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Aortic aneurysms are dilatations of the aorta that can rupture when left untreated. We used the aneurysmal Fibulin-4R/R mouse model to further unravel the underlying mechanisms of aneurysm formation. RNA sequencing of 3-month-old Fibulin-4R/R aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating the involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of Fibulin-4R/R VSMCs by revealing increased SA-ß-gal, p21, and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of Fibulin-4R/R|p21-luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that Fibulin-4R/R aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK/STAT and TGF-ß pathway inhibition, as well as senolytic treatment on Fibulin-4R/R VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.
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Introduction: Delayed graft function (DGF) is often defined as the need for dialysis treatment in the first week after a kidney transplantation. This definition, though readily applicable, is generic and unable to distinguish between "types" of DGF or time needed to recover function that may also significantly affect longer-term outcomes. We aimed to profile biological pathways in donation after circulatory death (DCD) kidney donors that correlate with DGF and different DGF durations. Methods: A total of N = 30 DCD kidney biopsies were selected from the UK Quality in Organ Donation (QUOD) biobank and stratified according to DGF duration (immediate function, IF n = 10; "short-DGF" (1-6 days), SDGF n = 10; "long-DGF" (7-22 days), LDGF n = 10). Samples were matched for donor and recipient demographics and analyzed by label-free quantitative (LFQ) proteomics, yielding identification of N = 3378 proteins. Results: Ingenuity pathway analysis (IPA) on differentially abundant proteins showed that SDGF kidneys presented upregulation of stress response pathways, whereas LDGF presented impaired response to stress, compared to IF. LDGF showed extensive metabolic deficits compared to IF and SDGF. Conclusion: DCD kidneys requiring dialysis only in the first week posttransplant present acute cellular injury at donation, alongside repair pathways upregulation. In contrast, DCD kidneys requiring prolonged dialysis beyond 7 days present minimal metabolic and antioxidant responses, suggesting that current DGF definitions might not be adequate in distinguishing different patterns of injury in donor kidneys contributing to DGF.
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BACKGROUND: The diagnosis of peripheral arterial disease (PAD) is commonly applied for symptoms related to atherosclerotic obstructions in the lower extremity, though its clinical manifestations range from an abnormal ankle-brachial index to critical limb ischemia. Subsequently, management and prognosis of PAD vary widely with the disease stage. A critical aspect is how this variation is addressed in administrative database-based studies that rely on diagnosis codes for case identification. The objective of this scoping review is to inventory the identification strategies used in studies on PAD that rely on administrative databases, to map the pros and cons of the International Classification of Diseases (ICD) codes applied, and to propose a first outline for a consensus framework for case identification in administrative databases. METHODS: Registry-based reports published between 2010 and 2021 were identified through a systematic PubMed search. Studies were subcategorized on the basis of the expressed study focus: claudication, critical limb ischemia, or general peripheral arterial disease, and the ICD code(s) applied for case identification mapped. RESULTS: Ninety studies were identified, of which 36 (40%) did not specify the grade of PAD studied. Forty-nine (54%) articles specified PAD grade studied. Five (6%) articles specified different PAD subgroups in methods and baseline demographics, but not in further analyses. Mapping of the ICD codes applied for case identification for studies that specified the PAD grade studied indicated a remarkable heterogeneity, overlap, and inconsistency. CONCLUSIONS: A large proportion of registry-based studies on PAD fail to define the study focus. In addition, inconsistent strategies are used for PAD case identification in studies that report a focus. These findings challenge study validity and interfere with inter-study comparison. This scoping review provides a first initiative for a consensus framework for standardized case selection in administrative studies on PAD. It is anticipated that more uniform coding will improve study validity and facilitate inter-study comparisons.
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Estudos Observacionais como Assunto , Doença Arterial Periférica , Humanos , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/classificação , Doença Arterial Periférica/fisiopatologia , Doença Arterial Periférica/terapia , Classificação Internacional de Doenças , Consenso , Valor Preditivo dos Testes , Bases de Dados Factuais , Sistema de RegistrosRESUMO
The utilization of kidneys from donors with acute kidney injury (AKI) is often limited by unpredictable post-transplantation outcomes. The aim of our study was to identify protein mediators implicated in either recovery or failure of these organs. Forty kidney biopsies from donors with (20) and without AKI (20) were selected and then subdivided according to the post-transplant outcome defined as a threshold of 45 ml/min for the eGFR at 1 year from transplantation. Tissue homogenates were analysed by western blot to assess how the levels of 17 pre-selected proteins varied across the four groups. Samples from AKI kidneys with a poor outcome showed a fourfold increase in the levels of PPARg and twofold reduction of STAT1 compared to the other groups (p < 0.05). On the contrary, antioxidant enzymes including TRX1 and PRX3 were increased in the AKI kidneys with a good outcome (p < 0.05). An opposite trend was observed for the detoxifying enzyme GSTp which was significantly increased in the AKI group with poor versus good outcome (p < 0.05). The importance of lipid metabolism (PPARg) and inflammatory signals (STAT1) in the function recovery of these kidneys hints to the therapeutical targeting of the involved pathways in the setting of organ reconditioning.
