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Background: Hypertension is frequently complicated by the development of atrial fibrillation (AF). However, the mechanisms of this link remain poorly understood. In addition, whether short-term hypertension can result in a substrate for AF is not known.Objective: The purpose of this study was to characterize the atrial substrate predisposing to AF due to short-duration hypertension.Methods: Sixteen sheep were studied: 10 had induced hypertension for 7 +/- 4 weeks via the "one-kidney, one-clip" model, and six were controls. Cardiac magnetic resonance imaging was used to assess functional changes. Open-chest electrophysiological study was performed using a custom-made 128-electrode epicardial plaque applied to both right (RA) and left atria (LA), including the Bachmann's bundle, to determine effective refractory periods (ERPs) and conduction velocity at four pacing cycle lengths from six sites. Tissue specimens were harvested for structural analysis.Results: The hypertensive group demonstrated the following compared with controls: higher blood pressure (P <.0001), enlarged LA (P <.05), reduced LA ejection fraction (P <.05), uniformly higher mean ERP (P <.001), slower mean conduction velocity (P <.001), higher conduction heterogeneity index (P <.0001), greater AF inducibility (P = .03), and increased AF durations (P = .04). Picrosirius red staining of atrial tissues revealed increased interstitial fibrosis (P <.0001). There was also evidence of increased inflammatory cell infiltrates (P <.0001).Conclusion: Short-duration hypertension is associated with significant atrial remodeling characterized by atrial enlargement/dysfunction, interstitial fibrosis, inflammation, slowed/heterogeneous conduction, increased ERP, and greater propensity for AF. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of published experience investigating novel treatment strategies in preclinical and clinical studies of nonischemic cardiomyopathy. We set out to validate an ovine model of doxorubicin-induced cardiomyopathy, using cardiac magnetic resonance (CMR) to assess cardiac function. Methods and Results: Ten Merino sheep (51 +/- 8 kg) underwent intracoronary infusions of doxorubicin (1 mg/kg dose) every 2 weeks. Cardiac magnetic resonance was performed at baseline and at 6 weeks after final doxorubicin dose, along with transthoracic echocardiography, measurement of right heart pressure, and cardiac output. After final CMR examination, heart specimens were harvested for histologic analysis. The total dose of doxorubicin administered per animal was 3.8 +/- 0.5 mg/kg. Two animals died prematurely during the study protocol, with evidence of myocarditis. In the remaining 8 sheep, left ventricular ejection fraction dropped from 46.2 +/- 4.7% to 31.3 +/- 8.5% (P < .001), accompanied by reductions in fractional shortening (31.6 +/- 1.8% baseline versus 18.2 +/- 3.9% final, P < .01), cardiac output (3.8 +/- 0.6 L/min versus 3.0 +/- 0.4 L/min, P < .05) and right ventricular ejection fraction (39.5 +/- 5.6% versus 28.9 +/- 9.6%, P < .05). However, significant end-diastolic dilatation of the left ventricle was not observed. Delayed gadolinium uptake was detected by CMR in 2 sheep, in a typical nonischemic pattern. Widespread, multifocal histologic abnormalities consisted of cardiomyocyte degeneration, vasculopathy, inflammatory infiltrates, and replacement fibrosis. Conclusions: Moderate-severe cardiac dysfunction was reproducibly achieved through high-dose intracoronary doxorubicin, with acceptable animal mortality. CMR provides a powerful tool for assessing myocardial function, structural remodeling, and viability in such models. [ABSTRACT FROM AUTHOR]

Reported in this paper is a cutting-edge computational investigation into the influence of geometric characteristics on abdominal aortic aneurysm (AAA) rupture risk, beyond the traditional measure of maximum aneurysm diameter. A Comprehensive fluid-structure interaction (FSI) analysis was employed to assess risk factors in a range of patient scenarios, with the use of three-dimensional (3D) AAA models reconstructed from patient-specific aortic data and finite element method. Wall shear stress (WSS), and its derivatives such as time-averaged WSS (TAWSS), oscillatory shear index (OSI), relative residence time (RRT) and transverse WSS (transWSS) offer insights into the force dynamics acting on the AAA wall. Emphasis is placed on these WSS-based metrics and seven key geometric indices. By correlating these geometric discrepancies with biomechanical phenomena, this study highlights the novel and profound impact of geometry on risk prediction. This study demonstrates the necessity of a multidimensional assessment approach, future efforts should complement these findings with experimental validations for an applicable approach for clinical use., (© 2024 John Wiley & Sons Ltd.)

