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Purpose Insulin-like growth factor-1 (IGF-1) has been associated with both protective and detrimental effects on the development of ischemic heart disease. The relationship between IGF-1 levels and major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients remains unclear. This study aimed to investigate the relationship between IGF-1 admission levels in hyperglycemic ACS patients and: (1) MACE over a 5 years follow-up, (2) type 2 diabetes at discharge, and (3) post-ACS myocardial infarct size and dysfunction. Methods This was a post hoc analysis of the BIOMArCS-2 randomized controlled trial. From July 2008 to February 2012, 276 ACS patients with admission plasma glucose level between 140 and 288 mg/dL were included. Records of the composite of all-cause mortality and recurrent non-fatal myocardial infarction were obtained during 5 years follow-up. Venous blood samples were collected on admission. IGF-1 was measured batchwise after study completion. Oral glucose tolerance test was performed to diagnose type 2 diabetes, whereas infarct size and left ventricular function were assessed by myocardial perfusion scintigraphy (MPS) imaging, 6 weeks post-ACS. Results Cumulative incidence of MACE was 24% at 5 years follow-up. IGF-1 was not independently associated with MACE (HR:1.00 (95%CI:0.99–1.00), p = 0.29). Seventy-eight patients (28%) had type 2 diabetes at discharge, and the highest quartile of IGF-1 levels was associated with the lowest incidence of diabetes (HR:0.40 (95%CI:0.17–0.95), p = 0.037). IGF-1 levels were not associated with post-ACS myocardial infarct size and dysfunction. Conclusions IGF-1 carries potential for predicting type 2 diabetes, rather than long-term cardiovascular outcomes and post-ACS myocardial infarct size and dysfunction, in hyperglycemic ACS patients.

In the BIOMArCS-2 Glucose (Randomized Trial to Evaluate the Clinical Value of Intensive Glucose Monitoring and Regulation in Myocardial Infarction) trial, intensive glucose control (IGC) did not reduce myocardial infarction (MI) size in ST-segment–elevation MI or non–ST-segment–elevation MI patients presenting with hyperglycemia. In fact, IGC was associated with excess in-hospital death or MI (8 versus 1 event).1 Because these findings were unexpected, we executed a longer-term extension of the original trial cohort. In BIOMArCS-2 Glucose, 280 MI patients with admission blood glucose 140 to 288 mg/dL were randomly assigned to either IGC with intravenous insulin for 48 hours aiming for plasma levels of 85 to 110 mg/dL versus conventional management (control).1 The protocol was approved by the local Medical Ethics committee, and all patients provided written informed consent. In January 2016, median follow-up was 5.1 years (interquartile range, 4.0–6.2). We obtained data on vital status from municipal registries and on MI by reviewing medical records. MI was defined as typical chest pain accompanied by a rise of troponins. Follow-up on all-cause death and MI was 99.3% and 97.5% of patients, respectively. Patients with incomplete follow-up data were censored after their last hospital …

Background Elevated plasma glucose levels on admission (APG) are very common in patients with acute coronary syndrome (ACS) and can be the first indication of diabetes mellitus. Objective To provide insight into the prevalence of previously undiagnosed diabetes and to compare different methods of diagnosing diabetes in patients with ACS. Methods Patients with ACS with elevated APG who participated in the BIOMArCS 2 glucose trial underwent an oral glucose tolerance test (OGTT) prior to discharge. 130 patients were included who underwent metabolic assessment. Of these, 109 had an OGTT and 13 patients had pre-existing diabetes. Results The OGTT results were categorised as (previously) undiagnosed diabetes in 35% of patients (fasting plasma glucose (FPG) ≥7.0 mmol/l or 2-h post-load glucose ≥11.1 mmol/l) and impaired glucose metabolism in 44% (FPG 6.1–6.9 mmol/l or post-load glucose 7.8–11.0 mmol/l), so only 21% had a normal glucose metabolism. Undiagnosed diabetes could not be adequately predicted with APG, FPG or HbA1c (area under the ROC curve 0.61, 0.75 and 0.72, respectively). Patients with abnormal glucose metabolism were significantly older, had higher admission HbA1c values, a higher Killip classification and more often had a prior stroke than patients with normal glucose metabolism. Conclusion 79% of hyperglycaemic patients with ACS were found to have abnormal glucose metabolism. As APG, HbA1c and FPG had a low sensitivity to detect undiagnosed diabetes, an OGTT appears to be the best test to assess the presence of previously undiagnosed diabetes or impaired glucose metabolism in hyperglycaemic patients with ACS.

