GLP-1 increases heart rate by a direct action on the sinus node.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. METHODS AND RESULTS: We employed a large animal model, the female landrace pig, and used multiple in-vivo and ex-vivo approaches including pharmacological challenges, electrophysiology and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta or combined alpha-beta blockade), ganglionic blockade (hexamethonium) nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing (snRNAseq) showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. CONCLUSION: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

Reoperation for bleeding in an elective cardiac surgical population - Does it affect survival?

Introduction: Earlier studies have shown that re-operation for bleeding after cardiac surgery is associated with increased mortality and morbidity in both acute and elective patients. The aim of the study was to assess the effect of re-operation for bleeding on short- and long-term survival and the causes of re-operation on an exclusively elective population. Methods: This was a single-center, retrospective study conducted at the Department of Cardiothoracic Surgery at Copenhagen University Hospital. Rigshospitalet, Denmark. We included all elective patients undergoing first-time coronary bypass, valve surgery or combinations hereof between January 1998 and February 2014. Data was obtained from the electronic patient records on demographics, cardiological risk profile, blood transfusion and surgical record. Results: A total of 11813 patients were included in the analysis of whom 626 (5.3%) patients underwent re-operation for bleeding. Patients were divided into two groups; non re-operated (NRO) and re-operated(RO). Baseline characteristics were comparable. Median survival was lover in the RO group (142 vs 160months (P = 0.001)). Morbidity and 30 day mortality was significantly higher in the RO group. Cox-regression analysis showed a significantly increased age-adjusted risk of death in the RO group (HR 1.21(1.07-1.37). P = 0.003). In 85% of the patients the site of bleeding was found during the re-operation. Conclusion: We found both short and long-term survival to be lower in the RO group. A surgical cause for re-operation was found in the majority of cases. The study shows the importance of meticulous hemostasis during cardiac surgery.

[Acute dyspnoea triggered by spontaneous pneumothorax in a pregnant woman with pulmonary agenesis].

A 29-year-old pregnant woman was admitted to hospital with chest pain and dyspnoea. A thoracal computed tomography (CT) was performed to rule out pulmonary embolism, and it revealed a left-sided pneumothorax, which was treated with tube thoracostomy. Three days after discharge she was readmitted with spontaneous pressure pneumothorax. Her clinical condition did not improve, and a pulmonary scintigraphy and a new thoracal CT showed unilateral right pulmonary agenesis. Pulmonary agenesis is very rare in adulthood, and in this case it was complicated with spontaneous pneumothorax.

No Effect of Rapamycin on Cardiac Adhesion Formation: A Drug-Loaded Bioresorbable Polylactone Patch in a Porcine Cardiac Surgical Model.

BACKGROUND: The fusing of the epicardium and sternum due to adhesion is a common problem during repeated cardiac surgery and carries with it an increased risk of bleeding. The use of barriers and patches has been tested to prevent the formation of adhesions, but the very presence of a patch can provoke adhesion formation. The objective of this study was, therefore, to investigate both biodegradable and bioresorbable polylactone patches [(polycaprolactone-poly(ethylene oxide)-polycaprolactone tri-block copolymer (PCE)]. The patches were also tested with a controlled release of rapamycin, which prevents cell migration and extracellular matrix deposition. The clinical effectiveness of rapamycin in pericardial patches has not previously been examined. MATERIALS AND METHODS: Three groups of 6 female Danish Landrace pigs underwent sternotomy and abrasion of the epicardium, before being randomized to either group 1--the control group (with no patch), group 2--PCE patch implanted between the sternum and epicardium, or group 3--PCE patch and slow-release 1.6-mg rapamycin. After a median time period of 26 days, the pigs were euthanized and their hearts removed en bloc with the sternum, for macroscopic, histological and pathological examination. RESULTS: Upon macroscopic examination, a significantly lower degree of adhesion in group 2, as compared to group 1 (p < 0.05), was found. Histological analysis of the tissues showed significantly more fibrosis, inflammation and foreign body granulomas (p < 0.05) in both group 2 and group 3, when compared to group 1. CONCLUSION: A PCE patch following sternotomy in animal subjects reduces postoperative macroscopic adhesions without reducing microscopic fibrosis or inflammation. Loading the patch with rapamycin was found not to increase the antifibrotic effect.