Objective: Reconstituted high-density lipoproteins (rHDL) improve wound healing in diabetes. We aimed to determine if rHDL elicit anti-inflammatory effects in diabetic wounds, as a mechanism to explain their wound healing benefits. Approach: Diabetes was induced using streptozotocin in C57Bl6/J mice. Two full-thickness wounds were placed on the subflanks of diabetic and nondiabetic (ND) mice. Phosphate-buffered saline (PBS) or rHDL (50 µg/wound/day) were applied topically. Wound closure was assessed daily. Inflammatory gene transcripts were measured by qPCR and proteins by Western blotting and enzyme-linked immunosorbent assay in wounds collected at baseline, 24 h, and 3 days postwounding. Wound macrophages were assessed by flow cytometry 7 days postwounding. The fate of fluorescent 3,3-dioctadecyloxacarbocyanine, perchlorate (DiO)-labeled rHDL was tracked by flow cytometry, fluorescent imaging, and microscopy. Results: In diabetic mice, rHDL increased wound closure rates at days 6 (+288%, p < 0.01) and 7 (+639%, p < 0.0001) postwounding, compared with PBS controls. After 3 days, rHDL-treated diabetic wounds had lower Rela (-65%) and C-C motif chemokine ligand 2 ( Ccl2 ) (-59%) mRNA levels and CCL2 protein (29%) than PBS controls, p < 0.05 for all. Wound macrophage content was higher in diabetic than ND wounds, but rHDL did not change macrophage content or polarity. DiO-rHDL were taken up by key wound cells including fibroblasts, macrophages, keratinocytes and endothelial cells, and retained in wounds for at least 48 h. Innovation: rHDL exerts anti-inflammatory effects in diabetic wounds early postwounding, which may contribute to its wound healing properties. Conclusion: The anti-inflammatory properties of rHDL in diabetic wounds present topical rHDL as a novel treatment option for improving healing in patients with diabetic foot ulcers.

Importance: Despite being recommended by clinical guidelines, substantial concerns remain regarding the use of high-sensitivity cardiac troponin assays and whether it is associated with increased resource use, myocardial infarction (MI) or myocardial injury diagnoses, and procedural rates., Objective: To characterize the association of reporting high-sensitivity cardiac troponin T (hs-cTnT) to the lowest limit of quantification vs conventional troponin reporting with clinical outcomes., Design, Setting, and Participants: This cohort study used a historically controlled baseline and follow-up design to compare clinical outcomes after changing hs-cTnT reporting to the lowest limit of quantification. All patients aged 18 years or older presenting to any public emergency department (ED) in the state of South Australia between February 1, 2020, and February 28, 2021, who had an hs-cTnT test in the 6 months before and after the change in troponin reporting practice were included. Outcomes were assessed after adjusting for patient characteristics using inverse probability treatment weighting. The data analysis was performed between May 1, 2022, and July 27, 2023., Exposure: hs-cTcnT reporting., Main Outcomes and Measures: The main outcomes were frequency of diagnosed MI, coronary angiography, percutaneous coronary intervention, and coronary artery bypass graft (CABG); hospital length of stay; and ED discharge rate as measured using time-to-event Cox regression models. The secondary outcome was the composite 12-month event rate of all-cause mortality, MI, and myocardial injury., Results: A total of 40 921 patients were included, of whom 20 206 were included in the unmasked hs-cTnT reporting group (median [IQR] age, 62.0 [46.0-77.0]; 10 120 females [50.1%]) and 20 715 were included in the conventional troponin reporting group (median [IQR] age, 63.0 [47.0-77.0] years; 10 752 males [51.9%]). Unmasked hs-cTnT reporting was associated with higher ED discharge rates (45.2% vs 39.0%; P < .001) and a shorter median hospital length of stay (7.68 [IQR, 4.32-46.80] hours vs 7.92 [IQR, 4.56-49.92] hours; P < .001). There was no difference in diagnosis of MI, coronary angiography, percutaneous coronary intervention, or coronary artery bypass graft. The composite of all-cause mortality, MI, and myocardial injury at 12 months was similar (adjusted hazard ratio, 0.95; 95% CI, 0.90-1.01; P = .09)., Conclusions and Relevance: This cohort study found that unrestricted reporting of hs-cTnT results to the lowest limit of quantification was not associated with an increase in the diagnosis of MI, invasive coronary procedures, or harm at 12 months but may be associated with improved hospital resource use.

Coronary artery blood flow is influenced by various factors including vessel geometry, hemodynamic conditions, timing in the cardiac cycle, and rheological conditions. Multiple patterns of disturbed coronary flow may occur when blood flow separates from the laminar plane, associated with inefficient blood transit, and pathological processes modulated by the vascular endothelium in response to abnormal wall shear stress. Current simulation techniques, including computational fluid dynamics and fluid-structure interaction, can provide substantial detail on disturbed coronary flow and have advanced the contemporary understanding of the natural history of coronary disease. However, the clinical application of these techniques has been limited to hemodynamic assessment of coronary disease severity, with the potential to refine the assessment and management of coronary disease. Improved computational efficiency and large clinical trials are required to provide an incremental clinical benefit of these techniques beyond existing tools. This contemporary review is a clinically relevant overview of the disturbed coronary flow and its associated pathological consequences. The contemporary methods to assess disturbed flow are reviewed, including clinical applications of these techniques. Current limitations and future opportunities in the field are also discussed.