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Injúria Renal Aguda , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , PPAR gama , Sobrevivência de Enxerto , Doadores de Tecidos , Rim/patologia , Injúria Renal Aguda/patologia , Biópsia , Estudos RetrospectivosRESUMO
Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP.
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Eritrócitos , Transplante de Rim , Preservação de Órgãos , Oxigênio , Perfusão , Eritrócitos/metabolismo , Preservação de Órgãos/métodos , Oxigênio/metabolismo , Humanos , Hemólise , Animais , Masculino , Rim/metabolismoRESUMO
The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.
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Aneurisma da Aorta Abdominal , Doenças Mitocondriais , Humanos , Doxiciclina/efeitos adversos , Doxiciclina/metabolismo , Aorta/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/prevenção & controle , Aneurisma da Aorta Abdominal/genética , Miócitos de Músculo Liso/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologiaRESUMO
AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables. METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study. CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.
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Insuficiência Cardíaca , Humanos , Idoso , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Estudos de Coortes , Volume Sistólico , Estudos Prospectivos , Proteômica , Proteínas Sanguíneas , PrognósticoRESUMO
Objective: Characterization of the atherosclerotic process fully relies on histological evaluation and staging through a consensus grading system. So far, a head-to-head comparison of atherosclerotic process in experimental models and tissue resources commonly applied in atherosclerosis research with the actual human atherosclerotic process is missing. Material and Methods: Aspects of the atherosclerotic process present in established murine atherosclerosis models and human carotid endarterectomy specimen were systematically graded using the modified American Heart Association histological classification (Virmani classification). Aspects were aligned with the atherosclerotic process observed in human coronary artery and aortic atherosclerosis reference tissues that were available through biobanks based on human tissue/organ donor material. Results: Apart from absent intraplaque hemorrhages in aortic lesions, the histological characteristics of the different stages of human coronary and aortic atherosclerosis are similar. Carotid endarterectomy samples all represent end-stage "fibrous calcified plaque" lesions, although secondary, progressive, and vulnerable lesions with gross morphologies similar to coronary/aortic lesions occasionally present along the primary lesions. For the murine lesions, clear histological parallels were observed for the intermediate lesion types ("pathological intimal thickening," and "early fibroatheroma"). However, none of the murine lesions studied progressed to an equivalent of late fibroatheroma or beyond. Notable contrasts were observed for disease initiation: whereas disease initiation in humans is characterized by a mesenchymal cell influx in the intima, the earliest murine lesions are exclusively intimal, with subendothelial accumulation foam cells. A mesenchymal (and medial) response are absent. In fact, it is concluded that the stage of "adaptive intimal thickening" is absent in all mouse models included in this study. Conclusions: The Virmani classification for coronary atherosclerosis can be applied for systematically grading experimental and clinical atherosclerosis. Application of this histological grading tool shows clear parallels for intermediate human and murine atherosclerotic lesions. However, clear contrasts are observed for disease initiation, and late stage atherosclerotic lesions. Carotid endarterectomy all represent end-stage fibrous calcified plaque lesions, although secondary earlier lesions may present in a subset of samples.
