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Abstract In the enduring challenge against disease, advancements in medical technology have empowered clinicians with novel diagnostic platforms. Whilst in some cases, a single test may provide a confident diagnosis, often additional tests are required. However, to strike a balance between diagnostic accuracy and cost-effectiveness, one must rigorously construct the clinical pathways. Here, we developed a framework to build multi-platform precision pathways in an automated, unbiased way, recommending the key steps a clinician would take to reach a diagnosis. We achieve this by developing a confidence score, used to simulate a clinical scenario, where at each stage, either a confident diagnosis is made, or another test is performed. Our framework provides a range of tools to interpret, visualize and compare the pathways, improving communication and enabling their evaluation on accuracy and cost, specific to different contexts. This framework will guide the development of novel diagnostic pathways for different diseases, accelerating the implementation of precision medicine into clinical practice.

Background: Accurate measurements of flow and ventricular volume and function are critical for clinical decision-making in cardiovascular medicine. Cardiac magnetic resonance (CMR) is the current gold standard for ventricular functional evaluation but is relatively expensive and time-consuming, thus limiting the scale of clinical applications. New volumetric acquisition techniques, such as four-dimensional flow (4D-flow) and three-dimensional volumetric cine (3D-cine) MRI, could potentially reduce acquisition time without loss in accuracy; however, this has not been formally tested on a large scale. Methods: 4DCarE (4D-flow MRI for cardiovascular evaluation) is a prospective, multi-centre study designed to test the non-inferiority of a compressed 20 min exam based on volumetric CMR compared with a conventional CMR exam (45–60 min). The compressed exam utilises 4D-flow together with a single breath-hold 3D-cine to provide a rapid, accurate quantitative assessment of the whole heart function. Outcome measures are (i) flow and chamber volume measurements and (ii) overall functional evaluation. Secondary analyses will explore clinical applications of 4D-flow-derived parameters, including wall shear stress, flow kinetic energy quantification, and vortex analysis in large-scale cohorts. A target of 1200 participants will enter the study across three sites. The analysis will be performed at a single core laboratory site. Pilot Results: We present a pilot analysis of 196 participants comparing flow measurements obtained by 4D-flow and conventional 2D phase contrast, which demonstrated moderate–good consistency in ascending aorta and main pulmonary artery flow measurements between the two techniques. Four-dimensional flow underestimated the flow compared with 2D-PC, by approximately 3 mL/beat in both vessels. Conclusions: We present the study protocol of a prospective non-inferiority study of a rapid cardiac MRI exam compared with conventional CMR. The pilot analysis supports the continuation of the study. Study Registration: This study is registered with the Australia and New Zealand Clinical Trials Registry (Registry number ACTRN12622000047796, Universal Trial Number: U1111-1270-6509, registered 17 January 2022—Retrospectively registered).

Background: Primary prevention programs utilising traditional risk scores fail to identify all individuals who suffer acute cardiovascular events. We aimed to model the impact and cost effectiveness of incorporating a Polygenic risk scores (PRS) into the cardiovascular disease CVD primary prevention program in Australia, using a whole-of-system model. Methods: System dynamics models, encompassing acute and chronic CVD care in the Australian healthcare setting, assessing the cost-effectiveness of incorporating a CAD-PRS in the primary prevention setting. The time horizon was 10-years. Results: Pragmatically incorporating a CAD-PRS in the Australian primary prevention setting in middle-aged individuals already attending a Heart Health Check (HHC) who are determined to be at low or moderate risk based on the 5-year Framingham risk score (FRS), with conservative assumptions regarding uptake of PRS, could have prevented 2, 052 deaths over 10-years, and resulted in 24, 085 QALYs gained at a cost of $19, 945 per QALY with a net benefit of $724 million. If all Australians overs the age of 35 years old had their FRS and PRS performed, and acted upon, 12, 374 deaths and 60, 284 acute coronary events would be prevented, with 183, 682 QALYs gained at a cost of $18, 531 per QALY, with a net benefit of $5, 780 million. Conclusions: Incorporating a CAD-PRS in a contemporary primary prevention setting in Australia would result in substantial health and societal benefits and is cost-effective. The broader the uptake of CAD-PRS in the primary prevention setting in middle-aged Australians, the greater the impact and the more cost-effective the strategy.

Background and Aims: Myeloperoxidase (MPO) plays a critical role in the innate immune response and has been suggested to be a surrogate marker of oxidative stress and inflammation, with elevated levels implicated in cardiovascular diseases, such as atherosclerosis and heart failure, as well as in conditions like rheumatoid arthritis and cancer. While MPO is well-known in leukocytes, its expression and function in human endothelial cells remain unclear. This study investigates MPO expression in patient-derived endothelial colony-forming cells (ECFCs) and its potential association with CAD and mitochondrial function. Methods: ECFCs were cultured from the peripheral blood of 93 BioHEART-CT patients. MPO expression and associated functions were examined using qRT-PCR, immunochemistry, flow cytometry, and MPO activity assays. CAD presence was defined using CT coronary angiography (CACS > 0). Results: We report MPO presence in patient-derived ECFCs for the first time. MPO protein expression occurred in 70.7% of samples (n = 41) which had nuclear co-localisation, an atypical observation given its conventional localisation in the granules of neutrophils and monocytes. This suggests potential alternative roles for MPO in nuclear processes. MPO mRNA expression was detected in 66.23% of samples (n = 77). CAD patients had a lower proportion of MPO-positive ECFCs compared to non-CAD controls (57.45% vs. 80%, p = 0.04), a difference that persisted in the statin-naïve sub-cohort (53.85% vs. 84.62%, p = 0.02). Non-CAD patients with MPO expression showed upregulated mitochondrial-antioxidant genes (AIFM2, TXNRD1, CAT, PRDX3, PRDX6). In contrast, CAD patients with MPO gene expression had heightened mROS production and mitochondrial mass and decreased mitochondrial function compared to that of CAD patients without MPO gene expression. Conclusions: MPO is present in the nucleus of ECFCs. In non-CAD ECFCs, MPO expression is linked to upregulated mitochondrial-antioxidant genes, whereas in CAD ECFCs, it is associated with greater mitochondrial dysfunction.

