Risks and benefits of optimised medical and revascularisation therapy in elderly patients with angina--on-treatment analysis of the TIME trial.

AIM: To assess treatment effects of optimised medical therapy and PCI or CABG surgery on one-year outcome in patients 75 years old with chronic angina. METHODS AND RESULTS: On-treatment analysis of the TIME data: all re-vascularised patients (REVASC n=174: 112 randomised to revascularisation and 62 to drugs with late revascularisation) were compared to all patients on continued drug therapy (MED n=127: 86 randomised to drugs and 41 to revascularisation only). Baseline characteristics of both groups were similar (age 80 +/- 4 years). Risk of death at one year (adjusted hazard ratio (HR)=1.31; 95%-CI: 0.58-2.99; P=0.52) and of death/infarction (adjusted hazard RATIO=1.77; 95%-CI 0.91-3.41; P=0.09) were comparable between REVASC and MED patients. Furthermore, the risk of death within 30 days was even slightly lower among REVASC patients (unadjusted hazard RATIO=0.73; 95%-CI: 0.21-2.53; P=0.98). Overall, REVASC patients had greater improvements in symptoms and well-being than MED patients (P<0.01). Surgical patients had similar mortality rates as angioplasty patients, but they also had greater symptomatic improvements (P<0.01). CONCLUSION: Treated medically, elderly patients with chronic angina have a similarly high 30-day and one-year mortality as patients of the same age being re-vascularised; however, they can expect lower improvements in symptoms and well being.     

The Importance of Interleukin 18, Glutathione Peroxidase, and Selenium Concentration Changes in Acute Pancreatitis

Cytokinemia and oxidative stress are important factors responsible for an inadequate immune response in the early course of acute pancreatitis (AP). The aim of the study was to evaluate the profiles of interleukin 18 (IL-18), glutathione peroxidase (GPx), and selenium concentrations in serum with respect to AP severity and to study the relationships between these parameters and recognized prognostic indicators of AP severity. Prospective clinical analyses were performed on 61 patients with mild and severe forms of AP and for 15 healthy volunteers. In both forms of AP severity, the IL-18 concentration in the serum was significantly higher than in healthy controls. In the severe form of AP, the IL-18 concentration was the highest and exceeded significantly the values recorded on the 1st, 2nd, 3rd, 5th, and 10th days of mild AP. A significantly lower GPx concentration in the serum was recorded in severe AP compared to the mild form and in the control group. There was a significantly lower selenium concentration in the severe form of AP. Significant correlations between GPx and selenium, between IL-18 and GPx, and between IL-18 and selenium were recorded. The ROC analysis shows a high prognostic accuracy of IL-18 and GPx concentrations in the determination of AP severity. IL-18 is released early in the course of AP and may be a key immunomodulator of the inflammatory response in the severe form of this disease. Low GPx and selenium concentrations in severe AP reflect the lower antioxidative ability in this form of AP. IL-18 and GPx may represent new indicators of AP severity.     

Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior.

Papillary thyroid microcarcinoma (mPTC), is a very frequent incidental finding with a frequency varying from a few percent to 35% at postmortem histopathologic examinations. However, the presence of mPTC in patients undergoing thyroidectomy for multinodular goiter (MNG) and for Graves' disease (GD) has been found to be lower. Patients with medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) association have been published as anecdotal case reports, as well as kindred with familial MTC or multiple endocrine neoplasia (MEN) 2A with some members simultaneously affected by MTC and PTC. We studied the prevalence and the biological behavior of MTC associated with PTC, with particular attention to those cases in which a mPTC was incidentally found. Twenty-seven of 196 (13.8%) MTC cases showed an association with PTC and in particular 21 of 190 (11.05%) with an incidental mPTC. This percentage is higher than that reported in the literature on the association of mPTC with GD (2.8%-4.5%) and MNG (3%). Also the percentage of the more general association of MTC/PTC, not restricted to mPTC, found in our series (13.8%) is higher than that reported in studies that analyzed the prevalence of PTC (any size) in patients treated for MNG (7.5%). A similarly high percentage of MTC/PTC had not been reported before and in particular there are no reports on large series of MTC/PTC. We also analyzed the epidemiologic, clinical, and pathologic features of MTC associated and not associated with PTC without finding any difference. In particular the outcome of the MTC did not appear to be influenced by the presence of the PTC and the specific radioiodine treatments. Moreover, although we cannot completely exclude a shared pathogenic event as the cause of both MTC and PTC, the molecular analysis of RET gene alterations did not show any common mutation.     

