Gene therapy strategies to target post-interventional vascular remodeling

The studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular proteases, both activated by mechanical and vascular injury caused by these interventions, are thought to contribute largely to the development of post-angioplasty restenosis and vein graft disease. Therefore, viral and non-viral gene therapy techniques were used in these studies to deliver genes encoding protective as well as inhibiting proteins in order to modulate the inflammatory cascade (i.e. IL-10 and the MCP-1/CCR-2 pathway) in the first part of this thesis and the plasminogen activator and MMP-system in the second part. Finally, the expression of several involving genes was blocked locally by RNA interference techniques in the last part of this thesis. The possibilities and effects of these gene therapy applications were studied in cell cultures, in a human saphenous vein organ culture model and in two mouse models of restenosis and vein graft disease. Altogether, these studies provided more insight into the pathophysiology of post-interventional remodeling and several potential therapeutic strategies were assessed.The Netherlands Heart Foundation, Bard Benelux N.V., B. Braun Medical B.V., Daan Traas Fund, Eli Lilly Nederland B.V., J.E. Jurriaanse Stichting, Terumo Europe N.V.UBL - phd migration 201

Parametric Optimization Of Magneto-Rheological Fluid Damper Using Particle Swarm Optimization

This paper presents a parametric modeling of a magneto-rheological (MR) damper using a Particle Swarm Optimization (PSO) method. The objective of this paper is to optimize the parameter values of the MR fluid damper behavior using the Bouc-Wen model. The parametric identification was imposed beforehand in replicating the behavior of the MR fluid damper. The algebraic function from a number of hysteresis models was steered by comparing selected models: Bingham, Bouc-Wen and BoucWen by Kwok. A simulation method was operated in investigating these models by employing MATLAB reliant from the model intricacy. The experimental data was presented in terms of the time histories of the displacement, the velocity and the force parameters, measured for both constant and variable current settings and at a selected frequency applied to the damper. The model parameters were determined using a set of experimental measurements corresponding to different current constant values. It has been shown that the MR damper model’s response via the proposed approach is in good agreement with the MR damper test rig counterpar

Partial right atrial inflow occlusion for transient systemic hypotension during deployment of thoracic stentgrafts

Purpose Temporary balloon occlusion of the inferior vena cava to lower cardiac output is a relatively infrequently used technique to induce controlled systemic hypotension. In this technical note, we describe the feasibility, reliability, and safety of partial occlusion of right atrial inflow and the effect on systemic blood pressure during the deployment of a thoracic stentgraft. Materials and Methods Twenty consecutive patients undergoing thoracic endovascular aortic repair, with proximal landing in zone 0-3 of the thoracic aorta, were prospectively included. Right atrial inflow occlusion was performed with a compliant occlusion balloon. Results Median time to reach a mean arterial pressure of 50 mmHg was 43 s. Median recovery time of blood pressure was 42 s. Conclusion Partial right atrial inflow occlusion with an occlusion balloon is feasible with reliable results and without procedure-related complications.Cardiovascular Aspects of Radiolog

Risk assessment in aortic aneurysm repair by medical specialists versus the American College of Surgeons National Surgical Quality Improvement Program risk calculator outcomes

Objective: The aim of this online clinical vignette-based survey study was to compare risk assessments by vascular surgeons, anaesthesiologists and interventional radiologists involved in treating patients with aortic aneurysms in the Netherlands with the NSQIP risk calculator outcomes.Methods: Participants, recruited using purposive sampling, provided their estimation of the likelihood of postoperative complications and events following aortic surgery in five fictional cases. These cases were subsequently scored using the NSQIP calculator. The risk assessments were statistically analysed using the ANOVA and student t-test.Results: All participating specialists i.e. twelve vascular surgeons, ten interventional radiologists and ten anaesthesiologists completed the survey. In the vast majority of outcomes and vignettes, no significant differences were found between various specialists, whereas significant differences were found between the NSQIP risk calculator outcomes and the combined risk assessments of the specialists. Overall, specialist risk assessments differ from the NSQIP, but neither particularly higher nor lower compared to the risk calculator.Conclusions: Risk assessment by vascular surgeons, anaesthesiologists and interventional radiologists differs significantly with NSQIP risk calculator outcomes, within the framework of both endovascular and open aortic aneurysm repair. Based on these results, implementing the NSQIP risk calculator in preoperative workup could be of added value in both patient planning as well as adequately informing patients for obtaining consent.Cardiovascular Aspects of Radiolog