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INTRODUCTION: Bicuspid aortic valve (BAV) patients have an increased risk to develop thoracic aortic complications. Little is known about the prevalence and severity of atherosclerosis in the BAV ascending aortic wall. This study evaluates and compares the prevalence of thoracic aortic atherosclerosis in BAV and tricuspid aortic valve (TAV) patients. METHODS: Atherosclerosis was objectified using three diagnostic modalities in two separate BAV patient cohorts (with and without an aortic dilatation). Within the first group, atherosclerosis was graded histopathologically according to the modified AHA classification scheme proposed by Virmani et al. In the second group, the calcific load of the ascending aorta and coronary arteries, coronary angiographies and cardiovascular risk factors were studied. Patients were selected from a surgical database (treated between 2006-2020), resulting in a total of 128 inclusions. RESULTS: Histopathology showed atherosclerotic lesions to be more prevalent and severe in all TAV as compared to all BAV patients (OR 1.49 (95%CI 1.14 - 1.94); p = 0.003). Computed tomography showed no significant differences in ascending aortic wall calcification between all BAV and all TAV patients, although a tendency of lower calcific load in favor of BAV was seen. Coronary calcification was higher in all TAV as compared to all BAV (OR 1.30 (95%CI 1.06 - 1.61); p = 0.014). CONCLUSION: Ascending aortic atherosclerotic plaques were histologically more pronounced in TAV as compared to the BAV patients, while CT scans revealed equal amounts of calcific depositions within the ascending aortic wall. This study confirms less atherosclerosis in the ascending aortic wall and coronary arteries of BAV patients as compared to TAV patients. These results were not affected by the presence of a thoracic aortic aneurysm.
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Doenças da Aorta , Aterosclerose , Doença da Válvula Aórtica Bicúspide , Doenças das Valvas Cardíacas , Humanos , Doença da Válvula Aórtica Bicúspide/complicações , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/epidemiologia , Doenças das Valvas Cardíacas/complicações , Estudos de Casos e Controles , Valva Aórtica/cirurgia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/epidemiologia , Doenças da Aorta/complicações , Aterosclerose/diagnóstico por imagem , Aterosclerose/epidemiologiaRESUMO
OBJECTIVE: The aim of this time-trend analysis is to estimate long-term excess mortality and associated cardiovascular risk for abdominal aortic aneurysm (AAA) patients after elective repair while addressing the changes in AAA management and patient selection over time. BACKGROUND: Despite the intensification of endovascular aneurysm repair and cardiovascular risk management, Swedish population data suggest that AAA patients retain a persistently high long-term mortality after elective repair. The question is whether this reflects suboptimal treatment, a changing patient population over time, or a national phenomenon. METHODS: Nationwide time-trend analysis including 40,730 patients (87% men) following elective AAA repair between 1995 and 2017. Three timeframes were compared, each reflecting changes in the use of endovascular aneurysm repair and intensification of cardiovascular risk management. Relative survival analyses were used to estimate disease-specific excess mortality. Competing risk of death analysis evaluated the risk of cardiovascular versus noncardiovascular death. Sensitivity analysis evaluated the impact of changes in patient selection over time. RESULTS: Short-term excess mortality significantly improved over time. Long-term excess mortality remained high with a doubled mortality risk for women (relative excess risk=1.87, 95% CI: 1.73-2.02). Excess mortality did not differ between age categories. The risk of cardiovascular versus noncardiovascular death remained similar over time, with a higher risk of cardiovascular death for women. Changes in patient population (ie, older and more comorbid patients in the latter period) marginally impacted excess mortality (2%). CONCLUSIONS: Despite changes in AAA care, patients retain a high long-term excess mortality after elective repair with a persistent high cardiovascular mortality risk. In this, a clear sex - but no age - disparity stands out.
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Hypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has been proposed as a biomarker of organ quality during HMP of donor livers, the aim of this study was to validate FMN as a biomarker for organ quality in the context of HMP preserved kidneys. Perfusate samples (n = 422) from the paired randomised controlled COPE-COMPARE-trial, comparing HMP with oxygenation (HMPO2) versus standard HMP in kidneys, were used. Fluorescence intensity (FI) was assessed using fluorescence spectroscopy (excitation 450nm; emission 500-600nm) and validated by fluorospectrophotometer and targeted liquid chromatography mass spectrometry (LC-MS/MS). Fluorescence intensity (FI)(ex450;em500-600) increased over time during machine perfusion in both groups (p<0.0001). This increase was similar for both groups (p = 0.83). No correlation, however, was found between FI(ex450;em500-600) and post-transplant outcomes, including day 5 or 7 serum creatinine (p = 0.11; p = 0.16), immediate graft function (p = 0.91), creatinine clearance and biopsy-proven rejection at one year (p = 0.14; p = 0.59). LC-MS/MS validation experiments of samples detected FMN in only one perfusate sample, whilst the majority of samples with the highest fluorescence (n = 37/38, 97.4%) remained negative. In the context of clinical kidney HMP, fluorescence spectroscopy unfortunately appears to be not specific and probably unsuitable for FMN. This study shows that FMN does not classify as a clinically relevant predictive biomarker of kidney graft function after transplantation.
