cAMP Imaging at Ryanodine Receptors Reveals ß2-Adrenoceptor Driven Arrhythmias.

[Figure: see text].

Hemodynamics and Diastolic Function after Native Aortic Valve Preserving vs. Replacing Surgery.

BACKGROUND: Alterations in left ventricular (LV) diastolic function following native tissue-preserving aortic valve (AV) procedures have not been systematically investigated. Furthermore, no comparisons have been made between these changes and those observed after prosthetic AV replacement. METHODS: From October 2017 to August 2020, 74 patients aged <65 years were referred to our institution for elective AV surgery. Preoperative and postoperative (i.e., discharge, 3-month and 1-year follow-up) transthoracic echocardiography was analyzed. RESULTS: Native tissue-preserving surgery was performed in 55 patients (AV repair: n = 42, Ross procedure: n = 13). The remaining 19 patients underwent prosthetic AV replacement. Preoperatively and at discharge, transvalvular hemodynamics and LV diastolic function were comparable in both groups. At 1-year follow-up, native valve (NV) patients showed significantly lower mean transvalvular gradient (7 ± 5 vs. 9 ± 3 mmHg, p = 0.046) and peak velocity (1.74 ± 0.51 vs. 2.26 ± 0.96 m/s, p = 0.004), and significantly better septal e' (9.1 ± 2.7 vs. 7.7 ± 2.5 cm/s, p = 0.043) and lateral e' (14.7 ± 3.1 vs. 11.7 ± 3.7 cm/s, p = 0.001). From preoperatively to 1-year postoperatively, septal and lateral e' and E/e' improved markedly after NV preservation (septal e': +0.7 cm/s, p = 0.075; lateral e': +2.3 cm/s, p < 0.001; E/e': -1.5, p = 0.001) but not after AV replacement (septal e': +0.2 cm/s, p = 0.809; lateral e': +0.8 cm/s, p = 0.574; E/e': -1.2, p = 0.347). Significant negative linear correlations between postoperative transvalvular gradients and absolute changes in lateral e' and E/e' were detected during follow-up. CONCLUSION: Preservation of native tissue in AV surgery results in superior transvalvular hemodynamics compared with prosthetic AV replacement. This may induce faster LV reverse remodeling and may explain more pronounced improvement in LV diastolic function.

Radiographic and clinical outcome of tibial plateau fractures treated with bone allograft.

BACKGROUND: To determine the clinical outcome of patients who had been treated with bone allografts during open reduction and internal fixation (ORIF) of tibial head fractures. METHODS: Patients who suffered a medial, lateral, or bicondylar fracture of the tibial plateau and underwent surgical treatment by open reduction and internal fixation (ORIF) using human femoral head bone allografts were included. Patients were invited to provide information for the following: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), EuroQol Five Dimension score (EQ-5D), Lower Extremity Functional Scale (LEFS) and Parker Mobility Score. Bone mineral density (BMD) of the allograft area and the healthy human bone tissue were measured by quantitative computed tomography. RESULTS: A total of 22 patients with a mean follow-up time of 2.88 ± 2.46 years were included in our study. The most common fractures observed in this study were classified as Schatzker II (11 patients, 50.0%) or AO/OTA 41.B3 (12 patients, 54.5%) fractures. Postoperative WOMAC total was 13.0 (IQR = 16.3, range 0-33). Median quality of life (EQ-5D) score was 0.887 ± 0.121 (range 0.361-1.000). Median Lower Extremity Functional Scale (LEFS) score was 57.5 ± 19.0 (range 33-79). Mean Parker Mobility Score was 9 (range 6-9). Median bone mineral density (BMD) for the whole group was 300.04 ± 226.02 mg/cm3 (range - 88.68 to 555.06 mg/cm3) for region of interest (ROI 5) (central), 214.80 ± 167.45 mg/cm3 (range - 7.16 to 597.21 mg/cm3) for ROI 1-4 (marginal zones: medial, lateral, ventral, dorsal) and 168.14 ± 65.54 mg/cm3 (range 17.47-208.97 mg/cm3) for healthy bone tissue (femur and tibia). CONCLUSION: Based on WOMAC scores, LEFS, ambulatory status, and quality of life findings, it can be concluded that following tibial head ORIF with allograft bone patients has promising results.

Circulating microRNAs in the prediction of BAV aortopathy: do the expression patterns correlate between blood and aortic tissue?

