Bioaccumulation and metabolic impact of environmental PFAS residue on wild-caught urban wetland tiger snakes (Notechis scutatus).

PFAS contamination of urban waters is widespread but understanding the biological impact of its accumulation is limited to humans and common ecotoxicological model organisms. Here, we combine PFAS exposure and bioaccumulation patterns with whole organism responses and omics-based ecosurveillance methods to investigate the potential impacts of PFAS on a top predator of wetlands, the tiger snake (Notechis scutatus). Tiger snakes (18 male and 17 female) were collected from four wetlands with varying PFAS chemical profiles and concentrations in Perth, Western Australia. Tiger snake livers were tested for 28 known PFAS compounds, and Σ28PFAS in liver tissues ranged between 322 ± 193 µg/kg at the most contaminated site to 1.31 ± 0.86 µg/kg at the least contaminated site. The dominant PFAS compound detected in liver tissues was PFOS. Lower body condition was associated with higher liver PFAS, and male snakes showed signs of high bioaccumulation whereas females showed signs of maternal offloading. Biochemical profiles of snake muscle, fat (adipose tissue), and gonads were analysed using a combination of liquid chromatography triple quadrupole (QqQ) and quadrupole time-of-flight (QToF) mass spectrometry methodologies. Elevated PFAS was associated with enriched energy production and maintenance pathways in the muscle, and had weak associations with energy-related lipids in the fat tissue, and lipids associated with cellular genesis and spermatogenesis in the gonads. These findings demonstrate the bioavailability of urban wetland PFAS in higher-order reptilian predators and suggest a negative impact on snake health and metabolic processes. This research expands on omics-based ecosurveillance tools for informing mechanistic toxicology and contributes to our understanding of the impact of PFAS residue on wildlife health to improve risk management and regulation.

Long-term outcomes in heritable thoracic aortic disease.

Heritable aortic aneurysm is an increasingly recognized cause of morbidity and mortality. Whilst Marfan syndrome (MFS) is well-known, the clinical presentation and prognosis of more newly described genetic syndromes is less familiar to clinicians. There is a particular lack of knowledge regarding clinical outcomes for non-syndromal heritable aortic disease. This study investigated the presentation, clinical course and survival of patients with syndromal [Loeys-Dietz, aneurysm-osteoarthritis, and aneurysm-cerebral arteriopathy (ACTA2) syndrome] and non-syndromal heritable aortic disease in comparison to MFS. The study group includes 536 individuals (283 Marfan, 176 non-syndromal heritable aortopathy, 36 aneurysm-osteoarthritis, 32 Loeys-Dietz, and 9 ACTA2 aneurysm) enrolled in a longitudinal clinical follow-up between 1990 and 2022. Age at diagnosis differed between groups: Marfan = 22.0 ± 16.6; Loeys-Dietz = 29.6 ± 21.5; aneurysm-osteoarthritis = 36.4 ± 18.8; ACTA2 aneurysm = 43.4 ± 18.6; non-syndromal heritable aortopathy = 47.2 ± 16.6 years (p < 0.001). Aortic dissection was the presenting event in 8% individuals with Marfan compared to 27% with non-syndromal heritable aortopathy and 34% with Loeys-Dietz syndrome (p < 0.01). Mean follow-up duration for the group was 16.4 years (range 0.2-30 years) and 74 individuals died during follow-up (Marfan = 52, Loeys-Dietz = 6, aneurysm-osteoarthritis = 4, ACTA2 aneurysm = 1, heritable non-syndromal aortopathy = 11). At 10 years follow-up, actuarial mean survivals were: aneurysm-osteoarthritis = 77.5 ± 10.4%; Loeys-Dietz = 90.0 ± 6.8%; Marfan = 94.6 ± 1.4%; heritable non-syndromal aortopathy = 95.9 ± 2.1% (NS). There were 60 aortic dissections (24 Type A, 36 Type B) during follow-up. At 10 years, survival free of dissection was comparable between groups: aneurysm-osteoarthritis = 90.7 ± 6.4%; Loeys-Dietz = 94.4 ± 5.4%; Marfan = 96.1 ± 1.2%; heritable non-syndromal aortopathy = 93.9 ± 2.3%, with similar findings at 20 years. Prophylactic aortic surgery was a first event during follow-up for 196 individuals (ACTA2 aneurysm = 3; aneurysm-osteoarthritis = 10; Loeys-Dietz = 19; Marfan = 119; heritable non-syndromal aortopathy = 45). A second surgical intervention was required in 45 individuals and a third intervention in 21 individuals. At 10 years follow-up, survival free of surgery differed between groups: aneurysm-osteoarthritis = 68.5 ± 10.1%; Loeys-Dietz = 40.8 ± 11.2%; Marfan = 75.5 ± 2.7%; heritable non-syndromal aortopathy = 63.8 ± 4.7% (p < 0.001). At 20 years follow-up mean survival free of surgery was: aneurysm-osteoarthritis = 26.6 ± 14.7%; Loeys-Dietz = 9.1 ± 8.2%; Marfan = 57.2 ± 3.4%; heritable non-syndromal aortopathy = 41.6 ± 8.2% (p < 0.001). Diagnosis of newer syndromic and non-syndromal heritable aortopathies is delayed compared to MFS, with associated complications of presentation with aortic dissection. Survival of individuals enrolled in follow-up surveillance is comparable between different genetic aortopathies, however aortic dissections still occur and need for surgical intervention is high.

