Right ventricular adaptation to pulmonary pressure load in patients with chronic thromboembolic pulmonary hypertension before and after successful pulmonary endarterectomy--a cardiovascular magnetic resonance study.

BACKGROUND: The aim of the study was to characterize RV adaptation to varying loading conditions in patients with chronic thromboembolic hypertension (CTEPH) before and after pulmonary endarterectomy (PEA). Nearly 4% of patients with pulmonary embolism develop CTEPH. PEA offers a cure with excellent outcome. By use of cardiovascular magnetic resonance (CMR) combined with hemodynamic measurements pulmonary arterial elastance (Ea-pulm_i), end-systolic right ventricular elastance (Ees-RV_i) and ventriculo-arterial coupling (Ea-pulm_i/Ees-RV_i) can be studied before and after PEA. METHODS: Sixty-five patients (mean age 41±12 years, 28 female) underwent CMR pre- and post-PEA. Ejection fraction (EF), end-diastolic (EDVi), end-systolic (ESVi), and stroke (SVi) volumes were indexed for body surface area. Ea-pulm_i was calculated as pulmonary artery mean pressure (mPAP)/SVi, and Ees-RV_i as mPAP/ESVi. RESULTS: mPAP decreased from 47±12 to 25±9 mmHg, p=0.0001. Ea-pulm_i was increased before PEA and normalized afterwards (2.8±2.1 vs. 0.85±0.4 mmHg/ml/m2, p=0.0001). Ees-RV_i was depressed before and after PEA (0.72±0.27 vs. 0.66±0.3 mmHg/ml/m2, p=0.13). EF improved from 25±12% to 46±10%, p=0.0001, because ventriculo-arterial coupling was restored (4.2±3 vs. 1.4±0.6, p=0.0001). EDVi and ESVi mproved significantly (EDVi 92±32 to 72±23 ml, p=0.0001; ESVi 69±31 to 41±18 ml, p=0.0001). CONCLUSION: RV function is largely determined by afterload and returns to normal once afterload is normalized. This is paralleled by a significant improvement of CMR indices of right ventricular remodelling.

Corrigendum: Characterization of Two Novel Bacteriophages Infecting Multidrug-Resistant (MDR) Acinetobacter baumannii and Evaluation of Their Therapeutic Efficacy in vivo.

[This corrects the article DOI: 10.3389/fmicb.2018.00696.].

Electrocardiographic and further predictors for permanent pacemaker requirement after transcatheter aortic valve implantation.

The objective of this study was to identify electrocardiographic (ECG) and further predictors for atrioventricular (AV) block with a need for pacemaker (PM) implantation after transcatheter aortic valve implantation (TAVI). Pre- and post-procedural ECGs of patients with severe aortic stenosis and ongoing TAVI were investigated in a prospective study. From 50 consecutive patients enrolled in the study (mean age 80 +/- 6 years, 46% men), 17 (34%) experienced an AV block with subsequent requirement of a permanent PM [16 of 36 (44.4%) with CoreValve System and 1 of 14 (7.1%) with Edwards Sapiens System]. In patients with right bundle branch block (RBBB), PM implantation had to be performed more frequently [6 of 6 (100%) with CoreValve System and none with Edwards Sapiens System], P = 0.005. An AV block (Mobitz II second degree and third degree) occurred mostly within the first 24 h (range: Days 0-13) after the index procedure. No recovery of AV conduction with a change in PM indication occurred in a mean follow-up time of 13 +/- 6 days. Our data demonstrate that patients with pre-operative RBBB and those receiving CoreValve prosthesis are at a significantly higher risk for PM implantation after TAVI. Therefore, patients with the presence of RBBB before TAVI may be at lower risk for PM implantation using the Edwards Sapiens System.

Transfemoral Implantation of the Acurate neo for the Treatment of Aortic Regurgitation.

