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

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

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

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

Perspectives of patients and professionals on patient education in complex endovascular aortic repair

Background: Misinterpretation of patient preferences in perioperative education can lead to an undesired treatment decision. This explorative interview study presents differences in perspectives of patients and professionals on patient education in complex endovascular aortic aneurysm management.Methods: Using convenience sampling, a cross-sectional interview study was performed among patients who were in various stages of the decision-making process for complex endovascular aortic repair. Five physicians were interviewed, representing the main providers of clinical information. Interviews were transcribed verbatim and analyzed inductively.Results: Twelve patients (mean age 76.6 [standard deviation: 6.4], 83% male) were interviewed. Ten (83%) felt like they had no other realistic option besides undergoing surgery, whereas all professionals (5/5) stressed the importance of delicate patient selection. Five patients out of 10 (50%) who commented on their preferred decisional role considered the professional's advice as decisive. All but 1 patient (11/12) reported that the information was easy to understand, whereas 4 out of 5 professionals (80%) doubted whether patients could fully comprehend everything. Patients experienced a lack of information on the recovery process, although professionals stated that this was addressed during consultation.Conclusions: Several differences were found in the perspectives of patients and professionals on education in complex aortic aneurysm management. In order to optimize patient involvement in decision-making, professionals should be aware of these possible discrepancies and address them during consultation. Future research could focus on these differences in more detail by including more patients depending on their treatment and decision stages.Vascular Surger

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

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

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

Clonal Evolution through Loss of Chromosomes and Subsequent Polyploidization in Chondrosarcoma

Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events

Influence of hypothermia on right atrial cardiomyocyte apoptosis in patients undergoing aortic valve replacement

BACKGROUND: There is increasing evidence that programmed cell death can be triggered during cardiopulmonary bypass (CPB) and may be involved in postoperative complications. The purpose of this study was to investigate whether apoptosis occurs during aortic valve surgery and whether modifying temperature during CPB has any influence on cardiomyocyte apoptotic death rate. METHODS: 20 patients undergoing elective aortic valve replacement for aortic stenosis were randomly assigned to either moderate hypothermic (ModHT group, n = 10, 28°C) or mild hypothermic (MiHT group, n = 10, 34°C) CPB. Myocardial samples were obtained from the right atrium before and after weaning from CPB. Specimens were examined for apoptosis by flow cytometry analysis of annexin V-propidium iodide (PI) and Fas death receptor staining. RESULTS: In the ModHT group, non apoptotic non necrotic cells (annexin negative, PI negative) decreased after CPB, while early apoptotic (annexin positive, PI negative) and late apoptotic or necrotic (PI positive) cells increased. In contrast, no change in the different cell populations was observed over time in the MiHT group. Fas expression rose after reperfusion in the ModHT group but not in MiHT patients, in which there was even a trend for a lower Fas staining after CPB (p = 0.08). In ModHT patients, a prolonged ischemic time tended to induce a higher increase of Fas (p = 0.061). CONCLUSION: Our data suggest that apoptosis signal cascade is activated at early stages during aortic valve replacement under ModHT CPB. This apoptosis induction can effectively be attenuated by a more normothermic procedure