TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis.

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2-/- mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2-/- and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

Psoas Muscle Area as a Predictor of Transcatheter Aortic Valve Implantation Outcomes.

BACKGROUND: Frailty is a well-recognised predictor of outcomes after transcatheter aortic valve implantation (TAVI). Psoas muscle area (PMA) is a surrogate marker for sarcopaenia and is a validated assessment tool for frailty. The objective of this study was to examine frailty as a predictor of outcomes in TAVI patients and assess the prognostic usefulness of adding PMA to established frailty assessments. METHODS: Frailty assessments were performed on 220 consecutive patients undergoing TAVI. These assessments used four markers (serum albumin, handgrip strength, gait speed, and a cognitive assessment), which were combined to form a composite frailty score. Preprocedural computed tomography scans were used to calculate cross-sectional PMA for each patient. The primary outcomes were all-cause mortality at 1-year and post-procedure length of hospital stay. RESULTS: Frailty status, as defined by the composite frailty score, was independently predictive of length of hospital stay (p=0.001), but not predictive of 1-year mortality (p=0.161). Albumin (p=0.036) and 5-metre walk test (p=0.003) were independently predictive of 1-year mortality. The PMA, when adjusted for gender, and normalised according to body surface area, was not predictive of 1-year mortality. Normalised PMA was associated with increased post-procedure length of stay within the female population (p=0.031). CONCLUSIONS: A low PMA is associated with increased length of hospital stay in female TAVI patients but does not provide additional predictive value over traditional frailty scores. The PMA was not shown to correlate with TAVI-related complications or 1-year mortality.

Prognostic value of left ventricular systolic function before vascular surgery: a systematic review.

BACKGROUND: Vascular surgery carries a high risk of post-operative cardiac complications. Recent studies have shown an association between asymptomatic left ventricular systolic dysfunction and increased risk of major adverse cardiovascular events (MACE). This systematic review aims to evaluate the prognostic value of left ventricular function as determined by left ventricular ejection fraction (LVEF) measured by resting echocardiography before vascular surgery. METHODS: This review conformed to PRISMA and MOOSE guidelines. PubMed, OVID Medline and Cochrane databases were searched from inception to 27 October 2022. Eligible studies assessed vascular surgery patients, with multivariable-adjusted or propensity-matched observational studies measuring LVEF via resting echocardiography and providing risk estimates for outcomes. The primary outcomes measures were all-cause mortality and congestive heart failure at 30 days. Secondary outcome included the composite outcome MACE. RESULTS: Ten observational studies were included (4872 vascular surgery patients). Studies varied widely in degree of left ventricular systolic dysfunction, symptom status, and outcome reporting, precluding reliable meta-analysis. Available data demonstrated a trend towards increased incidence of all-cause mortality, congestive heart failure and MACE in patients with pre-operative LVEF <50%. Methodological quality of the included studies was found to be of moderate quality according to the Newcastle Ottawa Checklist. CONCLUSION: The evidence surrounding the prognostic value of LVEF measurement before vascular surgery is currently weak and inconclusive. Larger scale, prospective studies are required to further refine cardiac risk prediction before vascular surgery.

Mass cytometry analysis reveals altered immune profiles in patients with coronary artery disease.

Objective: The importance of inflammation in atherosclerosis is well accepted, but the role of the adaptive immune system is not yet fully understood. To further explore this, we assessed the circulating immune cell profile of patients with coronary artery disease (CAD) to identify discriminatory features by mass cytometry. Methods: Mass cytometry was performed on patient samples from the BioHEART-CT study, gated to detect 82 distinct cell subsets. CT coronary angiograms were analysed to categorise patients as having CAD (CAD+) or having normal coronary arteries (CAD-). Results: The discovery cohort included 117 patients (mean age 61 ± 12 years, 49% female); 79 patients (68%) were CAD+. Mass cytometry identified changes in 15 T-cell subsets, with higher numbers of proliferating, highly differentiated and cytotoxic cells and decreases in naïve T cells. Five T-regulatory subsets were related to an age and gender-independent increase in the odds of CAD incidence when expressing CCR2 (OR 1.12), CCR4 (OR 1.08), CD38 and CD45RO (OR 1.13), HLA-DR (OR 1.06) and Ki67 (OR 1.22). Markers of proliferation and differentiation were also increased within B cells, while plasmacytoid dendritic cells were decreased. This combination of changes was assessed using SVM models in discovery and validation cohorts (area under the curve = 0.74 for both), confirming the robust nature of the immune signature detected. Conclusion: We identified differences within immune subpopulations of CAD+ patients which are indicative of a systemic immune response to coronary atherosclerosis. This immune signature needs further study via incorporation into risk scoring tools for the precision diagnosis of CAD.

Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review.

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.

A review on the biomechanical behaviour of the aorta.

Large aortic aneurysm and acute and chronic aortic dissection are pathologies of the aorta requiring surgery. Recent advances in medical intervention have improved patient outcomes; however, a clear understanding of the mechanisms leading to aortic failure and, hence, a better understanding of failure risk, is still missing. Biomechanical analysis of the aorta could provide insights into the development and progression of aortic abnormalities, giving clinicians a powerful tool in risk stratification. The complexity of the aortic system presents significant challenges for a biomechanical study and requires various approaches to analyse the aorta. To address this, here we present a holistic review of the biomechanical studies of the aorta by categorising articles into four broad approaches, namely theoretical, in vivo, experimental and combined investigations. Experimental studies that focus on identifying mechanical properties of the aortic tissue are also included. By reviewing the literature and discussing drawbacks, limitations and future challenges in each area, we hope to present a more complete picture of the state-of-the-art of aortic biomechanics to stimulate research on critical topics. Combining experimental modalities and computational approaches could lead to more comprehensive results in risk prediction for the aortic system.

Burden of mood symptoms and disorders in implantable cardioverter defibrillator patients: a systematic review and meta-analysis of 39 954 patients.

AIMS: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. Anxiety, depression, and post-traumatic stress disorder (PTSD) are underappreciated symptoms. We aimed to systematically synthesize prevalence estimates of mood disorders and symptom severities, pre- and post-ICD insertions. Comparisons were made with control groups, as well as within ICD patients by indication (primary vs. secondary), sex, shock status, and over time. METHODS: Databases (Medline, PsycINFO, PubMed, and Embase) were searched without limits from inception to 31 August 2022; 4661 articles were identified, 109 (39 954 patients) of which met criteria. RESULTS: Random-effects meta-analyses revealed clinically relevant anxiety in 22.58% (95%CI 18.26-26.91%) of ICD patients across all timepoints following insertion and depression in 15.42% (95%CI 11.90-18.94%). Post-traumatic stress disorder was seen in 12.43% (95%CI 6.90-17.96%). Rates did not vary relative to indication group. Clinically relevant anxiety and depression were more likely in ICD patients who experienced shocks [anxiety odds ratio (OR) = 3.92 (95%CI 1.67-9.19); depression OR = 1.87 (95%CI 1.34-2.59)]. Higher symptoms of anxiety were seen in females than males post-insertion [Hedges' g = 0.39 (95%CI 0.15-0.62)]. Depression symptoms decreased in the first 5 months post-insertion [Hedges' g = 0.13 (95%CI 0.03-0.23)] and anxiety symptoms after 6 months [Hedges' g = 0.07 (95%CI 0-0.14)]. CONCLUSION: Depression and anxiety are highly prevalent in ICD patients, especially in those who experience shocks. Of particular concern is the prevalence of PTSD following ICD implantation. Psychological assessment, monitoring, and therapy should be offered to ICD patients and their partners as part of routine care.

Fluid-structure interaction study for biomechanics and risk factors in Stanford type A aortic dissection.