The risk-factor-based prediction of atherosclerotic coronary artery disease (CAD) remains suboptimal, particularly in the absence of any of the standard modifiable cardiovascular risk factors (SMuRFs), making the discovery of biomarkers that correlate with atherosclerosis burden critically important. We hypothesized that cytokines and receptors associated with inflammation in CAD—tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interleukin-18 (IL-18), and osteoprotegerin (OPG)—would be independently associated with CAD. To determine this, we measured the serum biomarker levels of 993 participants from the BioHEART study who had CT coronary angiograms that were scored for severity of stenosis and plaque composition. We found that the quartiles of TRAIL, OPG, and IL-18 were significantly associated with disease scores, and that the IL-18/TRAIL and OPG/TRAIL ratios demonstrated significant differences between no CAD vs. STEMI whereas only the OPG/TRAIL ratio showed differences between no CAD and obstructive CAD (stenosis > 50%). However, these associations did not persist after adjustment for age, sex, SMuRFs, and a family history of CAD. In conclusion, TRAIL, IL-18, and OPG and the derived ratios of IL-18/TRAIL and OPG/TRAIL demonstrate significant associations with raw disease scores and risk factors, but these markers are not discriminatory biomarkers for the prediction of CAD when incorporated into multi-variable risk models.

Abstract INTRODUCTION The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World‐Wide FINGERS (WW‐FINGERS). As part of WW‐FINGERS, the Australian AU‐ARROW study mirrors aspects of FINGER, as well as US‐POINTER. METHOD AU‐ARROW is a randomized, single‐blind, multisite, 2‐year clinical trial (n = 600; aged 55–79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION The finalized AU‐ARROW protocol is expected to allow development of an evidence‐based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights Study protocol for a single‐blind, randomized controlled trial, the AU‐ARROW Study. The AU‐ARROW Study is a member of the World‐Wide FINGERS (WW‐FINGERS) initiative. AU‐ARROW's primary outcome measure is change in a global composite cognitive score. Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests. Leading to development of an innovative treatment plan to reduce cognitive decline.

Age is a key risk factor for cardiovascular disease, including atherosclerosis. However, pathophysiological disease processes in the arteries are not an inevitable feature of aging. Large cohort studies with arterial phenotyping along with clinical and demographic data are essential to better understand factors related to the susceptibility or resilience to age-related vascular pathophysiology in humans. This review explores the mechanisms by which vascular structure and function alters with age, and how these changes relate to cardiovascular pathophysiology and disease. Features of vascular aging in the coronary arteries have historically been difficult to quantify pre-mortem due to their size and location. However, non-invasive imaging modalities including CT Coronary Angiogram are now being used to assess coronary vascular age, and further advances in imaging analysis such as the CT Fat Attenuation Index will help provide further measurement of features associated with coronary vascular aging. Currently, markers of vascular aging are not used as therapeutic targets in routine clinical practice, but non-pharmacological interventions including aerobic exercise and low salt diet, as well as anti-hypertensives have been demonstrated to reduce arterial stiffness. Advances in imaging technology, both in acquisition and advanced analysis, as well as harmonisation of measurements for researchers across the globe will be invaluable in understanding what constitutes healthy vascular aging and in identifying features of vascular aging that are associated with coronary artery disease and its adverse outcomes. Assessing such images in large cohorts can facilitate improved definitions of resilient and susceptible phenotypes to vascular aging in the coronary arteries. This is a critical step in identifying further risk factors and biomarkers within these groups and driving forward the development of novel therapies aimed at slowing or stopping age-related vascular changes in the coronary arteries.

Abstract Potential benefits of precision medicine in cardiovascular disease (CVD) include more accurate phenotyping of individual patients with the same condition or presentation, using multiple clinical, imaging, molecular and other variables to guide diagnosis and treatment. An approach to realising this potential is the digital twin concept, whereby a virtual representation of a patient is constructed and receives real-time updates of a range of data variables in order to predict disease and optimise treatment selection for the real-life patient. We explored the term digital twin, its defining concepts, the challenges as an emerging field, and potentially important applications in CVD. A mapping review was undertaken using a systematic search of peer-reviewed literature. Industry-based participants and patent applications were identified through web-based sources. Searches of Compendex, EMBASE, Medline, ProQuest and Scopus databases yielded 88 papers related to cardiovascular conditions (28%, n = 25), non-cardiovascular conditions (41%, n = 36), and general aspects of the health digital twin (31%, n = 27). Fifteen companies with a commercial interest in health digital twin or simulation modelling had products focused on CVD. The patent search identified 18 applications from 11 applicants, of which 73% were companies and 27% were universities. Three applicants had cardiac-related inventions. For CVD, digital twin research within industry and academia is recent, interdisciplinary, and established globally. Overall, the applications were numerical simulation models, although precursor models exist for the real-time cyber-physical system characteristic of a true digital twin. Implementation challenges include ethical constraints and clinical barriers to the adoption of decision tools derived from artificial intelligence systems.

