Novel hardening bone putty enhances sternal closure and accelerates postoperative recovery.

OBJECTIVES: Regaining and maintaining sternal stability are key to recovery after cardiac surgery and resuming baseline quality of life. Montage (ABYRX) is a moldable, calcium phosphate-based putty that adheres to bleeding bone, hardens after application, and is resorbed and replaced with bone during the remodeling process. We evaluate the feasibility, safety, and efficacy of enhanced sternal closure with this novel putty to accelerate recovery in patients after sternotomy. METHODS: A single-center, single-blinded, randomized controlled trial was performed (NCT03365843). Patients undergoing elective cardiac surgery via sternotomy received sternal closure with either Montage bone putty and wire cerclage (enhanced sternal closure; n = 33) or wire cerclage alone (control; n = 27). Standardized patient-reported outcomes assessed health-related quality of life (EQ-5D Index) and physical disability (Health Assessment Questionnaire). A Likert-type 11-point scale quantified pain. Spirometry assessed respiratory function. Patients reached 6-week follow-up, with 1-year follow-up for safety end points. RESULTS: There were no device-related adverse events. Enhanced sternal closure improved physical functional recovery (reduced Healthcare Index and Quality) and quality of life (increased EQ-5D Index) at day 5/discharge, week 2, and week 4. Enhanced sternal closure reduced incisional pain while resting, breathing, sleeping, and walking at day 5/discharge. Enhanced sternal closure reduced chest wall and back pain at day 3 and day 5 discharge. A higher proportion of patients with enhanced sternal closure recovered to 60% of their baseline forced vital capacity by day 5/discharge. Enhanced sternal closure shortened hospital stay. CONCLUSIONS: Enhanced sternal closure improves and accelerates postoperative recovery compared with conventional wire closure. Earlier discharge may provide substantial cost benefits for the healthcare system.

Cardiac surgery elicits pericardial inflammatory responses that are distinct compared with postcardiopulmonary bypass systemic inflammation.

Objectives: Cardiac surgery using cardiopulmonary bypass contributes to a robust systemic inflammatory process. Local intrapericardial postsurgical inflammation is believed to trigger important clinical implications, such as postoperative atrial fibrillation and postsurgical intrathoracic adhesions. Immune mediators in the pericardial space may underlie such complications. Methods: In this prospective pilot clinical study, 12 patients undergoing isolated coronary artery bypass graft surgery were enrolled. Native pericardial fluid and venous blood samples (baseline) were collected immediately after pericardiotomy. Postoperative pericardial fluid and venous blood samples were collected 48-hours after cardiopulmonary bypass and compared with baseline. Flow cytometry determined proportions of specific immune cells, whereas multiplex analysis probed for inflammatory mediators. Results: Neutrophils are the predominant cells in both the pericardial space and peripheral blood postoperatively. There are significantly more CD163lo macrophages in blood compared with pericardial effluent after surgery. Although there are significantly more CD163hi macrophages in native pericardial fluid compared with baseline blood, after surgery there are significantly fewer of these cells present in the pericardial space compared with blood. Postoperatively, concentration of interleukin receptor antagonist 6, and interleukin 8 were significantly higher in the pericardial space compared with blood. After surgery, compared with blood, the pericardial space has a significantly higher concentration of matrix metalloproteinase 3, matrix metalloproteinase 8, and matrix metalloproteinase 9. The same trend was observed with transformational growth factor ß. Conclusions: Cardiac surgery elicits an inflammatory response in the pericardial space, which differs from systemic inflammatory responses. Future work should determine whether or not this distinct local inflammatory response contributes to postsurgical complications and could be modified to influence clinical outcomes.

Sternum-Sparing Left Ventricular Assist Device Insertion Reduces Perioperative Transfusions and Blood Loss: A Single-Centre Canadian Experience.

