Local and general anaesthesia do not influence outcome of transfemoral aortic valve implantation.

BACKGROUND: There is great variability for the type of anaesthesia used during TAVI, with no clear consensus coming from comparative studies or guidelines. We sought to detect regional differences in the anaesthetic management of patients undergoing transcatheter aortic valve implantation (TAVI) in Europe and to evaluate the relationship between type of anaesthesia and in-hospital and 1 year outcome. METHODS: Between January 2011 and May 2012 the Sentinel European TAVI Pilot Registry enrolled 2807 patients treated via a transfemoral approach using either local (LA-group, 1095 patients, 39%) or general anaesthesia (GA-group, 1712 patients, 61%). RESULTS: A wide variation in LA use was evident amongst the 10 participating countries. The use of LA has increased over time (from a mean of 37.5% of procedures in the first year, to 57% in last 6 months, p<0.01). MI, major stroke as well as in-hospital death rate (7.0% LA vs 5.3% GA, p=0.053) had a similar incidence between groups, confirmed in multivariate regression analysis after adjusting for confounders. Dividing our population in tertiles according to the Log-EuroSCORE we found similar mortality under LA, whilst mortality was higher in the highest risk tertile under GA. Survival at 1 year, compared by Kaplan-Meier analysis, was similar between groups (log-rank: p=0.1505). CONCLUSIONS: Selection of anaesthesia appears to be more influenced by national practice and operator preference than patient characteristics. In the absence of an observed difference in outcomes for either approach, there is no compelling argument to suggest that operators and centres should change their anaesthetic practice.

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.

Multicentre study using strain delay index for predicting response to cardiac resynchronization therapy (MUSIC study).

AIMS: Strain delay index (SDI) allows quantification of the wasted contraction or gain of myocardial contractility expected after cardiac resynchronization therapy (CRT). The present multicentre prospective study aimed to assess the accuracy of the SDI in predicting responses to CRT in real-life patients with wide and narrow (<130 ms) QRS complexes. METHODS AND RESULTS: Implantation of a CRT device was performed in 235 heart failure patients and echocardiography data were analysable in 80% (n= 189) of patients (age 65 ± 12 years, left ventricular ejection fraction = 26 ± 8%, 63 ischaemic, 51 with narrow QRS complexes). Mechanical dyssynchrony before CRT was quantified by the 12-segment standard deviation of peak longitudinal strain by speckle tracking (12SD-ε, 12 standard deviation of time to peak strain by speckle tracking), and SDI, defined as the sum of difference between end-systolic and peak-ε across the 16 segments. Response to CRT was defined as an end-systolic volume reduction (ESVR) at 6 months >15%. After CRT, ESVR>15% was observed in 60% (n= 114/189) of patients, and was greater in non-ischaemic (68 vs. 44%, P= 0.003) and wide QRS patients (65 vs. 49%, P= 0.04). Correlation between 12SD-ε and ESVR was poor (r = 0.18, P= 0.01). In contrast, SDI correlated with reverse remodelling (r = 0.61, P< 0.0001 for all) in both wide and narrow QRS patients and ischaemic and non-ischaemic patients. Decrease in SDI after CRT was greater in responders and correlated with ESVR. Finally, SDI > 25% identified responders to CRT (positive and negative predictive value of 80 and 84%, respectively) with 6% inter-observer variability. CONCLUSION: The present multicentre study suggests that SDI may identify responders to CRT in ischaemic and non-ischaemic patients.

Selenium diet-supplementation improves cocaine-induced myocardial oxidative stress and prevents cardiac dysfunction in rats.

Chronic cocaine abuse causes cardiac dysfunction and induces oxidative stress. The goal of this study was to evaluate whether an enhanced antioxidant pool, induced by the administration of selenium, may prevent the myocardial dysfunction induced by cocaine. Cocaine was administered for 7 days (15 mg/kg/day, i.p.) to rats pretreated for 4 weeks with selenium (1.16 mg/L/day, p.o.). Cardiac function was evaluated by cardiac index and left ventricular (LV) fractional shortening (FS) measured by echocardiography. The redox ratio and enzymatic activities of glutathione peroxidase (GPX) and superoxide dismutase (SOD) were measured in the LV myocardium. Cocaine administration induced a cardiac dysfunction, as evidenced by a decrease in cardiac index and LV FS as well as by an increase in LV diameters. Moreover, antioxidant markers and redox ratio were altered in rats after cocaine exposure. Selenite supplementation induced a significant limitation of cardiac index and FS alterations observed after cocaine administration. This improvement in cardiac function was associated with a redox ratio recovery while SOD and GPX activities remained unchanged. Thus, selenite reversed both the oxidative stress and the contractile dysfunction induced by cocaine administration. These results suggest a major role of oxidative stress in the cocaine-induced cardiotoxicity.