Models of cardiovascular surgery biobanking to facilitate translational research and precision medicine.

Biobanking in health care has evolved over the last few decades from simple biological sample repositories to complex and dynamic units with multi-organizational infrastructure networks and has become an essential tool for modern medical research. Cardiovascular tissue biobanking provides a unique opportunity to utilize cardiac and vascular samples for translational research into heart failure and other related pathologies. Current techniques for diagnosis, classification, and treatment monitoring of cardiac disease relies primarily on interpretation of clinical signs, imaging, and blood biomarkers. Further research at the disease source (i.e. myocardium and blood vessels) has been limited by a relative lack of access to quality human cardiac tissue and the inherent shortcomings of most animal models of heart disease. In this review, we describe a model for cardiovascular tissue biobanking and databasing, and its potential to facilitate basic and translational research. We share techniques to procure endocardial samples from patients with hypertrophic cardiomyopathy, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, in addition to aortic disease samples. We discuss some of the issues with respect to data collection, privacy, biobank consent, and the governance of tissue biobanking. The development of tissue biobanks as described here has significant scope to improve and facilitate translational research in multi-omic fields such as genomics, transcriptomics, proteomics, and metabolomics. This research heralds an era of precision medicine, in which patients with cardiovascular pathology can be provided with optimized and personalized medical care for the treatment of their individual phenotype.

Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities.

Background: The primary objective of this review was to explore the contribution of oxidative stress to the pathogenesis of genetically-triggered thoracic aortic aneurysm (TAA). Genetically-triggered TAAs manifest substantial variability in onset, progression, and risk of aortic dissection, posing a significant clinical management challenge. There is a need for non-invasive biomarkers that predict the natural course of TAA and therapeutics that prevent aneurysm progression.Methods: An online systematic search was conducted within PubMed, MEDLINE, Scopus and ScienceDirect databases using keywords including: oxidative stress, ROS, nitrosative stress, genetically triggered thoracic aortic aneurysm, aortic dilatation, aortic dissection, Marfan syndrome, Bicuspid Aortic Valve, familial TAAD, Loeys Dietz syndrome, and Ehlers Danlos syndrome.Results: There is extensive evidence of oxidative stress and ROS imbalance in genetically triggered TAA. Sources of ROS imbalance are variable but include dysregulation of redox mediators leading to either insufficient ROS removal or increased ROS production. Therapeutic exploitation of redox mediators is being explored in other cardiovascular conditions, with potential application to TAA warranting further investigation.Conclusion: Oxidative stress occurs in genetically triggered TAA, but the precise contribution of ROS to pathogenesis remains incompletely understood. Further research is required to define causative pathological relationships in order to develop therapeutic options.

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms.

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.

The RNA-binding fragile-X mental retardation protein and its role beyond the brain.

It is well-established that variations of a CGG repeat expansion in the gene FMR1, which encodes the fragile-X mental retardation protein (FMRP), cause the neurocognitive disorder, fragile-X syndrome (FXS). However, multiple observations suggest a general and complex regulatory role of FMRP in processes outside the brain: (1) FMRP is ubiquitously expressed in the body, suggesting it functions in multiple organ systems; (2) patients with FXS can exhibit a physical phenotype that is consistent with an underlying abnormality in connective tissue; (3) different CGG repeat expansion lengths in FMR1 result in different clinical outcomes due to different pathogenic mechanisms; (4) the function of FMRP as an RNA-binding protein suggests it has a general regulatory role. This review details the complex nature of FMRP and the different CGG repeat expansion lengths and the evidence supporting the essential role of the protein in a variety of biological and pathological processes.

Epigenetic influences on genetically triggered thoracic aortic aneurysm.

