressure both AdipoR1 and AdipoR2 mRNA remained independent determinants of PWV (R(2) = 0.35 and R(2) = 0.57, P < 0.05). IMT was also associated with AdipoR2 mRNA, AdipoR2 protein, and MMP-9 (P < 0.05). Increased expression of ADR2 mRNA significantly related to MMP-9 (r = 0.210), and CRP (r = 0.531) (P < 0.05). CONCLUSION: Increased mRNA and protein expression of adiponectin receptors is related with increased aortic stiffness, coronary and peripheral atherosclerosis in patients with CAD. The interrelation of AdipoR2 with inflammatory markers, PWV and IMT suggests a compensatory increase of these receptors to counteract the excess inflammatory and atherogenic process in CAD. Thus, adiponectin receptors may provide a potential therapeutic target of agents activating their beneficial action.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.42.

Detection of high-burden coronary artery disease by exercise-induced changes of the E/E' ratio.

To investigate whether exercise-induced changes of the E/E' average ratio can detect high-burden coronary artery disease (CAD) in patients with chest pain and normal left ventricular (LV) systolic function. The study population consisted of 359 patients admitted for chest pain (59.8 ± 9.8 years, 75% male). Patients underwent exercise echocardiography, scintigraphy and coronary angiography. The average of the lateral and septal ratios of early diastolic transmitral velocity to early diastolic tissue velocity (E/E') at baseline and immediately after exercise was calculated. Exercise induced wall motion abnormalities were also calculated. Coronary angiography showed flow limiting CAD in 238 patients (66%). The exercise-induced changes of E/E' average ratio had a sensitivity of 87.3% and a specificity of 75.2% for detection of flow limiting CAD, whereas myocardial scintigraphy showed 79.2% sensitivity and 80.1% specificity and exercise induced wall motion abnormalities had a sensitivity of 74.3% and a specificity of 66.9%. Likelihood ratio chi square showed an incremental value of the exercise-induced changes of E/E' average ratio over regional perfusion technique (from 121.37 to 194.15, P < 0.001) and over wall motion abnormalities (from 57.03 to 146.50, P < 0.001). The exercise-induced change of the E/E' average ratio detects flow limiting CAD in patients with chest pain and normal LV systolic function showing an incremental value over regional perfusion technique and wall motion abnormalities.

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

AIMS: The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca(2+), Na(+), K(+)) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes. METHODS AND RESULTS: Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis. CONCLUSION: The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. Clinicaltrials.gov identifier: NCT01209494.

Adiponectin levels and expression of adiponectin receptors in isolated monocytes from overweight patients with coronary artery disease.

BACKGROUND: Adiponectin has insulin-sensitizing and anti-atherosclerotic effects, partly mediated through its action on monocytes. We aimed to determine adiponectin levels and expression of its receptors (AdipoR1 and AdipoR2) in peripheral monocytes from overweight and obese patients with coronary artery disease (CAD). METHODS: Fifty-five overweight/obese patients, suspected for CAD, underwent coronary angiography: 31 were classified as CAD patients (stenosis ≥ 50% in at least one main vessel) and 24 as nonCAD. Quantitative RT-PCR and flow cytometry were used for determining mRNA and protein surface expression of adiponectin receptors in peripheral monocytes. A high sensitivity multiplex assay (xMAP technology) was used for the determination of plasma adiponectin and interleukin-10 (IL-10) secreted levels. RESULTS: Plasma adiponectin levels were decreased in CAD compared to nonCAD patients (10.9 ± 3.1 vs. 13.8 ± 5.8 µg/ml respectively, p = 0.033). In multivariable analysis, Matsuda index was the sole independent determinant of adiponectin levels. AdipoR1 and AdipoR2 protein levels were decreased in monocytes from CAD compared to nonCAD patients (59.5 ± 24.9 vs. 80 ± 46 and 70.7 ± 39 vs. 95.6 ± 47.8 Mean Fluorescence Intensity Arbitrary Units respectively, p < 0.05). No significant differences were observed concerning the mRNA levels of the adiponectin receptors between CAD and nonCAD patients. AdipoR2 protein levels were positively correlated with plasma adiponectin and Matsuda index (r = 0.36 and 0.31 respectively, p < 0.05 for both). Furthermore, basal as well as adiponectin-induced IL-10 release was reduced in monocyte-derived macrophages from CAD compared to nonCAD subjects. CONCLUSIONS: Overweight patients with CAD compared to those without CAD, had decreased plasma adiponectin levels, as well as decreased surface expression of adiponectin receptors in peripheral monocytes. This fact together with the reduced adiponectin-induced IL-10 secretion from CAD macrophages could explain to a certain extent, an impaired atheroprotective action of adiponectin.

C-reactive protein, interleukin 6, and N-terminal pro-brain natriuretic peptide following cardioversion of atrial fibrillation: is there a role of biomarkers in arrhythmia recurrence?