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Mononucleotídeo de Flavina , Preservação de Órgãos , Cromatografia Líquida , Preservação de Órgãos/métodos , Espectrometria de Massas em Tandem , Diálise Renal , Rim , Perfusão/métodos , BiomarcadoresRESUMO
Objective: The Nellix endovascular aneurysm sealing (EVAS) system was developed as an alternative to conventional endovascular aneurysm repair (EVAR) to minimize endoleaks. A significantly higher failure rate of EVAS may be related to an interaction between the filled endobags and the AAA wall. In general, biological information on aortic remodeling after traditional EVAR is scarce. In this light, we provide here the first histologic evaluation of aneurysm wall morphology after EVAR and EVAS. Methods: Fourteen histological human wall samples of EVAS and EVAR explantation were systematically analysed. Primary open aorta repair samples were included as reference. Results: Compared with primary open aortic repair samples, endovascular repair aortic samples were characterized by more pronounced fibrosis, a greater number of ganglionic structures, decreased cellular inflammation, less calcification, and a lower atherosclerotic load. EVAS was specifically associated with the presence of unstructured elastin deposits. Conclusions: The biological response of the aortic wall after endovascular repair resembles the maturation process of a scar rather than a bona fide healing response. Moreover, the inflammatory response in the aortic wall after placement of endovascular protheses is less prominent than after primary open repair. A specific post-EVAS aortic wall characteristic was unstructured elastin fragments.
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Bicuspid aortic valve (BAV) is the most common congenital heart malformation frequently associated with ascending aortic aneurysm (AscAA). Epithelial to mesenchymal transition (EMT) may play a role in BAV-associated AscAA. The aim of the study was to investigate the type of EMT associated with BAV aortopathy using patients with a tricuspid aortic valve (TAV) as a reference. The state of the endothelium was further evaluated. Aortic biopsies were taken from patients undergoing open-heart surgery. Aortic intima/media miRNA and gene expression was analyzed using Affymetrix human transcriptomic array. Histological staining assessed structure, localization, and protein expression. Migration/proliferation was assessed using ORIS migration assay. We show different EMT types associated with BAV and TAV AscAA. Specifically, in BAV-associated aortopathy, EMT genes related to endocardial cushion formation were enriched. Further, BAV vascular smooth muscle cells were less proliferative and migratory. In contrast, TAV aneurysmal aortas displayed a fibrotic EMT phenotype with medial degenerative insults. Further, non-dilated BAV aortas showed a lower miRNA-200c-associated endothelial basement membrane LAMC1 expression and lower CD31 expression, accompanied by increased endothelial permeability indicated by increased albumin infiltration. Embryonic EMT is a characteristic of BAV aortopathy, associated with endothelial instability and vascular permeability of the non-dilated aortic wall. KEY MESSAGES: Embryonic EMT is a feature of BAV-associated aortopathy. Endothelial integrity is compromised in BAV aortas prior to dilatation. Non-dilated BAV ascending aortas are more permeable than aortas of tricuspid aortic valve patients.
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Doença da Válvula Aórtica Bicúspide , Doenças das Valvas Cardíacas , MicroRNAs , Humanos , Doença da Válvula Aórtica Bicúspide/complicações , Doença da Válvula Aórtica Bicúspide/metabolismo , Doença da Válvula Aórtica Bicúspide/patologia , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/metabolismo , Transição Epitelial-Mesenquimal/genética , Valva Aórtica/metabolismo , MicroRNAs/metabolismo , Endotélio/metabolismo , Endotélio/patologiaRESUMO
OBJECTIVE: Previous studies imply a profound residual mortality risk following successful abdominal aorta aneurysm (AAA) repair. This excess mortality is generally attributed to increased cardiovascular risk. The aim of this study was (1) to quantify the excess residual mortality for patients with AAA, (2) to evaluate the cross sectional level of cardiovascular risk management, and (3) to estimate the potential of optimised cardiovascular risk management to reduce the excess mortality in these patients. METHODS: Excess mortality was estimated through a systematic review and meta-analysis, and through data from the Swedish National Health Registry. Cardiovascular risk profiles were individually assessed during eligibility screening of patients with AAA for two multicentre pharmaceutical AAA stabilisation trials. The potential of full implementation of cardiovascular risk management was estimated through the validated Second Manifestations of ARTerial disease (SMART) risk scores algorithm. RESULTS: The meta-analysis showed a similarly impaired survival for patients who received early repair (small AAA) or regular repair (≥ 55 mm), and a further impaired survival for patients under surveillance for a small AAA. Excess mortality was further quantified using Swedish population data. The data revealed a more than quadrupled and doubled five year mortality rate for women and men who had their AAA repaired, respectively. Evaluation of the level of risk management of 358 patients under surveillance in 16 Dutch hospitals showed that the majority of patients with AAA did not meet therapeutic targets set for risk management in high risk populations, and indicated a more pronounced prevention gap in women. Application of the SMART risk score algorithm predicted that optimal implementation of risk management guidelines would reduce the 10 year risk of major adverse cardiovascular events from 43% to 14%. CONCLUSION: Independent of the rupture risk, AAA is associated with a worryingly compromised life expectancy with a particularly poor prognosis for women. Optimal implementation of cardiovascular risk prevention guidelines is predicted to profoundly reduce cardiovascular risk.