While blood-contacting materials are widely deployed in medicine in vascular stents, catheters, and cannulas, devices fail in situ because of thrombosis and restenosis. Furthermore, microbial attachment and biofilm formation is not an uncommon problem for medical devices. Even incremental improvements in hemocompatible materials can provide significant benefits for patients in terms of safety and patency as well as substantial cost savings. Herein, a novel but simple strategy is described for coating a range of medical materials, that can be applied to objects of complex geometry, involving plasma-grafting of an ultrathin hyperbranched polyglycerol coating (HPG). Plasma activation creates highly reactive surface oxygen moieties that readily react with glycidol. Irrespective of the substrate, coatings are uniform and pinhole free, comprising O─C─O repeats, with HPG chains packing in a fashion that holds reversibly binding proteins at the coating surface. In vitro assays with planar test samples show that HPG prevents platelet adhesion and activation, as well as reducing (>3 log) bacterial attachment and preventing biofilm formation. Ex vivo and preclinical studies show that HPG-coated nitinol stents do not elicit thrombosis or restenosis, nor complement or neutrophil activation. Subcutaneous implantation of HPG coated disks under the skin of mice shows no evidence of toxicity nor inflammation., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: Biological age can be predicted using artificial intelligence (AI) trained on electrocardiograms (ECGs), which is prognostic for mortality and cardiovascular events., Objective: We developed an AI model to predict age from an ECG and compared baseline characteristics to identify determinants of advanced biological age., Methods: An AI model was trained on ECGs from cardiology inpatients aged 20-90 years. AI analysis used a convolutional neural network with data divided in an 80:20 ratio (development/internal validation), with external validation undertaken using data from the UK Biobank. Performance and subgroup comparison measures included correlation, difference, and mean absolute difference., Results: A total of 63,246 patients with 353,704 total ECGs were included. In internal validation, the correlation coefficient was 0.72, with a mean absolute difference between chronological age and AI-predicted age of 9.1 years. The same model performed similarly in external validation. In patients aged 20-29 years, AI-ECG-predicted biological age was greater than chronological age by a mean of 14.3 ± 0.2 years. In patients aged 80-89 years, biological age was lower by a mean of 10.5 ± 0.1 years. Women were biologically younger than men by a mean of 10.7 months (P = .023), and patients with a single ECG were biologically 1.0 years younger than those with multiple ECGs (P < .0001)., Conclusion: There are significant between-group differences in AI-ECG-predicted biological age for patient subgroups. Biological age was greater than chronological age in young hospitalized patients and lower than chronological age in older hospitalized patients. Women and patients with a single ECG recorded were biologically younger than men and patients with multiple recorded ECGs., Competing Interests: Disclosures Dr Roberts-Thomson has received speaking honoraria from Abbott and Edwards Lifesciences. Dr Psaltis has received consulting fees from Amgen, Eli Lilly, and Esperion and speaker honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Schering-Plough, Novartis, Novo Nordisk, Pfizer, and Sanofi. Dr Sanders reports serving on the medical advisory boards of Abbott, Medtronic, Boston Scientific, CathRx, and PaceMate. The University of Adelaide has received on behalf of Dr Sanders research funds from Boston Scientific, Medtronic, Abbott, and Becton Dickenson. All other authors declare that there is no conflicts of interest., (Copyright © 2024 Heart Rhythm Society. All rights reserved.)

