Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

Psychometric validation of the Perceived Perioperative Competence Scale-Revised Short Form.

AIM: To develop a parsimonious, shortened version of the Perceived Perioperative Competence Scale-Revised for perioperative nurses to complete as part of their specialty training while retaining good psychometric properties. DESIGN: A longitudinal online survey was adopted. METHODS: A national sample of perioperative nurses from Australia completed an online survey at two different time points 6 months apart between February and October 2021. Confirmatory factor analysis was conducted for item reduction and construct validity, while criterion, convergent validity and internal consistency were examined. RESULTS: Usable data for psychometric assessment were obtained from 485 operating room nurses at time 1 and 164 nurses at time 2. The original 40-item revised scale was reduced to an 18-item measure, maintaining its six domains. Cronbach's alpha for the 18-item scale was .92 at time 1 and .90 at time 2. Scale validation demonstrated moderate to weak positive relationships in perceived competence scores relative to general self-efficacy, years of operating room experience, postgraduate education and recency of training. CONCLUSIONS: Results suggest the 18-item Perceived Perioperative Competence Scale-Revised Short Form has initial robust psychometric properties and may be implemented in clinical settings as part of perioperative transition-to-practice, orientation programs and yearly professional development reviews. IMPLICATIONS FOR THE PROFESSION: This short-form scale can help prepare perioperative nurses to demonstrate clinical competence in a climate of increasing professional demands using a valid measure of competence required in clinical practice. IMPACT: Short and validated scales of perioperative competence are needed in clinical practice. Assessment of practising operating room nurses' perceived competence is essential in quality care provision, workforce planning and human resource management. This study provides an 18-item measure of the previously validated 40-item Perceived Perioperative Competence Scale-Revised. This scale can help provide an option for future testing of perioperative nurses' competence in clinical or research settings. PATIENT OR PUBLIC CONTRIBUTION: Perioperative nurses were involved in the design of the study, particularly in the assessment of validation of the tools used in the study.

Total arterial coronary artery bypass grafting in patients with preoperative anemia.

OBJECTIVES: Blood transfusions after coronary artery bypass grafting (CABG) has been associated to adverse outcomes, especially in anemic patients. However, little is known about the influence of the modality of revascularization. Total arterial revascularization (TAR) was shown to reduce postoperative transfusion when compared to saphenous vein-based (SV)-CABG (LIMA plus one/more SV grafts). We, therefore, aimed to investigate the impact of TAR-CABG versus SV-CABG on blood products use and perioperative outcomes in patients with preoperative anemia, normally at higher risk for postoperative transfusions. METHODS: From a cohort of 936 patients with mild preoperative anemia undergoing primary elective on-pump CABG, 166 matched pairs of patients undergoing either TAR- or SV-CABG were obtained. Anemia was defined as hemoglobin level <13 g/dl for men and <12 g/dl for women. The primary endpoint was the evaluation of red packed cells (RPC) use over the entire hospital stay. RESULTS: TAR patients showed significantly reduced RPC usage compared with SV (mean difference 0.45 units). TAR patients had a reduced intubation time (mean difference 7.6 h) and were discharged 1.24 days earlier than SV patients. Pneumonia and acute kidney injury were doubled among SV patients. Adjusted regression showed that TAR technique is a predictor of reduced RPC unit use regardless of age and EuroSCORE II (odds ratio: 0.63, p < .01). CONCLUSION: Patients with preoperative anemia might benefit from TAR regardless of age or calculated operative risk. TAR-CABG was associated to reduced postoperative use of blood products and postoperative length of stay in comparison with SV-CABG in this subset of patients.

Cells and extracellular matrix interplay in cardiac valve disease: because age matters.

Cardiovascular aging is a physiological process affecting all components of the heart. Despite the interest and experimental effort lavished on aging of cardiac cells, increasing evidence is pointing at the pivotal role of extracellular matrix (ECM) in cardiac aging. Structural and molecular changes in ECM composition during aging are at the root of significant functional modifications at the level of cardiac valve apparatus. Indeed, calcification or myxomatous degeneration of cardiac valves and their functional impairment can all be explained in light of age-related ECM alterations and the reciprocal interplay between altered ECM and cellular elements populating the leaflet, namely valvular interstitial cells and valvular endothelial cells, is additionally affecting valve function with striking reflexes on the clinical scenario. The initial experimental findings on this argument are underlining the need for a more comprehensive understanding on the biological mechanisms underlying ECM aging and remodeling as potentially constituting a pharmacological therapeutic target or a basis to improve existing prosthetic devices and treatment options. Given the lack of systematic knowledge on this topic, this review will focus on the ECM changes that occur during aging and on their clinical translational relevance and implications in the bedside scenario.