Aims The applicability of currently available risk prediction models for patients undergoing percutaneous coronary interventions (PCIs) is limited. We aimed to develop a model for the prediction of in-hospital mortality after PCI that is based on contemporary and representative data from a European perspective. Methods and results Our analyses are based on the Euro Heart Survey of PCIs, which contains information on 46 064 consecutive patients who underwent PCI for different indications in 176 participating European centres during 2005–08. Patients were randomly divided into a training ( n = 23 032) and a validation ( n = 23 032) set with similar characteristics. In these sets, 339 (1.5%) and 305 (1.3%) patients died during hospitalization, respectively. On the basis of the training set, a logistic model was constructed that related 16 independent patient or lesion characteristics with mortality, including PCI indication, advanced age, haemodynamic instability, multivessel disease, and proximal LAD disease. In both the training and validation data sets, the model had a good performance in terms of discrimination ( C -index 0.91 and 0.90, respectively) and calibration (Hosmer–Lemeshow P -value 0.39 and 0.18, respectively). Conclusion In-hospital mortality in PCI patients was well predicted by a risk score that contains 16 factors. The score has strong applicability for European practices.

Objective: Admission plasma glucose (APG) is a biomarker that predicts mortality in myocardial infarction (MI) patients. Therefore, APG may improve risk stratification based on the GRACE risk score. Methods: We collected data on baseline characteristics and long-term (median 55 months) outcome of 550 MI patients who entered our hospital in 2003 and 2006. We determined the GRACE risk score at admission for each patient, which was entered in a logistic regression model, together with APG, to evaluate their prognostic value for 6-month and 5-year mortality. Results: Patients with APG ≧7.8 mmol/l had a higher mortality than those with APG levels Conclusion: APG is a predictor of 6-month and 5-year mortality, each mmol/l increase in APG being associated with a mortality increase of 17 and 12%, respectively, independent of the GRACE risk score. However, adding APG to the GRACE model did not result in significantly improved clinical risk stratification.

Background It is uncertain if elevated admission plasma glucose (APG) remains an independent determinant of longer-term mortality in myocardial infarction (MI) patients with early restoration of coronary reperfusion by primary percutaneous coronary intervention. The objective of the study was to describe the relation between elevated APG and long-term mortality in MI patients undergoing invasive management. Methods We studied 1,185 consecutive MI patients treated in the Medical Center Alkmaar in the separate years 1996 and 1999 (preinvasive era) and 2003 and 2006 (invasive era). In both eras, APG was derived according to a standard protocol. A multivariate Cox regression model was created to study the relation between APG, reperfusion era, and 5-year mortality. Results During a median follow-up of 63 months, 261 patients had died. Mortality was lower in the invasive (19%) than in the preinvasive era (28%). Increased APG was associated with increased mortality, irrespective of the initial reperfusion strategy, although the relation was more pronounced in the preinvasive era (P value for heterogeneity of effects < .001). Each millimole-per- liter APG increase corresponded to a 7% increased mortality (adjusted hazard ratio 1.07, 95% CI 1.04-1.10). Patients with an APG > 11 mmol/L had nearly 2-fold higher mortality (hazard ratio 1.9, 95% CI 1.3-2.7) than those with lower values. Conclusion Elevated APG remains a determinant of long-term mortality in MI patients, irrespective of the advances that have been made in reperfusion therapy. (Am Heart J 2010;160:412-9.)

Primary percutaneous coronary intervention (PCI) performed in large community hospitals without cardiac surgery back-up facilities (off-site) reduces door-to-balloon time compared with emergency transferal to tertiary interventional centers (on-site). The present study was performed to explore whether off-site PCI for acute myocardial infarction results in reduced infarct size.One hundred twenty-eight patients with acute ST-segment elevation myocardial infarction were randomly assigned to undergo primary PCI at the off-site center (n = 68) or to transferal to an on-site center (n = 60). Three days after PCI, (99m)Tc-sestamibi SPECT was performed to estimate infarct size. Off-site PCI significantly reduced door-to-balloon time compared with on-site PCI (94 +/- 54 versus 125 +/- 59 min, respectively, p0.01), although symptoms-to-treatment time was only insignificantly reduced (257 +/- 211 versus 286 +/- 146 min, respectively, p = 0.39). Infarct size was comparable between treatment centers (16 +/- 15 versus 14 +/- 12%, respectively p = 0.35). Multivariate analysis revealed that TIMI 0/1 flow grade at initial coronary angiography (OR 3.125, 95% CI 1.17-8.33, p = 0.023), anterior wall localization of the myocardial infarction (OR 3.44, 95% CI 1.38-8.55, p0.01), and development of pathological Q-waves (OR 5.07, 95% CI 2.10-12.25, p0.01) were independent predictors of an infarct size12%.Off-site PCI reduces door-to-balloon time compared with transferal to a remote on-site interventional center but does not reduce infarct size. Instead, pre-PCI TIMI 0/1 flow, anterior wall infarct localization, and development of Q-waves are more important predictors of infarct size.