Genetically triggered thoracic aortic aneurysms (TAAs) account for 30% of all TAAs and can result in early morbidity and mortality in affected individuals. Epigenetic factors are now recognised to influence the phenotype of many genetically triggered conditions and have become an area of interest because of the potential for therapeutic manipulation. Major epigenetic modulators include DNA methylation, histone modification and non-coding RNA. This review examines epigenetic modulators that have been significantly associated with genetically triggered TAAs and their potential utility for translation to clinical practice.

Angiotensin, transforming growth factor ß and aortic dilatation in Marfan syndrome: Of mice and humans.

Marfan syndrome is consequent upon mutations in FBN1, which encodes the extracellular matrix microfibrillar protein fibrillin-1. The phenotype is characterised by development of thoracic aortic aneurysm. Current understanding of the pathogenesis of aneurysms in Marfan syndrome focuses upon abnormal vascular smooth muscle cell signalling through the transforming growth factor beta (TGFß) pathway. Angiotensin II (Ang II) can directly induce aortic dilatation and also influence TGFß synthesis and signalling. It has been hypothesised that antagonism of Ang II signalling may protect against aortic dilatation in Marfan syndrome. Experimental studies have been supportive of this hypothesis, however results from multiple clinical trials are conflicting. This paper examines current knowledge about the interactions of Ang II and TGFß signalling in the vasculature, and critically interprets the experimental and clinical findings against these signalling interactions.

ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype.

RATIONALE: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and reverse the disease phenotype. OBJECTIVE: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMCs), in the pathogenesis of TAA. METHODS AND RESULTS: Using human and mouse aortic samples, we report that ARHGAP18 levels were significantly reduced in the SMC layer of aortic aneurysms. Arhgap18 global knockout (Arhgap18-/-) mice exhibited a highly synthetic, proteolytic, and proinflammatory smooth muscle phenotype under basal conditions and when challenged with angiotensin II, developed TAA with increased frequency and severity compared with littermate controls. Chromatin immunoprecipitation studies revealed this phenotype is partly associated with strong enrichment of H3K4me3 and depletion of H3K27me3 at the MMP2 and TNF-α promoters in Arhgap18-deficient SMC. We further show that TAA formation in the Arhgap18-/- mice is associated with loss of Akt activation. The abnormal SMC phenotype observed in the Arhgap18-/- mice can be partially rescued by pharmacological treatment with the mTORC1 inhibitor rapamycin, which reduces the synthetic and proinflammatory phenotype of Arhgap18-deficient SMC. CONCLUSION: We have identified ARHGAP18 as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.

Management of aortic regurgitation and bilateral carotid occlusion in severe Takayasu arteritis.

We present a patient with Takayasu arteritis and severe aortic valve regurgitation and bilateral carotid artery occlusions, who underwent aortic valve replacement and aorto-bicarotid bypass. The management of the cardiovascular manifestations of Takayasu arteritis is reviewed.

Multi-Velocity Encoding Four-Dimensional Flow Magnetic Resonance Imaging in the Assessment of Chronic Aortic Dissection.

BACKGROUND: Chronic descending thoracic aortic dissection (CDTAD) following surgical repair of ascending aortic dissection requires long-term imaging surveillance. We investigated four-dimensional (4D)-flow magnetic resonance imaging (MRI) with a novel multi-velocity encoding (multi-VENC) technique as an emerging clinical method enabling the dynamic quantification of blood volume and velocity throughout the cardiac cycle. METHODS: Patients with CDTAD (n = 10; mean age, 55.1 years; standard deviation (SD) 10.8) and healthy volunteers (n = 9; mean age, 37.1 years; SD 11.4; p < 0.01) underwent 3T MRI, and standard views and 4D-flow data were obtained. Flow measurements were made in selected regions of interest within the ascending and descending thoracic aorta. RESULTS: The overall flow profile at peak systole was reduced in the false lumen (FL) compared with the true lumen (TL) and normal aortas (p < 0.05 for velocity < 0.4 m/s). Peak systolic flow rate per aortic lumen area (mL/s/cm2) was lower in the FL than in the TL (p < 0.05), and both rates were lower than that of control aortas (p < 0.05). Blood flow reversal was higher in the FL than in the TL throughout the descending aorta in CDTAD patients (p < 0.05). A derived pulsatility index was elevated in the TL compared with that in the FL in CDTAD patients. Generated pathline images demonstrated flow patterns in detail, including sites of communication between the true and FL. CONCLUSIONS: 4D-flow MRI revealed FL blood flow and reduced blood flow velocity and flow rate in the TL of CDTAD patients compared with normal aortas of healthy participants. Thus, multi-VENC 4D-flow MRI could serve as an adjunct in the long-term assessment of CDTAD following surgical repair of ascending aortic dissection.