Peri-operative nurses' knowledge and reported practice of pressure injury risk assessment and prevention: A before-after intervention study.

BACKGROUND: Patients are at risk of developing pressure injuries in the peri-operative setting. Studies evaluating the impact of educational interventions on peri-operative nurses' knowledge and reported practice are scarce. The purpose of this study was to evaluate the effect of a multifaceted intervention on peri-operative nurses' (a) knowledge of pressure injury risks, risk assessment and prevention strategies for patients in the operating suite; and (b) reported practice relating to risk assessment practices and implementation of prevention strategies for patients in the operating suite. METHODS: A before-after research design was used. A convenience sample of all registered and enrolled nurses employed in two hospitals' operating suites was recruited. A multifaceted intervention was delivered which comprised a short presentation, educational materials and reminder posters. A 48-item survey tool was completed pre-and post-intervention to measure self-reported knowledge and practice. RESULTS: 70 eligible peri-operative nurses completed both surveys. Post-intervention, statistically significant improvements were seen in knowledge of correct descriptions of pressure injury stages (p=0.001); appropriate reassessment for patients with a new pressure injury (p=0.05); appropriate actions for patients with an existing stage 1 (p=0.02) and stage 2 pressure injury (p=0.04). Statistical improvements were also seen in reported practice relating to an increase in the use of a risk assessment tool in conjunction with clinical judgement (p=0.0008); verbal handover of patients' pressure injury risk status from the operating room nurse to the recovery room (p=0.023) and from the recovery room nurse to the postoperative ward nurse (p=0.045). The number of participants reporting use of non-recommended and recommended pressure-relieving strategies was unchanged. CONCLUSION: A multi-faceted educational intervention can improve some aspects of perioperative nurses' knowledge and reported practice such as risk assessment practices but not others such as use of recommended pressure-relieving devices. Further research is required to ascertain effective interventions which improve all areas of practice and knowledge, particularly in the use of appropriate pressure-relieving devices in order to prevent pressure injuries in surgical patients.

New minimally invasive surgical approach for excision of left atrial myxoma.

A novel minimally invasive technique for left atrial myxoma surgery involving a combination of mini-sternotomy and restricted left atrial dome incision is described. Surgery is performed through a mini-J sternotomy at third intercostal space and a standard aorto-right atrial cannulation. Exposure of cardiac mass is obtained by a restricted incision of the left atrial dome which provides excellent view of the entire interatrial septum. Base of the tumor base is clearly visualized making the en-bloc excision extremely easy. Three cases were successfully treated with this technique and discharged with mild analgesic requirements. The limited invasiveness and the avoidance of wide incisions in the heart chambers are points of strength of this approach and allow to overcome the limitations of the currently used interatrial groove or transeptal approaches, as scarce visualization of the septum and site of tumor attachment and risk of conduction disturbances or traumatic injury to the mass.

TAVR vs SAVR: Rising Expectations and Changing Indications for Surgery in Response to PARTNER II.

Despite the criticisms and concerns raised on the data published in the PARTNER II trial and related analyses, we are undeniably witnessing a revolution in the management of aortic valve disease, in which conventional full sternotomy surgical aortic valve replacement (SAVR), with all related complications and clinical burden, will soon become a nonviable option. Several of the findings described in the PARTNER II trial, although considerable as points of incongruence and study biases in comparison with SAVR, could be taken as lessons to found a new course in SAVR and redesign the respective roles of surgery and interventional procedures in aortic disease. In particular, the results of these trials can actually be considered as a stimulus to invest more effort to improve the current surgical practice that should embrace alternative solutions and least invasive approaches to provide a competitive advantage over percutaneous procedures. An analysis of these points in light of the more recent findings on transcatheter valve durability, thrombosis, and postprocedural complications is provided. Considerations on the parallel progress of SAVR and on the need for a behavioral change in the surgical community are discussed.

From stem cells to viable autologous semilunar heart valve.