Circadian Variation and Waking Hour Dynamics of the QT Interval

Background: The incidence of sudden cardiac death is maximal in the morning hours. Although ventricular arrhythmias have been implicated as a potential mechanism, and several neurohumoral factors affecting myocardial excitability have been shown to be raised in the early morning hours, it is not known if there is any circadian variation in the dynamics of ventricular repolarization when studied on a beat-to-beat basis. The objective of this study was to examine the range, diurnal variations, and circadian distribution of the variability of the QT interval in healthy subjects. Method: We developed and validated a new method for continuous measurement of QT intervals from 24-hour Holter recordings. The QT intervals measured semi-automatically were corrected by a linear regression formula derived independently for each patient from his own QT and RR values in 32 healthy males (20 ± 0.4 years). QT variability was assessed by the mean standard deviation of the average of consecutive uncorrected QT intervals (SDA-QT Index) and corrected QT intervals (SDA-QTc index) over 5-minute segments. The rate-dependent changes of the QT interval were studied as a function of the slope of the regression line between the QT and RR values. Results: The average QTc range was mean (SD) 79 (± 28) ms; the average maximal QTc interval was 481 (± 24) ms. The 95% upper confidence limit for the mean 24-hour QTc interval was 443 ms. The RR, QT, and QTc intervals were longer, while the SDA-QT and SDA-QTc indices were shorter during sleep. Hourly averages of the SDA-QT and SDA- QTc index revealed a sudden increase in QT variability in the first hour of waking (P < 0.0001 and P = 0.006). Conclusion: The dynamic behavior of the QT interval shows significant diurnal variations. The maximal QTc interval over 24 hours is longer than previously assumed. The period shortly following awakening is characterized by a peak in the variability of the QT interval. These changes may be indicative of autonomic instability during the early waking hours and correspond with the peak incidence of sudden arrhythmic death.     

Cell wall lipids from Mycobacterium bovis BCG are inflammatory when inoculated within a gel matrix: characterization of a new model of the granulomatous response to mycobacterial components

The chronic inflammatory response to Mycobacterium generates complex granulomatous lesions that balance containment with destruction of infected tissues. To study the contributing factors from host and pathogen, we developed a model wherein defined mycobacterial components and leukocytes are delivered in a gel, eliciting a localized response that can be retrieved and analysed. We validated the model by comparing responses to the cell wall lipids from Mycobacterium bovis bacillus Calmette-Guerin (BCG) to reported activities in other models. BCG lipid-coated beads and bone marrow-derived macrophages (input macrophages) were injected intraperitoneally into BALB/c mice. Input macrophages and recruited peritoneal exudate cells took up fluorescently tagged BCG lipids, and matrix-associated macrophages and neutrophils produced tumor necrosis factor, interleukin-1alpha, and interleukin-6. Leukocyte numbers and cytokine levels were greater in BCG lipid-bearing matrices than matrices containing non-coated or phosphatidylglycerol-coated beads. Leukocytes arrived in successive waves of neutrophils, macrophages and eosinophils, followed by NK and T cells (CD4(+), CD8(+), or gammadelta) at 7 days and B cells within 12 days. BCG lipids also predisposed matrices for adherence and vascularization, enhancing cellular recruitment. We submit that the matrix model presents pertinent features of the murine granulomatous response that will prove to be an adaptable method for study of this complex response.     

Extracellular signal-regulated kinase 1/2 activation by myometrial oxytocin receptor involves Galpha(q)Gbetagamma and epidermal growth factor receptor tyrosine kinase activation

