Publications by authors named "Peter J Psaltis"

138 Publications

Institutional variation in early mortality following isolated coronary artery bypass graft surgery.

Int J Cardiol 2022 Apr 30. Epub 2022 Apr 30.

Department of Cardiology, The Prince Charles Hospital, Brisbane, Australia; School of Clinical Medicine, The University of Queensland, Brisbane, Australia. Electronic address:

Background: Thirty-day mortality following coronary artery bypass grafting (CABG) is a widely accepted marker for quality of care. Although surgical mortality has declined, the utility of this measure to profile quality has not been questioned. We assessed the institutional variation in risk-standardised mortality rates (RSMR) following isolated CABG within Australia and New Zealand (ANZ).

Methods: We used an administrative dataset from all public and most private hospitals across ANZ to capture all isolated CABG procedures recorded between 2010 and 2015. The primary outcome was all-cause death occurring in-hospital or within 30-days of discharge. Hospital-specific RSMRs and 95% CI were estimated using a hierarchical generalised linear model accounting for differences in patient characteristics.

Results: Overall, 60,953 patients (mean age 66.1 ± 10.1y, 18.7% female) underwent an isolated CABG across 47 hospitals. The observed early mortality rate was 1.69% (n = 1029) with 81.8% of deaths recorded in-hospital. The risk-adjustment model was developed with good discrimination (C-statistic = 0.81). Following risk-adjustment, a 3.9-fold variation was observed in RSMRs among hospitals (median:1.72%, range:0.84-3.29%). Four hospitals had RSMRs significantly higher than average, and one hospital had RSMR lower than average. When in-hospital mortality alone was considered, the median in-hospital RSMR was 1.40% with a 5.6-fold variation across institutions (range:0.57-3.19%).

Conclusions: Average mortality following isolated CABG is low across ANZ. Nevertheless, in-hospital and 30-day mortality vary among hospitals, highlighting potential disparities in care quality and the enduring usefulness of 30-day mortality as an outcome measure. Clinical and policy interventions, including participating in clinical quality registries, are needed to standardise CABG care.
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http://dx.doi.org/10.1016/j.ijcard.2022.04.080DOI Listing
April 2022

Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction.

JACC Cardiovasc Imaging 2022 Mar 16. Epub 2022 Mar 16.

South Australian Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School, University of Adelaide, Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.

Objectives: The purpose of this study was to determine the effect of evolocumab on optical coherence tomography (OCT) measures of plaque composition.

Background: The proprotein convertase subtilisin kexin type-9 inhibitor evolocumab produced coronary atheroma regression in statin-treated patients.

Methods: Patients with a non-ST-segment elevation myocardial infarction were treated with monthly evolocumab 420 mg (n = 80) or placebo (n = 81) for 52 weeks. Patients underwent serial OCT and intravascular ultrasound imaging within a matched arterial segment of a nonculprit vessel. The primary analysis determined the change in the minimum fibrous cap thickness and maximum lipid arc throughout the imaged arterial segment. Additional analyses determined changes in OCT features in lipid-rich plaque regions and plaque burden. Safety and tolerability were evaluated.

Results: Among treated patients, (age 60.5 ± 9.6 years; 28.6% women; low-density lipoprotein cholesterol [LDL-C], 141.3 ± 33.1 mg/dL), 135 had evaluable imaging at follow-up. The evolocumab group achieved lower LDL-C levels (28.1 vs 87.2 mg/dL; P < 0.001). The evolocumab group demonstrated a greater increase in minimum fibrous cap thickness (+42.7 vs +21.5 μm; P = 0.015) and decrease in maximum lipid arc (-57.5 vs. -31.4; P = 0.04) and macrophage index (-3.17 vs -1.45 mm; P = 0.04) throughout the arterial segment. Similar benefits of evolocumab were observed in lipid-rich plaque regions. Greater regression of percent atheroma volume was observed with evolocumab compared with placebo (-2.29% ± 0.47% vs -0.61% ± 0.46%; P = 0.009). The groups did not differ regarding changes in microchannels or calcium.

Conclusions: The combination of statin and evolocumab after a non-ST-segment elevation myocardial infarction produces favorable changes in coronary atherosclerosis consistent with stabilization and regression. This demonstrates a potential mechanism for the improved clinical outcomes observed achieving very low LDL-C levels following an acute coronary syndrome. (Imaging of Coronary Plaques in Participants Treated With Evolocumab; NCT03570697).
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http://dx.doi.org/10.1016/j.jcmg.2022.03.002DOI Listing
March 2022

Emerging evidence for the use of colchicine for secondary prevention of coronary heart disease.