BACKGROUND: An estimated 275,000 patients undergo heart valve replacement each year. However, existing solutions for valve replacement are complicated by the morbidity associated with lifelong anticoagulation of mechanical valves and the limited durability of bioprostheses. Recent advances in tissue engineering and our understanding of stem cell biology may provide a lifelong solution to these problems. METHODS AND RESULTS: Mesenchymal stem cells were isolated from ovine bone marrow and characterized by their morphology and antigen expression through immunocytochemistry, flow cytometry, and capacity to differentiate into multiple cell lineages. A biodegradable scaffold was developed and characterized by its tensile strength and stiffness as a function of time in cell-conditioned medium. Autologous semilunar heart valves were then created in vitro using mesenchymal stem cells and the biodegradable scaffold and were implanted into the pulmonary position of sheep on cardiopulmonary bypass. The valves were evaluated by echocardiography at implantation and after 4 months in vivo. Valves were explanted at 4 and 8 months and examined by histology and immunohistochemistry. Valves displayed a maximum instantaneous gradient of 17.2+/-1.33 mm Hg, a mean gradient of 9.7+/-1.3 mm Hg, an effective orifice area of 1.35+/-0.17 cm2, and trivial or mild regurgitation at implantation. Gradients changed little over 4 months of follow-up. Histology showed disposition of extracellular matrix and distribution of cell phenotypes in the engineered valves reminiscent of that in native pulmonary valves. CONCLUSIONS: Stem-cell tissue-engineered heart valves can be created from mesenchymal stem cells in combination with a biodegradable scaffold and function satisfactorily in vivo for periods of >4 months. Furthermore, such valves undergo extensive remodeling in vivo to resemble native heart valves.

First-in-Man Transcervical Surgical Aortic Valve Replacement Using the CoreVista System.

OBJECTIVE: This study aimed to evaluate a novel device system for surgical aortic valve replacement (SAVR) using a unique new less invasive access approach. The hypothesis is that SAVR can be performed through a short transverse incision in the neck, similar to that used for transcervical thymectomy avoiding chest disruption. METHODS: A new device system was developed to provide retraction, step-by-step illumination, and on-screen visualization for the new approach. Preliminary feasibility studies were performed in cadavers. Comprehensive risk analysis was performed, and training was implemented in Thiel preserved cadavers. For the first-in-man clinical case, a 63-year-old woman with symptomatic critical aortic stenosis (The Society of Thoracic Surgeons risk, 11%) and heavily calcified aortic valve was selected. A short transverse incision was made in the neck; the device was introduced, and the sternum was elevated; femorofemoral cardiopulmonary bypass was established; substernal dissection was guided by the sequenced illumination, and high-definition visualization was provided by the device, allowing for optimal exposition of the aorta and aortic valve; and a 23-mm Medtronic ENABLE sutureless valve prosthesis was implanted. Procedure success was evaluated according to the standardized composite end point definition of "device success" proposed by the Valve Academic Research Consortium. RESULTS: Access, delivery, and deployment of the valve prosthesis were successful. The correct position and intended performance of the valve were demonstrated (mean gradient, 6 mm Hg; aortic valve area, 2.5 cm) with the absence of moderate or severe prosthetic aortic regurgitation. Only one valve prosthesis was used. CONCLUSIONS: Transcervical SAVR with sutureless valve is feasible using this novel access system. The new approach has potential to offer patients substantially shorter stay and fewer, less serious complications, as has been observed in transcervical thymectomy. Further studies are merited.

Is it time to change how we think about incomplete coronary revascularization?

The optimal degree of revascularization for patients with chronic multivessel coronary artery disease remains an unsolved issue. Intuitively, complete revascularization decreases cardiovascular events and improves outcomes compared to incomplete procedures, but in recent years the concept of incomplete revascularization moved from a sub-optimal or a defective treatment towards the most appropriate revascularization technique in some categories of patients. A reasonable level of incomplete anatomic revascularization has been shown to be safe and achievable with both percutaneous (PCI) and surgical procedures (CABG), despite with different long-term outcomes. What are the mechanisms underlying the clinical benefits of an incomplete revascularization and what are the factors explaining the discrepancy in the long-term clinical outcomes between the two modes of revascularization PCI and CABG? The biological consequences of coronary reperfusion might provide valuable hints in this context and at the same time cast new light on the way we think about incomplete revascularization.