BACKGROUND: The limitation of aortic size-based criteria is gradually recognized in the prediction of aortic events especially in bicuspid aortic valve (BAV) cohorts, while most aortic events happen in patients with proximal aortic diameters <50 mm. Circulating microRNAs (miRs) have been addressed as a novel tool to improve risk stratification in patients with different aortopathies. We aimed to elucidate the correlation between peripheral whole blood and aortic tissue miRs in order to prove the potential availability as a biomarker in the clinical routine. METHODS: All patients who received elective aortic valve repair/replacement ± proximal aortic replacement to BAV disease (n = 65, 2013-2018) were prospectively included. The expression of 10 miRs (miR-1, miR-17, miR-18a, miR-19a, miR-20a, miR-21, miR-106a, miR-133a, miR-143 and miR-145) was analyzed in the intraoperatively acquired aortic tissue as well as in the peripheral blood before the surgery. RESULTS: We found a significant correlation between circulating miRs in the peripheral blood and aortic tissue levels of miR-21 (r = 0.293, p = 0.02), miR-133a (r = 0.43, p = 0.02), miR-143 (r = 0.68, p < 0.001), and miR-145 (r = 0.68, p < 0.001). Further, the multivariate logistic regression analysis revealed an association between blood and aortic tissue miR-143 levels each other (Odds Ratio [OR] 1.29, 95% Confidence Interval [CI] 1.11-1.67, p = 0.02; OR 1.36, 95% CI 1.19-2.01, p = 0.03, respectively) and a blood/aortic miR-143 level to dilated aorta (OR 3.61, 95% CI 1.62-9.02, p = 0.01; OR 2.92, 95% CI 1.81-7.05, p = 0.02, respectively). CONCLUSIONS: Our study demonstrates a significant correlation between peripheral whole blood and aortic tissue miRs, confirming the hypothesis that circulating miRs may reflect remodeling processes in the proximal aorta in bicuspid aortopathy patients.

Muscarinic Receptor Activation Reduces Force and Arrhythmias in Human Atria Independent of IK,ACh.

ABSTRACT: In human hearts, muscarinic receptors (M-R) are expressed in ventricular and atrial tissue, but the acetylcholine-activated potassium current (IK,ACh) is expressed mainly in the atrium. M-R activation decreases force and increases electrical stability in human atrium, but the impact of IK,ACh to both effects remains unclear. We used a new selective blocker of IK,ACh to elaborate the contribution of IK,ACh to M-R activation-mediated effects in human atrium. Force and action potentials were measured in rat atria and in human right atrial trabeculae. Cumulative concentration-effect curves for norepinephrine-induced force and arrhythmias were measured in the presence of carbachol (CCh; 1 µM) or CCh together with the IK,ACh -blocker XAF-1407 (1 µM) or in time-matched controls. To investigate the vulnerability to arrhythmias, we performed some experiments also in the presence of cilostamide (0.3 µM) and rolipram (1 µM), inhibiting PDE3 and PDE4. In rat atria and human right atrial trabeculae, CCh shortened the action potential duration persistently. However, the direct negative inotropy of CCh was only transient in human, but stable in rat atria. In rat and human atria, the negative inotropic effect was insensitive to blockage of IK,ACh by XAF-1407. In the presence of cilostamide and rolipram about 40% of trabeculae developed arrhythmias when exposed to norepinephrine. CCh prevented these concentration-dependent norepinephrine-induced arrhythmias, again insensitive to XAF-1407. Maximum catecholamine-induced force was not depressed by CCh. In human atrium, the direct and the indirect negative inotropic effect of CCh are independent of IK,ACh. The same applies to the CCh-mediated suppression of norepinephrine/PDE-inhibition-induced arrhythmias.

A novel technique to quantify aortic valve annulus deformation: A pilot study.

OBJECTIVES: We evaluated the potential of cardiac magnetic resonance (CMR)-derived strain to assess aortic valve (AV) annulus deformation during the cardiac cycle in regurgitant and well-functioning AVs. METHODS: Four patients with severe aortic regurgitation and seven healthy controls underwent CMR. Assessment of longitudinal strain was performed by hypothesizing the AV annulus would be the left ventricle in long-axis orientation. Longitudinal strain of the segments belonging to the muscular and fibrous AV annulus was weighted and averaged to obtain regional values (RLS). RESULTS: Comparison of RLS between regurgitant and well-functioning AVs showed a considerably different deformation of the muscular AV annulus (i.e., median RLS: 4.18 % [patients] vs. -10.41 % [controls], p = .024). The fibrous AV annulus demonstrated comparable deformational changes in both groups. CONCLUSION: CMR-derived strain allows for quantification of AV annulus deformation during the cardiac cycle and shows an altered RLS in the muscular AV annulus in patients with severe aortic regurgitation.