Aortic dissection is a life-threatening condition with a rising prevalence in the elderly population, possibly as a consequence of the increasing population life expectancy. Untreated aortic dissection can lead to myocardial infarction, aortic branch malperfusion or occlusion, rupture, aneurysm formation and death. This study aims to assess the potential of a biomechanical model in predicting the risks of a non-dilated thoracic aorta with Stanford type A dissection. To achieve this, a fully coupled fluid-structure interaction model was developed under realistic blood flow conditions. This model of the aorta was developed by considering three-dimensional artery geometry, multiple artery layers, hyperelastic artery wall, in vivo-based physiological time-varying blood velocity profiles, and non-Newtonian blood behaviours. The results demonstrate that in a thoracic aorta with Stanford type A dissection, the wall shear stress (WSS) is significantly low in the ascending aorta and false lumen, leading to potential aortic dilation and thrombus formation. The results also reveal that the WSS is highly related to blood flow patterns. The aortic arch region near the brachiocephalic and left common carotid artery is prone to rupture, showing a good agreement with the clinical reports. The results have been translated into their potential clinical relevance by revealing the role of the stress state, WSS and flow characteristics as the main parameters affecting lesion progression, including rupture and aneurysm. The developed model can be tailored for patient-specific studies and utilised as a predictive tool to estimate aneurysm growth and initiation of wall rupture inside the human thoracic aorta.

Thirty-Day Unplanned Readmissions Following Elective and Acute Percutaneous Coronary Intervention.

BACKGROUND: Prior studies have reported a high rate of unplanned readmissions following acute percutaneous coronary intervention (PCI). Data outside the USA comparing 30-day unplanned readmissions following elective PCI to those who undergo acute PCI remain limited. METHODS: Patients who underwent a PCI procedure in Australia and New Zealand between 2010 and 2015 were included. We determined the rates, causes and predictors of 30-day unplanned readmissions, as well as rates of repeat revascularisation procedures, for patients who underwent an elective or acute PCI. Predictors of readmissions were identified using logistic regression. RESULTS: A total of 199,686 PCI encounters were included, of which 74,890 (37.5%) were elective and 124,796 (62.5%) were acute procedures. Overall, 10.6% of patients had at least one unplanned readmission within 30 days of discharge with lower rates following elective PCI (7.0%) compared to acute PCI (12.7%) (p<0.01). Non-specific chest pain was the commonest cause of readmission after elective and acute PCI, accounting for 20.7% and 21.5% of readmission diagnoses, respectively. Readmissions for acute myocardial infarction (13.0% vs 4.6%, p<0.01) and heart failure (6.5% vs 3.3%, p<0.01) were higher following acute PCI compared to elective PCI. Among readmitted patients, 16.7% had a coronary catheterisation, 12.2% had a PCI and 0.7% had coronary artery bypass surgery. Multivariable predictors of 30-day unplanned readmission included female sex and comorbidities such as heart failure, metastatic disease, chronic lung disease and renal failure (p<0.0001 for all). CONCLUSIONS: Unplanned readmissions following elective or acute PCI are high. Clinical and quality-control measures are required to prevent avoidable readmissions in both settings.

The effects of computerised cognitive training on post-CABG delirium and cognitive change: A prospective randomised controlled trial.

Background: Cognitive impairments, including delirium, are common after coronary artery bypass grafting (CABG). Improving cognition pre- and post-operatively using computerised cognitive training (CCT) may be an effective approach to improve cognitive outcomes in CABG patients. Objectives: Investigate the effect of remotely supervised CCT on cognitive outcomes, including delirium, in older adults undergoing CABG surgery. Methods: Thirty-six participants, were analysed in a single-blinded randomised controlled trial (CCT Intervention: n = 18, Control: n = 18). CCT was completed by the intervention group pre-operatively (every other day, 45-60-minute sessions until surgery) and post-operatively, beginning 1-month post-CABG (3 x 45-60-minute sessions/week for 12-weeks), while the control group maintained usual care plus weekly phone calls. Cognitive assessments were conducted pre- and post-operatively at multiple follow-ups (discharge, 4-months and 6-months). Post-operative delirium incidence was assessed daily until discharge. Cognitive change data were calculated at each follow-up for each cognitive test (Addenbrooke's Cognitive Examination III and CANTAB; z-scored). Results: Adherence to the CCT intervention (completion of three pre-operative or 66% of post-operative sessions) was achieved in 68% of pre-CABG and 59% of post-CABG participants. There were no statistically significant effects of CCT on any cognitive outcome, including delirium incidence. Conclusion: Adherence to the CCT program was comparatively higher than previous feasibility studies, possibly due to the level of supervision and support provided (blend of face-to-face and home-based training, with support phone calls). Implementing CCT interventions both pre- and post-operatively is feasible in those undergoing CABG. No statistically significant benefits from the CCT interventions were identified for delirium or cognitive function post-CABG, likely due to the sample size available (study recruitment greatly impacted by COVID-19). It also may be the case that multimodal intervention would be more effective.