Preliminary In Vivo Evaluation of a Hybrid Armored Vascular Graft Combining Electrospinning and Additive Manufacturing Techniques.

In this study, we tested in vivo effectiveness of a previously developed poly-l-lactide/poly-ε-caprolactone armored vascular graft releasing heparin. This bioprosthesis was designed in order to overcome the main drawbacks of tissue-engineered vascular grafts, mainly concerning poor mechanical properties, thrombogenicity, and endothelialization. The bioprosthesis was successfully implanted in an aortic vascular reconstruction model in rabbits. All grafts implanted were patent at four weeks postoperatively and have been adequately populated by endogenous cells without signs of thrombosis or structural failure and with no need of antiplatelet therapy. The results of this preliminary study might warrant for further larger controlled in vivo studies to further confirm these findings.

Redox proteomic analysis of serum from aortic anerurysm patients: insights on oxidation of specific protein target.

OBJECTIVES: oxidative stress is undoubtedly one of the main players in abdominal aortic aneurysm (AAA) pathophysiology. Recent studies in AAA patients reported an increase in the indices of oxidative damage at the tissue level and in biological fluids coupled with the loss of counter-regulatory mechanisms of protection from oxidative stress. We recently reported, in a proteomic analysis of AAA patient sera, changes in the expression of several proteins exerting important modulatory activities on cellular proliferation, differentiation and response to damage. This study aimed to explore the involvement of protein oxidation, at peripheral levels, in AAA. METHODS: a redox proteomic approach was used to investigate total and specific protein carbonylation and protein-bound 4-hydroxy-2-nonenal (HNE) in the serum of AAA patients compared with age-matched controls. RESULTS: our results show increased oxidative damage to protein as indexed by the total carbonyl levels and total protein-bound HNE. By redox proteomics we identified specific carbonylation of three serum proteins: serum retinol-binding protein, vitamin D-binding protein and fibrinogen α-chain HNE. We also identified increased protein-bound HNE levels for hemopexin, IgK chain C region and IgK chain V-III region SIE. In addition we found a high correlation between specific protein carbonylation and protein-bound HNE and the aortic diameter. Moreover the analysis of serum proteins with antioxidant activity demonstrates the oxidation of albumin together with the overexpression of transferrin, haptoglobin and HSPs 90, 70, 60 and 32. CONCLUSIONS: this study support the involvement of oxidative stress in the pathogenesis of AAA and might provide a further degree of knowledge in the cause-effect role of oxidative stress shedding new light on the molecular candidates involved in the disease.

Old Myths, New Concerns: the Long-Term Effects of Ascending Aorta Replacement with Dacron Grafts. Not All That Glitters Is Gold.

Synthetic grafts are widely used in cardiac and vascular surgery since the mid-1970s. Despite their general good performance, inability of mimicking the elastomechanical characteristics of the native arterial tissue, and the consequent lack of adequate compliance, leads to a cascade of hemodynamic and biological alterations deeply affecting cardiovascular homeostasis. Those concerns have been reconsidered in more contemporaneous surgical and experimental reports which also triggered some research efforts in the tissue engineering field towards the realization of biomimetic arterial surrogates. The present review focuses on the significance of the "compliance mismatch" phenomenon occurring after aortic root or ascending aorta replacement with prosthetic grafts and discusses the clinical reflexes of this state of tissue incompatibility, as the loss of the native elastomechanical properties of the aorta can translate into detrimental effects on the normal efficiency of the aortic root complex with impact in the long-term results of patients undergoing aortic replacement.

Effect of Preoperative Aspirin Replacement With Enoxaparin in Patients Undergoing Primary Isolated On-Pump Coronary Artery Bypass Grafting.