Complete Left-Atrial Lesion Set versus Pulmonary Vein Isolation Only in Patients with Paroxysmal AF Undergoing CABG or AVR.

Background and Objectives: In patients with paroxysmal atrial fibrillation (AF) undergoing CABG or aortic valve surgery, many surgeons are not willing to open the left atrium to perform a complete left-sided Cox-Maze lesion set. Pulmonary vein isolation (PVI) is often favored in those patients. We investigated the outcome of patients with isolated pulmonary vein isolation compared to those receiving an extended left atrial (LA) lesion set. Materials and Methods: Between 2003 and 2016, 817 patients received concomitant surgical AF ablation in our institution. A total of 268 patients with paroxysmal AF were treated by surgical ablation concomitant to AVR or CABG. Of those, 86 patients underwent a complete left-sided lesion set, while 182 patients were treated with an isolated pulmonary vein isolation. The primary endpoint was freedom from atrial fibrillation at 12 months' follow-up. Results: There were no statistically significant differences regarding baseline characteristics. No major ablation-related complications were observed in any of the groups. In the PVI group, three patients (1.6%) had an intraoperative stroke, while two (2.3%) patients experienced a stroke in the LA ablation group (p = 0.98). In-hospital mortality was 3.4% in the PVI group, and 2.8% in the extended LA group (p = 0.33). Freedom from AF at 12 months' follow-up was 76% in the extended LA ablation group and 70% in the PVI group, showing no statistically significant difference (p = 0.32). Conclusion: Surgical AF ablation concomitant to CABG or AVR in patients with paroxysmal AF is safe and effective. There was no statistically significant difference between the compared lesion sets in terms of freedom from AF, survival or stroke rate after 12 months.

Safety and efficacy of transvenous lead extraction in octogenarians using powered extraction sheaths.

BACKGROUND: In the aging population equipped with cardiac implantable electronic devices, an increasing number of octogenarians require lead extractions. This patient population is often considered as a high-risk group for surgical procedures. We, therefore, investigated the safety and efficacy of transvenous lead extraction in octogenarians using powered extraction sheaths. METHODS: Between January 2013 and March 2017, 403 patients underwent lead extraction at two high-volume lead extraction centers. A total of 71 octogenarians were treated with laser lead extraction and were included in this analysis. Primary extraction method was laser lead extraction, with additional use of mechanical rotational sheaths or femoral snares, if necessary. Patient-based and procedural data were collected and analyzed retrospectively. RESULTS: Mean age was 83.5 ± 3.3 years, 64.7% were males. A total of 152 leads were extracted. The mean lead dwell time of treated leads was 10.2 ± 5.2 years. Complete procedural success rate was 92.9%, while clinical success was achieved in 98.6%. Failure of extraction occurred in one patient (1.4%). In six (7.7%) patients, additional mechanical rotational sheaths or femoral snares were used. Overall complication rate was 4.2%, including one (1.4%) major (RA perforation) and two (2.8%) minor complications. No procedure-related mortality was observed in any of the patients. CONCLUSION: Transvenous lead extraction in octogenarians with old leads is safe and effective when performed in experienced centers. Patient's age should therefore not be considered as contraindication for lead extraction using powered extraction sheaths.

Persistence of Reduced Left Ventricular Function after Aortic Valve Surgery for Aortic Valve Regurgitation: Bicuspid versus Tricuspid.