Abstract Breath-held (BH) cardiac magnetic resonance imaging (CMR) is the gold standard for volumetric quantification. However, large animals for pre-clinical research are unable to voluntarily breath-hold, necessitating general anaesthesia and mechanical ventilation, increasing research costs and affecting cardiovascular physiology. Conducting CMR in lightly sedated, free-breathing (FB) animal subjects is an alternative strategy which can overcome these constraints, however, may result in poorer image quality due to breathing motion artefact. We sought to assess the reproducibility of CMR metrics between FB and BH CMR in a porcine model of ischaemic cardiomyopathy. FB or BH CMR was performed in 38 porcine subjects following percutaneous induction of myocardial infarction. Analysis was performed by two independent, blinded observers according to standard reporting guidelines. Subjective and objective image quality was significantly improved in the BH cohort (image quality score: 3.9/5 vs. 2.4/5; p 5% in FB; Bland–Altman limits of agreement: 10 in FB). Interstudy variation between approaches was used to calculate sample sizes, with BH CMR resulting in greater than 85% reduction in animal numbers required to show clinically significant treatment effects. In summary, BH porcine CMR produces superior image quality, shorter scan acquisition, greater reproducibility, and requires smaller sample sizes for pre-clinical trials as compared to FB acquisition.

PurposeCurrent intervention guidelines for bicuspid aortic valve (BAV) associated ascending aorta (AAo) dilatation are suboptimal predictors of clinical outcome. There is growing interest in identifying better biomarkers such as wall shear stress (WSS) to help risk stratify BAV aortopathy. The aim of the systematic review is to synthesize existing evidence of the relationship between WSS and aortopathy in the BAV population.MethodsA comprehensive literature search of available major databases was performed in May 2022 to include studies that used four-dimensional flow cardiac magnetic resonance (4D-flow) MRI to quantify WSS in the AAo in adult BAV populations. Summary results and statistical analysis were provided for key numerical results. A narrative summary was provided to assess similarities between studies.ResultsA total of 26 studies that satisfied selection criteria and quality assessment were included in the review. The presence of BAV resulted in significantly elevated WSS magnitude and circumferential WSS, but not axial WSS. The presence of aortic stenosis had additional impact on WSS and flow alterations. BAV phenotypes were associated with different WSS distributions and flow profiles. Altered protein expression in the AAo wall associated with WSS supported the contribution of altered hemodynamics to aortopathy in addition to genetic factors.ConclusionWSS has the potential to be a valid biomarker for BAV aortopathy. Future work would benefit from larger study cohorts with longitudinal evaluations to further characterize WSS association with aortopathy, mortality, and morbidities.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022337077, identifier CRD42022337077.

Abstract 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.

Mass spectrometry-based metabolomics is a powerful method for profiling large clinical cohorts but batch variations can obscure biologically meaningful differences. Here, the authors develop a computational workflow that removes unwanted data variation while preserving biologically relevant information.

IntroductionA higher 30-day mortality has been observed in patients with first-presentation ST elevation myocardial infarction (STEMI) who have no standard modifiable cardiovascular risk factors (SMuRFs), i. e., diabetes, hypertension, hyperlipidemia, and current smoker. In this study, we evaluate the clinical outcomes and CMR imaging characteristics of patients with and without SMuRFs who presented with first-presentation STEMI.MethodsPatients from the Third DANish Study of Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI-3) with first-presentation STEMI were classified into those with no SMuRFs vs. those with at least one SMuRF.ResultsWe identified 2,046 patients; 283 (14%) SMuRFless and 1,763 (86%) had >0 SMuRF. SMuRFless patients were older (66 vs. 61 years, p < 0.001) with more males (84 vs. 74%, p < 0.001), more likely to have left anterior descending artery (LAD) as the culprit artery (50 vs. 42%, p = 0.009), and poor pre-PCI (percutaneous coronary intervention) TIMI (thrombolysis in myocardial infarction) flow ≤1 (78 vs. 64%; p < 0.001). There was no difference in all-cause mortality, non-fatal reinfarction, or hospitalization for heart failure at 30 days or at long-term follow-up. CMR imaging was performed on 726 patients. SMuRFless patients had larger acute infarct size (17 vs. 13%, p = 0.04) and a smaller myocardial salvage index (42 vs. 50%, p = 0.02). These differences were attenuated when the higher LAD predominance and/or TIMI 0-1 flow were included in the model.ConclusionDespite no difference in 30-day mortality, SMuRFless patients had a larger infarct size and a smaller myocardial salvage index following first-presentation STEMI. This association was mediated by a larger proportion of LAD culprits and poor TIMI flow pre-PCI.Clinical trial registrationclinicaltrials.gov, unique identifier: NCT01435408 (DANAMI 3-iPOST and DANAMI 3-DEFER) and NCT01960933 (DANAMI 3-PRIMULTI).