Med J Aust 2022 05 8;216(8):385-387. Epub 2022 Apr 8.

Heart and Vascular Research Institute, Harry Perkins Institute of Medical Research, Perth, WA.

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http://dx.doi.org/10.5694/mja2.51488DOI Listing
May 2022

Prevalence and real-world management of NSTEMI with multivessel disease.

Cardiovasc Diagn Ther 2022 Feb;12(1):1-11

Department of Cardiology, Central Adelaide Local Health Network (CALHN), Adelaide, Australia.

Background: Non-ST elevation myocardial infarction (NSTEMI) has higher post-discharge mortality than ST-elevation myocardial infarction (STEMI). Prognosis worsens in those with multivessel coronary disease (MVD). However, information about the prevalence and extent of MVD in NSTEMI is limited, in turn limiting insights into optimal treatment strategies. This study aimed to define the prevalence and extent of MVD, preferred treatment strategies and the predictors of MVD in a real-world NSTEMI population.

Methods: The Coronary Angiogram Database of South Australia (CADOSA) was used to identify consecutive patients presenting to major teaching hospitals with NSTEMI between 2012 and 2016. Obtaining clinical and angiographic details, patients were stratified by the number of significantly diseased vessels (0,1,2,3-VD), defined by a stenosis of ≥70%, or ≥50% in the left main coronary artery. Data was analysed retrospectively.

Results: The prevalence of MVD (2- or 3-VD) was 42% amongst 3,722 NSTEMI presentations. Multivariate logistic regression modelling showed age, male gender, diabetes, dyslipidaemia and prior myocardial infarction predicted MVD over 1-VD or 0-VD. Percutaneous coronary intervention (PCI) was performed in 42% of patients with MVD. This comprised 61% of 2-VD patients and only 22% of 3-VD patients, with 24% and 66% of each group referred for coronary bypass grafting, respectively. Among MVD patients treated with PCI, 76% had their culprit lesion treated alone in the index admission.

Conclusions: In this NSTEMI cohort, over 40% had MVD. Notably, a minority of patients with MVD undergoing PCI received multivessel revascularisation. This real-world practice emphasises that further evaluation is required to determine whether complete revascularisation is beneficial in NSTEMI, as reported for STEMI.
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http://dx.doi.org/10.21037/cdt-21-518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898694PMC
February 2022

3D-Printed Micro Lens-in-Lens for In Vivo Multimodal Microendoscopy.

Small 2022 Apr 1;18(17):e2107032. Epub 2022 Mar 1.

Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, SA, 5005, Australia.

Multimodal microendoscopes enable co-located structural and molecular measurements in vivo, thus providing useful insights into the pathological changes associated with disease. However, different optical imaging modalities often have conflicting optical requirements for optimal lens design. For example, a high numerical aperture (NA) lens is needed to realize high-sensitivity fluorescence measurements. In contrast, optical coherence tomography (OCT) demands a low NA to achieve a large depth of focus. These competing requirements present a significant challenge in the design and fabrication of miniaturized imaging probes that are capable of supporting high-quality multiple modalities simultaneously. An optical design is demonstrated which uses two-photon 3D printing to create a miniaturized lens that is simultaneously optimized for these conflicting imaging modalities. The lens-in-lens design contains distinct but connected optical surfaces that separately address the needs of both fluorescence and OCT imaging within a lens of 330 µm diameter. This design shows an improvement in fluorescence sensitivity of >10x in contrast to more conventional fiber-optic design approaches. This lens-in-lens is then integrated into an intravascular catheter probe with a diameter of 520 µm. The first simultaneous intravascular OCT and fluorescence imaging of a mouse artery in vivo is reported.
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http://dx.doi.org/10.1002/smll.202107032DOI Listing
April 2022

Equivalent Carbon Number and Interclass Retention Time Conversion Enhance Lipid Identification in Untargeted Clinical Lipidomics.

Anal Chem 2022 03 14;94(8):3476-3484. Epub 2022 Feb 14.

Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5000, South Australia, Australia.