Familial non-syndromal thoracic aortic aneurysms and dissections - Incidence and family screening outcomes.

BACKGROUND: Non-syndromal thoracic aortic aneurysm and dissection (ns-TAAD) is a genetic aortopathy, with uncertain incidence. This study documented the incidence of ns-TAAD and outcomes of family screening over 15years. METHODS: Consecutive series of 2385 patients with aortic disease in prospective registry (2000 to 2014), including 675 undergoing surgery. Diagnosis of ns-TAAD included family history, aortic imaging, tissue pathology and mutation testing. Screening was offered to relatives of ns-TAAD probands, with follow-up for affected individuals. RESULTS: There were 270 ns-TAAD probands (74% males), including 116 (43%) presenting with aortic dissection. Among surgical cases, a diagnosis of ns-TAAD was established for 116 (17%). Age of probands was 50.4±14.1years, with aortic diameter of 51±12mm. Screening of 581 at-risk relatives identified 216 new ns-TAAD cases (detection rate=37%). Among 71 probands with known family history, screening identified 130 new affected relatives and among 53 probands with no family history, screening identified 86 new affected relatives. Mean age of new affected relatives at diagnosis was 44±18years, with aortic diameter of 42±7mm, including 42 with diameter>50mm. Ten-year mortality was similar for probands without dissection (7.7±3.1%) and new affected relatives (11.4±4.0%) but greater for probands surviving initial dissection (27.6±7.8%, p=0.003). CONCLUSIONS: Up to 1 in 6 patients undergoing aortic surgery have features of ns-TAAD, frequently presenting as aortic dissection but at later age than other genetic aortopathies. Family screening identifies affected relatives in up to half of ns-TAAD probands, many of whom already have significant aortic dilatation.

Nonsyndromic Thoracic Aortic Aneurysm and Dissection: Outcomes With Marfan Syndrome Versus Bicuspid Aortic Valve Aneurysm.

BACKGROUND: Genetic aortopathy (GA) underlies thoracic aortic aneurysms (TAA) in younger adults. Comparative survival and predictors of outcomes in nonsyndromic TAA (NS-TAA) are incompletely defined compared to Marfan syndrome (MFS) and bicuspid aortic valve (BAV). OBJECTIVES: The study sought to compare survival and clinical outcomes for individuals with NS-TAA, MFS, and BAV. METHODS: From 1988 to 2014, all patients presenting with GA 16 to 60 years of age were enrolled in a prospective study of clinical outcomes. Risk factors for death and aortic dissection were identified by Cox proportional hazards modeling and a mortality risk score developed. RESULTS: Diagnosis of GA was made for 760 patients (age 36.9 ± 13.6 years, 26.8% female; NS-TAA, n = 311; MFS, n = 221; BAV, n = 228). MFS patients were younger than NS-TAA and BAV. Presentation with aortic dissection was more common for NS-TAA than MFS or BAV. The 687 patients surviving >30 days after presentation were followed for a median of 7 years. Calculated 10-year mortality was 7.8% for NS-TAA, 8.7% for MFS, and 3.5% for BAV (NS-TAA and MFS vs. BAV p <0.05). Factors associated with all-cause mortality were MFS (p = 0.04), age at presentation, and family history of dissection. CONCLUSIONS: Clinical outcomes for MFS and NS-TAA are similar but worse than BAV. Independent predictors of mortality, including family history of aortic dissection and age, can be included in an Aortopathy Mortality Risk Score to predict survival. Management of NS-TAA, including surgical intervention, should be similar to that of MFS.

Long Term Outcomes Following Freestyle Stentless Aortic Bioprosthesis Implantation: An Australian Experience.

BACKGROUND: The Freestyle stentless bioprosthesis (FSB) has been demonstrated to be a durable prosthesis in the aortic position. We present data following Freestyle implantation for up to 10 years post-operatively and compare this with previously published results. METHODS: A retrospective cohort analysis of 237 patients following FSB implantation occurred at five Australian hospitals. Follow-up data included clinical and echocardiographic outcomes. RESULTS: The cohort was 81.4% male with age 63.2±13.0 years and was followed for a mean of 2.4±2.3 years (range 0-10.9 years, total 569 patient-years). The FSB was implanted as a full aortic root replacement in 87.8% patients. The 30-day all cause mortality was 4.2% (2.0% for elective surgery). Cumulative survival at one, five and 10 years was 91.7±1.9%, 82.8±3.8% and 56.5±10.5%, respectively. Freedom from re-intervention at one, five and 10 years was 99.5±0.5%, 91.6±3.7% and 72.3±10.5%, respectively. At latest echocardiographic review (mean 2.3±2.1 years post-operatively), 92.6% had trivial or no aortic regurgitation. Predictors of post-operative mortality included active endocarditis, acute aortic dissection and peripheral vascular disease. CONCLUSIONS: We report acceptable short and long term outcomes following FSB implantation in a cohort of comparatively younger patients with thoracic aortic disease. The durability of this bioprosthesis in the younger population remains to be confirmed.