Abstract Despite improvements in revascularization after a myocardial infarction, coronary disease remains a major contributor to global mortality. Neutrophil infiltration and activation contributes to tissue damage, via the release of myeloperoxidase (MPO) and formation of the damaging oxidant hypochlorous acid. We hypothesized that elevation of thiocyanate ions (SCN−), a competitive MPO substrate, would modulate tissue damage. Oral dosing of rats with SCN−, before acute ischemia–reperfusion injury (30 min occlusion, 24 h or 4 week recovery), significantly reduced the infarct size as a percentage of the total reperfused area (54% versus 74%), and increased the salvageable area (46% versus 26%) as determined by MRI imaging. No difference was observed in fractional shortening, but supplementation resulted in both left-ventricle end diastolic and left-ventricle end systolic areas returning to control levels, as determined by echocardiography. Supplementation also decreased antibody recognition of HOCl-damaged myocardial proteins. SCN− supplementation did not modulate serum markers of damage/inflammation (ANP, BNP, galectin-3, CRP), but returned metabolomic abnormalities (reductions in histidine, creatine and leucine by 0.83-, 0.84- and 0.89-fold, respectively), determined by NMR, to control levels. These data indicate that elevated levels of the MPO substrate SCN−, which can be readily modulated by dietary means, can protect against acute ischemia–reperfusion injury.

Risk-factor-based scoring systems for atherosclerotic coronary artery disease (CAD) remain concerningly inaccurate at the level of the individual and would benefit from the addition of biomarkers that correlate with atherosclerosis burden directly. We hypothesized that serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) would be independently associated with CAD and investigated this in the BioHEART study using 968 participants with CT coronary angiograms, which were scored for disease burden in the form of coronary artery calcium scores (CACS), Gensini scores, and a semi-quantitative soft-plaque score (SPS). Serum sLOX-1 was assessed by ELISA and was incorporated into regression models for disease severity and incidence. We demonstrate that sLOX-1 is associated with an improvement in the prediction of CAD severity when scored by Gensini or SPS, but not CACS. sLOX-1 also significantly improved the prediction of the incidence of obstructive CAD, defined as stenosis in any vessel >75%. The predictive value of sLOX-1 was significantly greater in the subgroup of patients who did not have any of the standard modifiable cardiovascular risk factors (SMuRFs). sLOX-1 is associated with CAD severity and is the first biomarker shown to have utility for risk prediction in the SMuRFless population.

The current coronary artery disease (CAD) risk scores for predicting future cardiovascular events rely on well-recognized traditional cardiovascular risk factors derived from a population level but often fail individuals, with up to 25% of first-time heart attack patients having no risk factors. Non-invasive imaging technology can directly measure coronary artery plaque burden. With an advanced lipidomic measurement methodology, for the first time, we aim to identify lipidomic biomarkers to enable intervention before cardiovascular events. With 994 participants from BioHEART-CT Discovery Cohort, we collected clinical data and performed high-performance liquid chromatography with mass spectrometry to determine concentrations of 683 plasma lipid species. Statin-naive participants were selected based on subclinical CAD (sCAD) categories as the analytical cohort (n = 580), with sCAD+ (n = 243) compared to sCAD− (n = 337). Through a machine learning approach, we built a lipid risk score (LRS) and compared the performance of the existing Framingham Risk Score (FRS) in predicting sCAD+. We obtained individual classifiability scores and determined Body Mass Index (BMI) as the modifying variable. FRS and LRS models achieved similar areas under the receiver operating characteristic curve (AUC) in predicting the validation cohort. LRS enhanced the prediction of sCAD+ in the healthy-weight group (BMI < 25 kg/m2), where FRS performed poorly and identified individuals at risk that FRS missed. Lipid features have strong potential as biomarkers to predict CAD plaque burden and can identify residual risk not captured by traditional risk factors/scores. LRS compliments FRS in prediction and has the most significant benefit in healthy-weight individuals.

Abstract Background As the average age of patients with severe aortic stenosis (AS) who receive procedural intervention continue to age, the need for non-invasive modalities that provide accurate diagnosis and operative planning is increasingly important. Advances in cardiovascular magnetic resonance (CMR) over the past two decades mean it is able to provide haemodynamic data at the aortic valve, along with high fidelity anatomical imaging. Methods Electronic databases were searched for studies comparing CMR to transthoracic echocardiography (TTE) and transoesophageal echocardiography (TEE) in the diagnosis of AS. Studies were included only if direct comparison was made on matched patients, and if diagnosis was primarily through measurement of aortic valve area (AVA). Results Twenty-three relevant, prospective articles were included in the meta-analysis, totalling 1040 individual patients. There was no significant difference in AVA measured as by CMR compared to TEE. CMR measurements of AVA size were larger compared to TTE by an average of 10.7% (absolute difference: + 0.14cm2, 95% CI 0.07–0.21, p

Abstract Background The T 1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T 1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T 1 measurement repeatability across centers describing sequence, magnet, and vendor performance. Methods Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B 0 and B 1, and “reference” slow T 1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T 1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T 1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T 1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T 1 variation. Results Over 2 years, phantom gel integrity remained intact (no rips/tears), B 0 and B 1 homogenous, and “reference” T 1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T 1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T 1 times with “reference” T 1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R 2 ranges for both field strengths, 0.99–1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs

Background: This work aims at defining the Effective Orifice Area (EOA) derived from the acoustic source term (AST) method from 4D Phase-Contrast MRI data to provide a reference for the assessment of MRI valvular prostheses as part of a comprehensive cardiac exam. Methods: Three different Bileaflet Mechanical Heart Valves (BMHV) and a dysfunctional BMHV were tested in-vitro using 4D Phase-Contrast MRI and a numerical design of the experimental study was performed, including the influence of internal diameter, stroke volume, and heart rate. The EOA AST was computed based on the MRI 4D Phase-Contrast acquisition. Results: EOAAST values vary by 15 mm from the BMHV center and should be computed between 8 to 10 mm after the metallic “blurring” artefact (ranging from 18.9 to 23.4 mm from the BMHV). EOAAST values were found to be lower compared with numerical results in the appropriate plane. Detection of the BMHV dysfunction by continuity equation computed from 4D flow acquisition is limited based on EOAAST computations, while EOAc and velocities after the valves could more directly highlight a blocked leaflet. Conclusion: This multi-disciplinary study demonstrates the suitability of the EOA AST method to assess BMHV function using MRI. Translation to the clinic is feasible using an optimized 2D Phase-Contrast flow stack or a 4D Phase-Contrast minimal volume based on the recommendations provided.