The mechanisms by which oxytocin (OT) stimulates extracellular signal-regulated kinase 1/2 (ERK1/2) are only partially understood. OT receptor (OTR) signals predominantly through Galpha(q), but ERK1/2 phosphorylation (ERK1/2-P) in PHM1 myometrial cells was not eliminated by inhibition of downstream effectors such as phospholipase C or protein kinase C. Inconsistent with a Galpha(i)-coupled response, pertussis toxin inhibition of OT-induced ERK1/2-P was reversed by the protein kinase A inhibitors Rp-cAMPS and KT5720. Consistent with an inhibitory role for protein kinase A, pertussis toxin pretreatment raised cellular cAMP and 8-(4-chlorophenylthio)-cAMP inhibited OT-induced ERK1/2-P. Attenuation of the OT response by the Gbetagamma scavenger carboxyl terminus of the beta-adrenergic receptor kinase implicated a Gbetagamma-mediated pathway. In both COSM6 cells overexpressing OTR (OTR-COSM6) and in PHM1 cells, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 markedly reduced OT-induced ERK1/2-P, whereas the platelet-derived growth factor receptor tyrosine kinase inhibitor AG1296 had no effect. Furthermore, OT increased EGFR tyrosine phosphorylation in OTR-COSM6 cells, which was inhibited by AG1478 or EGTA plus thapsigargin pretreatment. AG1478 did not affect inositol 1,4,5-triphosphate production by OT or protein kinase C-stimulated ERK1/2-P but completely blocked ionomycin-induced ERK1/2-P and EGFR tyrosine phosphorylation. In both OTR-COSM6 and PHM1 cells, EGTA reduced OT-stimulated ERK1/2-P; no ERK1/2-P was observed when intracellular calcium increases were blocked by pretreatment with thapsigargin plus EGTA. These data are consistent with activation of a Gbetagamma-mediated pathway as a consequence of Galpha(q) activation in myometrium and OTR-COSM6 cells that results in increased ERK1/2-P. This pathway involves both EGFR activation and an influence of calcium.     

Pulmonary Hypertension in Patients With Severe Aortic Stenosis: Prognostic Impact After Transcatheter Aortic Valve Replacement: Pulmonary Hypertension in Patients Undergoing TAVR

Objectives

The authors investigated the development of pulmonary hypertension (PH), predictors of PH regression, and its prognostic impact on short, mid-, and long-term outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS).

Quality of diabetes care predicts the development of cardiovascular events: results of the QuED study

Background and aimIn the context of the QuED Study we assessed whether a quality of care summary score was able to predict the development of cardiovascular (CV) events in patients with type 2 diabetes.Methods and resultsThe score was calculated using process and intermediate outcome indicators (HbA_1c, blood pressure, low-density lipoprotein cholesterol, microalbuminuria) and ranged from 0 to 40. Overall, 3235 patients were enrolled, of whom 492 developed a CV event after a median follow-up of 5 years. The incidence rate (per 1000 person-years) of CV events was 62.4 in patients with a score ≤10, 54.8 in those with a score between 15 and 20, and 39.8 in those with a score >20. In adjusted multilevel regression models, the risk to develop a CV event was 89% greater in patients with a score of ≤10 (rate ratio [RR] = 1.89; 95% confidence interval [CI] 1.43–2.50) and 43% higher in those with a score between 10 and 20 (RR = 1.43; 95% CI 1.14–1.79), as compared to those with a score >20. A difference between centers of 5 points in the mean quality score was associated with a difference of 16% in CV event risk (RR = 0.84; 95% CI 0.72–0.98).ConclusionOur study documented for the first time a close relationship between a score of quality of diabetes care and long-term outcomes.     

Anxiety and depression after coronary artery bypass graft surgery: most get better, some get worse

BACKGROUND: To target interventions, patients at risk for poor outcomes after a cardiac event need to be identified. We investigated trajectories of anxiety and depression after coronary artery bypass graft surgery (CABGS) and identified patients at risk of persistent or worsening anxiety and depression. METHODS: A consecutive sample of 184 patients on the waiting list for CABGS at The Royal Melbourne Hospital completed self-report questionnaires before surgery, and at 2 and 6 months postsurgery. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale. Growth mixture modelling identified trajectories of anxiety and depression. RESULTS: Two possible trajectories emerged for anxiety, whereas three trajectories emerged for depression. Most patients (92%) followed a trajectory of minor presurgical anxiety that remitted in 6 months after CABGS, with the remainder (8%) following a trajectory of major anxiety that remitted in the same period. Minor remitted depression was also common (72% patients). Two less common depression trajectories indicated worsening or unresolved depression. One trajectory began with major presurgical depression that partially remitted by 6 months (14% patients) and the other began with minor presurgical depression that worsened by 6 months (14% patients). Unpartnered patients, smokers, those with presurgical anxiety, high cholesterol, angina, more severe disease or having repeat CABGS were at increased risk for a poor depression trajectory. CONCLUSION: Although initial anxiety and depression resolved or lessened for most patients, some patients experienced persistent or worsening depression after CABGS. Interventions can be targeted toward 'at risk' patients.