Geir Øystein Andersen

Strong and weak aspects of an established post-resuscitation treatment protocol—A five-year observational study

AIM OF STUDY Favourable hospital survival increased from 26% to 56% in the implementation phase of a new standard operating procedure (SOP) for treatment after out-of hospital cardiac arrest (OHCA) in 2003. We now evaluate protocol adherence and survival rates after five years with this established SOP. METHODS This observational study is based on prospectively collected registry data from all OHCA patients with cardiac aetiology admitted with spontaneous circulation to Ulleval Hospital between September 2003 and January 2009. Three patient categories are described based on early assessment in the emergency department: conscious, comatose, and comatose patients receiving only palliative care, with main focus on comatose patients receiving active treatment. RESULTS Of 248 patients, 22% were consciousness on admission, 70% were comatose and received active treatment, while 8% received only palliative care. Favourable survival from admittance to discharge remained at 56% throughout the study period. Among actively treated patients 83% received emergency coronary angiography and 48% underwent subsequent percutaneous coronary intervention. In this cohort 63% had an acute myocardial infarction, ten of whom did not receive emergency coronary angiography. Among actively treated comatose patients, 6% survived with unfavourable neurology, while 51% of the deaths followed treatment withdrawal after prognostication of severe brain injury. CONCLUSION The previously reported doubling in survival rate remained throughout a five-year study period. Establishing reliable indication for emergency coronary angiography and interventions and validating prognostication rules in the hypothermia era are important challenges for future studies.

Abnormal glucose regulation in patients with acute ST- elevation myocardial infarction-a cohort study on 224 patients

BackgroundA high prevalence of impaired glucose tolerance and unknown type 2-diabetes in patients with coronary heart disease and no previous diagnosis of diabetes have been reported. The aims of the present study were to investigate the prevalence of abnormal glucose regulation (AGR) 3 months after an acute ST-elevation myocardial infarction (STEMI) in patients without known glucometabolic disturbance, to evaluate the reliability of a 75-g oral glucose tolerance test (OGTT) performed very early after an acute STEMI to predict the presence of AGR at 3 months, and to study other potential predictors measured in-hospital for AGR at 3 months.MethodsThis was an observational cohort study prospectively enrolling 224 STEMI patients treated with primary PCI. An OGTT was performed very early after an acute STEMI and was repeated in 200 patients after 3 months. We summarised the exact agreement observed, and assessed the observed reproducibility of the OGTTs performed in-hospital and at follow up. The patients were classified into glucometabolic categories defined according to the World Health Organisation criteria. AGR was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.ResultsThe prevalence of AGR at three months was 24.9% (95% CI 19.1, 31.4%), reduced from 46.9% (95% CI 40.2, 53.6) when measured in-hospital. Only, 108 of 201 (54%) patients remained in the same glucometabolic category after a repeated OGTT. High levels of HbA1c and admission plasma glucose in-hospital significantly predicted AGR at 3 months (p < 0.001, p = 0.040, respectively), and fasting plasma glucose was predictive when patients with large myocardial infarction were excluded (p < 0.001).ConclusionThe prevalence of AGR in STEMI patients was lower than expected. HbA1c, admission plasma glucose and fasting plasma glucose measured in-hospital seem to be useful as early markers of longstanding glucometabolic disturbance. An OGTT performed very early after a STEMI did not provide reliable information on long-term glucometabolic state and should probably not be recommended.