Introduction There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the β3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating β3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication.Methods and analysis The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care.Ethics and dissemination The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes.Trial registration number ACTRN12619000423112; Results.

There is increasing recognition of the value of four-dimensional flow cardiovascular magnetic resonance (4D-flow MRI) as a potential means to detect and measure abnormal flow behaviour that occurs during early left ventricular (LV) dysfunction. We performed a systematic review of current literature on the role of 4D-flow MRI-derived flow parameters in quantification of LV function with a focus on potential clinical applicability. A comprehensive literature search was performed in March 2022 on available databases. A total of 1186 articles were identified, and 30 articles were included in the final analysis. All the included studies were ranked as “highly clinically applicable”. There was considerable variability in the reporting of methodologies and analyses. All the studies were small-scale feasibility or pilot studies investigating a diverse range of flow parameters. The most common primary topics of investigation were energy-related flow parameters, flow components and vortex analysis which demonstrated potentials for quantifying early diastolic dysfunction, whilst other parameters including haemodynamic forces, residence time distribution and turbulent kinetic energy remain in need of further evaluation. Systematic quantitative comparison of study findings was not possible due to this heterogeneity, therefore limiting the collective power of the studies in evaluating clinical applicability of the flow parameters. To achieve broader clinical application of 4D-flow MRI, larger scale investigations are required, together with standardisation of methodologies and analytical approach.

Objective: Phenylketonuria (PKU) is an autosomal recessive disorder whereby deficiencies in phenylalanine metabolism cause progressive neurological dysfunction. Managing PKU is challenging, with disease monitoring focussed on short-term phenylalanine control rather than measures of neuronal damage. Conventional imaging lacks sensitivity, however diffusion kurtosis imaging (DKI), a new MRI method may reveal subclinical white matter structural changes in PKU. Methods: This cohort study involved adults with PKU recruited during routine clinical care. MRI, neurocognitive assessment and historical phenylalanine (Phe) levels were collected. A hypothesis-generating case study comparing diet-compliant and non-compliant siblings confirmed that DKI metrics are sensitive to dietary adherence and prompted a candidate metric (Krad/KFA ratio). We then tested this metric in a Replication cohort (PKU = 20; controls = 43). Results: Both siblings scored outside the range of controls for all DKI-based metrics, with severe changes in the periventricular white matter and a gradient of severity toward the cortex. Krad/KFA provided clear separation by diagnosis in the Replication cohort (p

We have previously shown that a severely energy-restricted diet leads to greater loss of weight, fat, lean mass and bone mineral density (BMD) at 12 months in postmenopausal women with obesity than a moderately energy-restricted diet. We now aim to evaluate whether these effects are sustained longer term (ie, at 36 months). 101 postmenopausal women were randomized to either 12 months of moderate (25 to 35%) energy restriction with a food-based diet (moderate intervention), or 4 months of severe (65 to 75%) energy restriction with a total meal replacement diet followed by moderate energy restriction for 8 months (severe intervention). Body weight and composition were measured at 0, 24 and 36 months. Participants in the severe intervention lost ~1.5 to 1.7 times as much weight, waist circumference, whole-body fat mass and visceral adipose tissue compared to those in the moderate intervention, and were 2.6 times more likely (42% versus 16%) to have lost 10% or more of their initial body weight at 36 months (P < 0.01 for all). However, those in the severe versus moderate intervention lost ~1.4 times as much whole-body lean mass (P < 0.01), albeit this was proportional to total weight lost and there was no greater loss of handgrip strength, and they also lost ~2 times as much total hip BMD between 0 and 36 months (P < 0.05), with this bone loss occurring in the first 12 months. Thus, severe energy restriction is more effective than moderate energy restriction for reducing weight and adiposity in postmenopausal women in the long term (3 years), but attention to BMD loss in the first year is required. Trial registration: Australian New Zealand Clinical Trials Registry Reference Number: 12612000651886, anzctr.org.au.

Objective: Mild traumatic brain injury (mTBI) is associated with depressed mood acutely post-injury, but there is little evidence regarding long-term depression. The aim of this study was to determine the odds ratio (OR) of depression chronically following mTBI.Methods: We searched Medline (PubMed), ProQuest, and Web of Science from date of database creation to January 23, 2019, for eligible studies examining depression at least 6 months post-injury in adult subjects with mTBI of any etiology, including civilians and military. Three authors independently reviewed titles and abstracts for study eligibility. Data were extracted and collated by two investigators. Risk of bias was assessed with the SIGN methodology. Study data were pooled using random-effects meta-analysis. The primary exposure was mTBI, and the primary outcome was depression. Secondary exploratory variables were time of assessment, age at injury, age at assessment, sex, and etiology.Results: We included 47 cross-sectional studies (n = 25,103 mTBI and 29,982 control), 26 cohort studies (n = 70,119 mTBI, 262,034 control), four prospective observational studies (n = 1,058 mTBI and 733 control), two prospective longitudinal studies (n = 119 mTBI, 81 control), two case-control studies (n = 56 mTBI, 56 control), and one randomized controlled trial (n = 252 mTBI, 3,214 control). mTBI was associated with a 3.29-fold increased risk of depression (OR 3.29, 95% CI 2.68–4.03, I2 = 96%). The OR for depression did not change when subjects were assessed at 6–12 months (OR 2.43, 1.45–4.07), years 1–2 (OR 4.12, 2.10–8.07); 2–10 (OR 3.28, 2.42–4.46), or 10+ (OR 3.42, 1.51–7.77). Similar risk of depression was sustained across different age at injury (35: OR 2.69, 1.42–5.10) and different age at assessment (40 years: OR 4.57, 2.54–8.24). Female sex had a non-significant increase in OR (OR 19.97, 2.39–166.93) compared to male (OR 3.0, 2.33–3.86). mTBI etiology had no impact on depression.Conclusions: Those experiencing mTBI are more than three times more likely to experience depression compared to those without a history of mTBI, and this risk remains decades beyond the mTBI event. Future longitudinal studies are needed to identify and mitigate this risk.