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Aneurisma da Aorta Abdominal , Doenças Cardiovasculares , Masculino , Humanos , Feminino , Fatores de Risco , Estudos Transversais , Fatores de Risco de Doenças Cardíacas , Aneurisma da Aorta Abdominal/cirurgiaRESUMO
Objective: The aim of this study was to identify risk factors for 90 day death after elective open surgical repair (OSR) of abdominal aortic aneurysms (AAAs) in women. Methods: This was a multicentre case control study. The nationwide Dutch Surgical Aneurysm Audit registry (2013-2019) was solely used to identify women who underwent elective OSR as eligible patients. Data for this study were subsequently collected from the patients' medical files. Women with AAA were included and those who died (cases) were compared with those who survived (controls) 90 days after surgery. Inflammatory, mycotic, or symptomatic or ruptured AAA were excluded. The association between pre- and peri-operative risk factors and death was assessed by logistic regression analysis in the whole sample and after matching cases to controls of the same age at the time of repair. Mesenteric artery patency was also assessed on pre-operative computed tomography and used in the analysis. Results: In total, 266 patients (30 cases and 236 controls) from 21 hospitals were included. Cases were older (median [interquartile range; IQR] 75 years [71, 78.3] vs. 71 years [66, 77]; p = .002) and more often had symptomatic peripheral arterial disease (PAD) (14/29 [48%] vs. 49/227 [22%]; p = .002). Intra-operative blood loss (median [IQR] 1.6 L [1.1, 3.0] vs. 1.2 L [0.7, 1.8]), acute myocardial infarction (AMI) (10/30 [33%] vs. 8/236 [3%]), renal failure (17/30 [57%] vs. 33/236 [14%]), and bowel ischaemia (BI) (17/29 [59%] vs. 12/236 [5%]) were more prevalent among cases. Older age (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.03-1.19) and PAD (OR 3.91, 95% CI 1.57-9.74) were associated with death. Multivariable analysis demonstrated that, after adjustment for age, AMI (OR 9.34, 95% CI 1.66-52.4) and BI (OR 35.6, 95% CI 3.41-370) were associated with death. Superior mesenteric artery stenosis of >70% had a clinically relevant association with BI (OR 5.23, 95% CI 1.43-19.13; p = .012). Conclusion: Age, symptomatic PAD, AMI, and BI were risk factors for death after elective OSR in women. The association between a >70% SMA stenosis and BI may call for action in selected cases.
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INTRODUCTION: Vasoplegia is a common complication after cardiac surgery and is associated with poor prognosis. It is characterised by refractory hypotension despite normal or even increased cardiac output. The pathophysiology is complex and includes the systemic inflammatory response caused by cardiopulmonary bypass (CPB) and surgical trauma. Patients with end-stage heart failure (HF) are at increased risk for developing vasoplegia. The CytoSorb adsorber is a relatively new haemoadsorption device which can remove circulating inflammatory mediators in a concentration based manner. The CytoSorb-HF trial aims to evaluate the efficacy of CytoSorb haemoadsorption in limiting the systemic inflammatory response and preventing postoperative vasoplegia in HF patients undergoing cardiac surgery with CPB. METHODS AND ANALYSIS: This is an investigator-initiated, single-centre, randomised, controlled clinical trial. In total 36 HF patients undergoing elective cardiac surgery with an expected CPB duration of more than 120 min will be randomised to receive CytoSorb haemoadsorption along with standard surgical treatment or standard surgical treatment alone. The primary endpoint is the change in systemic vascular resistance index with phenylephrine challenge after CPB. Secondary endpoints include inflammatory markers, sublingual microcirculation parameters and 30-day clinical indices. In addition, we will assess the cost-effectiveness of using the CytoSorb adsorber. Vascular reactivity in response to phenylephrine challenge will be assessed after induction, after CPB and on postoperative day 1. At the same time points, and before induction and on postoperative day 4 (5 time points in total), blood samples will be collected and the sublingual microcirculation will be recorded. Study participants will be followed up until day 30. ETHICS AND DISSEMINATION: The trial protocol was approved by the Medical Ethical Committee of Leiden The Hague Delft (METC LDD, registration number P20.039). The results of the trial will be published in peer-reviewed medical journals and through scientific conferences. TRIAL REGISTRATION NUMBER: NCT04812717.