AIMS: We investigated the role of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and N-terminal pro-brain natriuretic peptide (NTpro-BNP), in atrial fibrillation (AF) recurrence rate. METHODS: A total of 80 patients with first AF episode were studied prospectively. Echocardiography (ECG), Holter ECG, and measurements of hsCRP, IL-6, and NTproBNP were performed immediately post conversion and at 1 month. RESULTS: Recurrence was positively related to left atrial volume (P < .001), with no difference in NTpro-BNP, hsCRP, and IL-6. Decreased NTpro-BNP was observed in all at 1 month (P < .001, F = 63.4) and was positively related to left atrial volume (P < .01). In the lone AF subgroup, NTpro-BNP was lower and dropped significantly at 1 month (interaction F = 6.53, P < .01). CONCLUSIONS: Atrial volume was related to AF recurrence, whereas hsCRP, IL-6, and NTpro-BNP were not reliable for AF relapse. Relation of NTpro-BNP to left atrial volume could indicate a role in the atrial remodeling process.

Relationship between individual cardiovascular risk factors and localization of coronary atherosclerotic lesions.

OBJECTIVE: The localization of coronary atherosclerotic lesions in patients with coronary artery disease is important. We investigated the relationship between individual cardiovascular risk factors and lesion localization in the coronary arteries. METHODS: We studied 200 consecutive patients with suspected or known coronary artery disease who were referred for coronary angiography because of chest pain. We assessed the following cardiovascular risk factors: male gender, hypercholesterolemia, smoking, arterial hypertension, positive family history, and diabetes. We evaluated atherosclerotic lesions creating a stenosis ≥ 50% in the 3 coronary arteries and lesions creating a stenosis ≥ 30% in the left main stem. RESULTS: Of the 200 study patients, 155 (78%) showed at least 1 coronary artery lesion with a luminal stenosis ≥ 50%. With an increasing number of risk factors, there was a significant progressive increase of diseased arteries (P < .001). There was a differential association between individual risk factors and lesions in the 3 coronary arteries. Male gender, hypercholesterolemia, and diabetes were predictors of lesions in the left anterior descending artery (odds ratios 2.365, 2.510, and 1.998, respectively). Predictors of left circumflex artery lesions were male gender, smoking, and diabetes (odds ratios 2.581, 1.913, and 2.280, respectively), whereas the only independent predictor of right coronary artery lesions was male gender (odds ratio 2.995). Diabetes was also significantly associated with lesions in the diagonal branches of the left anterior descending artery and the marginal branches of the left circumflex artery. CONCLUSION: Individual cardiovascular risk factors are associated with the localization of atherosclerotic lesions in the coronary circulation.

Right atrial myxoma presenting as syncope due to pulmonary embolism in a previously asymptomatic patient.

Tumours of the heart are rare, and in the vast majority of cases are myxomas that have a benign profile. According to their location, their clinical manifestations differ but there are cases that are completely asymptomatic [M. Yuce, S. Dagdelen, M. Ergelen, N. Eren, N. Caglar, A huge obstructive myxoma located in the right heart without causing any symptom. Int J Cardiol 2007;114:405-406.], found only post-mortem. Herein we describe the case of a 45-year-old female patient previously asymptomatic who presented with syncope due to a large right atrial myxoma with extracardiac localization as embolic phenomenon in the pulmonary artery tree.

Instantaneous electrocardiographic changes and transient sinus rhythm restoration in severe hyperkalaemia.

Severe hyperkalaemia is a life threatening electrolyte abnormality that if not treated urgently, might cause electric death. Hyperkalaemia induced electrocardiogram (ECG) alterations vary according to the levels and rate of increase of potassium concentration ([K(+)]) in the extracellular milieu but the paradox is that not all these cases provide ECG changes. We describe the first case in the literature of transient sinus rhythm (SR) recovery despite severe hyperkalaemia in a 57-year-old (yo) male patient with impressive ECG changes considering the heart rhythm and QRS morphology. We also review the literature for the mechanism of ECG alterations induced by hyperkalaemia.

Recurrent apical ballooning syndrome "The masquerading acute cardiac syndrome".

Left ventricle (LV) apical ballooning syndrome (ABS) is a recently established reversible cardiomyopathy (CM) that presents as acute coronary syndrome (ACS) with ST segment elevation and specific echocardiographic (Echo) findings in the absence of significant coronary artery disease. Synonyms of ABS include "stress-induced CM" and "Takotsubo CM", terms that describe primarily the pathophysiology and the Echo findings of the syndrome respectively. This syndrome is a rare entity, accounting for the 2.2% of the ST segment elevation ACS, while recurrence rates reach 10% four years after the initial episode [1]. Herein we describe the first case in the literature of an 83 year-old (yo), female patient who suffered two episodes of ABS, the first in 1999 when the syndrome was unknown and diagnosis was "ST segment elevation myocardial infraction (STEMI)'' and the other one eight years later in 2007.