MRI in Chronic Aortic Dissection: A Systematic Review and Future Directions.

The acute event of thoracic aortic dissection carries with it high mortality and morbidity. Despite optimal initial surgical or medical management strategies, the risk of further complications in the long-term, including aneurysmal dilatation and false lumen (FL) expansion, are not insignificant. Adequate follow-up of such conditions requires dedicated imaging where relevant prognostic indicators are accurately assessed. We perform a systematic review of the literature and report the current evidence for the use of magnetic resonance imaging (MRI) in assessment of chronic aortic dissection. We then make a comparison with traditional imaging modalities including computed tomography and echocardiography. We discuss new ways in which MRI may extend existing aortic assessment, including identification of blood-flow dynamics within the TL and FL using phase-contrast imaging.

Adjustment and Coping Mechanisms for Individuals with Genetic Aortic Disorders.

BACKGROUND: Advances in diagnosis and management of Genetic Aortic (GA) Disorders have improved prognosis for affected individuals, yet many do not adhere to key management recommendations, and some may experience clinically significant levels of psychological distress. These issues are often not communicated to treating clinicians. Poor adjustment and coping may adversely impact on prognosis, but little is known about the processes contributing to negative outcomes. This study investigated adjustment to GA disorders to determine which processes facilitated or hindered good adherence and psychological outcomes. METHODS: Semi-structured interviews involving 21 individuals (12M, 9 F; age 19-62 years) with a GA Disorder and psychosocial measures of depression/stress/anxiety (DASS), coping (COPE) and involvement in treatment (CPS) were used. Qualitative data were analysed using grounded theory and a model of adjustment was developed. RESULTS: Although most participants adhered to physician management recommendations and experienced minimal emotional distress, a subset reported poor adherence and/or sub/clinical levels of depression/anxiety/stress (29%). Dysfunctional coping mechanisms were infrequent, however 22% participants reported 'little or no' acceptance and 43% avoided life planning in response to a diagnosis of GA disorder. Interviews revealed an overarching theme: Negotiating perception of self and GA disorder, supported by five sub-themes: Restrictions upon Lifestyle, Destabilisation, Future, Support, and Unmet Needs. Accepting restrictions and having support were conducive to better adherence, whilst destabilisation and loss of control had a negative impact. A model of adjustment is proposed to explain how patients reached one of four outcomes relating to psychological distress and adherence to physician recommendations. The central tenet of the model is founded on how realistically patients appraise their vulnerability to GA threat and whether they are able to integrate their perceptions of illness with their sense of self-identity. CONCLUSIONS: This study indicates that individuals with GA are at risk of experiencing psychosocial distress and coping difficulties, even years after diagnosis. Key factors likely to be associated with impaired coping among GA patients include inability to integrate the illness into one's identity/life, or to follow physician recommendations. Potential unmet needs were identified, including the provision of more relevant information and opportunities for peer support. These findings may also be applicable to other inherited cardiac disorders.

The freestyle aortic bioprosthesis: a systematic review.

BACKGROUND: The Medtronic Freestyle bioprosthesis (FSB) provides an alternative to other prostheses for both aortic valve and aortic root surgery. This paper is a systematic review of the post-operative outcomes in patients with aortic valve and/or aortic root disease following FSB implantation. METHODS: Electronic databases were searched for primary analysis, prospective randomised studies comparing the FSB with an alternative aortic prosthesis were included. Additionally, case series that included data for at least 100 individual operated patients were used for secondary analysis. RESULTS: Among three identified randomised studies, 199 FSB cases were compared with homografts, and stented and an alternative stentless bioprosthesis. The FSB showed comparable hospital mortality (4.5% vs. 5.3%) and eight-year actuarial survival (80±5.0% versus 77±6.0%) with the homograft (respectively) and comparable reduction in left ventricular mass index relative to other prosthesis types. Over 6000 individual patients were included in the selected 15 case series. Weighted mean operative mortality, neurological event rate and five-year actuarial survival was 5.2%, 5.5% and 77.8%, respectively. CONCLUSION: The FSB performed comparably against alternative prostheses regarding in-hospital mortality, long-term survival and reduction in left ventricular mass index. Included case series demonstrated robust post-operative outcomes in both the short and long term.