OBJECTIVES: We report an international experience of transfemoral transcatheter aortic valve replacement (TAVR) using the self-expanding Acurate neo valve (Boston Scientific) in aortic regurgitation. METHODS: This series comprises 20 patients with pure aortic regurgitation undergoing transfemoral TAVR with the Acurate neo prosthesis at nine centers in Europe and Israel. RESULTS: Mean age was 79 ± 8 years and mean STS score was 8.3 ± 9.3%. Leaflet calcification was none/minimal in 19 patients (95%). Prosthesis size selection was based on perimeter-derived annular diameter, with a tendency to over-size in cases of borderline annuli. One patient required implantation of a second valve. Device success rate was 18/20 (90%). At discharge, aortic regurgitation was none in 14 patients (70%), mild in 5 patients (25%), and moderate in 1 patient (5%). Left ventricular end-diastolic diameter decreased from 58 ± 7 mm at baseline to 53 ± 7 mm before discharge (P<.001). At 30-day follow-up, there was no mortality, no stroke, and 3 patients (15%) had received a permanent pacemaker. New York Heart Association class had improved significantly compared to baseline (85% in class I/II compared to 15% at baseline; P<.001). CONCLUSIONS: In a selected patient population, transfemoral TAVR using the Acurate neo transcatheter heart valve was successful in treating aortic regurgitation, significantly reduced left ventricular dimensions, and improved clinical symptoms.

Characterization of Two Novel Bacteriophages Infecting Multidrug-Resistant (MDR) Acinetobacter baumannii and Evaluation of Their Therapeutic Efficacy in Vivo.

Acinetobacter baumannii is emerging as a challenging nosocomial pathogen due to its rapid evolution of antibiotic resistance. We report characterization of two novel bacteriophages, PBAB08 and PBAB25, infecting clinically isolated, multidrug-resistant (MDR) A. baumannii strains. Both phages belonged to Myoviridae of Caudovirales as their morphology observed under an electron microscope. Their genomes were double stranded linear DNAs of 42,312 base pairs and 40,260 base pairs, respectively. The two phages were distinct from known Acinetobacter phages when whole genome sequences were compared. PBAB08 showed a 99% similarity with 57% sequence coverage to phage AB1 and PBAB25 showed a 97% similarity with 78% sequence coverage to phage IME_AB3. BLASTN significant alignment coverage of all other known phages were <30%. Seventy six and seventy genes encoding putative phage proteins were found in the genomes of PBAB08 and PBAB25, respectively. Their genomic organizations and sequence similarities were consistent with the modular theory of phage evolution. Therapeutic efficacy of a phage cocktail containing the two and other phages were evaluated in a mice model with nasal infection of MDR A. baumannii. Mice treated with the phage cocktail showed a 2.3-fold higher survival rate than those untreated in 7 days post infection. In addition, 1/100 reduction of the number of A. baumannii in the lung of the mice treated with the phage cocktail was observed. Also, inflammatory responses of mice which were injected with the phage cocktail by intraperitoneal, intranasal, or oral route was investigated. Increase in serum cytokine was minimal regardless of the injection route. A 20% increase in IgE production was seen in intraperitoneal injection route, but not in other routes. Thus, the cocktail containing the two newly isolated phages could serve as a potential candidate for therapeutic interventions to treat A. baummannii infections.

Short-Term Outcome and Hemodynamic Performance of Next-Generation Self-Expanding Versus Balloon-Expandable Transcatheter Aortic Valves in Patients With Small Aortic Annulus: A Multicenter Propensity-Matched Comparison.