Mechanisms involved in the individual susceptibility to atherosclerotic coronary artery disease (CAD) beyond traditional risk factors are poorly understood. Here, we describe the utility of cultured patient-derived endothelial colony-forming cells (ECFCs) in examining novel mechanisms of CAD susceptibility, particularly the role of dysregulated redox signalling. ECFCs were selectively cultured from peripheral blood mononuclear cells from 828 patients from the BioHEART-CT cohort, each with corresponding demographic, clinical and CT coronary angiographic imaging data. Spontaneous growth occurred in 178 (21.5%) patients and was more common in patients with hypertension (OR 1.45 (95% CI 1.03–2.02), p = 0.031), and less likely in patients with obesity (OR 0.62 [95% CI 0.40–0.95], p = 0.027) or obstructive CAD (stenosis > 50%) (OR 0.60 [95% CI 0.38–0.95], p = 0.027). ECFCs from patients with CAD had higher mitochondrial production of superoxide (O2−–MitoSOX assay). The latter was strongly correlated with the severity of CAD as measured by either coronary artery calcium score (R2 = 0.46; p = 0.0051) or Gensini Score (R2 = 0.67; p = 0.0002). Patient-derived ECFCs were successfully cultured in 3D culture pulsatile mini-vessels. Patient-derived ECFCs can provide a novel resource for discovering mechanisms of CAD disease susceptibility, particularly in relation to mitochondrial redox signalling.

Abstract Background Femoroacetabular impingement syndrome (FAI), a hip disorder affecting active young adults, is believed to be a leading cause of hip osteoarthritis (OA). Current management approaches for FAI include arthroscopic hip surgery and physiotherapy-led non-surgical care; however, there is a paucity of clinical trial evidence comparing these approaches. In particular, it is unknown whether these management approaches modify the future risk of developing hip OA. The primary objective of this randomised controlled trial is to determine if participants with FAI who undergo hip arthroscopy have greater improvements in hip cartilage health, as demonstrated by changes in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to those who undergo physiotherapy-led non-surgical management. Methods This is a pragmatic, multi-centre, two-arm superiority randomised controlled trial comparing hip arthroscopy to physiotherapy-led management for FAI. A total of 140 participants with FAI will be recruited from the clinics of participating orthopaedic surgeons, and randomly allocated to receive either surgery or physiotherapy-led non-surgical care. The surgical intervention involves arthroscopic FAI surgery from one of eight orthopaedic surgeons specialising in this field, located in three different Australian cities. The physiotherapy-led non-surgical management is an individualised physiotherapy program, named Personalised Hip Therapy (PHT), developed by a panel to represent the best non-operative care for FAI. It entails at least six individual physiotherapy sessions over 12 weeks, and up to ten sessions over six months, provided by experienced musculoskeletal physiotherapists trained to deliver the PHT program. The primary outcome measure is the change in dGEMRIC score of a ROI containing both acetabular and femoral head cartilages at the chondrolabral transitional zone of the mid-sagittal plane between baseline and 12 months. Secondary outcomes include patient-reported outcomes and several structural and biomechanical measures relevant to the pathogenesis of FAI and development of hip OA. Interventions will be compared by intention-to-treat analysis. Discussion The findings will help determine whether hip arthroscopy or an individualised physiotherapy program is superior for the management of FAI, including for the prevention of hip OA. Trial registration Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015 (retrospectively registered).

Sports-related concussion (SRC) is sustained by millions of people per year, yet the spatiotemporal patterns of white matter (WM) injury remain poorly understood. Several SRC studies have implemented the standardised approach Tract-Based Spatial Statistics (TBSS). The aim of this image-based meta-analysis was to identify consensus patterns of SRC-related WM injury across TBSS studies. We included studies comparing the diffusion MRI measurement fractional anisotropy (FA) in SRC or subconcussive injury vs. controls using TBSS, as FA is the most frequently examined diffusion tensor imaging metric. Authors of eligible studies were contacted to request unthresholded statistical map outputs from TBSS, and image-based meta-analyses were performed using Seed-Based d-Mapping. Eight studies contributed to our meta-analyses, comprising 174 SRC or subconcussive injury participants and 160 controls. Our primary meta-analysis (n = 8), encompassing subjects with acute SRC (n = 2), chronic SRC (n = 4) and subconcussive injuries (n = 2) revealed dominant bilateral increased FA in the superior longitudinal fasciculus (SLF) and internal capsule. Subconcussive injury was associated with small clusters of increased and decreased FA in the arcuate fasciculus compared to control. In acute SRC, we found diffuse foci of raised FA at WM/grey matter border-zone associated with the bilateral SLF and right inferior fronto-occipital fasciculus. In contrast, chronic SRC had a pattern of deep WM alteration, asymmetrically located in the right optic radiations and arcuate fasciculus. Our findings represent the most powerful analysis of TBSS data in SRC, supporting the use of this approach to analyse diffusion data. TBSS is sensitive to WM abnormalities resulting from SRC or subconcussive injury over a range of temporal and clinical scenarios. Our data show spatially concordant patterns of WM injury unique to subconcussive, acute and chronic phases, highlighting the future utility of diffusion MRI for concussion diagnosis.