Background: Left ventricular assist devices (LVADs) improve survival and quality of life, as either destination therapy or a bridge to transplantation. Although less-invasive hemisternotomy approaches for LVAD implantation are well studied, only a paucity of data is available in the literature on sternum-sparing bilateral minithoracotomy (BMT). Our centre has one of Canada's most extensive experiences with the BMT approach. Herein, we compared LVAD implantation via BMT with patients who received full median sternotomy or hemisternotomy. Methods: A single-centre retrospective review of data from Foothills Medical Centre (Calgary, Canada) was performed. Patients underwent LVAD insertion from 2012 to 2019, receiving either BMT (n = 11) or sternotomy (full median sternotomy or upper hemisternotomy with left minithoracotomy; n = 38). Intraoperative and early postoperative outcomes were assessed. Results: Patients who received BMT had significantly fewer transfusions of red blood cells, fresh frozen plasma, and platelets. The BMT group had lower chest-tube output in the first 12 hours. No significant differences occurred in ventilation time, intensive care unit length of stay, mortality, stroke, or reoperation for bleeding. Conclusions: Outcomes suggest that sternum-sparing LVAD implantation is a feasible alternative to sternotomy, leading to less postoperative blood loss and transfusion in the early postoperative period. Less transfusion is particularly valuable in this patient population, to reduce antigen-related sensitization prior to transplantation. Additional study is needed to assess potential benefits related to right heart function, postoperative mobility, and re-entry for transplantation.

Introduction: Les dispositifs d'assistance ventriculaire gauche (DAVG) contribuent à améliorer la survie et la qualité de vie, soit en traitement définitif ou en attente d'une transplantation. Bien que des approches d'hémisternotomie moins invasives lors de l'implantation d'un DAVG font l'objet d'un bon nombre d'études, seules de rares données sont disponibles dans la littérature sur la minithoracotomie bilatérale (MTB) sans ouverture du sternum. Notre centre possède l'une des expériences les plus approfondies au Canada de l'approche par MTB. Dans le présent article, nous avons comparé l'implantation du DAVG par MTB chez les patients qui avaient subi une sternotomie médiane complète ou une hémisternotomie. Méthodes: Nous avons réalisé une revue rétrospective unicentrique des données du Foothills Medical Centre (Calgary, Canada). Les patients avaient subi l'insertion d'un DAVG de 2012 à 2019, soit par MTB (n = 11) ou par sternotomie (sternotomie médiane complète ou hémisternotomie supérieure associée à une minithoracotomie gauche ; n = 38). Nous avons évalué les résultats peropératoires et postopératoires précoces. Résultats: Les patients qui avaient subi une MTB avaient eu significativement moins de transfusions de globules rouges, de plasma frais congelé et de plaquettes. Le groupe de MTB avait un plus faible débit du drain thoracique dans les 12 premières heures. Aucune différence significative dans la durée de ventilation, la durée du séjour aux soins intensifs, la mortalité, l'accident vasculaire cérébral ou la réopération en raison d'un saignement n'a été observée. Conclusions: Les résultats montrent que l'implantation de DAVG sans ouverture du sternum est une alternative à la sternotomie, qui entraîne moins de pertes de sang postopératoires et de transfusions en phase postopératoire précoce. Un moins grand nombre de transfusions est particulièrement important au sein de cette population de patients afin de réduire la sensibilisation aux antigènes avant la transplantation. D'autres études sont nécessaires pour évaluer les avantages potentiels liés à la fonction du cœur droit, la mobilité après l'opération et la réadmission pour une transplantation.

Comprehensive characterization of the postoperative pericardial inflammatory response: Potential implications for clinical outcomes.

Objective: There is a paucity of data on the inflammatory response that takes place in the pericardial space after cardiac surgery. This study provides a comprehensive assessment of the local postoperative inflammatory response. Methods: Forty-three patients underwent cardiotomy, where native pericardial fluid was aspirated and compared with postoperative pericardial effluent collected at 4, 24, and 48 hours' postcardiopulmonary bypass. Flow cytometry was used to define the levels and proportions of specific immune cells. Samples were also probed for concentrations of inflammatory cytokines, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). Results: Preoperatively, the pericardial space mainly contains macrophages and T cells. However, the postsurgical pericardial space was populated predominately by neutrophils, which constituted almost 80% of immune cells present, and peaked at 24 hours. When surgical approaches were compared, minimally invasive surgery was associated with fewer neutrophils in the pericardial space at 4 hours' postsurgery. Analysis of the intrapericardial concentrations of inflammatory mediators showed interleukin-6, MMP-9, and TIMP-1 to be highest postsurgery. Over time, MMP-9 concentrations decreased significantly, whereas TIMP-1 levels increased, resulting in a significant reduction of the ratio of MMP:TIMP after surgery, suggesting that active inflammatory processes may influence extracellular matrix remodeling. Conclusions: These results show that cardiac surgery elicits profound alterations in the immune cell profile in the pericardial space. Defining the cellular and molecular mediators that drive pericardial-specific postoperative inflammatory processes may allow for targeted therapies to reduce immune-mediated complications.

