Domenico Pagano

Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease

IntroductionInflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood.MethodsFor these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation.ResultsThe expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 ± 1.57 μg/mL vs CABG: 9.11 ± 15.7 μg/mL; p < 0.001) and resistin (control: 10.53 ± 0.81 ng/mL vs CABG: 16.8 ± 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 ± 14.8 μg/mL vs CABG: 11.9 ± 6.0 μg/mL; p < 0.05) when compared to BMI matched controls.ConclusionEpicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease.

Weekend hospitalization and additional risk of death: An analysis of inpatient data

Objective To assess whether weekend admissions to hospital and/or already being an inpatient on weekend days were associated with any additional mortality risk. Design Retrospective observational survivorship study. We analysed all admissions to the English National Health Service (NHS) during the financial year 2009/10, following up all patients for 30 days after admission and accounting for risk of death associated with diagnosis, co-morbidities, admission history, age, sex, ethnicity, deprivation, seasonality, day of admission and hospital trust, including day of death as a time dependent covariate. The principal analysis was based on time to in-hospital death. Participants National Health Service Hospitals in England. Main Outcome Measures 30 day mortality (in or out of hospital). Results There were 14,217,640 admissions included in the principal analysis, with 187,337 in-hospital deaths reported within 30 days of admission. Admission on weekend days was associated with a considerable increase in risk of subsequent death compared with admission on weekdays, hazard ratio for Sunday versus Wednesday 1.16 (95% CI 1.14 to 1.18; P < .0001), and for Saturday versus Wednesday 1.11 (95% CI 1.09 to 1.13; P < .0001). Hospital stays on weekend days were associated with a lower risk of death than midweek days, hazard ratio for being in hospital on Sunday versus Wednesday 0.92 (95% CI 0.91 to 0.94; P < .0001), and for Saturday versus Wednesday 0.95 (95% CI 0.93 to 0.96; P < .0001). Similar findings were observed on a smaller US data set. Conclusions Admission at the weekend is associated with increased risk of subsequent death within 30 days of admission. The likelihood of death actually occurring is less on a weekend day than on a mid-week day.

Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure

Objective To compare the predictive value of dobutamine echocardiography (DE) and positron emission tomography (PET) in identifying reversible chronic left ventricular (LV) dysfunction (hibernating myocardium) in patients with coronary artery disease (CAD) and overt heart failure. Patients 30 patients (four women) with CAD and heart failure undergoing coronary artery bypass grafting (CABG). Methods Myocardial viability was assessed with DE (5 and 10 μg/kg/min) and PET with [18F] 2-fluoro-2-deoxy-D-glucose (FDG) under hyperinsulinaemic euglycaemic clamp. Regional (echo) and global LV function (MUGA) were assessed at baseline and six months after CABG. Results 192 of the 336 (57%) dysfunctional LV segments improved function following CABG (hibernating) and the LV ejection fraction (EF) increased from 23(7) to 32(9)% (p < 0.0001) (in 17 patients > 5%). DE and PET had similar positive predictive values (68% and 66%) in the identification of hibernating myocardium, but DE had a significantly lower negative predictive value than PET (54% v 96%; p < 0.0001). A significant linear correlation was found between the number of PET viable segments and the changes in EF following CABG (r = 0.65; p = 0.0001). Stepwise logistic regression identified the number of PET viable segments as an independent predictor of improvement in EF > 5%, whereas the number of DE viable segments, the baseline LVEF, and wall motion were not. Conclusions DE has a higher false negative rate than PET in identifying recoverable LV dysfunction in patients with severe postischaemic heart failure. The amount of PET viable myocardium correlates with the functional outcome following CABG.

Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting

Background—Risk stratification algorithms for coronary artery bypass grafting (CABG) do not include a weighting for preoperative mild renal impairment defined as a serum creatinine 130 to 199 &mgr;mol/L (1.47 to 2.25 mg/dL), which may impact mortality and morbidity after CABG. Methods and Results—We reviewed prospectively collected data between 1997 and 2004 on 4403 consecutive patients undergoing first-time isolated CABG with a preoperative serum creatinine <200 &mgr;mol/L (2.26 mg/dL)] in a single institution. The in-hospital mortality was 2.5% (112 of 4403), the need for new dialysis/hemofiltration was 1.3% (57 of 4403), and the stroke rate was 2.5% (108 of 4403). There were 458 patients with a serum creatinine 130 to 199 &mgr;mol/L or 1.47 to 2.25 mg/dL (mild renal dysfunction group) and 3945 patients with a serum creatinine <130 &mgr;mol/L (<1.47 mg/dL). Operative mortality was higher in the mild renal dysfunction group (2.1% versus 6.1%; P<0.001) and increased with increasing preoperative serum creatinine level. New dialysis/hemofiltration (0.8%versus 5.2%; P<0.001) and postoperative stroke (2.2% versus 5.0%; P<0.01) were also more common in the patients with mild renal impairment. Multivariate analysis adjusting for known risk factors confirmed preoperative mild renal impairment (creatinine 130 to 199 &mgr;mol/L or 1.47 to 2.25 mg/dL; odd ratio, 1.91; 95% CI, 1.18 to 3.03; P=0.007) or glomerular filtration rate estimates <60 mL/min per 1.73 m2, derived using the Cockroft-Gault formula, (odds ratio, 1.98; 95% CI, 1.16 to 3.48; P=0.015) as independent predictors of in-hospital mortality. Preoperative mild renal dysfunction adversely affected the 3-year survival probability after CABG (93% versus 81%; P<0.001). Conclusions—Mild renal dysfunction is an important predictor of outcome in terms of in-hospital mortality, morbidity, and midterm survival in patients undergoing CABG.

Insulin resistance in patients with cardiac hypertrophy

OBJECTIVE Animal studies suggest that left ventricular hypertrophy might be associated with insulin resistance and alterations in glucose transporters. We have previously demonstrated myocardial insulin resistance in patients with post-ischemic heart failure. The aim was to investigate whether myocardial insulin resistance could be demonstrated in human cardiac hypertrophy in the absence of hypertension, diabetes and coronary artery disease. METHODS Eleven normotensive nondiabetic patients with cardiac hypertrophy due to aortic stenosis and angiographically normal coronary arteries were compared to 11 normal volunteers. Myocardial glucose uptake (MGU) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose during fasting (low insulinemia) or during euglycemic-hyperinsulinemic clamp (physiologic hyperinsulinemia). Myocardial biopsies were obtained in order to investigate changes in insulin-independent (GLUT-1) and insulin-dependent (GLUT-4) glucose transporters. RESULTS During fasting, plasma insulin (7 +/- 1 vs. 6 +/- 1 mU/l) and MGU (0.12 +/- 0.05 vs. 0.11 +/- 0.04 mumol/min/g) were comparable in patients and controls. By contrast, during clamp, MGU was markedly reduced in patients (0.48 +/- 0.02 vs. 0.70 +/- 0.03 mumol/min/g, p < 0.01) despite similar plasma insulin levels (95 +/- 6 vs. 79 +/- 6 mU/l). A decreased GLUT-4/GLUT-1 ratio was shown by Western blot analysis in patients. CONCLUSIONS Insulin resistance seems to be a feature of the hypertrophied heart even in the absence of hypertension, coronary artery disease and diabetes and may be explained, at least in part, by abnormalities in glucose transporters.

Coronary artery bypass surgery as treatment for ischemic heart failure: the predictive value of viability assessment with quantitative positron emission tomography for symptomatic and functional outcome