Management of preoperative antiplatelet therapy in coronary artery bypass grafting (CABG) is variable among surgeons: guidelines collide with prejudices because replacement of aspirin with low-molecular-weight heparin is still performed because of a presumed minor bleeding risk. This study aims to analyze postoperative bleedings and complications in patients scheduled for elective primary isolated on-pump CABG, depending on preoperative aspirin treatment or its replacement with enoxaparin. In this cohort study, we propensity score matched 200 patients in whom aspirin was stopped at least 5 days before CABG and replaced with enoxaparin and 200 patients who continued aspirin therapy until the day before surgery. Postoperative bleedings and complications were monitored during hospitalization. Among patients who continued aspirin treatment, mean overall bleeding was 701.0 ± 334.6 ml, whereas in the matched enoxaparin group, it was significantly greater (882.6 ± 64.6 ml, p value <0.001); this was associated with reduced postoperative complications, lower values of postoperative C-reactive protein in aspirin takers, and a presumed protective effect for statins. After propensity score adjustment, aspirin treatment carried a protective effect against major postoperative bleeding (odds ratio 0.312, p = 0.001). In conclusion, postoperative bleeding is reduced in patients who continued aspirin, likely due to a reduction in postoperative inflammation. The practice of empirically discontinuing aspirin and replacing it with enoxaparin before CABG should be abandoned. Patients with coronary artery disease referred to CABG should continue antiplatelet medications until the surgical procedure. Those results might be extended to patients under oral anticoagulant therapy requiring CABG.

Off-pump coronary artery bypass grafting versus optimal medical therapy alone: effectiveness of incomplete revascularization in high risk patients.

BACKGROUND: Geriatric patients with multivessel coronary artery disease (CAD) are a challenging group to treat; these cases elicit discussion within heart teams regarding the actual benefit of undertaking major surgery on these patients and often lead to abandon the surgical option. Percutaneous procedures represent an important option, but coronary anatomy may be unfavorable. Off-pump coronary artery bypass (OPCAB) provides good quality graft on left anterior descending (LAD) without exposing the patient to cardiopulmonary bypass, and might be the ideal choice in patients with multiple comorbidities, not eligible to percutaneous or on-pump procedures. The objective of this study was to compare survival during a mid-term follow-up in high-risk patients with no percutaneous alternative, either treated with OPCAB or discharged in medical therapy. METHODS: We retrospectively evaluated from June 2008 to June 2013, 83 high-risk patients with multivessel CAD were included: 42 were treated with incomplete off-pump revascularization using left internal mammary artery (LIMA) on LAD; 41 were discharged in optimal medical therapy (OMT), having refused surgery. Follow-up ended in March 2015, with a telephonic interview. Primary endpoint was survival from all-cause mortality; secondary endpoints were survival from cardiac-related mortality and freedom from non-fatal major adverse cardiac events (MACEs). RESULTS: During follow up, 11 deaths in OPCAB group and 27 deaths in OMT group occurred. Death was due to cardiac factors in 6 and 15 patients, respectively. MACEs were observed in 6 patients in OPCAB group and in 4 patients in OMT group. With regards to survival from all-cause mortality, patients who underwent OPCAB survived more than those discharged in OMT (Log Rank < 0.001), and OMT group carries a propensity score-adjusted hazard ratio of 3.862 (P < 0.001). With regards to survival from cardiac-related events, patients who underwent OPCAB survived more than those discharged in OMT (Log Rank = 0.002), and OMT group carries a propensity score-adjusted hazard ratio of 3.663 (P = 0.010). There is no statistically significant difference concerning freedom from MACEs (Log Rank = 0.273). CONCLUSIONS: For high-risk patients with multivessel CAD, not eligible to on-pump complete revascularization surgery or percutaneous procedures, incomplete revascularization with OPCAB LIMA-on-LAD offers benefits in survival when compared to OMT alone.

The independent role of cyclic flexure in the early in vitro development of an engineered heart valve tissue.

Tissue engineered heart valves (TEHV) are being investigated as an alternative to current non-viable prosthetic valves and valved conduits. Studies suggest that pulse duplicator bioreactors can stimulate TEHV development. In the current study, a model system was used to determine if cyclic flexure, a major mode of heart valve deformation, has independent effects on TEHV cell and extracellular matrix (ECM) development. Ovine vascular smooth muscle cells (SMC) were seeded for 30 h onto strips of non-woven 50:50 polyglycolic acid (PGA) and poly-L-lactic acid (PLLA) scaffold. After 4 days of incubation, SMC-seeded and unseeded scaffolds were either maintained under static conditions (static group), or subjected to unidirectional cyclic three-point flexure at a physiological frequency and amplitude in a bioreactor (flex group) for 3 weeks. After seeding or incubation, the effective stiffness (E) was measured, with SMC-seeded scaffolds further characterized by DNA, collagen, sulfated glycosaminoglycan (S-GAG), and elastin content, as well as by histology. The seeding period was over 90% efficient, with a significant accumulation of S-GAG, no significant change in E, and no collagen detected. Following 3 weeks of incubation, unseeded scaffolds exhibited no significant change in E in the flex or static groups. In contrast, E of SMC-seeded scaffolds increased 429% in the flex group (p<0.01) and 351% in the static group (p<0.01), with a trend of increased E, a 63% increase in collagen (p<0.05), increased vimentin expression, and a more homogenous transmural cell distribution in the flex versus static group. Moreover, a positive linear relationship (r2=0.996) was found between the mean E and mean collagen concentration. These results show that cyclic flexure can have independent effects on TEHV cell and ECM development, and may be useful in predicting the mechanical properties of TEHV constructed using novel scaffold materials.