Background: Robust and accurate prediction of cardiovascular disease (CVD) risk facilitates early intervention to benefit patients. The intricate relationship between mental health disorders and CVD is widely recognized. However, existing models often overlook psychological factors, relying on a limited set of clinical and lifestyle parameters, or being developed on restricted population subsets., Objectives: This study aims to assess the impact of integrating psychological data into a novel machine learning (ML) approach on enhancing CVD prediction performance., Methods: Using a comprehensive UK Biobank data set (n = 375,145), the correlation between CVD and traditional and psychological risk factors was examined. CVD included hypertensive disease, ischemic heart disease, heart failure, and arrhythmias. An ensemble ML model containing 5 constituent algorithms (decision tree, random forest, XGBoost, support vector machine, and deep neural network) was tested for its ability to predict CVD based on 2 training data sets: using traditional CVD risk factors alone, or using a combination of traditional and psychological risk factors., Results: A total of 375,145 subjects with normal health status and with CVD were included. The ensemble ML model could predict CVD with 71.31% accuracy using traditional CVD risk factors alone. However, by adding psychological factors to the training data, accuracy increased to 85.13%. The accuracy and robustness of the ensemble ML model outperformed all 5 constituent learning algorithms., Conclusions: Incorporating mental health assessment data within an ensemble ML model results in a significantly improved, highly accurate, CVD prediction model, outperforming traditional risk factor prediction alone., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Delirium is a common and acute neurocognitive disorder in older adults associated with increased risk of dementia and death. Understanding the interaction between brain vulnerability and acute stressors is key to delirium pathophysiology, but the neurophysiology of delirium vulnerability is not well defined. This study aimed to identify pre-operative resting-state EEG and event-related potential markers of incident delirium and its subtypes in older adults undergoing elective cardiac procedures. This prospective observational study included 58 older participants (mean age = 75.6 years, SD = 7.1; 46 male/12 female); COVID-19 restrictions limited recruitment. Baseline assessments were conducted in the weeks before elective cardiac procedures and included a 4-min resting-state EEG recording (2-min eyes open and 2-min eyes closed), a 5-min frequency auditory oddball paradigm recording, and cognitive and depression examinations. Periodic peak power, peak frequency and bandwidth measures, and aperiodic offsets and exponents were derived from resting-state EEG data. Event-related potentials were measured as mean component amplitudes (first positive component, first negative component, early third positive component, and mismatch negativity) following standard and deviant auditory stimuli. Incident delirium occurred in 21 participants: 10 hypoactive, 6 mixed, and 5 hyperactive. Incident hyperactive delirium was associated with higher pre-operative eyes open ( P = 0.045, d = 1.0) and closed ( P = 0.036, d = 1.0) aperiodic offsets. Incident mixed delirium was associated with significantly larger pre-operative first positive component amplitudes to deviants ( P = 0.037, d = 1.0) and larger third positive component amplitudes to standards ( P = 0.025, d = 1.0) and deviants ( P = 0.041, d = 0.9). Other statistically non-significant but moderate-to-large effects were observed in relation to all subtypes. We report evidence of neurophysiological markers of delirium risk weeks prior to elective cardiac procedures in older adults. Despite being underpowered due to COVID-19-related recruitment impacts, these findings indicate pre-operative dysfunction in neural excitation/inhibition balance associated with different delirium subtypes and warrant further investigation on a larger scale., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Indigenous Australians are known to have a higher prevalence of coronary artery disease (CAD) than non-Indigenous counterparts. Atherogenic lipid profiles, characterised by low serum levels of high-density lipoprotein (HDL) and higher serum triglycerides, have been shown to be more prevalent in Indigenous Australians. The use of computed tomography coronary angiography (CTCA) for risk stratification and diagnosis of CAD has been validated in moderate risk populations, but limited data exists in specific high-risk populations such as Indigenous Australians. Through a retrospective study of patient records, we aimed to confirm if an atherogenic lipid profile occurred in Indigenous Australians undergoing CTCA in the Northern Territory of Australia and if so, whether this correlated with the prevalence or burden of CAD. We demonstrate that Indigenous Australians have similar prevalence (52.6% vs . 50.3%, P=0.80) and burden of CAD (Leaman score 6.03±4.66 vs . 6.96±4.82, P=0.44) on CTCA as non-Indigenous patients, but were 8 years younger (41.9±8.9 vs . 50.0±11.9 years, P<0.001) at the time of examination. We confirmed the presence of an atherogenic lipid profile in Indigenous patients and showed low serum-HDL was associated with very premature (patients aged 18-35 years) CAD in comparison to premature (patients aged 36-55 years) and mature-onset (patients aged 56 years and older) CAD (0.71±0.25 vs . 1.09±0.35 vs . 1.18±0.36 mmol/L, P=0.009). Future clinical guidelines should consider the role of CTCA in Indigenous Australians and whether younger patients may benefit. The causes of premature CAD, including atherogenic lipid profiles, require an ongoing focus in order to achieve equitable cardiovascular outcomes for Indigenous and non-Indigenous Australians., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-458/coif). P.J.P. serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from July 2022 to June 2024. D.W. serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from February 2023 to January 2025. P.J.P. reports that he received speaker honoraria ad hoc from AstraZeneca and Boehringer Ingelheim related to antiplatelet/anticoagulant management of coronary syndromes; received support from Eli Lilly and NovoNordisk; and served as unpaid president of Australian Atherosclerosis Society. The other authors have no conflicts of interest to declare., (2024 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT)., Methods and Results: COCOMO-ACS was a double-blind, placebo-controlled trial that randomized 64 patients (median age 61.5 years; 9.4% female) with acute non-ST-segment elevation MI to colchicine 0.5 mg daily or placebo for a median of 17.8 months in addition to guideline-recommended therapy. Participants underwent serial OCT imaging within a matched segment of non-culprit coronary artery which contained at least one lipid-rich plaque causing ≥20% stenosis. The primary outcome was the change in minimum fibrous cap thickness (FCT) in non-culprit segments from baseline to final visit. Of those randomized, 57 (29 placebo, 28 colchicine) had evaluable imaging at baseline and follow-up. Overall, colchicine had no effect on relative (placebo +48.0±35.1% vs. colchicine +62.4±38.1%, P=0.18) or absolute changes in minimum FCT (+29.2±20.9 µm vs. +37.2±21.3 µm, P=0.18), or change in maximum lipid arc (-38.8±32.2° vs. -54.8±46.9°, P=0.18) throughout the imaged non-culprit segment. However, in patients assigned colchicine, cap rupture was less frequent (placebo 27.6% vs. colchicine 3.6%, P=0.03). In post-hoc analysis of 43 participants who had been followed for at least 16 months, minimum FCT increased to a greater extent in the colchicine group (placebo +38.7±25.4% vs. colchicine +64.7±34.1%, P=0.005)., Conclusion: In this study, OCT failed to detect an effect of colchicine on the minimum FCT or maximum lipid arc of plaques in non-culprit segments post-MI. The post-hoc observation that minimum FCT increased to a greater extent with colchicine after more prolonged treatment suggests longer-term studies may be required to detect the effect of anti-inflammatory therapies on plaque morphology by OCT., Trial Registration: Australian New Zealand Clinical Trials Registry Identifier, ACTRN12618000809235, registered on the 11th of May 2018., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Converging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX 3 CR1 + and CSF1R + source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and formation of perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally., (© 2024. The Author(s).)