OBJECTIVES To determine the predictive value of quantitative evaluation of myocardial viability on changes in left ventricular function, exercise capacity, and quality of life after coronary artery bypass grafting in patients with ischemic heart failure (congestive heart failure, New York Heart Association class > or = III) with and without angina. METHODS Thirty-five patients, 14 with congestive heart failure and angina (CHF-angina) and 21 with congestive heart failure without angina (CHF-no angina) were studied at baseline and 6 months after coronary bypass grafting. Left ventricular function was evaluated with transthoracic echocardiography and radionuclide ventriculography. Myocardial viability was assessed with [18F]-2-fluoro-2-deoxy-D-glucose using positron emission tomography. Peak aerobic capacity (peak oxygen consumption) and anaerobic threshold were assessed with treadmill exercise test and quality of life with a questionnaire. RESULTS A total of 286 of 336 dysfunctional left ventricular segments were viable. There were two perioperative deaths (5.7%) and three late deaths. Left ventricular ejection fraction increased from 23% +/- 7% to 32% +/- 9% (p < 0.0001), and a linear correlation was found between the number of viable segments and the changes in ejection fraction (r = 0.65; p = 0.0001). Receiver operating characteristics curve identified eight viable segments as the best predictor for increase of ejection fraction more than 5 percentage points. Peak oxygen consumption increased from 15 +/- 4 to 22 +/- 5 ml/kg per minute (p < 0.0001). Preoperatively, anaerobic threshold was identified in one patient from the CHF-angina group and in all from the CHF-no angina group and increased from 13 +/- 4 to 19 +/- 4 ml/kg per minute (p < 0.0001). Quality of life scores improved significantly in both groups. No correlation was found between the amount of viable dysfunctional myocardium and changes in exercise capacity or quality of life. CONCLUSIONS In patients with postischemic congestive heart failure the amount of viable myocardium dictates the degree of improvement in left ventricular function after revascularization.

Selective Antegrade Cerebral Perfusion Attenuates Brain Metabolic Deficit in Aortic Arch Surgery A Prospective Randomized Trial

Background—Aortic arch surgery has a high incidence of brain injury. This may in part be caused by a cerebral metabolic deficit observed after hypothermic circulatory arrest (HCA). We hypothesized that selective antegrade cerebral perfusion (SACP) would attenuate this phenomenon. Methods and Results—In a prospective randomized trial, 42 adult patients were allocated to either HCA (22) or SACP. HCA occurred at a nasopharyngeal temperature of 15°C and SACP at a corporeal temperature of 25°C with cerebral perfusion at 15°C. Paired arterial and jugular venous samples were taken before and after arrest. Continuous transcranial Doppler monitoring of middle cerebral artery velocity (MCAV) was performed. Neuropsychometric testing was performed preoperatively and at 6 and 12 weeks postoperatively. There were 3 hospital deaths (7.1%), 2 strokes (4.8%), and 6 episodes of transient neurological deficit (14.3%). From before to after arrest, jugular bulb pO2 changed by −21.67 mm Hg (26.4) in the HCA group versus +2.27 mm Hg (18.8) in the SACP group (P=0.007). Oxygen extraction changed by +1.7 mL/dL (1.3) in the HCA group versus −1 mL/dL (2.4) in the SACP group (P<0.001). MCAV increased by 6.25 cm/s (9.1) in the HCA group and 19.2 cm/s (10.1) in the SACP group (P=0.001). Incidence of neuropsychometric deficit at 6 weeks was 6/12 (50%) in HCA patients and 8/10 (80%) in SACP patients (P=0.2), and at 12 weeks was 6/16 (38%) in HCA patients and 4/11 (36%) in SACP patients (P=1). Conclusions—SACP attenuates the metabolic changes seen after HCA. Further studies are required to assess optimal perfusion conditions and clinical outcome.

Epicardial Adipose Tissue as a Source of Nuclear Factor-κB and c-Jun N-Terminal Kinase Mediated Inflammation in Patients with Coronary Artery Disease

CONTEXT Visceral adipose tissue (AT) is known to confer a significantly higher risk of type 2 diabetes and cardiovascular disease. Epicardial AT has been shown to be related to cardiovascular disease and myocardial function through unidentified mechanisms. Epicardial AT expresses an inflammatory profile of proteins; however, the mechanisms responsible are yet to be elucidated. OBJECTIVES The objectives of the study were to: 1) examine key mediators of the nuclear factor-kappaB (NFkappaB) and c-Jun N-terminal kinase (JNK) pathways in paired epicardial and gluteofemoral (thigh) AT from coronary artery disease (CAD) and control patients and 2) investigate circulating endotoxin levels in CAD and control subjects. DESIGN Serums and AT biopsies (epicardial and thigh) were obtained from CAD (n = 16) and non-CAD (n = 18) patients. Inflammation was assessed in tissue and serum samples through Western blot, real-time PCR, ELISAs, and activity studies. RESULTS Western blotting showed epicardial AT had significantly higher NFkappaB, inhibitory-kappaB kinase (IKK)-gamma, IKKbeta, and JNK-1 and -2 compared with thigh AT. Epicardial mRNA data showed strong correlations between CD-68 and toll-like receptor-2, toll-like receptor-4, and TNF-alpha. Circulating endotoxin was elevated in patients with CAD compared with matched controls [CAD: 6.80 +/- 0.28 endotoxin unit(EU)/ml vs. controls: 5.52 +/- 0.57 EU/ml; P<0.05]. CONCLUSION Epicardial AT from patients with CAD shows increased NFkappaB, IKKbeta, and JNK expression compared with both CAD thigh AT and non-CAD epicardial AT, suggesting a depot-specific as well as a disease-linked response to inflammation. These studies implicate both NFkappaB and JNK pathways in the inflammatory profile of epicardial AT and highlight the role of the macrophage in the inflammation within this tissue.