Right anterior mini thoracotomy approach for isolated aortic valve replacement: Early outcomes at a Canadian center.

OBJECTIVE: The goal of this manuscript was to report the clinical outcomes of the initial series of 100 consecutive Right Anterior Mini Thoracotomy (RAMT) aortic valve replacement (AVR) implantations at a Canadian Center. METHODS: This retrospective study reported the clinical outcomes of the first 100 patients who underwent the RAMT approach for isolated surgical AVR in Calgary, Canada, between 2016 and 2020. Primary outcomes were death within 30 days of surgery and disabling stroke. Secondary outcomes included surgical times, the need for permanent pacemaker (PPM), incidence of postoperative blood transfusion in the intensive care unit (ICU), postsurgical atrial fibrillation (AF), length of ICU/hospital stay, postsurgical AF, residual paravalvular leak (PVL), postoperative transvalvular gradient, need for postsurgical intravenous opioids, duration of invasive ventilation in the ICU, and chest tube output in the first 12 h postsurgery. RESULTS: In this study, 54 patients were male, and the average age of the cohort was 72 years. Mortality within 30 days of surgery was 1% with no disabling postoperative strokes. Mean cardiopulmonary bypass and cross clamp was 84 and 55 min, respectively. PPM rate was 3%, incidence of blood transfusion in the ICU was 4%, and the rate of postoperative AF was 23%. Median length of ICU and hospital stay was 1 and 5 days, respectively. Rate of mild or greater residual PVL was 3%, while the average residual transvalvular mean gradient was 8.5 mmHg. CONCLUSION: The sternum-sparing RAMT approach can be safely integrated into surgical practice as a minimally invasive alternative for isolated AVR, and can reduce postoperative bleeding and narcotic requirements.

Left ventricular assist devices: A comprehensive review of major clinical trials, devices, and future directions.

Heart failure is an increasingly prevalent medical condition associated with significant morbidity and mortality. In spite of optimal medical therapy, a large number of patients continue to deteriorate clinically and could potentially benefit from advanced therapies. While cardiac transplantation is an established therapy for end-stage heart failure, there are a limited number of donor hearts, and many patients may not be candidates. Over the past two decades, mechanical circulatory support and left ventricular assist devices (LVAD) have altered the heart failure management landscape. Herein we review the indications for LVAD implantation and how they have changed over time. We will also outline major technological evolutions in LVADs and summarize the landmark clinical trials pertaining to them. We also highlight the adverse events associated with LVADs and assess the limitations of the existing literature. Finally, we look ahead to the future of LVAD therapy for patients with advanced heart failure.

LVAD with concomitant rapid deployment valve implantation - a case report.

BACKGROUND: Aortic valve insufficiency can have significant hemodynamic consequences for patients with left ventricular assist devices. A circulation loop can limit systemic blood flow and increase left ventricular filling pressure. CASE PRESENTATION: A 64-year-old male with non-ischemic dilated cardiomyopathy underwent Heartware™ HVAD left ventricular assist device implantation with successful concomitant aortic valve replacement with an Edwards Intuity rapid deployment prosthetic valve. CONCLUSIONS: The use of this rapid deployment valve may have benefits over other techniques including shorter cross clamp times during surgery, intermediate-long term durability, and preservation of aortic valve opening to allow for potential ventricular recovery. The Intuity rapid deployment valve should thus be considered a viable and suitable option for aortic insufficiency intervention during LVAD implantation.

The catalytic activity and secretion of zebrafish RNases are essential for their in vivo function in motor neurons and vasculature.