Chromatography is often used as a method for reducing sample complexity prior to analysis by mass spectrometry, and the use of retention time (RT) is becoming increasingly popular to add valuable supporting information in lipid identification. The RT of lipids with the same headgroup in reversed-phase separation can be predicted using the equivalent carbon number (ECN) model. This model describes the effects of acyl chain length and degree of saturation on lipid RT. For the first time, we have found a robust correlation in the chromatographic separation of lipids with different headgroups that share the same fatty acid motive. This relationship can be exploited to perform interclass RT conversion (IC-RTC) by building a model from RT measurements from lipid standards that allows the prediction of RT of one lipid subclass based on another. Here, we utilize ECN modeling and IC-RTC to build a glycerophospholipid RT library with 517 entries based on 136 tandem mass spectrometry-characterized lipid RTs from NIST SRM-1950 plasma and lipid standards. The library was tested on a patient cohort undergoing coronary artery bypass grafting surgery ( = 37). A total of 156 unique circulating glycerophospholipids were identified, of which 52 (1 LPG, 24 PE, 5 PG, 18 PI, and 9 PS) were detected with IC-RTC, thereby demonstrating the utility of this technique for the identification of lipid species not found in commercial standards.
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http://dx.doi.org/10.1021/acs.analchem.1c03770DOI Listing
March 2022

Optical Coherence Tomography Based Biomechanical Fluid-Structure Interaction Analysis of Coronary Atherosclerosis Progression.

J Vis Exp 2022 01 15(179). Epub 2022 Jan 15.

Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI); Adelaide Medical School, University of Adelaide; Department of Cardiology, Central Adelaide Local Health Network.

In this paper, we present a complete workflow for the biomechanical analysis of atherosclerotic plaque in the coronary vasculature. With atherosclerosis as one of the leading causes of global death, morbidity and economic burden, novel ways of analyzing and predicting its progression are needed. One such computational method is the use of fluid-structure interaction (FSI) to analyze the interaction between the blood flow and artery/plaque domains. Coupled with in vivo imaging, this approach could be tailored to each patient, assisting in differentiating between stable and unstable plaques. We outline the three-dimensional reconstruction process, making use of intravascular Optical Coherence Tomography (OCT) and invasive coronary angiography (ICA). The extraction of boundary conditions for the simulation, including replicating the three-dimensional motion of the artery, is discussed before the setup and analysis is conducted in a commercial finite element solver. The procedure for describing the highly nonlinear hyperelastic properties of the artery wall and the pulsatile blood velocity/pressure is outlined along with setting up the system coupling between the two domains. We demonstrate the procedure by analyzing a non-culprit, mildly stenotic, lipid-rich plaque in a patient following myocardial infarction. Established and emerging markers related to atherosclerotic plaque progression, such as wall shear stress and local normalized helicity, respectively, are discussed and related to the structural response in the artery wall and plaque. Finally, we translate the results to potential clinical relevance, discuss limitations, and outline areas for further development. The method described in this paper shows promise for aiding in the determination of sites at risk of atherosclerotic progression and, hence, could assist in managing the significant death, morbidity, and economic burden of atherosclerosis.
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http://dx.doi.org/10.3791/62933DOI Listing
January 2022

Eukaryotic elongation factor 2 kinase regulates foam cell formation via translation of CD36.

FASEB J 2022 02;36(2):e22154

Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical protein kinase that controls protein synthesis in cells under stress. Although well studied in cancer, less is known about its roles in chronic inflammatory diseases. Here, we examined its regulation of macrophage cholesterol handling in the context of atherosclerosis. eEF2K mRNA expression and protein activity were upregulated in murine bone marrow-derived macrophages (BMDMs) exposed to oxidized low-density lipoprotein cholesterol (oxLDL). When incubated with oxLDL, BMDMs from eEF2K knockout (Eef2k ) mice formed fewer Oil Red O foam cells than Eef2k BMDMs (12.5% ± 2.3% vs. 32.3% ± 2.0%, p < .01). Treatment with a selective eEF2K inhibitor, JAN-384, also decreased foam cell formation for C57BL/6J BMDMs and human monocyte-derived macrophages. Disabling eEF2K selectively decreased protein expression of the CD36 cholesterol uptake receptor, mediated by a reduction in the proportion of translationally active Cd36 mRNA. Eef2k mice bred onto the Ldlr background developed aortic sinus atherosclerotic plaques that were 30% smaller than Eef2k -Ldlr mice after 16 weeks of high cholesterol diet (p < .05). Although accompanied by a reduction in plaque CD36 staining (p < .05) and lower CD36 expression in circulating monocytes (p < .01), this was not associated with reduced lipid content in plaques as measured by oil red O staining. Finally, EEF2K and CD36 mRNA levels were higher in blood mononuclear cells from patients with coronary artery disease and recent myocardial infarction compared to healthy controls without coronary artery disease. These results reveal a new role for eEF2K in translationally regulating CD36 expression and foam cell formation in macrophages. Further studies are required to explore therapeutic targeting of eEF2K in atherosclerosis.
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http://dx.doi.org/10.1096/fj.202101034RDOI Listing
February 2022