Dual Serotonergic Regulation of Ventricular Contractile Force Through 5-HT2A and 5-HT4 Receptors Induced in the Acute Failing Heart

Cardiac responsiveness to neurohumoral stimulation is altered in congestive heart failure (CHF). In chronic CHF, the left ventricle has become sensitive to serotonin because of appearance of Gs-coupled 5-HT4 receptors. Whether this also occurs in acute CHF is unknown. Serotonin responsiveness may develop gradually or represent an early response to the insult. Furthermore, serotonin receptor expression could vary with progression of the disease. Postinfarction CHF was induced in male Wistar rats by coronary artery ligation with nonligated sham-operated rats as control. Contractility was measured in left ventricular papillary muscles and mRNA quantified by real-time reverse-transcription PCR. Myosin light chain-2 phosphorylation was determined by charged gel electrophoresis and Western blotting. Ca2+ transients in CHF were measured in field stimulated fluo-4-loaded cardiomyocytes. A novel 5-HT2A receptor-mediated inotropic response was detected in acute failing ventricle, accompanied by increased 5-HT2A mRNA levels. Functionally, this receptor dominated over 5-HT4 receptors that were also induced. The 5-HT2A receptor-mediated inotropic response displayed a triphasic pattern, shaped by temporally different activation of Ca2+-calmodulin-dependent myosin light chain kinase, Rho-associated kinase and inhibitory protein kinase C, and was accompanied by increased myosin light chain-2 phosphorylation. Ca2+ transients were slightly decreased by 5-HT2A stimulation. The acute failing rat ventricle is, thus, dually regulated by serotonin through Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT4 receptors.

Effect of Ischemic Postconditioning on Infarct Size in Patients With ST-Elevation Myocardial Infarction Treated by Primary PCI Results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) Randomized Trial

Background Reduction of infarct size by ischemic postconditioning (IPost) has been reported in smaller proof‐of‐concept clinical studies, but has not been confirmed in other smaller studies. The principle needs to be evaluated in larger groups of ST‐elevation myocardial infarction (STEMI) patients before being implemented in clinical practice. This study assessed the effect of ischemic postcoditioning (IPost) on infarct size in patients with STEMI treated by primary percutaneous coronary intervention (PCI). Methods and Results Patients with first‐time STEMI, <6 hours from symptom onset, referred to primary PCI were randomized to IPost or control groups. IPost was administered by 4 cycles of 1‐minute reocclusion and 1‐minute reperfusion, starting 1 minute after opening, followed by stenting. In the control group, stenting was performed immediately after reperfusion. The primary endpoint was infarct size measured by cardiac magnetic resonance after 4 months. A total of 272 patients were randomized. Infarct size (percent of left ventricular mass) after 4 months (median values and interquartile range) was 14.4% (7.7, 24.6) and 13.5% (8.1, 19.3) in the control group and IPost group, respectively (P=0.18). No significant impact of IPost was found when controlling for baseline risk factors of infarct size in a multivariate linear regression model (P=0.16). The effects of IPost on secondary endpoints, including markers of necrosis, myocardial salvage, and ejection fraction, as well as adverse cardiac events during follow‐up, were consistently neutral. Conclusions In contrast to several smaller trials reported previously, we found no significant effects of IPost on infarct size or secondary study outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT.No.PO1506.

Increased circulating mitochondrial DNA after myocardial infarction

DBP (R=0.022; p=0.01), LVM index (R=0.124 pb0.001) and body surface area (R=0.068; pb0.001) associated with AoRD in a model adjusted for age, gender, diabetes mellitus, hypertension, brachial supine SBP and triglycerides. This report provided novel knowledge that either in subjects with low cardiovascular risk (sample A) or in individuals with cardiovascular risk factors (sample B), leg BP, but not brachial BP, was independently related to AoRD. Moreover, the present results showed that changes in body posture influenced this relationship. These findings might have clinical implications. First, they could provide a novel indication for lower limbBPmeasurementas a predictor of AoRD,whichmightexpand its use in clinical practice. Currently, leg BP evaluation is not routinely performed, except when there is suspicion of aortic constriction or peripheral artery insufficiency [9,10]. Second, they suggest that evaluation of leg BP in orthostatic posture might be useful, at least in subjects with cardiovascular risk factors. To our knowledge, there are no reference values for leg BP measured in standing position and no previous study evaluated the relationship between orthostatic leg BP and vascular phenotypes. Conversely, current guidelines recommend assessmentof legBPonly inhorizontal position [9]. Therefore our results may shed novel light in a neglected BP measurement. In conclusion, our study demonstrated that leg BP was associated with AoRD in individuals with or without cardiovascular risk factors, and further showed that changes in body posture played a role in this relationship. Despite the underlying mechanisms, these findings suggest that leg BP evaluation might be an alternative approach in order to predict AoRD. However, further studies in other populations are necessary to confirm this assumption.

