Endothelial cells are key-players in pilocarpine-induced epileptogenesis

In recent years, the concept of the neurovascular unit (NVU) has emerged as a new paradigm for investigating both physiology and pathology in the CNS. This concept proposes that a purely neurocentric focus is not sufficient, and emphasizes that all cell types in the brain including neuronal, glial and vascular components (endothelial cells, blood cells, including immunity cells) must be examined in an integrated context. Cell–cell signaling and coupling between these different compartments thus form the basis for normal function (Lok et al. 2007). We tested the hypothesis that disordered signaling and perturbed coupling of these different components can be the basis for epileptogenesis in the pilocarpine model of epilepsy. We thus determined that pilocarpine can act on endothelial cells via receptors, comparing the response of the same stimulation in neurons as well

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M1-M5) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M2, M3, and M5 correlates with their respective protein abundance, but a mismatch exists for M1 and M4 mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M1 and M3 are the most abundant receptors, only a small fraction of M1 is present in the plasma membrane and functions in ACh-induced Ca(2+) signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M1 and M3 receptors

Baseline risk factors of in-hospital mortality after surgery for acute type A aortic dissection: an ERTAAD study

Background Surgery for type A aortic dissection (TAAD) is associated with high risk of mortality. Current risk scoring methods have a limited predictive accuracy.Methods Subjects were patients who underwent surgery for acute TAAD at 18 European centers of cardiac surgery from the European Registry of Type A Aortic Dissection (ERTAAD).Results Out of 3,902 patients included in the ERTAAD, 2,477 fulfilled the inclusion criteria. In the validation dataset (2,229 patients), the rate of in-hospital mortality was 18.4%. The rate of composite outcome (in-hospital death, stroke/global ischemia, dialysis, and/or acute heart failure) was 41.2%, and 10-year mortality rate was 47.0%. Logistic regression identified the following patient-related variables associated with an increased risk of in-hospital mortality [area under the curve (AUC), 0.755, 95% confidence interval (CI), 0.729-0.780; Brier score 0.128]: age; estimated glomerular filtration rate; arterial lactate; iatrogenic dissection; left ventricular ejection fraction <= 50%; invasive mechanical ventilation; cardiopulmonary resuscitation immediately before surgery; and cerebral, mesenteric, and peripheral malperfusion. The estimated risk score was associated with an increased risk of composite outcome (AUC, 0.689, 95% CI, 0.667-0.711) and of late mortality [hazard ratio (HR), 1.035, 95% CI, 1.031-1.038; Harrell's C 0.702; Somer's D 0.403]. In the validation dataset (248 patients), the in-hospital mortality rate was 16.1%, the composite outcome rate was 41.5%, and the 10-year mortality rate was 49.1%. The estimated risk score was predictive of in-hospital mortality (AUC, 0.703, 95% CI, 0.613-0.793; Brier score 0.121; slope 0.905) and of composite outcome (AUC, 0.682, 95% CI, 0.614-0.749). The estimated risk score was predictive of late mortality (HR, 1.035, 95% CI, 1.031-1.038; Harrell's C 0.702; Somer's D 0.403), also when hospital deaths were excluded from the analysis (HR, 1.024, 95% CI, 1.018-1.031; Harrell's C 0.630; Somer's D 0.261).Conclusions The present analysis identified several baseline clinical risk factors, along with preoperative estimated glomerular filtration rate and arterial lactate, which are predictive of in-hospital mortality and major postoperative adverse events after surgical repair of acute TAAD. These risk factors may be valuable components for risk adjustment in the evaluation of surgical and anesthesiological strategies aiming to improve the results of surgery for TAAD.Clinical Trial Registration https://clinicaltrials.gov, identifier NCT04831073

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p < 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p &lt; 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

The nociceptive response during adult cardiac surgery measured by the qNOX index: A feasibility study

Background. Monitoring nociception during general anaesthesia remains a substantial challenge. The Conox monitor uses two EEG indices, the qCon and the qNox. The qNox refers to the probability that a nociceptive stimulation triggers a movement of the patient and the response probability of reaction to nociceptive stimulation. We decided to test the feasibility of monitoring the qNOX index during adult cardiac surgery and to investigate whether this index correlates with hemodynamic and hormonal signs of nociceptive stimulation. Method. We enrolled 19 patients undergoing elective cardiac surgery. These were randomised to 2 groups receiving different doses of sufentanil via target controlled infusion: group A (n=9) 0.25 ng/mL and group B (n=10) 0.75 ng/mL. All patients were maintained at the same depth of anaesthesia. We recorded the Conox monitor indices (qNOX, qCON, electromyographic), hemodynamic variables and plasmatic levels of cortisol and noradrenaline. Results. There was significantly higher blood pressure (P=0.013) and plasmatic cortisol (P=0.003) in group A and a significant increase in plasmatic noradrenaline with increasing intensity of surgical stimulation in both groups: A (P=0.001), B (P=0.008). We found no significant corresponding changes in the qNOX index. There was a positive correlation between qNOX and hemodynamic signs of stimulation (P=0.012) and between the qNOX and EMG indices (P=0.013) after endotracheal intubation, but not later after EMG index dropped. Conclusion. Our results do not support the assumption that signs of nociceptive stimulation during adult cardiac surgery will be reflected by the qNOX index. This may be related to compounding of qNOX processing and use of muscle relaxants. Further investigation on this field is needed