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Procedimentos Cirúrgicos Cardíacos , Insuficiência Cardíaca , Vasoplegia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/prevenção & controle , Humanos , Mediadores da Inflamação , Fenilefrina , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Resposta Inflamatória SistêmicaRESUMO
A bicuspid aortic valve (BAV) is the most prevalent congenital cardiac anomaly, in which the valve has only two leaflets, instead of the normal three. Patients with a BAV have an increased risk of aneurysm formation and the development of an aortic dissection. Vascular smooth muscle cells in both the non- and dilated aortic wall are characterized by a maturation defect in all BAV patients, as compared to patients with a tricuspid aortic valve, which can contribute to inherent developmental susceptibility. Besides structural abnormalities of the vascular wall, a turbulent blood flow, caused by bicuspid valve geometry, could expedite the pathological process in the aortic wall, leading to aortopathy. Although the risk for aortopathy is significant, not all BAV patients experience (acute) aortic complications in their lifespan, highlighting the complexity of the pathogenetic process. Recent studies have focused on the embryonic development of semilunar valves and the ascending aortic wall. Their findings highlight that a defect in the embryogenesis could not only explain the development of a malformed aortic valve but also the increased risk for ascending aorta and arch pathology. This review presents an overview of the normal and abnormal development of the aortic valve and the aortic wall: a common defect in early embryogenesis causes the development of a BAV and associated aortopathy.
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Background: Donor-characteristics and donor characteristics-based decision algorithms are being progressively used in the decision process whether or not to accept an available donor kidney graft for transplantation. While this may improve outcomes, the performance characteristics of the algorithms remains moderate. To estimate the impact of donor factors of grafts accepted for transplantation on transplant outcomes, and to test whether implementation of donor-characteristics-based algorithms in clinical decision-making is justified, we applied an instrumental variable analysis to outcomes for kidney donor pairs transplanted in different individuals. Methods: This analysis used (dis)congruent outcomes of kidney donor pairs as an instrument and was based on national transplantation registry data for all donor kidney pairs transplanted in separate individuals in the Netherlands (1990-2018, 2,845 donor pairs), and the United Kingdom (UK, 2000-2018, 11,450 pairs). Incident early graft loss (EGL) was used as the primary discriminatory factor. It was reasoned that a scenario with a dominant impact of donor variables on transplantation outcomes would result in high concordance of EGL in both recipients, whilst dominance of asymmetrical outcomes could indicate a more complex scenario, involving an interaction of donor, procedural and recipient factors. Findings: Incidences of congruent EGL (Netherlands: 1·2%, UK: 0·7%) were slightly lower than the arithmetical (stochastic) incidences, suggesting that once a graft has been accepted for transplantation, donor factors minimally contribute to incident EGL. A long-term impact of donor factors was explored by comparing outcomes for functional grafts from donor pairs with asymmetrical vs. symmetrical outcomes. Recipient survival was similar for both groups, but a slightly compromised graft survival was observed for grafts with asymmetrical outcomes in the UK cohort: (10-years Hazard Ratio for graft loss: 1·18 [1·03-1·35] p<0·018); and 5 years eGFR (48·6 [48·3-49·0] vs. 46·0 [44·5-47·6] ml/min in the symmetrical outcome group, p<0·001). Interpretation: Our results suggest that donor factors for kidney grafts deemed acceptable for transplantation impact minimally on transplantation outcomes. A strong reliance on donor factors and/or donor-characteristics-based decision algorithms could result in unjustified rejection of grafts. Future efforts to optimize transplant outcomes should focus on a better understanding of the recipient factors underlying transplant outcomes. Funding: None.