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease., (© 2024 The Author(s). Medicinal Research Reviews published by Wiley Periodicals LLC.)

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management.

Despite the emergence of novel diagnostic, pharmacological, interventional, and prevention strategies, atherosclerotic cardiovascular disease remains a significant cause of morbidity and mortality. Nanoparticle (NP)-based platforms encompass diverse imaging, delivery, and pharmacological properties that provide novel opportunities for refining diagnostic and therapeutic interventions for atherosclerosis at the cellular and molecular levels. Macrophages play a critical role in atherosclerosis and therefore represent an important disease-related diagnostic and therapeutic target, especially given their inherent ability for passive and active NP uptake. In this review, we discuss an array of inorganic, carbon-based, and lipid-based NPs that provide magnetic, radiographic, and fluorescent imaging capabilities for a range of highly promising research and clinical applications in atherosclerosis. We discuss the design of NPs that target a range of macrophage-related functions such as lipoprotein oxidation, cholesterol efflux, vascular inflammation, and defective efferocytosis. We also provide examples of NP systems that were developed for other pathologies such as cancer and highlight their potential for repurposing in cardiovascular disease. Finally, we discuss the current state of play and the future of theranostic NPs. Whilst this is not without its challenges, the array of multifunctional capabilities that are possible in NP design ensures they will be part of the next frontier of exciting new therapies that simultaneously improve the accuracy of plaque diagnosis and more effectively reduce atherosclerosis with limited side effects., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Vascular inflammation plays a crucial role in the development of atherosclerosis and atherosclerotic plaque rupture resulting in acute coronary syndrome (ACS). Pericoronary adipose tissue (PCAT) attenuation quantified from routine coronary computed tomography angiography (CCTA) has emerged as a promising non-invasive imaging biomarker of coronary inflammation. However, a detailed understanding of the natural history of PCAT attenuation is required before it can be used as a surrogate endpoint in trials of novel therapies targeting coronary inflammation. This article aims to explore the natural history of PCAT attenuation and its association with changes in plaque characteristics., Methods: The Australian natuRal hISTOry of periCoronary adipose tissue attenuation, RAdiomics and plaque by computed Tomographic angiography (ARISTOCRAT) registry is a multi-centre observational registry enrolling patients undergoing clinically indicated serial CCTA in 9 centres across Australia. CCTA scan parameters will be matched across serial scans. Quantitative analysis of plaque and PCAT will be performed using semiautomated software., Discussion: The primary endpoint is to explore temporal changes in patient-level and lesion-level PCAT attenuation by CCTA and their associations with changes in plaque characteristics. Secondary endpoints include evaluating: (I) impact of statin therapy on PCAT attenuation and plaque characteristics; and (II) changes in PCAT attenuation and plaque characteristics in specific subgroups according to sex and risk factors. ARISTOCRAT will further our understanding of the natural history of PCAT attenuation and its association with changes in plaque characteristics., Trial Registration: This study has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621001018808)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-392/coif). P.J.P. serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from July 2022 to June 2024. S.J.N. as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from September 2023 to August 2025. D.T.L.W. serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from February 2021 to January 2023. K.C. was supported by the National Health and Medical Research Council postgraduate scholarship (No. APP2002573), which covers a portion of the research-related expenses and stipend to help with living expenses, research-related travel costs and other expenses associated with research project. S.J.N. received consulting fees from Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi- Regeneron, Vaxxinity, CSL Sequiris, and Novo Nordisk; received grants from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx and Sanofi-Regeneron. D.T.L.W. received honoraria for lectures from Eli-Lilly, Pfizer and Boehringer. The other authors have no conflicts of interest to declare., (2024 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Although dual antiplatelet therapy (DAPT) improves the outcomes of patients undergoing percutaneous coronary intervention (PCI), sex-specific differences in efficacy and safety of DAPT remain unresolved. We