Levosimendan in acute heart failure following primary percutaneous coronary intervention-treated acute ST-elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo-controlled study.

The calcium sensitizer levosimendan may counteract stunning after reperfusion of ischaemic myocardium, but no randomized placebo‐controlled trials exist regarding its use in PCI‐treated ST‐segment elevation infarction (STEMI). We evaluated the efficacy and safety of levosimendan in patients with a primary PCI‐treated STEMI complicated by symptomatic heart failure (HF).

Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest.

Objective: Comatose patients resuscitated after out-of-hospital cardiac arrest receive therapeutic hypothermia. Bradycardia is frequent during therapeutic hypothermia, but its impact on outcome remains unclear. We explore a possible association between bradycardia during therapeutic hypothermia and neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Design: Retrospective cohort study, from January 2009 to January 2011. Setting: University hospital medical and cardiac ICUs. Patients: One hundred eleven consecutive comatose out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Interventions: Patients treated with standardized treatment protocol after cardiac arrest. Measurements and Main Results: All out-of-hospital cardiac arrest patients’ records were reviewed. Hemodynamic data were obtained every fourth hour during the first days. The patients were in temperature target range (32–34°C) 8 hours after out-of-hospital cardiac arrest and dichotomized into bradycardia and nonbradycardia groups depending on their actual heart rate less than or equal to 60 beats/min or more than 60 beats/min at that time. Primary endpoint was Cerebral Performance Category score at hospital discharge. More nonbradycardia group patients received epinephrine during resuscitation and epinephrine and norepinephrine in the early in-hospital period. They also had lower base excess at admission. Survival rate with favorable outcome was significantly higher in the bradycardia than the nonbradycardia group (60% vs 37%, respectively, p = 0.03). For further heart rate quantification, patients were divided into quartiles: less than or equal to 49 beats/min, 50–63 beats/min, 64–77 beats/min, and more than or equal to 78 beats/min, with respective proportions of patients with good outcome at discharge of 18 of 27 (67%), 14 of 25 (56%), 12 of 28 (43%), and 7 of 27 (26%) (p = 0.002). Patients in the lowest quartile had significantly better outcome than the higher groups (p = 0.027), whereas patients in the highest quartile had significantly worse outcome than the lower three groups (p = 0.013). Conclusions: Bradycardia during therapeutic hypothermia was associated with good neurologic outcome at hospital discharge. Our data indicate that bradycardia should not be aggressively treated in this period if mean arterial pressure, lactate clearance, and diuresis are maintained at acceptable levels. Studies, both experimental and clinical, are warranted.

Substrate Specificities of G Protein-Coupled Receptor Kinase-2 and -3 at Cardiac Myocyte Receptors Provide Basis for Distinct Roles in Regulation of Myocardial Function