Importance Elevated plasma glucose levels in patients with acute coronary syndrome (ACS) on hospital admission are associated with increased mortality. Clinical trials of glucose regulation have provided inconsistent results with respect to cardiovascular outcomes, perhaps because target glucose levels have been suboptimal. Objective To study the effectiveness and safety of intensive glucose management in patients with ACS who have hyperglycemia, aiming at strict blood glucose normalization. Design, Setting, and Participants Single-center, prospective, open-label, randomized clinical trial in a large teaching hospital. Patients with ACS with an admission plasma glucose level of 140 to 288 mg/dL were eligible for inclusion and enrolled from July 23, 2008, to February 8, 2012. Patients with insulin-dependent diabetes mellitus were excluded. Informed consent was obtained from 294 patients, who were randomized. Of these, 93.6% received percutaneous coronary intervention (PCI). Interventions Intensive glucose management strategy, aiming at a plasma glucose level of 85 to 110 mg/dL by using intravenous insulin, or to conventional expectative glucose management. Main Outcomes and Measures End points were assessed according to the intention-to-treat principle. The primary end point was high-sensitivity troponin T value 72 hours after admission (hsTropT72); secondary end points, area under the curve of creatine kinase, myocardial band (AUC–CK-MB), release and myocardial perfusion scintigraphy findings at 6 weeks’ follow-up. Results In the intensive management arm, median hsTropT72 was 1197 ng/L (25th and 75th percentiles of distribution, 541-2296 ng/L) vs 1354 ng/L (530-3057 ng/L) in the conventional arm ( P = .41). Median AUC–CK-MB was 2372 U/L (1242-5004 U/L) vs 3171 U/L (1620-5337 U/L) ( P = .18). The difference in median extent of myocardial injury measured by myocardial perfusion scintigraphy was not significant (2% vs 4%) ( P = .07). Severe hypoglycemia ( P = .04). Conclusions and Relevance Intensive glucose regulation did not reduce infarct size in hyperglycemic patients with ACS treated with PCI, and was associated with harm. Future studies should focus on patients with ACS who have persistently elevated blood glucose after PCI, and should evaluate alternative strategies for optimizing glycemia. Trial Registration www.trialregister.nlIdentifier:NTR1205

Repetitive exposure of neonates to noxious events is inherent to their health status monitoring in neonatal intensive care units (NICU). Altered basal nociception in the absence of an injury in later life has been demonstrated in ex-NICU children, but the impact on pain hypersensitivity following an injury in later life is unknown. Also, underlying mechanisms for such long-term changes are relatively unknown. The objective of this study is to investigate acute and long-term effects of neonatal repetitive painful skin-breaking procedures on nociception and to investigate plasticity of the nociceptive circuit. The repetitive needle prick animal model was used in which neonatal rats received four needle pricks into the left hind paw per day during the first postnatal week and control animals received nonpainful tactile stimuli. Repetitive needle pricking during the first week of life induced acute hypersensitivity to mechanical stimuli. At the age of 8 weeks, increased duration of postoperative hypersensitivity to mechanical stimuli after ipsilateral hind paw incision was shown in needle prick animals. Basal nociception from 3 to 8 weeks of age was unaffected by neonatal repetitive needle pricking. Increased calcitonin gene-related peptide expression was observed in the ipsilateral and contralateral lumbar spinal cord but not in the hind paw of needle prick animals at the age of 8 weeks. Innervation of tactile A beta-fibers in the spinal cord was not affected. Ourresults indicate both acute and long-term effects of repetitive neonatal skin breaking procedures on nociception and long-term plasticity of spinal but not peripheral innervation of nociceptive afferents. (C) 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2013