compared sex differences for DAPT outcomes and DAPT durations (1-3 months [short-term], 6 months [mid-term], and >12 months [extended] vs. 12 months)., Methods: We searched databases through 31 December 2023 for trials reporting DAPT after PCI. The endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), net adverse clinical and cerebrovascular events (NACCE), and any bleeding. Extracted data were pooled in a frequentist network and pairwise, random-effects meta-analysis., Results: Twenty-two trials (99,591 participants, 25.2% female) were included. Female sex was significantly associated with a higher 1-year MACCE risk (hazard ratio 1.14 [95% confidence interval 1.02-1.28]) and bleeding (1.13 [1.00-1.28]), but not NACCE (1.12 [0.96-1.31]). In sub-analyses, the association between female sex and MACCE was related to use of clopidogrel as the second antiplatelet agent (1.11 [1.03-1.20]), whereas higher bleeding events were related to newer P2Y12 inhibitors (P2Y12i) (1.58 [1.01-2.46]). For DAPT duration, short-term DAPT followed by P2Y12i monotherapy was non-inferior for MACCE in females and males (0.95 [95% CI 0.83-1.10; and 0.96 [0.80-1.16]) but tended to be superior in males for NACCE versus 12-month DAPT (0.96 [0.91-1.01]); mid-term DAPT tended to be associated with a lower bleeding risk in males (0.43 [0.17-1.09])., Conclusions: Female sex is associated with higher MACCE and bleeding when newer P2Y12i agents are used. Short-term DAPT followed by P2Y12i monotherapy is safe and effective in both sexes undergoing PCI., Clinical Trials Registration: PROSPERO ID: CRD42021278663., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Atherosclerosis is the build-up of fatty plaques within blood vessel walls, which can occlude the vessels and cause strokes or heart attacks. It gives rise to both structural and biomolecular changes in the vessel walls. Current single-modality imaging techniques each measure one of these two aspects but fail to provide insight into the combined changes. To address this, our team has developed a dual-modality imaging system which combines optical coherence tomography (OCT) and fluorescence imaging that is optimized for a porphyrin lipid nanoparticle that emits fluorescence and targets atherosclerotic plaques. Atherosclerosis-prone apolipoprotein (Apo)e -/- mice were fed a high cholesterol diet to promote plaque development in descending thoracic aortas. Following infusion of porphyrin lipid nanoparticles in atherosclerotic mice, the fiber-optic probe was inserted into the aorta for imaging, and we were able to robustly detect a porphyrin lipid-specific fluorescence signal that was not present in saline-infused control mice. We observed that the nanoparticle fluorescence colocalized in areas of CD68 + macrophages. These results demonstrate that our system can detect the fluorescence from nanoparticles, providing complementary biological information to the structural information obtained from simultaneously acquired OCT., (© 2024. The Author(s).)

Objectives: The identification of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia (VITT) followed the recognition of a hitherto uncommon clinical syndrome frequently associated with cerebral venous sinus thrombosis (CVST), termed 'thrombosis with thrombocytopenia' syndrome (TTS). While anecdotally recognised as rare, the background incidence of TTS is unknown. We therefore aimed to investigate the background incidence of CVST with TTS in a large, well-defined population-based CVST cohort., Methods: We performed an analysis of our previously obtained retrospective population-based cohort of patients with CVST from Adelaide, Australia (2005-2011, comprising an adult population of 953 390) to identify the background incidence of CVST associated with TTS., Results: Among 105 people with CVST, the background population-based incidence of TTS-associated CVST was 1.2 per million per year (95% CI 0.5 to 2.4). A single case of a severe CVST VITT-like syndrome with multiorgan thrombosis was identified, occurring 3 weeks postrotavirus infection., Conclusions: In our population-based study, the background incidence of CVST with associated TTS was very low, and the sole clinically severe case with multiorgan thrombosis occurred following a rotaviral precipitant. Our study establishes a benchmark against which to measure future potential 'TTS' clusters and suggests that viruses other than adenovirus may trigger this syndrome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined., Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses., Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses., Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56-73) and the median interval between angiograms was 2.1 years (IQR 1.2-3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04-4.63, p  < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21-2.7, p  = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity., Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier B.V.)