BACKGROUND: Surgical aortic valve replacement in patients with small annular dimensions is challenging because they are at increased risk for prosthesis-patient mismatch and impaired outcomes. Transcatheter aortic valve replacement might be a good alternative; however, comparative data on different transcatheter heart valves are missing. METHODS AND RESULTS: This multicenter, propensity score-matched study compared hemodynamics and early clinical outcomes in 246 patients with an aortic annulus area <400 mm2 undergoing transcatheter aortic valve replacement with either a self-expanding transcatheter heart valve (Symetis ACURATE neo, n=129) or a balloon-expandable transcatheter heart valve (Edwards SAPIEN 3, n=117). The 1:1 propensity score matching resulted in 92 matched pairs. For ACURATE neo versus SAPIEN 3-treated patients, 30-day mortality (0.0% versus 1.0%), 1-year mortality (8.3% versus 13.3%), incidence of stroke (3.3% versus 2.2%), life-threatening bleeding (1.1% versus 1.1%), and major vascular complications (2.2% versus 6.5%), as well as pacemaker implantation rate (12.0% versus 15.2%), were similar. Paravalvular regurgitation ≥moderate was rare in both groups (4.5% versus 3.6%). The ACURATE neo presented lower mean transvalvular gradients (9.3 versus 14.5 mm Hg; P<0.001), larger indexed effective orifice areas (0.96 versus 0.80 cm2/m2; P=0.003), and lower rates of severe prosthesis-patient mismatch (3% versus 22%; P=0.004). Hemodynamics were sustained at 1-year follow-up. CONCLUSIONS: Albeit a similar safety profile with low clinical event rates, transcatheter aortic valve replacement with the ACURATE neo valve resulted in lower transvalvular gradients and consequently less prosthesis-patient mismatch compared with the SAPIEN 3 in patients with small annulus. These results emphasize the need of careful prosthesis selection in each individual patient.

Identification of Periprocedural Myocardial Infarction Using a High-Sensitivity Troponin I Assay in Patients Who Underwent Transcatheter Aortic Valve Implantation.

Periprocedural myocardial infarction (MI), a rare complication after transcatheter aortic valve implantation (TAVI), is associated with worse outcome. According to the Valve Academic Research Consortium (VARC-2), MI is defined by an increase in cardiac troponin (cTn) and creatine kinase MB (CK-MB) levels; however, many patients show periprocedurally elevated cTn without clinical evidence of MI. The aims of this study were to establish reference values of cardiac troponin I measured with a high-sensitivity assay (hs-cTnI) and to assess the periprocedural diagnostic value of this biomarker in patients who underwent TAVI. Hs-cTnI and CK-MB levels were assessed before and up to 3 days after transfemoral (TF) or transapical (TA) TAVI in 515 patients. A high proportion (61.2%) of patients had elevated hs-cTnI at baseline. According to VARC-2 criteria, almost all TA-patients (99.5%) showed an MI based on hs-cTnI compared with 4.2% based on CK-MB. In TF-patients, 81.1% had an MI based on hs-cTnI compared with 9.0% based on CK-MB. Only 10 patients (2%), however, had a type 1 MI. The ninety-ninth percentile for hs-cTnI was 285 ng/L in the TAVI cohort. After applying a TAVI-specific cutoff the frequency of MI was lower and more realistic (TF: 5% vs 81.1%; p <0.001; TA: 22.2% vs 99.5%; p <0.001). In conclusion, the VARC-2 definition leads to an overestimation of periprocedural MI. Our new TAVI-specific reference values yield a more realistic estimation of the myocardial ischemic risk. hs-cTnI, however, does not seem to be the biomarker of choice for MI detection in this setting.

Comparison between Immunization Routes of Live Attenuated Salmonella Typhimurium Strains Expressing BCSP31, Omp3b, and SOD of Brucella abortus in Murine Model.

Live, attenuated Salmonella Typhimurium vaccine candidate expressing BCSP31, Omp3b, and SOD proteins of Brucella abortus was constructed. Thirty BALB/c mice were divided equally into three groups, Group A, were intraperitoneally (IP) inoculated with 100 µl of approximately 1.2 × 10(6) colony-forming units (CFUs)/ml of the Salmonella containing vector only in 100 µl as a control. And groups B and C mice were orally and IP immunized with approximately 1.2 × 10(9) CFU/ml of the mixture of three delivery strains in 10 µl and IP immunized with approximately 1.2 × 10(6) CFU/ml of the mixture in 100 µl, respectively. The serum IgG, TNF-α and IFN-γ concentrations in groups B (except Omp3b) and C were significantly higher than those in group A. Following challenge with B. abortus strain 544; challenge strain was detected <10(3) CFU from the spleen of all mice of group C. These results suggest that IP immunization with the mixture of the vaccine candidate can induce immune responses, and can effectively protect mice against brucellosis.