OBJECTIVE: Long-term prognosis of patients with aortic regurgitation (AR) and reduced left ventricular ejection fraction (LVEF) who undergo aortic valve surgery (AVS) is unknown. Due to the congenital origin, bicuspid aortic valve (BAV) morphotype might be associated with a more severe cardiomyopathy. We aimed to evaluate the LVEF recovery after aortic valve replacement (AVR) surgery in patients with AR and reduced preoperative LVEF. METHODS: This retrospective analysis included 1,170 consecutive patients with moderate to severe AR who underwent AVS at our institution between January 2005 and April 2016. Preoperative echocardiography revealed 154 (13%) patients with predominant AR and baseline LVEF < 50%. A total of 60 (39%) patients had a BAV (BAV group), while the remaining 94 (61%) patients had a tricuspid morphotype (tricuspid aortic valve [TAV] group). Follow-up protocol included clinical interview using a structured questionnaire and echocardiographic follow-up. RESULTS: A total of 154 patients (mean age 63.5 ± 12.4 years, 71% male) underwent AVS for AR in the context of reduced LVEF (mean LVEF 42 ± 8%). Fifteen (10%) patients had a severely reduced preoperative LVEF ≤ 30%. Mean STS (Society of Thoracic Surgeons) score was 1.36 ± 1.09%. Mean follow-up was comparable between both the study groups (BAV: 50 ± 40 months vs. TAV: 40 ± 38 months, p = 0.140). A total of 25 (17%) patients died during follow-up. Follow-up echocardiography demonstrated similar rate of postoperatively reduced LVEF in both groups (i.e., 39% BAV patients vs. 43% TAV patients; p = 0.638). Cox's regression analysis showed no significant impact of BAV morphotype (i.e., as compared with TAV) on the postoperative LVEF recovery (odds ratio [OR]: 1.065; p = 0.859). Severe left ventricular (LV) dysfunction at baseline (i.e., LVEF ≤ 30%) was a strong predictor for persistence of reduced LVEF during follow-up (OR: 3.174; 95% confidence interval: 1.517-6.640; p = 0.002). Survival was significantly reduced in patients with persisting LV dysfunction versus those in whom LVEF recovered (log rank: p < 0.001). CONCLUSION: Our study demonstrates that reduced LVEF persists postoperatively in 40 to 45% patients who present with relevant AR and reduced LVEF at baseline. Postoperative LVEF recovery is independent of aortic valve morphotype (i.e., BAV vs. TAV). Severe LV dysfunction (LVEF ≤ 30%) at baseline is a strong predictor for persistence of reduced LVEF in patients with AR and results in significantly reduced long-term survival.

Economic impact of enhanced recovery after surgery protocol in minimally invasive cardiac surgery.

BACKGROUND: ERAS (Enhanced Recovery After Surgery) is a multidisciplinary and integrative approach with the goal of optimizing the postoperative recovery. We aimed to analyze the economic impact of a newly established ERAS protocol in minimally invasive heart valve surgery at our institution. METHODS: ERAS protocol was implemented in 61 consecutive patients who were referred for elective minimally-invasive aortic or mitral valve surgery, between February 1, 2018 and March 31, 2019 (ERAS-group). Another 69 patients who underwent elective minimally-invasive heart valve surgery during the same time period were managed according to the hospital standards (Control-group). A detailed cost comparison analysis was carried out from a hospital perspective using a micro-costing approach. RESULTS: The total in-hospital stay was significantly shorter in the ERAS-group compared to the Control-group (6.1 ± 2.6 vs 7.7 ± 3.8 days; p = 0.008) resulting in significant cost savings of €1087.2 per patient (p = 0.003). Due to the intensified physiotherapy in the ERAS protocol, the costs for physiotherapy were €94.3 higher compared to the Control-group (p < 0.001). The total costs in the ERAS cohort were €11,200.0 ± 3029.6/patient compared to € 13,109.8 ± 4527.5/patient in the Control-Group resulting in cost savings of €1909.8 patient due to the implementation of the ERAS protocol (p = 0.006). CONCLUSION: Implementation of an ERAS-protocol in minimally-invasive cardiac surgery can be carried out safely with a fast postoperative recovery of the patient. ERAS results in a financial benefit of up to €1909 per patient and therefore will play a key role in modern cardiac surgery in the near future.

Hybrid transvenous lead extraction during cardiac surgery for valvular endocarditis.

