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.

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.

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.

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.

Clinical utility of magnetic resonance imaging in the follow-up of chronic aortic type B dissection.

Several imaging modalities are utilised in the assessment of disease progression in chronic aortic dissection. We present the case of a 66 year-old male who underwent ascending aorta repair for Stanford type A aortic dissection. On follow-up the persisting dissection of the descending thoracic aorta was observed to regress on magnetic resonance imaging (MRI). MRI has several advantages over computed tomography (CT) scanning and echocardiography in the follow-up phase of this disease.

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.

Replacement of the aortic root with a composite valve-graft conduit: risk factor analysis in 246 consecutive patients.

BACKGROUND: Composite valve-graft (CVG) replacement of the aortic root is a well-studied and recognised treatment for various aortic root conditions, including valvular disease with associated aortopathy. There have been few previous studies of the procedure in large numbers in an Australian setting. METHOD: From January 2006 to June 2013, 246 successive patients underwent CVG root replacements at our institution. Mean age was 56.8 years, 85.4% were male, and 87 had evidence of bicuspid aortic valve. Indications for operation included ascending aortic aneurysm in 222 patients, annuloaortic ectasia in 67 patients, and aortic dissection in 38 patients. RESULTS: The overall unit 30-day mortality was 5.7%, including: elective 30-day mortality of 2.2%, and emergent 30-day mortality of 17.2%. Statistically significant multivariate predictors of 30-day mortality were: acute aortic dissection (OR=20.07), peripheral vascular disease (OR=11.17), new ventricular tachycardia (OR=30.17), re-operation for bleeding (OR=14.42), concomitant mitral stenosis (OR=68.30), and cerebrovascular accident (OR=144.85). CONCLUSIONS: Low postoperative mortality in our series matches closely with results from similar sized international studies, demonstrating that this procedure can be performed with low risk in centres with sufficient experience in the operative procedure.

Aortic stiffness in heritable aortopathies: relationship to aneurysm growth rate.

OBJECTIVE: This study compared aortic biomechanics in different heritable aortopathy syndromes and examined the clinical utility of aortic stiffness measurements. METHODS AND RESULTS: In 218 patients (55 Marfan, 47 bicuspid aortic valve (BAV), 47 isolated familial thoracic aneurysm (FTAD) and 69 matched controls) aortic biomechanics were measured by echocardiography with simultaneous blood pressure measurements. Patients were stratified by age as ≤40 years or >40 years. Aortic stiffness increased with age and aortic biomechanics were abnormal in all aortopathies, particularly in BAV and FTAD. Increased stiffness and pulse wave velocity were seen in BAV and FTAD in both age cohorts (p<0.001) and both were stiffer than Marfan patients (p<0.01). Marfan patients aged ≤40 years had stiffer aortas than controls, but those >40 years were similar to controls. Multivariate regression identified age as the dominant correlate with increased stiffness, and also aortic diameter and mean blood pressure (R(2)=0.64; p<0.001). Aortopathy patients with stiffness index>16 had lower rate of increase in aortic diameter (0.25±0.30 mm/year) than those with normal stiffness (0.68±0.39 mm/year, p<0.001). Whilst positive predictive value of increased stiffness for detection of aortopathy was high (93% in age≤40 years, 87%, in age>40 years), negative predictive accuracy was low (55% and 34% respectively). CONCLUSION: Abnormal biomechanics are common to all aortopathies, with greater abnormality in BAV and FTAD than in Marfan. Increased aortic stiffness is associated with slower rate of aneurysm progression.

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.

Evolution in the techniques and outcomes of aortic arch surgery: a 22 year single centre experience.

BACKGROUND: Aortic arch replacement is a complicated and high risk procedure. There have been many advances over recent years. We review the changes in our unit's techniques and outcomes over the past 22 years. METHODS: Data were collated from databases and medical records for all patients who underwent aortic arch replacement surgery from January 1989 to December 2010. The patients were divided into two groups - Group A (1989-2005) and Group B (2006-2010). Data were analysed to compare early and late series patients' outcomes. Logistic regression was used to identify variables that predicted mortality. RESULTS: Seventy-five eligible patients (56 males; mean age: 57.5 years; Group A: 40, Group B 35) were identified. There were great changes in the technique and the methods of cerebral protection. The overall mortality rate was 30.7% - Group A: 50% and Group B: 8.6% (p<0.001). Overall permanent neurological dysfunction was 23.7% - Group A: 40% and Group B: 11.8% (p=0.012). Cardiovascular disease and circulatory arrest time were significant predictors of mortality. CONCLUSIONS: Increased experience and volume and advances in techniques over 22 years have resulted in major improvements in outcomes for patients having aortic arch replacement, allowing the procedure to be performed with greatly improved outcomes.

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 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.

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.

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.