Angiogenin (hANG), a member of the Ribonuclease A superfamily has angiogenic, neurotrophic and neuroprotective activities. Mutations in hANG have been found in patients with Amyotrophic lateral sclerosis (ALS). The zebrafish (Danio rerio) rnasel-1, 2 and 3 are orthologues of hANG and of these only Rnasel-1 and Rnasel-2 have been shown to be angiogenic. Herein we show that NCI-65828, a potent and specific small molecule inhibitor of hANG inhibits Rnasel-1 to a similar extent. Treatment of early zebrafish embryos with NCI-65828, or with terrein, a fungal metabolite which prevents the secretion of hANG, resulted in spinal neuron aberrations as well defects in trunk vasculature. Our detailed expression analysis and inhibitor studies suggest that Rnasel-1 plays important roles in neuronal migration and pathfinding as well as in angiogenesis in zebrafish. Our studies suggest the usefulness of the zebrafish as a model to dissect the molecular consequences of the ANG ALS variants.

Initial Canadian Experience With Bilateral Minithoracotomy Approach for HeartMate 3 Left Ventricular Assist Device Implantation.

Left ventricular assist devices provide hemodynamic support to improve quality of life and long-term survival in patients with end-stage heart failure. The HeartMate 3 (Abbott, Abbott Park, IL) left ventricular assist device uses magnetically levitated impeller technology, improving durability and reducing pump thrombosis. Sternum-sparing implantation may reduce perioperative bleeding and infection, improve mobility, decrease hospitalization duration, and reduce right ventricular dysfunction. We describe the first Canadian HeartMate 3 implantation via bilateral minithoracotomy. Our case supports the compatibility of the HeartMate 3 device with sternum-sparing approaches and highlights the feasibility of intrapericardial tunnelling of the outflow graft.

Les dispositifs d'assistance ventriculaire gauche procurent un soutien hémodynamique permettant d'améliorer la qualité de vie et la survie à long terme chez les patients présentant une insuffisance cardiaque terminale. Le dispositif d'assistance ventriculaire gauche HeartMate 3 (Abbott, Abbott Park, IL) fait appel à une pompe à flux centrifuge à lévitation magnétique, qui rehausse la durabilité de l'appareil et réduit le risque de thrombose de la pompe. L'implantation sans sternotomie peut diminuer le risque d'hémorragie périopératoire et d'infection, favoriser la mobilité, réduire la durée de l'hospitalisation et atténuer la dysfonction ventriculaire droite. Nous décrivons la première implantation d'un dispositif HeartMate 3 réalisée au Canada par minithoracotomie bilatérale. Le cas présenté montre la possibilité d'implanter le dispositif HeartMate 3 sans sternotomie et met en lumière la faisabilité d'une tunnellisation intrapéricardique de la prothèse d'éjection.

The decision to germinate is regulated by divergent molecular networks in spores and seeds.

Dispersal is a key step in land plant life cycles, usually via formation of spores or seeds. Regulation of spore- or seed-germination allows control over the timing of transition from one generation to the next, enabling plant dispersal. A combination of environmental and genetic factors determines when seed germination occurs. Endogenous hormones mediate this decision in response to the environment. Less is known about how spore germination is controlled in earlier-evolving nonseed plants. Here, we present an in-depth analysis of the environmental and hormonal regulation of spore germination in the model bryophyte Physcomitrella patens (Aphanoregma patens). Our data suggest that the environmental signals regulating germination are conserved, but also that downstream hormone integration pathways mediating these responses in seeds were acquired after the evolution of the bryophyte lineage. Moreover, the role of abscisic acid and diterpenes (gibberellins) in germination assumed much greater importance as land plant evolution progressed. We conclude that the endogenous hormone signalling networks mediating germination in response to the environment may have evolved independently in spores and seeds. This paves the way for future research about how the mechanisms of plant dispersal on land evolved.

An ancient and conserved function for Armadillo-related proteins in the control of spore and seed germination by abscisic acid.