INTRODUCTION: In patients with endocarditis and cardiac implantable electronic devices (CIED), lead extraction is recommended according to current guidelines. In patients with short lead implant duration, lead extraction by manual traction might be sufficient for intraoperative lead removal. However, in patients with long implant duration, specialized extraction tools like laser or mechanical rotational sheaths are necessary. We report our experience with transvenous lead extraction during concomitant cardiac surgery for valvular endocarditis using mechanical rotational sheaths. METHODS AND RESULTS: Between December 2018 and April 2020, 12 patients were treated with transvenous lead extraction during open-heart surgery using mechanical rotational sheaths. Cardiac surgery was performed due to mitral, aortic, or tricuspid valve endocarditis. All patient-related and procedural data were collected, and in-hospital outcome was analyzed retrospectively. Mean patients' age was 65.2 ± 16.4 years, and 75.0% were male. Nine atrial, 15 ventricular, and 2 coronary sinus leads had to be extracted. The mean time from initial lead implantation was 94.3 ± 39.7 months. Complete procedural success was achieved in all patients with no major but one minor complication (pocket hematoma) occurring during lead extraction. Four patients with pacemaker dependency received epicardial leads, seven patients were treated in a two-step approach with endocardial leads, whereas one patient had no further CIED indication. No procedure-related mortality was seen. In-hospital survival was 91.7%. CONCLUSIONS: Valvular endocarditis surgery in combination with lead extraction using mechanical rotational sheaths is safe and feasible. It results in a high procedural success rate with prompt infection control by immediate removal of all infected lead materials.

Bicuspid aortopathy - molecular involvement of microRNAs and MMP-TIMP.

OBJECTIVES: We aimed to elucidate the correlation between expression patterns of aortic tissue microRNAs and the aortopathy formation in bicuspid aortic valve (BAV) disease. METHODS: All 65 patients who underwent elective aortic valve repair/replacement +/- proximal aortic replacement due to BAV disease with or without concomitant aortic aneurysm were identified from our BAV registry. Aortic tissue was collected intraoperatively from the ascending aorta at the greater and lesser curvature. Aortic tissue microRNAs analysis included 11 microRNAs (miR-1, miR-17, miR-18a, miR-19a, miR-20a, miR-21, miR-29b, miR-106a, miR-133a, miR-143 and miR-145). Furthermore, analysis of MMP2, TIMP1/2 mRNA and the protein expression was subsequently performed. The primary study endpoint was the correlation between microRNAs and MMP2, TIMP1/2 mRNA/protein expression. RESULTS: We found a significant association between miR-133a and TIMP1 mRNA (r = 0.870, p < 0.001), an inverse correlation between miR-143a and MMP2 protein expression (r= -0.614, p = 0.044) and a positive correlation between miR-133a and TIMP-2 protein expression (r = 0.583, p = 0.036) at the greater curvature. CONCLUSION: Our findings indicate that aortic tissue microRNAs may reflect remodelling processes of the proximal aorta in BAV aortopathy. Specific aortic tissue microRNAs may exert their regulatory effects on the aortopathy through their impact on MMPs/TIMPs homeostasis at the level of the greater curvature.

4D flow cardiovascular magnetic resonance for monitoring of aortic valve repair in bicuspid aortic valve disease.

BACKGROUND: Aortic valve repair has become a treatment option for adults with symptomatic bicuspid (BAV) or unicuspid (UAV) aortic valve insufficiency. Our aim was to demonstrate the feasibility of 4D flow cardiovascular magnetic resonance (CMR) to assess the impact of aortic valve repair on changes in blood flow dynamics in patients with symptomatic BAV or UAV. METHODS: Twenty patients with adult congenital heart disease (median 35 years, range 18-64; 16 male) and symptomatic aortic valve regurgitation (15 BAV, 5 UAV) were prospectively studied. All patients underwent 4D flow CMR before and after aortic valve repair. Aortic valve regurgitant fraction and systolic peak velocity were estimated. The degree of helical and vortical flow was evaluated according to a 3-point scale. Relative flow displacement and wall shear stress (WSS) were quantified at predefined levels in the thoracic aorta. RESULTS: All patients underwent successful aortic valve repair with a significant reduction of aortic valve regurgitation (16.7 ± 9.8% to 6.4 ± 4.4%, p < 0.001) and systolic peak velocity (2.3 ± 0.9 to 1.9 ± 0.4 m/s, p = 0.014). Both helical flow (1.6 ± 0.6 vs. 0.9 ± 0.5, p < 0.001) and vortical flow (1.2 ± 0.8 vs. 0.5 ± 0.6, p = 0.002) as well as both flow displacement (0.3 ± 0.1 vs. 0.25 ± 0.1, p = 0.031) and WSS (0.8 ± 0.2 N/m2 vs. 0.5 ± 0.2 N/m2, p < 0.001) in the ascending aorta were significantly reduced after aortic valve repair. CONCLUSIONS: 4D flow CMR allows assessment of the impact of aortic valve repair on changes in blood flow dynamics in patients with bicuspid aortic valve disease.

Atrial fibrillation surgery with a focus on patients with reduced left ventricular function and heart failure.