Introduction Coronary artery disease (CAD) persists as a major cause of morbidity and mortality worldwide despite intensive identification and treatment of traditional risk factors. Data emerging over the past decade show a quarter of patients have disease in the absence of any known risk factor, and half have only one risk factor. Improvements in quantification and characterisation of coronary atherosclerosis by CT coronary angiography (CTCA) can provide quantitative measures of subclinical atherosclerosis—enhancing the power of unbiased ‘omics’ studies to unravel the missing biology of personal susceptibility, identify new biomarkers for early diagnosis and to suggest new targeted therapeutics.Methods and analysis BioHEART-CT is a longitudinal, prospective cohort study, aiming to recruit 5000 adult patients undergoing clinically indicated CTCA. After informed consent, patient data, blood samples and CTCA imaging data are recorded. Follow-up for all patients is conducted 1 month after recruitment, and then annually for the life of the study. CTCA data provide volumetric quantification of total calcified and non-calcified plaque, which will be assessed using established and novel scoring systems. Comprehensive molecular phenotyping will be performed using state-of-the-art genomics, metabolomics, proteomics and immunophenotyping. Complex network and machine learning approaches will be applied to biological and clinical datasets to identify novel pathophysiological pathways and to prioritise new biomarkers. Discovery analysis will be performed in the first 1000 patients of BioHEART-CT, with validation analysis in the following 4000 patients. Outcome data will be used to build improved risk models for CAD.Ethics and dissemination The study protocol has been approved by the human research ethics committee of North Shore Local Health District in Sydney, Australia. All findings will be published in peer-reviewed journals or at scientific conferences.Trial registration number ACTRN12618001322224.

Background Silent brain infarcts (SBI) are increasingly being recognized as an important complication of cardiac procedures as well as a potential surrogate marker for studies on brain injury. The extent of subclinical brain injury is poorly defined. Methods and Results We conducted a systematic review and meta‐analysis utilizing studies of SBIs and focal neurologic deficits following cardiac procedures. Our final analysis included 42 studies with 49 separate intervention groups for a total of 2632 patients. The prevalence of SBIs following transcatheter aortic valve implantation was 0.71 (95% CI 0.64‐0.77); following aortic valve replacement 0.44 (95% CI 0.31‐0.57); in a mixed cardiothoracic surgery group 0.39 (95% CI 0.28‐0.49); coronary artery bypass graft 0.25 (95% CI 0.15‐0.35); percutaneous coronary intervention 0.14 (95% CI 0.10‐0.19); and off‐pump coronary artery bypass 0.14 (0.00‐0.58). The risk ratio of focal neurologic deficits to SBI in aortic valve replacement was 0.22 (95% CI 0.15‐0.32); in off‐pump coronary artery bypass 0.21 (95% CI 0.02‐2.04); with mixed cardiothoracic surgery 0.15 (95% CI 0.07‐0.33); coronary artery bypass graft 0.10 (95% CI 0.05‐0.18); transcatheter aortic valve implantation 0.10 (95% CI 0.07‐0.14); and percutaneous coronary intervention 0.06 (95% CI 0.03‐0.14). The mean number of SBIs per patient was significantly higher in the transcatheter aortic valve implantation group (4.58 ± 2.09) compared with both the aortic valve replacement group (2.16 ± 1.62, P=0.03) and the percutaneous coronary intervention group (1.88 ± 1.02, P=0.03). Conclusions SBIs are a very common complication following cardiac procedures, particularly those involving the aortic valve. The high frequency of SBIs compared with strokes highlights the importance of recording this surrogate measure in cardiac interventional studies. We suggest that further work is required to standardize reporting in order to facilitate the use of SBIs as a routine outcome measure.

Despite effective prevention programs targeting cardiovascular risk factors, coronary artery disease (CAD) remains the leading cause of death. Novel biomarkers are needed for improved risk stratification and primary prevention. To assess for independent associations between plasma metabolites and specific CAD plaque phenotypes we performed liquid chromatography mass-spectrometry on plasma from 1002 patients in the BioHEART-CT study. Four metabolites were examined as candidate biomarkers. Dimethylguanidino valerate (DMGV) was associated with presence and amount of CAD (OR) 1.41 (95% Confidence Interval [CI] 1.12–1.79, p = 0.004), calcified plaque, and obstructive CAD (p < 0.05 for both). The association with amount of plaque remained after adjustment for traditional risk factors, ß-coefficient 0.17 (95% CI 0.02–0.32, p = 0.026). Glutamate was associated with the presence of non-calcified plaque, OR 1.48 (95% CI 1.09–2.01, p = 0.011). Phenylalanine was associated with amount of CAD, ß-coefficient 0.33 (95% CI 0.04–0.62, p = 0.025), amount of calcified plaque, (ß-coefficient 0.88, 95% CI 0.23–1.53, p = 0.008), and obstructive CAD, OR 1.84 (95% CI 1.01–3.31, p = 0.046). Trimethylamine N-oxide was negatively associated non-calcified plaque OR 0.72 (95% CI 0.53–0.97, p = 0.029) and the association remained when adjusted for traditional risk factors. In targeted metabolomic analyses including 53 known metabolites and controlling for a 5% false discovery rate, DMGV was strongly associated with the presence of calcified plaque, OR 1.59 (95% CI 1.26–2.01, p = 0.006), obstructive CAD, OR 2.33 (95% CI 1.59–3.43, p = 0.0009), and amount of CAD, ß-coefficient 0.3 (95% CI 0.14–0.45, p = 0.014). In multivariate analyses the lipid and nucleotide metabolic pathways were both associated with the presence of CAD, after adjustment for traditional risk factors. We report novel associations between CAD plaque phenotypes and four metabolites previously associated with CAD. We also identified two metabolic pathways strongly associated with CAD, independent of traditional risk factors. These pathways warrant further investigation at both a biomarker and mechanistic level.

