Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression.

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.

The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy.

In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac function.

Increased Serum Levels of the Notch Ligand DLL1 are Associated with Diastolic Dysfunction, Reduced Exercise Capacity, and Adverse Outcome in Chronic Heart Failure.

BACKGROUND: Notch receptors and ligands have been demonstrated in myocardial tissue in experimental as well as clinical heart failure (HF), and a role for Notch signaling in myocardial remodeling and disease progression may be anticipated. We hypothesized that serum levels of the Notch ligand Delta-like-1 (DLL1) would be associated with clinical and hemodynamic variables in patients with HF. METHODS AND RESULTS: We measured serum DLL1 in 183 patients with chronic HF and 50 age- and sex-matched healthy control subjects by means of enzyme immunoassay. Our main findings were that (i) HF patients had significantly higher serum DLL1 levels than healthy control subjects, (ii) DLL1 levels were significantly correlated with neurohormonal activation, systemic inflammation, and impaired kidney function, (iii) high DLL1 levels were associated with diastolic dysfunction and reduced exercise capacity, but not with impaired systolic function, and (iv) in univariate analysis, but not after multivariable adjustment, high levels of DDL1 were associated with adverse outcome. CONCLUSIONS: Our findings may imply that DLL1 and the Notch signaling pathways are involved in the pathophysiology of HF, potentially affecting diastolic function.

[Regional analgesia--risks and benefits]. / Regionalanalgesi--fordeler og ulemper.

BACKGROUND: Local anaesthetics may alleviate pain more effectively than any other anaesthetic method. In regional anaesthesia/analgesia, rare but serious complications make it necessary to always consider the risk-benefit ratio. The article discusses these issues and gives advice on effective and safe conduct. MATERIAL AND METHODS: The article is based on non-systematic literature searches in the PubMed and Cochrane databases and our own experience from research and clinical work. RESULTS: Regional anaesthesia is obtained by administering local anaesthetics near the spinal cord and nerve roots (spinal, epidural), spinal nerves (paravertebral), or close to peripheral nerves. Parts of the body will then become numb and paralysed. The same techniques are used for regional analgesia, but this is obtained by using more dilute solutions of local anaesthetics, and other analgesic drugs are often added. Pain impulses are inhibited, but sensation of touch and muscle functions are intact. Regional analgesia gives superior relief of pain provoked by movement. This facilitates early postoperative mobilization of patients, even after major surgery in weak patients. For these patients optimally performed regional analgesia may reduce postoperative morbidity and mortality better than general anaesthesia and opioid and non-opioid analgesics administered postoperatively. Infiltration of the wound with local anaesthetics followed by optimally dosed non-opioid and opioid analgesics is a good alternative for some types of surgery. The risk of spinal bleeding has increased due to increased patient age, routine thromboprophylaxis and frequent use of antihaemostatic drugs, including platelet inhibitors. Infections in the spinal cord are caused by insufficient hygiene. Selection of patients who are likely to benefit from regional anaesthesia/analgesia, strict hygienic precautions, optimal technique, close monitoring, and assistance from an acute pain team, as well as hospital protocols for handling rare but serious complications, have reduced the occurrence and consequences of serious complications. INTERPRETATION: Optimal regional anaesthesia/analgesia may improve the postoperative result.

A systematic review of comparative studies indicates that paravertebral block is neither superior nor safer than epidural analgesia for pain after thoracotomy.

Background The "gold standard" for pain relief after thoracotomy has been thoracic epidural analgesia (TEA). The studies comparing TEA with paravertebral block (PVB) and recent reviews recommend PVB as a novel, safer method than TEA. Methods A systematic search of the Cochrane and PubMed databases for prospective, randomized trials (RCTs) comparing TEA and PVB for post-thoracotomy analgesia was done. We assessed how TEA and PVB were performed, methods of randomization, assessment of pain relief, and complications. Abstracts only were excluded. Results Ten studies were included, comprising 224 patients randomized to TEA, 243 to PVB. The studies were heterogeneous. Therefore, a systematic narrative review with our evaluations is presented. Only 3/10 trials reported the method of randomization. Pain during coughing was reported in only 5/10, pain assessment not specified in 5/10. Only 1/10 trials found PVB superior to TEA, but placed TEA catheters too low (