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., (© 2024 Royal Australasian College of Surgeons.)

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.

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., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

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., Competing Interests: Funding Support and Author Disclosures The Centre for Research Excellence is supported by National Health & Medical Research Council of Australia (grant number GNT1196629). Dr Figtree is funded by a National Health & Medical Research Council Practitioner Fellowship (GNT1135920). Dr Ellinor is supported by grants from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 1R01HL157635), by a grant from the American Heart Association Strategically Focused Research Networks (18SFRN34110082), and by a grant from the European Union (MAESTRIA 965286). Dr Psaltis is funded by a National Heart Foundation Level 3 Future Leader Fellowship (106656). Dr Redfern is supported by grants from the National Health & Medical Research Council of Australia (GNT2007946 and GNT1182301). Dr Wilson is supported by grants from the National Health & Medical Research Council of Australia (GNT119600, GNT9100001, GNT1153479). Dr Guzik is funded by the British Heart Foundation and European Research Council (ERC-InflammaTENSION 726318). Dr Arnott has received honoraria from Amgen and AstraZeneca. Dr Brown has received consulting fees from Novartis. Dr Bhatt has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Pharmaceuticals, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89bio; has received royalties from Elsevier; has received consulting fees from Broadview Ventures, Hims, and McKinsey; has received payment or honoraria from the American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Slack Publications, WebMD, Wiley, and Society of Cardiovascular Patient Care; has received payment for expert testimony from Arnold and Porter law firm; has received travel or meeting support from the American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association; has been named (no income) on a patent application for sotagliflozin, assigned to Brigham and Women’s Hospital, who assigned to Lexicon; serves on a Data Safety Monitoring Board for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, and Population Health Research Institute; has served on an Advisory Board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for the American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft; has stock or stock options with AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; has financial or other nonfinancial interests in Clinical Cardiology, NCDR-ACTION Registry Steering Committee, Contego Medical, American Heart Association Quality Oversight Committee, VA CART Research and Publications Committee; and is a coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical, Phillips SpectraWAVE, Svelte, and Vascular Solutions. Dr Brieger has received research grant support from Novartis and has received honoraria from BMS/Pfizer. Dr Chong has received consulting fees from Implicit Bioscience Pty; and has a provisional patent for a cell surface marker signature for arrhythmogenic pluripotent stem cell-derived cardiomyocyte. Dr Cistulli has received research grant support from ResMed and SomnoMed; has received consulting fees from RedMed, SomnoMed, and Signifier Medical Technologies; and has received honoraria from ResMed and SomnoMed. Dr Ellinor has received sponsored research support from Bayer AG and IBM Research; and has served on Advisory Boards or consulted for Bayer AG, MyoKardia, and Novartis. Dr Figtree has received personal fees from Amgen, AstraZeneca, Bayer, CSL, and Janssen; has received grants from Abbott Diagnostic and Sanofi; is a founding director and chief medical officer of Prokardia; has a patent, “Biomarkers and Oxidative Stress,” awarded in the United States in May 2017 (US9638699B2) licensed to Northern Sydney Local Health District; has a patent, “Use of P2X7R Antagonists in Cardiovascular Disease” (PCT/AU2018/050905), licensed to Prokardia; has a patent, “Methods for Treatment and Prevention of Vascular Disease” (PCT/AU2015/000548) licensed to the University of Sydney/Northern Sydney Local Health District; and has a filed provisional patent application, “Methods for Predicting Coronary Artery Disease” (USYD Ref: 2022-009-PRO-0; 2022902660) to the University of Sydney/Northern Sydney Local Health District. Dr Hagström has received research grant support to his institution from Amgen and Pfizer; and has received honoraria from Amgen, AstraZeneca, Bayer, Novo Nordisk, Amarin, and Sanofi. Dr Jenkins has received research grant support from Abbott, Medtronic, and Mylan; and has served on Advisory Boards for Abbott Diabetes Care, Amgen, Insulet, and Medtronic. Dr Keech has received grant support from Abbott, Amgen, and Mylan; has received consulting fees from AstraZeneca, Pfizer, and Sanofi; and has participated as a Data Safety Monitoring Board member for the PROMINENT trial (Kowa Research Institute). Dr Kritharides has received research grant support from Amgen; and has received consulting fees from Seqiris. Dr Meikle has a license agreement with Juvenescence Ltd; and has received consultancy payments (made to Baker Institute) from BCAL Scientific and Juvenescence Ltd. Dr Mehran has received research grant support to her institution from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Applied Therapeutics, Arena, AstraZeneca, AtriCure, BAIM, Bayer, Beth Israel Deaconess Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi-Sankyo, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe AG, Magenta, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, RenalPro, RM Global, Shockwave, and Vivasure Zoll; has received consulting fees from Cine-Med Research; has served on an Advisory Board with all payments made to institution for Abbott, Janssen, Medtronic, and Novartis; and she and/or her spouse has stock or stock options in Applied Therapeutics, ControlRad, Elixir Medical, and Stel. Dr Natarajan has received research grant support from Apple, Amgen, AstraZeneca, Boston Scientific, and Novartis; has received consulting fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genetech/Roche, Invitae, Novartis, and TenSixteen Bio; has served on Advisory Boards for Esperion Therapeutics, geneXwell, and TenSixteen Bio; and holds stock or stock options in TenSixteen Bio and geneXwell. Dr Nicholls has received research grant support from AstraZeneca, Amgen, Anthera, Cerenis, Eli Lilly, Esperion, InfraReDx, LipoScience, The Medicines Company, New Amsterdam Pharma, Novartis, Resverlogix, Roche, and Sanofi-Regeneron; and has received consulting fees from Akcea, Amarin, Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Omthera, Merck, Resverlogix, Sanofi-Regeneron, Takeda, and Vaxxinity. Dr Psaltis has received consulting fees from Amgen, Esperion Therapeutics, and Novartis; has received speaker honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Sanofi; has received meeting travel support from Amgen and AstraZeneca; and has submitted a provisional patent for a method and composition for promoting neovascularization. Dr Sundström has stock or stock options with Anagram Kommunikation AB and Symptoms Europe AB. Dr Steg has received research grant support from Amarin, Bayer, Sanofi, and Servier Laboratories; has received consulting fees from Amgen, AstraZeneca, BMS/Myokardia, Merck, Novo Nordisk, and Regeneron; has served on Steering Committees or Critical Event Committees for Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Novartis, PhaseBio, Pfizer, Sanofi, and Servier; has received honoraria from AstraZeneca, Novartis, and Novo Nordisk; and has served on Data Safety Monitoring Boards for Servier, Sanofi, and PHRI. Dr Guzik has received research funding from the European Commission (ImmuneHyperCog and BrainGutCVD studies); has served as Editor-in-Chief for Cardiovascular Research; and has served as Board Committee member for the European Society of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