The closely related G protein-coupled receptor kinases GRK2 and GRK3 are both expressed in cardiac myocytes. Although GRK2 has been extensively investigated in terms of regulation of cardiac β-adrenergic receptors, the substrate specificities of the two GRK isoforms at G protein-coupled receptors (GPCR) are poorly understood. In this study, the substrate specificities of GRK2 and GRK3 at GPCRs that control cardiac myocyte function were determined in fully differentiated adult cardiac myocytes. Concentration-effect relationships of GRK2, GRK3, and their respective competitive inhibitors, GRK2ct and GRK3ct, at endogenous endothelin, α1-adrenergic, and β1-adrenergic receptor-generated responses in cardiac myocytes were achieved by adenovirus gene transduction. GRK3 and GRK3ct were highly potent and efficient at the endothelin receptors (IC50 for GRK3, 5 ± 0.7 pmol/mg of protein; EC50 for GRK3ct, 2 ± 0.2 pmol/mg of protein). The α1-adrenergic receptor was also a preferred substrate of GRK3 (IC50,7 ± 0.4 pmol/mg of protein). GRK2 lacked efficacy at both endothelin and α1-adrenergic receptors despite massive overexpression. On the contrary, both GRK2ct and GRK3ct enhanced β1-adrenergic receptor-induced cAMP production with comparable potencies. However, the potency of GRK3ct at β1-adrenergic receptors was at least 20-fold lower than that at endothelin receptors. In conclusion, this study demonstrates distinct substrate specificities of GRK2 and GRK3 at different GPCRs in fully differentiated adult cardiac myocytes. As inferred from the above findings, GRK2 may play its primary role in regulation of cardiac contractility and chronotropy by controlling β1-adrenergic receptors, whereas GRK3 may play important roles in regulation of cardiac growth and hypertrophy by selectively controlling endothelin and α1-adrenergic receptors.

Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size

Background Increased serum osteoprotegerin has been shown to be associated with increased mortality and heart failure development in patients with acute coronary syndromes. The aim of the present study was to elucidate a possible association between serum osteoprotegerin measured acutely in patients with ST-elevation myocardial infarction (STEMI) and final infarct size. Methods Serum osteoprotegerin was measured in fasting blood samples from 199 patients with acute STEMI, sampled at a median time of 16 h after primary percutaneous coronary intervention (PCI). After 3 months, final infarct size (in percentage of left ventricular mass; LVM) was assessed by single-photon emission CT. The outcome variable final infarct size was dichotomised using the 75th percentile as the cutoff value (large infarct size ≥29.0%). A multivariable analysis was performed adjusting for multiple clinical and biochemical covariates. Results Median (IQR) osteoprotegerin concentration was 1.4 (1.0, 2.1) ng ml−1 and patients with high osteoprotegerin level (> median) at baseline had larger infarct size at 3 months compared with patients with low osteoprotegerin levels (< median) (25 (8, 40) vs 6 (0, 19)% of LVM, respectively, p<0.0001). A high osteoprotegerin level was also associated with an approximately sevenfold increase in the odds of developing a large myocardial infarct (OR 7.0; 3.2, 15.5, p<0.001). After adjustment for potential confounders including peak troponin T, the adjusted OR was 5.2 (2.0, 13.1) p<0.001. Conclusion High levels of circulating osteoprotegerin measured the first morning after a PCI-treated acute STEMI were strongly associated with final infarct size.

Rationale and Design of the POSTEMI (Postconditioning in ST-Elevation Myocardial Infarction) Study

Rapid reperfusion of the infarct-related coronary artery is essential in the treatment of acute ST-elevation myocardial infarction (STEMI). Paradoxically, restoration of the blood flow to the ischemic area may result in further injury to the myocardium. This phenomenon is described as ‘ischemia/reperfusion injury’ and the pathophysiological mechanisms are not fully elucidated. A cardioprotective effect of ischemic postconditioning (short repetitive cycles of reperfusion and re-occlusion) has been demonstrated in experimental studies and in pilot studies on patients with acute STEMI treated with primary percutaneous coronary intervention. We present the study design of the Postconditioning in ST-Elevation Myocardial Infarction (POSTEMI) study, which is a prospective, randomized, open-label clinical trial with blinded endpoint evaluation designed to evaluate the effect of postconditioning on final infarct size. Patients with acute STEMI with symptoms of less than 6 h and proximal or mid-coronary artery occlusion will be included. The primary endpoint is infarct size, assessed by cardiac MRI after 4 months. The secondary endpoints are to evaluate the effect of postconditioning on TIMI myocardial perfusion grade, resolution of ST-segment elevation, release of markers of ischemia, left ventricular function and final infarct size related to the area at risk. A total of 260 patients will be included in the study.