Armadillo-related proteins regulate development throughout eukaryotic kingdoms. In the flowering plant Arabidopsis thaliana, Armadillo-related ARABIDILLO proteins promote multicellular root branching. ARABIDILLO homologues exist throughout land plants, including early-diverging species lacking true roots, suggesting that early-evolving ARABIDILLOs had additional biological roles. Here we investigated, using molecular genetics, the conservation and diversification of ARABIDILLO protein function in plants separated by c. 450 million years of evolution. We demonstrate that ARABIDILLO homologues in the moss Physcomitrella patens regulate a previously undiscovered inhibitory effect of abscisic acid (ABA) on spore germination. Furthermore, we show that A. thaliana ARABIDILLOs function similarly during seed germination. Early-diverging ARABIDILLO homologues from both P. patens and the lycophyte Selaginella moellendorffii can substitute for ARABIDILLO function during A. thaliana root development and seed germination. We conclude that (1) ABA was co-opted early in plant evolution to regulate functionally analogous processes in spore- and seed-producing plants and (2) plant ARABIDILLO germination functions were co-opted early into both gametophyte and sporophyte, with a specific rooting function evolving later in the land plant lineage.

An ex-vivo quantitative assessment to determine the optimal aortotomy closure technique.

BACKGROUND: After performing an aortotomy, there are a variety of techniques utilized for suture closure. There is no published data comparing the efficacy of various suture techniques. The goal of this study is to provide an ex-vivo quantitative assessment of resistance to leakage and dehiscence for three aortotomy closure techniques. MATERIALS AND METHODS: An ex-vivo model was developed utilizing explanted porcine aorta. Aortotomies were closed using one of three techniques: 1) single layer baseball stitch 2) double layer baseball stitch 3) horizontal mattress stitch with a top layer baseball stitch. The aorta was pressurized with saline using an apparatus which captured all leaked fluid. The intra-aortic pressure was adjusted over 8 increments from 110 to 375 mmHg. Leakage rates were determined at each pressure level. Ten aortotomies were performed for each technique, resulting in 240 calculated leakage rates. RESULTS: At all pressures, the horizontal mattress group was measured to have significantly less leakage when compared to single or double layer baseball stitch closures (p < 0.005). There was a trend towards a lower leakage rate in the double layer baseball compared to the single layer baseball stitch. However, this difference is statistically significant only at 300 and 335 mmHg. There were no instances of rupture. CONCLUSION: This study provides the first quantitative comparison of three commonly used aortotomy closure techniques. The running horizontal mattress stitch combined with a baseball stitch provides the greatest resistance to leakage at all pressures. This technique may be superior in clinical scenarios with challenging hemostasis.

Paraduodenal herniation: An internal herniation in a virgin abdomen.

INTRODUCTION: A paraduodenal hernia is an uncommon hernia that results from an abnormal rotation of the midgut. Commonly, these hernias are congenital in nature, and are reported to cause 1.5-5.8% of intestinal obstructions. These hernias occur when a part of the jejunum herniates through the posterior portion of the ligament of Treitz. Diagnosing these hernias preoperatively has been shown to be difficult, despite the studies that are available. Early diagnosis is imperative to the patient in order to avoid strangulation of the bowel, which is associated with a high mortality. PRESENTATION OF CASE: In this case, we present a case of a left-sided paraduodenal hernia in a virgin abdomen in a 38-year-old African American male with a herniation of a loop of jejunum through a defect of the posterior portion of the ligament of Treitz. The patient also had a volvulized segment of the proximal jejunum, and part of this bowel was found to be ischemic. DISCUSSION: Acute intestinal obstruction caused by a left paraduodenal hernia is a rare cause of intestinal obstruction. A literary search of PubMed between 1980 and 2012 indicated only 44 cases of intestinal obstruction secondary to a left paraduodenal hernia. CONCLUSION: The patient underwent exploratory laparotomy, and the herniated bowel was found to be ischemic. The hernia was reduced, and the ischemic bowel resected. The defect was closed, and the patient had a non-complicated recovery.

Crystal structures of murine angiogenin-2 and -3-probing 'structure--function' relationships amongst angiogenin homologues.