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-1β 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., (© 2023 Federation of American Societies for Experimental Biology.)

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., Competing Interests: Declaration of Competing Interest P.J.P. has received research support from Abbott Vascular; has received consulting fees from Amgen and Esperion; and has received speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Merck Schering-Plough, and Pfizer. All other authors declare no other relationships relevant to this paper to disclose., (Copyright © 2023. Published by Elsevier B.V.)

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., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

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.

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 30 th 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., (© 2023 JGC All rights reserved; www.jgc301.com.)

Introduction: Recurrent event rates after myocardial infarction (MI) remain unacceptably high, in part because of the continued growth and destabilization of residual coronary atherosclerotic plaques, which may occur despite lipid-lowering therapy. Inflammation is an important contributor to this ongoing risk. Recent studies have shown that the broad-acting anti-inflammatory agent, colchicine, may reduce adverse cardiovascular events in patients post-MI, although the mechanistic basis for this remains unclear. Advances in endovascular arterial wall imaging have allowed detailed characterization of the burden and compositional phenotype of coronary plaque, along with its natural history and responsiveness to treatment. One such example has been the use of optical coherence tomography (OCT) to demonstrate the plaque-stabilizing effects of statins on both fibrous cap thickness and the size of lipid pools within plaque., Methods: The Phase 2, multi-centre, double-blind colchicine for coronary plaque modification in acute coronary syndrome (COCOMO-ACS) study will evaluate the effect of colchicine 0.5 mg daily on coronary plaque features using serial OCT imaging in patients following MI. Recruitment for the trial has been completed with 64 participants with non-ST elevation MI randomized 1:1 to colchicine or placebo in addition to guideline recommended therapies, including high-intensity statins. The primary endpoint is the effect of colchicine on the minimal fibrous cap thickness of non-culprit plaque over an 18-month period. The COCOMO-ACS study will determine whether addition of colchicine 0.5 mg daily to standard post-MI treatment has incremental benefits on high-risk features of coronary artery plaques. If confirmed, this will provide new mechanistic insights into how colchicine may confer clinical benefits in patients with atherosclerotic cardiovascular disease., Trial Registration: ANZCTR trial registration number: ACTRN12618000809235. Date of trial registration: 11th of May 2018., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)