Background: Major depressive disorder (MDD) is a chronic disease with a large global impact. There are currently no clinically useful predictors of treatment outcome, and the development of biomarkers to inform clinical treatment decisions is highly desirable. Methods: In this exploratory study we performed fixel-based analysis of diffusion MRI data from the International Study to Predict Optimized Treatment in Depression with the aim of identifying novel biomarkers at baseline that may relate to diagnosis and outcome to treatment with antidepressant medications. Analyses used MR data from individuals with MDD (n = 221) and healthy controls (n = 67). Results: We show focal, gender-specific differences in the anterior limb of the internal capsule (males) and bilaterally in the genu of the corpus callosum (females) associated with diagnosis. Lower fibre cross-section in the tapetum, the conduit between the right and left hippocampi, were also associated with a decreased probability of remission. Analysis of conventional fractional anisotropy showed scattered abnormalities in the corona radiata, cerebral peduncles and mid-brain which were much lower in total volume compared to fixel-based analysis. Conclusions: Fixel-based analysis appeared to identify different underlying abnormalities than conventional tensor-based metrics, with almost no overlap between significant regions. We show that MDD is associated with gender specific abnormalities in the genu of the corpus callosum (females) and in the anterior limb of the internal capsule (males), as well as gender-independent differences in the tapetum that predict remission. Diffusion MRI may play a key role in future guidance of clinical decision-making for MDD. Keywords: Magnetic resonance imaging, Diffusion tensor imaging, Major depressive disorder, Biomarker predictors, Remission, iSPOT-D

Objective: To construct a clinical diagnostic biomarker using state-of-the-art microstructural MRI in the motor cortex of people with amyotrophic lateral sclerosis (ALS). Methods: Clinical and MRI data were obtained from 21 ALS patients (aged 54 ± 14 years, 33% female) and 63 age- and gender-matched controls (aged 48 ± 18 years, 43% female). MRI was acquired at 3T and included T1-weighted scan (for volumetrics), arterial spin labelling (for cerebral blood flow), susceptibility-weighted angiography (for iron deposition) and multiband diffusion kurtosis imaging (for tissue microstructure). Group differences in imaging measures in the motor cortex were tested by general linear model and relationships to clinical variables by linear regression. Results: The ALS group had mild-to-moderate impairment (disease duration: 1.8 ± 0.8 years; ALS functional rating scale 40.2 ± 6.0; forced vital capacity 83% ± 22%). No age or gender differences were present between groups. We found significant group differences in diffusion kurtosis metrics (apparent, mean, radial and axial kurtosis: p

Increasing evidence suggests the presence of structural changes affecting the right ventricular outflow tract (RVOT) in patients with Brugada Syndrome (BrS). The aim of this study was to characterise the RV morphology in BrS and explore associations between morphologic, clinical, electrical, and genetic parameters using non-invasive multimodality testing.Consecutive BrS patients (recruited 2013-2015) underwent clinical assessment, dedicated RV imaging using cardiac magnetic resonance (CMR) imaging (unless contra-indicated), electrical assessment (electrocardiogram, Holter monitoring, signal-averaged ECG[SAECG]) and genotyping. Morphologic data were compared to matched control and unmatched ARVC (arrhythmogenic right ventricular cardiomyopathy) cohorts, and potential associations between morphologic parameters and other variables were explored.BrS patients (n = 42, male 86%, age 46±12 years) exhibited normal global RV volume and function, comparable to control, in contrast to significantly larger, impaired RVs in ARVC cohort (RVESV p = 0.0001; RVEDV p

Background: Less than 50% of patients with Major Depressive Disorder (MDD) reach symptomatic remission with their initial antidepressant medication (ADM). There are currently no objective measures with which to reliably predict which individuals will achieve remission to ADMs. Methods: 157 participants with MDD from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) underwent baseline MRIs and completed eight weeks of treatment with escitalopram, sertraline or venlafaxine-ER. A score at week 8 of 7 or less on the 17 item Hamilton Rating Scale for Depression defined remission. Receiver Operator Characteristics (ROC) analysis using the first 50% participants was performed to define decision trees of baseline MRI volumetric and connectivity (fractional anisotropy) measures that differentiated non-remitters from remitters with maximal sensitivity and specificity. These decision trees were tested for replication in the remaining participants. Findings: Overall, 35% of all participants achieved remission. ROC analyses identified two decision trees that predicted a high probability of non-remission and that were replicated: 1. Left middle frontal volume 6 · 3 mL identified 55% of non-remitters with 85% accuracy; and 2. Fractional anisotropy values in the left cingulum bundle