Hyperglycemia upon admission of myocardial infarction patients predicts inferior clinical outcomes. Current strategies investigating hyperglycemia correction mostly use glucose-driven protocols. Implementation of these often labor-intensive protocols might be facilitated with the approach of a clinical pathway. Therefore, we evaluated the implementation of our glucose-driven protocol.We adapted a protocol for use in our coronary care unit (CCU), which was implemented according to the steps of a clinical pathway. To compensate for carbohydrates in meals we additionally developed a regimen of subcutaneous insulin.Protocol adherence was facilitated with a Web-based insulin calculator. All hyperglycemic patients admitted to the CCU were eligible for treatment according to this protocol.In a 4-month period, 643 glucose measurements were obtained in hyperglycemic patients admitted to our CCU. Patients were treated intensively with IV insulin for 35 hours and had 23 glucose measurements in this time span on average. This regimen achieved a median glucose of 6.2 mmol/L. Severe hypoglycemia occurred in only 1.1% of measurements and was without severe clinical side effects.Introduction of new intensive insulin protocol according to the steps of a clinical pathway is safe and feasible. The presence of a clinical pathway coordinator and sound communication are important conditions for successful introduction, which can be further aided with a computerized calculator.

Hyperglycemia is common among patients admitted with acute coronary syndromes (ACS) and is associated with less favorable clinical outcomes. Guidelines for the treatment of hyperglycemia in myocardial infarction are confusing, partly because of lack of sufficient evidence. Neither do we know what the everyday practice on hyperglycemia in ACS is. Therefore the aim of our study is to describe current glucose management in ACS patients in The Netherlands. We designed a multiple-choice questionnaire that was emailed to all 94 independent cardiology departments of each of the 114 hospitals within The Netherlands. We interviewed cardiologists about their specific hospital setting, the presence, content, and actual use of a dedicated hyperglycemia protocol in the setting of ACS. Ninety-four questionnaires were returned (response rate 100%). Only 32% of the respondents reported to have a routinely applied, dedicated hyperglycemia protocol in the setting of ACS. An admission glucose of 13.0 mmol/L is considered a stress value by 60% of respondents. Treatment of hyperglycemia is postponed until after the acute phase (ie, after >6 hours) in 41% of the cardiology departments and in 76% HbA1c is not routinely measured before discharge. Only a minority of Dutch cardiology departments have a routinely applied, dedicated hyperglycemia protocol for patients admitted with ACS. Different views exist on the interpretation of admission hyperglycemia in patients without previously diagnosed diabetes. Dedicated protocols with well-established treatment goals allow early treatment and are mandatory to improve timely metabolic regulation.

We thank Dr Huang and coworkers for their interest in our article comparing the predictive value of admission glucose in the invasive versus the preinvasive era. Unfortunately, we have no data on the specific diabetic medication used by the patients. Therefore, it is hard to assess how this influenced glycemic control and clinical outcomes. We would like to add that it is important to identify two different intensive strategies: one in the clinical phase during admission for a myocardial infarction and the other in an outpatient setting. As illustrated in our article, conflicting evidence exists regarding the first. Therefore, we currently try to clarify this matter in a randomized clinical trial; BIOMArCS 2 glucose. In a more stable outpatient setting, reviews indeed suggest a beneficial effect of intensive glucose regulation. Finally, we would like to emphasize that it is essential to screen (hyperglycemic) myocardial infarction patients for previously undiagnosed diabetes, as this occurs in up to 31% when tested with an oral glucose tolerance test. This early detection allows early lifestyle and medical measures.

Corresponding author: M de Mulder, Department of Cardiology, Medical Centre Alkmaar, The Netherlands. Tel: +31 725484444 Fax: +31 725482156 Email: m.de.mulder@mca.nl In the November 2008 issue of this journal Goyal et al. gave a good overview of past and present studies concerning glucose regulation in acute coronary syndromes. We would like to extend the observational overview with the BIOMArCS 2 glucose study. In July 2008 we started a single centre prospective randomised open-label clinical trial to systematically evaluate hyperglycaemia in ACS patients. We aim to randomise 300 ACS patients with an admission glucose > 7.7 mmol/L and no previous use of insulin. They either receive intensive or expectative hyperglycaemia management. In the intensive treatment group we aim for normoglycaemia using intravenous insulin; naturally caution is warranted to avoid hypoglycaemia. We hypothesise that systematic, frequent and intensive glucose level control, in those with abnormal levels, will improve LV haemodynamics; it will preserve myocardial tissue and LV function in ACS patients. We expect that the beneficial effects of this strategy will be modified by treatment delay (i.e. early treatment results in better outcomes), especially in ST segment elevation-ACS patients. Our primary endpoint is infarct size defined by cardiac Troponin T at 72 h after randomisation. Secondary endpoints include ST segment resolution, NT pro-BNP levels and LVEF and infarct size determined by using a 99mTc-sestamibi SPECT 6 weeks after randomisation. Furthermore we expect that the effects of intensive glucose level control will result in a more favourable wash out pattern of biomarkers of (vascular) inflammation, hypercoagulability and neurohumoral activation.