Ibuprofen - a Safe Analgesic During Cardiac Surgery Recovery? A Randomized Controlled Trial.

INTRODUCTION: Postoperative pain-management with non-steroid anti-inflammatory drugs has been controversial, due to related side-effects. We investigated whether there was a significant difference between an oxycodone-based pain-management regimen versus a slow-release ibuprofen based regimen, in a short term post-cardiac surgery setting. Particular attention was given to the rate of myocardial infarction, sternal healing, gastro-intestinal complications, renal failure and all-cause mortality. METHODS: This was a single-centre, open label parallel design randomised controlled study. Patients, who were undergoing cardiac surgery for the first time, were randomly allocated either to a regimen of slow-release oxycodone (10 mg twice daily) or slow-release ibuprofen (800 mg twice daily) combined with lansoprazole. Data relating to blood-tests, angiographies, surgical details and administered medicine were obtained from patient records. The follow-up period was 1 to 37 months (median 25 months). RESULTS: One hundred eighty-two patients were included in the trial and available for intention to treat analysis. There were no significant difference between the groups (P>0.05) in the rates of sternal healing, postoperative myocardial infarction or gastrointestinal bleeding. The preoperative levels of creatinine were found to increase by 100% in nine patients (9.6%) in the ibuprofen group, resulting in an acute renal injury (in accordance with the RIFLE-criteria). Eight of these patients returned to normal renal function within 14 days. The levels of creatinine in patients in the oxycodone group were not found to increase to the same magnitude. CONCLUSION: The results of this study suggest that patients treated postoperatively, following cardiac surgery, are at no greater risk of harm if short term slow release ibuprofen combined with lansoprazole treatment is used when compared to an oxycodone based regimen. Renal function should, however, be closely monitored and in the event of any decrease in renal function ibuprofen must be discontinued.

High morbidity after laparoscopic emergency colectomy for inflammatory bowel disease.

INTRODUCTION: Only limited data are available on subtotal laparoscopic colectomy (STC) in patients with in inflammatory bowel disease. We present the first Danish experiences with intended laparoscopic STC for inflammatory bowel disease (IBD). The primary outcome was 30-day morbidity. MATERIAL AND METHODS: The present study is a retrospective single-centre study with consecutive enrolment of patients undergoing intended STC for IBD from 1 January 2005 to 31 July 2009. The results were analysed as either emergency or elective operations. Only the most severe complication was noted for each patient. Data on medical treatment, blood tests and complications and death within 30 days were registered. RESULTS: A total of 32 patients underwent surgery (15 elective and 17 emergency procedures). Patients in the emergency group had significantly more severe disease activity than elective patients. Severe complications were recorded in 47% and 20% of the patients undergoing emergency and elective STC, respectively (p = 0.15). The overall morbidity was 72%. One emergency patient died. Five of eight emergency patients and one of three elective patients underwent conversion and experienced a major complication (p = 0.55). The overall conversion rate was 32% (p = 0.15). CONCLUSION: We found high morbidity and conversion rates in patients undergoing SLC for IBD. A prospective national Danish survey on early postoperative outcome is suggested. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

[Clinical examination has impact on general well-being]. / Eksamen påvirker alment velbefindende.

INTRODUCTION: Objective structured clinical examination (OSCE) is a new and professionally acknowledged examination used in the evaluation of medical students. Students have criticized OSCE for being unnecessarily stressful. This study examines the effects of OSCE on students, examiners and examination supervisors' general well-being. MATERIAL AND METHODS: A controlled prospective, non-blinded, single centre-study. Before and after OSCE all subjects filled in a structured questionnaire concerning nervousness, discomfort, fatigue, nausea, and pain. RESULTS: A total of 119 students and 22 examiners and examination supervisors participated in the study. The students were overrepresented by women and were younger and healthier than the group of examiners/examination supervisors. The students experienced significantly more nervousness, discomfort, fatigue, and nausea before OSCE than the examiners/examination supervisors. After OSCE the students experienced a significant reduction of the symptoms while the examiners/examination supervisors reported a non-significant increase of nausea and pain. The students experienced significantly larger fluctuations (before and after values) in symptoms than the examiners/examination supervisors. CONCLUSION: We found that OSCE made the students feel significantly better while examiners/examination supervisors felt only slightly worse. The effects of OSCE on examiners/examination supervisors have not been studied previously. There are most likely multiple factors to explain our findings in the present study.