Pharmacologic Approaches Against Advanced Glycation End Products (AGEs) in Diabetic Cardiovascular Disease.

CONTEXT: Advanced Glycation End-Products (AGEs) are signaling proteins associated to several vascular and neurological complications in diabetic and non-diabetic patients. AGEs proved to be a marker of negative outcome in both diabetes management and surgical procedures in these patients. The reported role of AGEs prompted the development of pharmacological inhibitors of their effects, giving rise to a number of both preclinical and clinical studies. Clinical trials with anti-AGEs drugs have been gradually developed and this review aimed to summarize most relevant reports. EVIDENCE ACQUISITION: Evidence acquisition process was performed using PubMed and ClinicalTrials.gov with manually checked articles. RESULTS: Pharmacological approaches in humans include aminoguanidine, pyridoxamine, benfotiamine, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statin, ALT-711 (alagebrium) and thiazolidinediones. The most recent promising anti-AGEs agents are statins, alagebrium and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical settings and these newer anti-AGEs drugs would undergo clinical evaluation in the next years. Compounds with anti-AGEs activity but still not available for clinical scenarios are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF. CONCLUSIONS: Despite most studies confirm the efficacy of these pharmacological approaches, other reports produced conflicting evidences; in almost any case, these drugs were well tolerated. At present, AGEs measurement has still not taken a precise role in clinical practice, but its relevance as a marker of disease has been widely shown; therefore, it is important for clinicians to understand the value of new cardiovascular risk factors. Findings from the current and future clinical trials may help in determining the role of AGEs and the benefits of anti-AGEs treatment in cardiovascular disease.

A novel bioreactor for the dynamic flexural stimulation of tissue engineered heart valve biomaterials.

Dynamic flexure is a major mode of deformation in the native heart valve cusp, and may effect the mechanical and biological development of tissue engineered heart valves (TEHV). To explore this hypothesis, a novel bioreactor was developed to study the effect of dynamic flexural stimulation on TEHV biomaterials. It was implemented in a study to compare the effect of uni-directional cyclic flexure on the effective stiffness of two candidate TEHV scaffolds: a non-woven mesh of polyglycolic acid (PGA) fibers, and a non-woven mesh of PGA and poly L-lactic acid (PLLA) fibers, both coated with poly 4-hydroxybutyrate (P4HB). The bioreactor has the capacity to dynamically flex 12 rectangular samples (25 x 7.5 x 2mm) under sterile conditions in a cell culture incubator. Sterility was maintained in the bioreactor for at least 5 weeks of incubation. Flexure tests to measure the effective stiffness in the "with-flexure" (WF) and opposing "against-flexure" (AF) directions indicated that dynamically flexed PGA/PLLA/P4HB scaffolds were approximately 72% (3 weeks) and 76% (5 weeks) less stiff than static controls (p<0.01), and that they developed directional anisotropy by 3 weeks of incubation (stiffer AF, p<0.01). In contrast, both dynamically flexed and static PGA/P4HB scaffolds exhibited a trend of decreased stiffness with incubation, with no development of directional anisotropy. Dynamically flexed PGA/P4HB scaffolds were significantly less stiff than static controls at 3 weeks (p<0.05). Scanning electron microscopy revealed signs of heterogeneous P4HB coating and fiber disruption, suggesting possible explanations for the observed mechanical properties. These results indicate that dynamic flexure can produce quantitative and qualitative changes in the mechanical properties of TEHV scaffolds, and suggest that these differences need to be accounted for when comparing the effects of mechanical stimulation on the development of cell-seeded TEHV constructs.