Angiogenin (Ang) is a potent inducer of neovascularization. Point mutations in human Ang have been linked to cancer progression and two neurodegenerative diseases: amyotrophic lateral sclerosis and Parkinson's disease. Intensive structural and functional analyses of Ang have been paramount in assigning functions to this novel homologue of bovine pancreatic RNase A. However, inhibitor-binding studies with crystalline Ang (for designing potential anti-cancer drugs) have been hampered as a result of the inaccessibility of the active site. Experiments with the murine homologues of Ang have not only overcome the obvious practical limitations encountered when studying the role of a human protein in healthy individuals, but also the crystal structures of murine angiogenins (mAng and mAng-4) have revealed themselves to have greater potential for the visualization of small-molecule inhibitor binding at the active site. In the present study, we report the crystal structures of two more murine Ang paralogues, mAng-2 and mAng-3, at 1.6 and 1.8 Å resolution, respectively. These constitute the first crystal structures of an Ang with a zinc ion bound at the active site and provide some insight into the possible mode of inhibition of the ribonucleolytic activity of the enzyme by these divalent cations. Both structures show that the residues forming the putative P(1), B(1) and B(2) subsites occupy positions similar to their counterparts in human Ang and are likely to have conserved roles. However, a less obtrusive conformation of the C-terminal segment in mAng-3 and the presence of a sulfate ion in the B(1) subsite of mAng-2 suggest that these proteins have the potential to be used for inhibitor-binding studies. We also discuss the biological relevance of the structural similarities and differences between the different Ang homologues.

Crystal structure of Onconase at 1.1 Å resolution--insights into substrate binding and collective motion.

Onconase(®) (ONC) is an amphibian member of the pancreatic ribonuclease superfamily that is selectively toxic to tumor cells. It is a much less efficient enzyme than the archetypal ribonuclease A and, in an attempt to gain further insight, we report the first atomic resolution crystal structure of ONC, determined in complex with sulfate ions at 100 K. The electron density map is of a quality sufficient to reveal significant nonplanarity in several peptide bonds. The majority of active site residues are very well defined, with the exceptions being Lys31 from the catalytic triad and Lys33 from the B(1) subsite, which are relatively mobile but rigidify upon nucleotide binding. Cryocooling causes a compaction of the unit cell and the protein contained within. This is principally the result of an inward movement of one of the lobes of the enzyme (lobe 2), which also narrows the active site cleft. Binding a nucleotide in place of sulfate is associated with an approximately perpendicular movement of lobe 2 and has little further effect on the cleft width. Aspects of this deformation are present in the principal axes of anisotropy extracted from C(α) atomic displacement parameters, indicating its intrinsic nature. The three lowest-frequency modes of ONC motion predicted by an anisotropic network model are compaction/expansion variations in which lobe 2 is the prime mover. Two of these have high similarity to the cryocooling response and imply that the essential 'breathing' motion of ribonuclease A is conserved in ONC. Instead, shifts in conformational equilibria may contribute to the reduced ribonucleolytic activity of ONC.

Influence of naturally-occurring 5'-pyrophosphate-linked substituents on the binding of adenylic inhibitors to ribonuclease a: an X-ray crystallographic study.

Ribonuclease A is the archetype of a functionally diverse superfamily of vertebrate-specific ribonucleases. Inhibitors of its action have potential use in the elucidation of the in vivo roles of these enzymes and in the treatment of pathologies associated therewith. Derivatives of adenosine 5'-pyrophosphate are the most potent nucleotide-based inhibitors known. Here, we use X-ray crystallography to visualize the binding of four naturally-occurring derivatives that contain 5'-pyrophosphate-linked extensions. 5'-ATP binds with the adenine occupying the B(2) subsite in the manner of an RNA substrate but with the gamma-phosphate at the P(1) subsite. Diadenosine triphosphate (Ap(3)A) binds with the adenine in syn conformation, the beta-phosphate as the principal P(1) subsite ligand and without order beyond the gamma-phosphate. NADPH and NADP(+) bind with the adenine stacked against an alternative rotamer of His119, the 2'-phosphate at the P(1) subsite, and without order beyond the 5'-alpha-phosphate. We also present the structure of the complex formed with pyrophosphate ion. The structural data enable existing kinetic data on the binding of these compounds to a variety of ribonucleases to be rationalized and suggest that as the complexity of the 5'-linked extension increases, the need to avoid unfavorable contacts places limitations on the number of possible binding modes.