This review article aims to give an overview on the different surgical treatment options for atrial fibrillation It includes concomitant- as well as stand-alone surgical ablation therapy and outlines the main issues in patients with heart failure and reduced LVEF.

Occult intra-operative periprosthetic fractures of the acetabulum may affect implant survival.

PURPOSE: Occult intra-operative periprosthetic acetabular fracture is a seldom-reported complication of primary total hip arthroplasty (THA). It may potentially be associated with cup instability and implant loosening. The present study aimed to investigate clinical consequences of this complication. METHODS: Between 2003 and 2012, a total of 3390 cementless total hip arthroplasties (THA) were performed at our institution. Their medical histories were retrospectively reviewed to identify all patients who received a thin-layer computer tomography (CT) scan of the pelvis including the acetabulum within the first 30 post-operative days. They were evaluated and classified by two radiologists independently with respect to the presence of recent acetabular fractures. All cases with acetabular and periacetabular fractures were included in this study. Electronic medical records were reviewed to assess implant revision. Cup stability was measured with EBRA (Einzel-Bild-Röntgen-Analyse) from plain X-rays. RESULTS: Periprosthetic fractures of the acetabulum were identified in 58 (50.4%) of 115 selected patients. Fractures close to but not including the acetabulum were identified in 45% (n = 26/58) of the patients, at the superolateral wall in 17% (n = 10/58), at the anterior wall of the acetabulum in 16% (n = 9/58) and in 10% (n = 6/58) each at the medial wall, and at the posterior wall respectively. One out of these 58 fractures could not be classified. Three of a total of six occult medial wall fractures had to be revised, and another two showed a high implant migration. The highest cup migration values however were found after fractures of the superolateral wall. Incomplete column fractures did not influence implant survival. CONCLUSION: Central wall acetabular fractures, although unrecognized intra- and post-operatively may impair implant survival after THA.

Cardiopulmonary bypass reduces myocardial oxidative stress, inflammation and increases c-kit+CD45- cell population in newborns.

BACKGROUND: The aim of this study was to characterize the influence of cardiopulmonary bypass (CPB) on myocardial remodeling in newborns and children. METHODS: Biopsies from the right atrium were taken before and after CPB from 4 newborns (5-11 days old) and 7 children (8 months-16 years old). Immunostainings on 10 µm heart tissue frozen sections were performed to detect c-kit+ cells, leukocytes (CD45+ cells), Ki67+ cycling cells. The percentage of 8-hydroxy-guanosine (8-dOHG)+cardiomyocytes and non-cardiomyocytes [(8-dOHG)+-index] were determined to quantify oxidative stress. RESULTS: Δ c-kit+CD45- cells (resident cardiac stem cells) were increased in newborns (2.2 ± 1.9/mm2) and decreased in children - 1.5 ± 0.7/mm2, p < 0.01. The (8-dOHG)+-index was reduced by 43% in newborns and by 20% in children. CPB did not influence cardiac cell turnover; high cell proliferation was seen in newborns before and after CPB. Cardiopulmonary bypass significantly decreased the leucocyte infiltration in newborns to 40 ± 8%, p < 0.05, but not in children. Infiltration with eosinophils (eosinophils/CD45%) was completely abolished in the myocardium of newborns p < 0.05 and reduced to 22 ± 8% in children after CPB, n.s. CONCLUSIONS: Immediate response and remodeling of the myocardium to CPB differs between newborns, older infants and children. Especially an increased number of c-kit expressing CD45 cells after CPB were seen in neonates in comparison to children. The clinical value of such observation needs to be further assessed in larger cohorts of patients.

Pyrrolidone Modification Prevents PAMAM Dendrimers from Activation of Pro-Inflammatory Signaling Pathways in Human Monocytes.