Increased aortic exclusion in endovascular treatment of complex aortic aneurysms

Purpose: Perioperative risk assessments for complex aneurysms are based on the anatomical extent of the aneurysm and do not take the length of the aortic exclusion into account, as it was developed for open repair. Nevertheless, in the endovascular repair (ER) of complex aortic aneurysms, additional segments of healthy aorta are excluded compared with open repair (OR). The aim of this study was to assess differences in aortic exclusion between the ER and OR of complex aortic aneurysms, to subsequently assess the current classification for complex aneurysm repair. Methods: This retrospective observational study included patients that underwent complex endovascular aortic aneurysm repair by means of fenestrated endovascular aneurysm repair (FEVAR), fenestrated and branched EVAR (FBEVAR), or branched EVAR (BEVAR). The length of aortic exclusion and the number of patent segmental arteries were determined and compared per case in ER and hypothetical OR, using a Wilcoxon signed-rank test. Results: A total of 71 patients were included, who were treated with FEVAR (n = 44), FBEVAR (n = 8), or BEVAR (n = 19) for Crawford types I (n = 5), II (n = 7), III (n = 6), IV (n = 7), and V (n = 2) thoracoabdominal or juxtarenal (n = 44) aneurysms. There was a significant increase in the median exclusion of types I, II, III, IV, and juxtarenal aneurysms (p < 0.05) in ER, compared with hypothetical OR. The number of patent segmental arteries in the ER of type I-IV and juxtarenal aneurysms was significantly lower than in hypothetical OR (p < 0.05). Conclusion: There are significant differences in the length of aortic exclusion between ER and hypothetical OR, with the increased exclusion in ER resulting in a lower number of patent segmental arteries. The ER and OR of complex aortic aneurysms should be regarded as distinct modalities, and as each approach deserves a particular risk assessment, future efforts should focus on reporting on the extent of exclusion per treatment modality, to allow for appropriate comparison.Vascular Surger

Green Additives in Chitosan-based Bioplastic Films: Physical, Mechanical, and Chemical Properties

To switch to alternatives for fossil-fuel-based polymer materials, renewable raw materials from green resources should be utilized. Chitosan is such a material that is a strong, but workable derivative from chitin, obtained from crustaceans. However, various applications ask for specific plastic properties, such as certain flexibility, hardness and transparency. With different additives, also obtainable from green resources, chitosan-based composites in the form of self-supporting films, ranging from very hard and brittle to soft and flexible were successfully produced. The additives turned out to belong to one of three categories, namely linear, non-linear, or crosslinking additives. The non-linear additives could only be taken up to a certain relative amount, whereas the uptake of linear additives was not limited within the range of our experiments. Additives with multiple functional groups tend to crosslink chitosan even at room temperature in an acidic medium. Finally, it was shown that dissolving the chitosan in acetic acid and subsequently drying the matrix as a film results in reacetylation compared to the starting chitosan source, resulting in a harder material. With these findings, it is possible to tune the properties of chitosan-based polymer materials, making a big step towards application of this renewable polymer within consumer goods

COVID-19 vaccination in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. Our aims were to investigate the effects of COVID-19 vaccination in ITP patients on platelet count, bleeding complications and ITP exacerbation (any of: ≥50% decline in platelet count; or nadir platelet count 20% decrease from baseline; or use of rescue therapy). Platelet counts of ITP patients and healthy controls were collected immediately before, 1 and 4 weeks after first and second vaccination. Linear mixed-effects modelling was applied to analyze platelet counts over time. We included 218 ITP patients (50.9% female, mean age 55 years and median platelet count of 106x109/L) and 200 healthy controls (60.0% female, mean age 58 years and median platelet count of 256x109/L). Platelet counts decreased by 6.3% after vaccination. We observed no difference in decrease between the groups. Thirty ITP patients (13.8%, 95%CI 9.5%-19.1%) had an exacerbation and 5 (2.2%, 95%CI 0.7%-5.3%) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count <50x109/L (OR 5.3, 95%CI 2.1-13.7), ITP treatment at time of vaccination (OR 3.4, 95%CI 1.5-8.0) and age (OR 0.96 per year, 95%CI 0.94-0.99). Our study highlights safety of COVID-19 vaccination in ITP patients and importance of close monitoring platelet counts in a subgroup of ITP patients. ITP patients with exacerbation responded well on therapy

Functional performance after complex endovascular aortic repair: a single-center retrospective cohort study

Purpose Complex endovascular aortic repair (EVAR) procedures provide a treatment option for patients with aortic aneurysms involving visceral branches. Good technical results and short-term outcomes have been reported. Whether complex EVAR provides acceptable functional outcomes is not clear. The current study aims to describe postoperative functional outcomes in complex EVAR patients-an older and relatively frail patient group. Materials and Methods A single-center retrospective cohort study was performed, using data from a computerized database of consecutive patients who underwent complex EVAR in the Leiden University Medical Center (LUMC, The Netherlands) between July 2013 and September 2020. As of May 2017, patients scheduled for complex EVAR were referred to a geriatric care pathway to determine (Instrumental) Activities of Daily Living ((I)ADL) scores at baseline and, if informed consent was given, after 12 months. For the total patient group, adverse functional performance outcomes were: discharge to a nursing home and 12-month mortality. For the patients included in geriatric follow-up, the additional outcome was the incidence of functional decline (defined by a >= 2 point increase in (I)ADL-score) at 12-month follow-up Results Eighty-two patients underwent complex EVAR, of which 68 (82.9%) were male. Mean age was 73.3 years (SD=6.3). Within 30 days postsurgery, 6 patients (7.3%) died. Mortality within 12 months for the total patient group was 14.6% (n=12). After surgery, no patients had to be discharged to a nursing home. Fifteen patients (18.3%) were discharged to a rehabilitation center. Twenty-three patients gave informed consent and were included in geriatric follow-up. Five patients (21.7%) presented functional decline 12 months postsurgery and 4 patients had died (17.4%) by that time. This means that 39.1% of the patients in the care pathway suffered an adverse outcome. Conclusion To our knowledge, this is the only study that examined functional performance after complex EVAR, using a prospectively maintained database. No patients were newly discharged to a nursing home and functional performance results at 12 months are promising. Future multidisciplinary research should focus on determining which patients are most prone to deterioration of function, so that efforts can be directed toward preventing postoperative functional decline.Cardiovascular Aspects of Radiolog