Aortic valve replacement reduces mortality in moderate aortic stenosis: a systematic review and meta-analysis.

BACKGROUND: With the introduction of transcatheter aortic valve replacement and an evolving understanding of the natural progression and history of aortic stenosis, the potential for earlier intervention in appropriate patients is promising; however, the benefit of aortic valve replacement in moderate aortic stenosis remains unclear. METHODS: Pubmed, Embase, and the Cochrane Library databases were searched up until 30th of December 2021 using keywords including moderate aortic stenosis and aortic valve replacement. Studies reporting all-cause mortality and outcomes in early aortic valve replacement (AVR) compared to conservative management in patients with moderate aortic stenosis were included. Hazard ratios were generated using random-effects meta-analysis to determine effect estimates. RESULTS: 3470 publications were screened with title and abstract review, which left 169 articles for full-text review. Of these studies, 7 met inclusion criteria and were included, totalling 4,827 patients. All studies treated AVR as a time-dependent co-variable in cox-regression multivariate analysis of all-cause mortality. Intervention with surgical or transcatheter AVR was associated with a 45% decreased risk of all-cause mortality (HR = 0.55 [0.42-0.68], I 2 = 51.5%, P < 0.001). All studies were representative of the overall cohort with appropriate sample sizes, with no evidence of publication, detection, or information biases in any of the studies. CONCLUSION: In this systematic review and meta-analysis, we report a 45% reduction in all-cause mortality in patients with moderate aortic stenosis who were treated with early aortic valve replacement compared to a strategy of conservative management. Randomised control trials are awaited to determine the utility of AVR in moderate aortic stenosis.

Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.

On the nonlinear relationship between wall shear stress topology and multi-directionality in coronary atherosclerosis.

BACKGROUND AND OBJECTIVE: In this paper we investigate twelve multi-directional/topological wall shear stress (WSS) derived metrics and their relationships with the formation of coronary plaques in both computational fluid dynamics (CFD) and dynamic fluid-structure interaction (FSI) frameworks. While low WSS is one of the most established biomechanical markers associated with coronary atherosclerosis progression, alone it is limited. Multi-directional and topological WSS derived metrics have been shown to be important in atherosclerosis related mechanotransduction and near-wall transport processes. However, the relationships between these twelve WSS metrics and the influence of both FSI simulations and coronary dynamics is understudied. METHODS: We first investigate the relationships between these twelve WSS derived metrics, stenosis percentage and lesion length through a parametric, transient CFD study. Secondly, we extend the parametric study to FSI, both with and without the addition of coronary dynamics, and assess their correlations. Finally, we present the case of a patient who underwent invasive coronary angiography and optical coherence tomography imaging at two time points 18 months apart. Associations between each of the twelve WSS derived metrics in CFD, static FSI and dynamic FSI simulations were assessed against areas of positive/negative vessel remodelling, and changes in plaque morphology. RESULTS: 22-32% stenosis was the threshold beyond which adverse multi-directional/topological WSS results. Each metric produced a different relationship with changing stenoses and lesion length. Transient haemodynamics was impacted by coronary dynamics, with the topological shear variation index suppressed by up to 94%. These changes appear more critical at smaller stenosis levels, suggesting coronary dynamics could play a role in the earlier stages of atherosclerosis development. In the patient case, both dynamics and FSI vs CFD changes altered associations with measured changes in plaque morphology. An appendix of the linear fits between the various FSI- and CFD-based simulations is provided to assist in scaling CFD-based results to resemble the compliant walled characteristics of FSI more accurately. CONCLUSIONS: These results highlight the potential for coronary dynamics to alter multi-directional/topological WSS metrics which could impact associations with changes in coronary atherosclerosis over time. These results warrant further investigation in a wider range of morphological settings and longitudinal cohort studies in the future.