How does EuroSCORE II perform in UK cardiac surgery; an analysis of 23 740 patients from the Society for Cardiothoracic Surgery in Great Britain and Ireland National Database

Objective The original EuroSCORE models are poorly calibrated for predicting mortality in contemporary cardiac surgery. EuroSCORE II has been proposed as a new risk model. The objective of this study was to assess the performance of EuroSCORE II in UK cardiac surgery. Design A cross-sectional analysis of prospectively collected multi-centre clinical audit data, from the Society for Cardiothoracic Surgery in Great Britain and Ireland Database. Setting All NHS hospitals, and some UK private hospitals performing adult cardiac surgery. Patients 23 740 procedures at 41 hospitals between July 2010 and March 2011. Main outcome measures The main outcome measure was in-hospital mortality. Model calibration (Hosmer–Lemeshow test, calibration plot) and discrimination (area under receiver operating characteristic curve) were assessed in the overall cohort and clinically defined sub-groups. Results The mean age at procedure was 67.1 years (SD 11.8) and 27.7% were women. The overall mortality was 3.1% with a EuroSCORE II predicted mortality of 3.4%. Calibration was good overall but the model failed the Hosmer–Lemeshow test (p=0.003) mainly due to over-prediction in the highest and lowest-risk patients. Calibration was poor for isolated coronary artery bypass graft surgery (Hosmer–Lemeshow, p<0.001). The model had good discrimination overall (area under receiver operating characteristic curve 0.808, 95% CI 0.793 to 0.824) and in all clinical sub-groups analysed. Conclusions EuroSCORE II performs well overall in the UK and is an acceptable contemporary generic cardiac surgery risk model. However, the model is poorly calibrated for isolated coronary artery bypass graft surgery and in both the highest and lowest risk patients. Regular revalidation of EuroSCORE II will be needed to identify calibration drift or clinical inconsistencies, which commonly emerge in clinical prediction models.

Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.

Background— Both glucose-insulin-potassium (GIK) and tri-iodothyronine (T3) may improve cardiovascular performance after coronary artery surgery (CABG) but their effects have not been directly compared and the effects of combined treatment are unknown. Methods and Results— In 2 consecutive randomized double-blind placebo-controlled trials, in patients undergoing first time isolated on-pump CABG between January 2000 and September 2004, 440 patients were recruited and randomized to either placebo (5% dextrose) (n=160), GIK (40% dextrose, K+ 100 mmol · L−1, insulin 70 u · L−1) (0.75 mL · kg−1 h−1) (n=157), T3 (0.8 &mgr;g · kg−1 followed by 0.113 &mgr;g · kg−1 h−1) (n=63) or GIK+T3 (n=60). GIK/placebo therapy was administered from start of operation until 6 hours after removal of aortic cross-clamp (AXC) and T3/placebo was administered for a 6-hour period from removal of AXC. Serial hemodynamic measurements were taken up to 12 hours after removal of AXC and troponin I (cTnI) levels were assayed to 72 hours. Cardiac index (CI) was significantly increased in both the GIK and GIK/T3 group in the first 6 hours compared with placebo (P<0.001 for both) and T3 therapy (P=0.009 and 0.029, respectively). T3 therapy increased CI versus placebo between 6 and 12 hours after AXC removal (P=0.01) but combination therapy did not. Release of cTnI was lower in all treatment groups at 6 and 12 hours after removal of AXC. Conclusions— Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery. Combination therapy does not provide added hemodynamic effect.