The biological features of dendrimers are affected by the character of highly reactive terminal moieties. In some polyamine dendrimer types the surface charge makes them bioincompatible and prevent their direct medical application. Moreover, foreign particles can induce the immune response which is undesirable due to the adverse side effects in vivo. The reduction of cytotoxicity of positively charged macromolecules is possible through chemical modifications of terminal groups. In our study, we have developed new derivatives of PAMAM dendrimers modified with 4-carbomethoxypyrrolidone and evaluated their immunomodulatory properties. The experiments were conducted on two human cancer myeloid cell lines: THP-1 and U937. To evaluate the cytotoxicity of dendrimers, the reasazurin assay was applied. The expression level of NF-κB targets (NFKBIA, BTG2) and cytokine genes (IL1B, TNF) was determined by quantitative real-time RT-PCR. The measurement of binding of NF-κB to a consensus DNA probe was determined by electrophoretic mobility shift assay. The ELISA cytokine assay was performed to measure protein concentration of IL-1ß and TNFα. We have found that PAMAM-pyrrolidone dendrimers did not impact THP-1 and U937 viability even at high concentrations (up to 200 µM). The surface modification prevented PAMAM dendrimers from stimulating NF-κB-related signal transduction, which have been determined on the level of nuclear translocation, gene expression and protein secretion. Pyrrolidone modification efficiently prevents PAMAM dendrimers from stimulating pro-inflammatory response in human cancer myeloid cell lines, thus it can be used to improve the biocompatibility of positively charged dendrimers and to broaden the scope of their biological applications.

Differential expression of microRNAs following cardiopulmonary bypass in children with congenital heart diseases.

BACKGROUND: Children with congenital heart defects (CHDs) are at high risk for myocardial failure after operative procedures with cardiopulmonary bypass (CPB). Recent studies suggest that microRNAs (miRNA) are involved in the development of CHDs and myocardial failure. Therefore, the aim of this study was to determine alterations in the miRNA profile in heart tissue after cardiac surgery using CPB. METHODS: In total, 14 tissue samples from right atrium were collected from patients before and after connection of the CPB. SurePrint™ 8 × 60K Human v21 miRNA array and quantitative reverse transcription-polymerase chain reaction (RT-qPCR) were employed to determine the miRNA expression profile from three patients before and after connection of the CPB. Enrichment analyses of altered miRNA expression were predicted using bioinformatic tools. RESULTS: According to miRNA array, a total of 90 miRNAs were significantly altered including 29 miRNAs with increased and 61 miRNAs with decreased expression after de-connection of CPB (n = 3) compared to before CPB (n = 3). Seven miRNAs had been validated using RT-qPCR in an independent cohort of 11 patients. Enrichment analyses applying the KEGG database displayed the highest correlation for signaling pathways, cellular community, cardiovascular disease and circulatory system. CONCLUSION: Our result identified the overall changes of the miRNome in right atrium tissue of patients with CHDs after CPB. The differentially altered miRNAs lay a good foundation for further understanding of the molecular function of changed miRNAs in regulating CHDs and after CPB in particular.

Update on bicuspid aortic valve aortopathy.

PURPOSE OF REVIEW: The appropriate treatment of bicuspid aortic valve (BAV)-associated aortopathy is still controversial. We aimed to summarize recent evidence from the literature that focused on the prediction of aortopathy progression and adverse aortic events. RECENT FINDINGS: Following the detailed description of valvulo-aortic phenotypes in BAV disease in the previous imaging studies, the most current research focused on the definition of hemodynamic markers that may affect the progression of BAV-associated aortopathy and search for blood-born biomarkers to improve the prediction of adverse aortic events. Furthermore, genetic analyses are ongoing and some preliminary data will be presented. SUMMARY: Serological biomarkers are a novel and promising diagnostic tool for screening thoracic aortic aneurysmal disease and prediction future adverse aortic events. In combination with rheological imaging as well as traditional risk factors diagnostic accuracy and cost-effectiveness of care in BAV-associated aortopathy will improve significantly. VIDEO ABSTRACT: http://links.lww.com/HCO/A44.

Expanded Indacene-Tetrathiafulvalene Scaffolds: Structural Implications for Redox Properties and Association Behavior.

Redox-controlled dimerization of tetrathiafulvalene (TTF) derivatives is an important tool for achieving reversible assemblies. Herein, the synthesis and characterization of indacene-TTF hybrids, in which the central core is fused to naphtho or benzothieno units, are reported. The orientation of these units has a strong influence on the redox properties, with regard to the number of electrons involved in the first oxidation event and the ability of the oxidized forms to associate. The formation of mixed-valence and π-dimer complexes is turned off for those systems in which geometrical constraints provide nonplanar π-systems. Introduction of bulky substituents presents another way of preventing association, as revealed by studies of indenofluorene and diindenoanthracene scaffolds with (triisopropylsilyl)ethynyl groups. Horner-Wadsworth-Emmons reactions present a general synthetic protocol to access superextended TTFs, by using diones of polycyclic conjugated hydrocarbons as substrates.