Perioperative Outcomes of Adjunctive Hypnotherapy Compared with Conscious Sedation Alone for Patients Undergoing Transfemoral Transcatheter Aortic Valve Implantation.

Transcatheter aortic valve implantation (TAVI) using a transfemoral approach under local anesthesia with conscious sedation (LACS) is becoming an increasingly common TAVI strategy. However, patients who are awake during the TAVI procedure can experience stress, anxiety, and pain, even when LACS is used. Clinical hypnotherapy is an anxiolytic intervention that can be beneficial for patients undergoing invasive surgery. This study aimed to assess the perioperative outcomes of adjunctive hypnotherapy undergoing transfemoral TAVI with LACS.Consecutive patients (n = 143) with symptomatic severe aortic stenosis who underwent transfemoral TAVI with LACS only (n = 107) or with LACS and hypnotherapy (n = 36) between January 2015 and April 2016 were retrospectively included in the study. The clinical outcomes were compared between the two groups. The LACS with hypnotherapy group had a significantly shorter length of stay in the intensive care unit (ICU; LACS only versus LACS with hypnotherapy: 4.0 (4.0-5.5) days versus 3.0 (3.0-5.0) days, P < 0.01). Moreover, the use of anesthetics (propofol and remifentanil) and norepinephrine was significantly lower in the LACS with hypnotherapy group (e.g., for propofol, LACS only versus LACS with hypnotherapy: 96.4 ± 104.7 mg versus 15.0 ± 31.8 mg, P < 0.001). The multiple regression analysis showed that being male, hypnotherapy, and the composite complication score were independently associated with the length of stay in the ICU.The adjunctive hypnotherapy on LACS among transfemoral TAVI patients may facilitate perioperative management. However, a prospective randomized study is necessary to confirm the efficacy of hypnotherapy among TAVI patients.

Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions.

Retinal pigment epithelial cells exert an important supporting role in the eye and develop adaptive responses to oxidative stress or high glucose levels, as observed during diabetes. Endogenous antioxidant defences are mainly regulated by Nrf2, a transcription factor that is activated by naturally-derived and electrophilic compounds. Here we investigated the effect of the Nrf2 activators dimethylfumarate (DMF) and carnosol on antioxidant pathways, oxygen consumption rate and wound healing in human retinal pigment epithelial cells (ARPE-19) cultured in medium containing normal (NG, 5mM) or high (HG, 25 mM) glucose levels. We also assessed wound healing using an in vivo corneal epithelial injury model. We found that Nrf2 nuclear translocation and heme oxygenase activity increased in ARPE cells treated with 10 µM DMF or carnosol irrespective of glucose culture conditions. However, HG rendered retinal cells more sensitive to regulators of glutathione synthesis or inhibition and caused a decrease of both cellular and mitochondrial reactive oxygen species. Culture in HG also reduced ATP production and mitochondrial function as measured with the Seahorse XF analyzer and electron microscopy analysis revealed morphologically damaged mitochondria. Acute treatment with DMF or carnosol did not restore mitochondrial function in HG cells; conversely, the compounds reduced cellular maximal respiratory and reserve capacity, which were completely prevented by N-acetylcysteine thus suggesting the involvement of thiols in this effect. Interestingly, the scratch assay showed that wound closure was faster in cells cultured in HG than NG and was accelerated by carnosol. This effect was reversed by an inhibitor of heme oxygenase activity. Moreover, topical application of carnosol to the cornea of diabetic rats significantly accelerated wound healing. In summary, these data indicate that culture of retinal epithelial cells in HG does not affect the activation of the Nrf2/heme oxygenase axis but influences other crucial oxidative and mitochondrial-dependent cellular functions. The additional effect on wound closure suggests that results obtained in in vitro experimental settings need to be carefully evaluated in the context of the glucose concentrations used in cell culture.

Clinical outcomes and safety of transfemoral aortic valve implantation under general versus local anesthesia: subanalysis of the French Aortic National CoreValve and Edwards 2 registry.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) performed under local anesthesia (LA) is becoming increasingly common. We aimed to compare the clinical outcomes in patients who underwent transfemoral-TAVI under general anesthesia (GA) and LA. METHODS AND RESULTS: Data from 2326 patients in the French Aortic National CoreValve and Edwards 2 (FRANCE 2) registry who underwent transfemoral-TAVI were analyzed. During the study period, the percentage of LA procedures increased gradually from 14% in January 2010 to 59% in October 2011. The clinical outcomes for GA (n=1377) and LA (n=949) were compared. Numerous baseline characteristics differed between the 2 groups, and the use of transesophageal echocardiographic guidance was more common in GA than in LA (76.3% versus 16.9%; P<0.001). Device success and cumulative 30-day survival rates were similar in the 2 groups (97.6% versus 97.0%; P=0.41 and 91.6% versus 91.3%; P=0.69, respectively), whereas the incidence of postprocedural aortic regurgitation≥mild was significantly lower in GA than in LA (15.0% versus 19.1%; P=0.015). The groups were also analyzed using a propensity-matching model, including transesophageal echocardiographic usage (GA [n=401] versus LA [n=401]). This model indicated that there were no significant differences between the 2 groups in the rates of 30-day survival (GA [91.4%] versus LA [89.3%]; P=0.27] and postprocedural aortic regurgitation≥mild (GA [12.7%] versus LA [16.2%]; P=0.19). CONCLUSIONS: The less invasive transfemoral-TAVI under LA is preferred in clinical settings and seems to be acceptable; however, the higher incidence of postprocedural aortic regurgitation is emphasized. Therapeutic efforts should be made to reduce such complications during transfemoral-TAVI under LA.

Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension.

BACKGROUND: Induction of cellular senescence through activation of the p53 tumor suppressor protein is a new option for treating proliferative disorders. Nutlins prevent the ubiquitin ligase MDM2 (murine double minute 2), a negative p53 regulator, from interacting with p53. We hypothesized that cell senescence induced by Nutlin-3a exerted therapeutic effects in pulmonary hypertension (PH) by limiting the proliferation of pulmonary artery smooth muscle cells (PA-SMCs). METHODS AND RESULTS: Nutlin-3a treatment of cultured human PA-SMCs resulted in cell growth arrest with the induction of senescence but not apoptosis; increased phosphorylated p53 protein levels; and expression of p53 target genes including p21, Bax, BTG2, and MDM2. Daily intraperitoneal Nutlin-3a treatment for 3 weeks dose-dependently reduced PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia or SU5416/hypoxia. Nutlin-3a treatment also partially reversed PH in chronically hypoxic or transgenic mice overexpressing the serotonin-transporter in SMCs (SM22-5HTT+ mice). In these mouse models of PH, Nutlin-3a markedly increased senescent p21-stained PA-SMCs; lung p53, p21, and MDM2 protein levels; and p21, Bax, PUMA, BTG2, and MDM2 mRNA levels; but induced only minor changes in control mice without PH. Marked MDM2 immunostaining was seen in both mouse and human remodeled pulmonary vessels, supporting the use of Nutlins as a PH-targeted therapy. PH prevention or reversal by Nutlin-3a required lung p53 stabilization and increased p21 expression, as indicated by the absence of Nutlin-3a effects in hypoxia-exposed p53(-/-) and p21(-/-) mice. CONCLUSIONS: Nutlin-3a may hold promise as a prosenescence treatment targeting PA-SMCs in PH.

Effect of local anesthetic management with conscious sedation in patients undergoing transcatheter aortic valve implantation.

The present study sought to assess the effectiveness of local anesthesia with conscious sedation (LACS) during transcatheter aortic valve implantation (TAVI). On its introduction, TAVI was mostly performed with the patient under general anesthesia (GA); however, evidence supporting the use of less-invasive LACS has been increasing. The data from 174 consecutive patients who underwent TAVI by way of the femoral artery from December 2007 to December 2011 were analyzed. GA was mainly used in early phase of the study (n = 44); this was gradually shifted to LACS in the late phase (n = 130). The clinical outcomes were compared for those patients who received GA versus LACS. The incidence and causes of "LACS failure," defined as conversion to GA from LACS during TAVI, were also assessed. The rates of procedural success and 30-day mortality were not different between the 2 groups (93.3% vs 95.3%, p = 0.60; 6.7% vs 7.8%, p = 0.55, respectively). Although the clinical backgrounds of the patients showed differences, these results were not significant after adjusting for other influential confounders. The intensive care unit stay and hospital stay were longer in the GA group than in the LACS group (3.9 ± 2.2 vs 3.3 ± 1.5 days, p = 0.044; and 12.2 ± 8.3 vs 8.1 ± 6.5 days, p = 0.001, respectively). LACS failure occurred in 6 patients (4.6%), and the causes were multifactorial, as follows: cardiac tamponade in 2, cardiac arrest in 2, myocardial infarction in 1, and stroke in 1. In conclusion, transfemoral TAVI with the patient under LACS could be successfully performed in most patients, with the advantage of early recovery, although the perioperative risks involved in the TAVI procedure should be considered.

N-acetylcysteine treatment normalizes serum tumor necrosis factor-alpha level and hinders the progression of cardiac injury in hypertensive rats.

BACKGROUND: Studies in isolated cardiomyocytes showed that replenishment in cellular glutathione, achieved with the glutathione precursor N-acetylcysteine (NAC), abrogated deleterious effects of tumor necrosis factor-alpha (TNF-alpha). METHODS AND RESULTS: We examined the ability of NAC to limit the progression of cardiac injury in the rat model of hypertension, induced by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg per day SC) and high-salt diet (HS) (8% NaCl). Four-week HS/L-NAME administration induced hypertension (193+/-8 versus 122+/-4 mm Hg for low-salt diet [LS] group) and left ventricular (LV) dysfunction, revealed by echocardiography and characterized by decreased LV shortening fraction (38+/-2% versus 49+/-4% for LS group; P<0.05) and decreased LV posterior wall thickening (49+/-3% versus 70+/-4% for LS group; P<0.05). LV dysfunction worsened further after 6-week HS/L-NAME administration. Importantly, increase in serum TNF-alpha level was strongly correlated with shortening fraction decrease and cardiac glutathione depletion. NAC (75 mg/d) was given as a therapeutic treatment in a subgroup of HS/L-NAME animals during weeks 5 and 6 of HS/L-NAME administration. NAC treatment, which replenished cardiac glutathione, had no effect on hypertension but reduced LV remodeling and dysfunction, normalized serum TNF-alpha level, and limited activation of matrix metalloproteinases -2 and -9 and collagen deposition in LV tissues. CONCLUSIONS: These findings suggest that glutathione status determines the adverse effects of TNF-alpha in cardiac failure and that TNF-alpha antagonism may be achieved by glutathione supplementation.