Contemporary Chest Pain Evaluation: The Australian Case for Cardiac CT.

Computed tomography coronary angiography (CTCA) is a non-invasive diagnostic modality that provides a comprehensive anatomical assessment of the coronary arteries and coronary atherosclerosis, including plaque burden, composition and morphology. The past decade has witnessed an increase in the role of CTCA for evaluating patients with both stable and acute chest pain, and recent international guidelines have provided increasing support for a first line CTCA diagnostic strategy in select patients. CTCA offers some advantages over current functional tests in the detection of obstructive and non-obstructive coronary artery disease, as well as for ruling out obstructive coronary artery disease. Recent randomised trials have also shown that CTCA improves prognostication and guides the use of guideline-directed preventive therapies, leading to improved clinical outcomes. CTCA technology advances such as fractional flow reserve, plaque quantification and perivascular fat inflammation potentially allow for more personalised risk assessment and targeted therapies. Further studies evaluating demand, supply, and cost-effectiveness of CTCA for evaluating chest pain are required in Australia. This discussion paper revisits the evidence supporting the use of CTCA, provides an overview of its implications and limitations, and considers its potential role for chest pain evaluation pathways in Australia.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

The Australian New Zealand Spontaneous Coronary Artery Dissection (ANZ-SCAD) Registry - A Multi-Centre Cohort Study: Protocol, Background and Significance.

INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is an under-recognised cause of acute coronary syndrome (ACS) with a strong female predominance. There are currently limited prospective studies and no randomised controlled trials that inform on SCAD's best clinical care. Little is also known about predictors of acute SCAD deterioration or recurrence. We describe the study design of a multi-centre prospective and historical cohort study recruiting patients with SCAD across 15-20 sites in Australia/New Zealand (NZ). The primary aim is to describe the clinical presentation, management and outcomes along with predictors of acute deterioration and recurrence in a large Australian/NZ SCAD cohort, with international data pooling. METHODS AND ANALYSIS: Consented patients diagnosed with SCAD during a hospital admission for an ACS will be prospectively followed at 30 days then yearly, for up to 5 years. Each recruiting site will also retrospectively identify historical cases of SCAD from the proceeding 10 years, with a waiver of consent. For historical cases, data will be collected in a de-identified manner with date of last follow-up or death obtained from the medical records. All cases undergo core laboratory adjudication of coronary angiography and any accompanying imaging to confirm SCAD diagnosis. The primary endpoint will be occurrence of major adverse cardiovascular events; a composite of all-cause mortality, recurrent myocardial infarction (including SCAD recurrence), stroke/transient ischaemic attack, heart failure, cardiogenic shock, cardiac arrest/ventricular arrhythmia, heart transplantation and, repeat/unplanned revascularisation. Secondary endpoints will include each individual primary outcome as well as acute SCAD extension and quality of life/Seattle Angina Score in prospectively recruited participants. Endpoints will be assessed at the end of the hospital admission and at 30-days, 1 year, and median long-term follow-up. ETHICS: Multicentre ethics approval has been granted from the Western Sydney Local Health District Human Research Ethics Committee (2021/ETH00040). DISSEMINATION OF RESULTS: The analysed results will be published in peer-reviewed journals on completion of the historical data collection and then on completion of the prospective data collection. REGISTRATION DETAILS: The ANZ-SCAD registry has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621000824864).