Pulmonary vascular remodeling before and after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a cardiac magnetic resonance study.

Phase-contrast magnetic resonance imaging (PC-MRI) offers a range of surrogate markers to quantify the hemodynamic changes associated with chronic thromboembolic pulmonary hypertension (CTEPH). Our aim was to noninvasively monitor effects of pulmonary vascular remodeling before and after endarterectomy (PEA) in patients with CTEPH by using PC-MRI. Fifty-seven consecutive patients (mean age 56.7 ± 16, 28 female) underwent PC-MRI before and after PEA as part of their peri-operative routine workup. Pulmonary artery (PA) maximum flow velocity (maxV), acceleration time/ejection time (AT/ET), distensibility [(PA maximum area - PA minimum area)/PA minimum area], mid-systolic flow deceleration (notch), and the timing of deceleration (notch ratio) were recorded. Mean PA pressure was obtained from standard right heart catheter procedures. maxV and AT/ET were decreased before PEA and significantly improved afterwards (60.8 ± 16 vs. 73.8 ± 19 cm/s, p = 0.007; 0.32 ± 0.06 vs. 0.36 ± 0.09, p = 0.0015). Surprisingly, distensibility did not change significantly (30 ± 19 vs. 26 ± 12%, p = 0.11). Forty-five patients (78%) had a systolic notch before PEA that persisted in only 10 (18%; p = 0.00001). Among patients with a persisting notch, the notch ratio did not significantly increase (1.3 ± 0.2 vs. 1.6 ± 1.5, p = 0.32). Our data show early PA reverse remodeling after PEA. Flow velocities increase while PA flow wave reflections represented by mid-systolic flow deceleration are abolished. In some patients a mid-systolic notch persists, suggesting increased downstream resistance as a consequence of small vessel arteriopathy.

Phosphorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8- and -9-mediated apoptotic pathways in dopaminergic neurons.

We evaluated the contribution of p38 mitogen-activated protein kinase and the events upstream/downstream of p38 leading to dopaminergic neuronal death. We utilized MN9D cells and primary cultures of mesencephalic neurons treated with 6-hydroxydopamine. Phosphorylation of p38 preceded apoptosis and was sustained in 6-hydroxydopamine-treated MN9D cells. Co-treatment with PD169316 (an inhibitor of p38) or expression of a dominant negative p38 was neuroprotective in death induced by 6-hydroxydopamine. The superoxide dismutase mimetic and the nitric oxide chelator blocked 6-hydroxydopamine-induced phosphorylation of p38, suggesting a role for superoxide anion and nitric oxide in eliciting a neurotoxic signal by activating p38. Following 6-hydroxydopamine treatment, inhibition of p38 prevented both caspase-8- and -9-mediated apoptotic pathways as well as generation of truncated Bid. Consequently, 6-hydroxydopamine-induced cell death was rescued by blockading activation of caspase-8 and -9. In primary cultures of mesencephalic neurons, the phosphorylation of p38 similarly appeared in tyrosine hydroxylase-positive, dopaminergic neurons after 6-hydroxydopamine treatment. This neurotoxin-induced phosphorylation of p38 was inhibited in the presence of superoxide dismutase mimetic or nitric oxide chelator. Co-treatment with PD169316 deterred 6-hydroxydopamine-induced loss of dopaminergic neurons and activation of caspase-3 in these neurons. Furthermore, inhibition of caspase-8 and -9 significantly rescued 6-hydroxydopamine-induced loss of dopaminergic neurons. Taken together, our data suggest that superoxide anion and nitric oxide induced by 6-hydroxydopamine initiate the p38 signal pathway leading to activation of both mitochondrial and extramitochondrial apoptotic pathways in our culture models of Parkinson's disease.