DelIrium VULnerability in GEriatrics (DIVULGE) study: a protocol for a prospective observational study of electroencephalogram associations with incident postoperative delirium.

BMJ Neurol Open 2021 6;3(2):e000199. Epub 2021 Dec 6.

Cognitive Ageing and Impairment Neurosciences Laboratory, Justice and Society, University of South Australia, Adelaide, South Australia, Australia.

Introduction: Delirium is a neurocognitive disorder common in older adults in acute care settings. Those who develop delirium are at an increased risk of dementia, cognitive decline and death. Electroencephalography (EEG) during delirium in older adults is characterised by slowing and reduced functional connectivity, but markers of vulnerability are poorly described. We aim to identify EEG spectral power and event-related potential (ERP) markers of incident delirium in older adults to understand neural mechanisms of delirium vulnerability. Characterising delirium vulnerability will provide substantial theoretical advances and outcomes have the potential to be translated into delirium risk assessment tools.

Methods And Analysis: We will record EEG in 90 participants over 65 years of age prior to elective coronary artery bypass grafting (CABG) or transcatheter aortic valve implantation (TAVI). We will record 4-minutes of resting state (eyes open and eyes closed) and a 5-minute frequency auditory oddball paradigm. Outcome measures will include frequency band power, 1/f offset and slope, and ERP amplitude measures. Participants will undergo cognitive and EEG testing before their elective procedures and daily postoperative delirium assessments. Group allocation will be done retrospectively by linking preoperative EEG data according to postoperative delirium status (presence, severity, duration and subtype).

Ethics And Dissemination: This study is approved by the Human Research Ethics Committee of the Royal Adelaide Hospital, Central Adelaide Local Health Network and the University of South Australia Human Ethics Committee. Findings will be disseminated through peer-reviewed journal articles and presentations at national and international conferences.

Trial Registration Number: ACTRN12618001114235 and ACTRN12618000799257.
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http://dx.doi.org/10.1136/bmjno-2021-000199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653776PMC
December 2021

Patient Endothelial Colony-Forming Cells to Model Coronary Artery Disease Susceptibility and Unravel the Role of Dysregulated Mitochondrial Redox Signalling.

Antioxidants (Basel) 2021 Sep 29;10(10). Epub 2021 Sep 29.

Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia.

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), = 0.031), and less likely in patients with obesity (OR 0.62 [95% CI 0.40-0.95], = 0.027) or obstructive CAD (stenosis > 50%) (OR 0.60 [95% CI 0.38-0.95], = 0.027). ECFCs from patients with CAD had higher mitochondrial production of superoxide (O-MitoSOX assay). The latter was strongly correlated with the severity of CAD as measured by either coronary artery calcium score (R = 0.46; = 0.0051) or Gensini Score (R = 0.67; = 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.
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http://dx.doi.org/10.3390/antiox10101547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532880PMC
September 2021

The Role of miR-181c in Mechanisms of Diabetes-Impaired Angiogenesis: An Emerging Therapeutic Target for Diabetic Vascular Complications.

Front Pharmacol 2021 13;12:718679. Epub 2021 Aug 13.

Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Diabetes mellitus is estimated to affect up to 700 million people by the year 2045, contributing to an immense health and economic burden. People living with diabetes have a higher risk of developing numerous debilitating vascular complications, leading to an increased need for medical care, a reduced quality of life and increased risk of early death. Current treatments are not satisfactory for many patients who suffer from impaired angiogenesis in response to ischaemia, increasing their risk of ischaemic cardiovascular conditions. These vascular pathologies are characterised by endothelial dysfunction and abnormal angiogenesis, amongst a host of impaired signaling pathways. Therapeutic stimulation of angiogenesis holds promise for the treatment of diabetic vascular complications that stem from impaired ischaemic responses. However, despite significant effort and research, there are no established therapies that directly stimulate angiogenesis to improve ischaemic complications such as ischaemic heart disease and peripheral artery disease, highlighting the immense unmet need. However, despite significant effort and research, there are no established therapies that directly stimulate angiogenesis in a clinical setting, highlighting the immense unmet need. MicroRNAs (miRNAs) are emerging as powerful targets for multifaceted diseases including diabetes and cardiovascular disease. This review highlights the potential role of microRNAs as therapeutic targets for rescuing diabetes-impaired angiogenesis, with a specific focus on miR-181c, which we have previously identified as an important angiogenic regulator. Here we summarise the pathways currently known to be regulated by miR-181c, which include the classical angiogenesis pathways that are dysregulated in diabetes, mitochondrial function and axonal guidance, and describe how these relate both directly and indirectly to angiogenesis. The pleiotropic actions of miR-181c across multiple key angiogenic signaling pathways and critical cellular processes highlight its therapeutic potential as a novel target for treating diabetic vascular complications.
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http://dx.doi.org/10.3389/fphar.2021.718679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414254PMC
August 2021

Identifying New Factors Associated With Cognitive Decline and Delirium After Transcatheter Aortic Valve Implantation: A Study Protocol.

Front Cardiovasc Med 2021 11;8:657057. Epub 2021 Aug 11.

Cognitive Ageing and Impairment Neurosciences Laboratory, Justice and Society, University of South Australia, Adelaide, SA, Australia.

Transcatheter aortic valve implantation (TAVI) has become the standard-of-care for treatment of severe symptomatic aortic stenosis and is also being increasingly recommended for low-risk patients. While TAVI boasts positive post-procedural outcomes, it is also associated with cognitive complications, namely delirium and cognitive decline. There is a pressing need for accurate risk tools which can identify TAVI patients at risk of delirium and cognitive decline, as risk scores designed for general cardiovascular surgery fall short. The present effect-finding exploratory study will assess the utility of various measures in the context of aging and frailty in predicting who will and who will not develop delirium or cognitive impairment following TAVI. The measures we propose include gait, visual symptoms, voice, swallowing, mood and sleep. This is an observational prospective cohort study focused on identifying pre-procedural risk factors for the development of delirium and cognitive decline following TAVI. Potential risk factors will be measured prior to TAVI. Primary outcomes will be post-procedure cognitive decline and delirium. Secondary outcomes include activities of daily living, quality of life, and mortality. Delirium presence will be measured on each of the first 2 days following TAVI. All other outcomes will be assessed at 3-, 6-, and 12-months post-operatively. A series of logistic regressions will be run to investigate the relationship between potential predictors and outcomes (presence vs. absence of either delirium or cognitive decline). This study will assess the strengths of associations between a range of measures drawn from frailty and aging literature in terms of association with cognitive decline and delirium following TAVI. Identified measures can be used in future development of TAVI risk prediction models, which are essential for the accurate identification of cognitive at-risk patients and successful application of pre-procedural interventions. This trial is registered with the Australian New Zealand Clinical Trials Registry. [https://bit.ly/2PAotP5], [ACTRN12618001114235].
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http://dx.doi.org/10.3389/fcvm.2021.657057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385234PMC
August 2021

Assessing the Impact of Colchicine on Coronary Plaque Phenotype After Myocardial Infarction with Optical Coherence Tomography: Rationale and Design of the COCOMO-ACS Study.

Cardiovasc Drugs Ther 2021 Aug 25. Epub 2021 Aug 25.

Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.

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.
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http://dx.doi.org/10.1007/s10557-021-07240-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384919PMC
August 2021

The Emerging Role of CT-Based Imaging in Adipose Tissue and Coronary Inflammation.

Cells 2021 05 13;10(5). Epub 2021 May 13.

Monash Cardiovascular Research Centre, Victorian Heart Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University and Monash Heart, Monash Health, Clayton, VIC 3168, Australia.

A large body of evidence arising from recent randomized clinical trials demonstrate the association of vascular inflammatory mediators with coronary artery disease (CAD). Vascular inflammation localized in the coronary arteries leads to an increased risk of CAD-related events, and produces unique biological alterations to local cardiac adipose tissue depots. Coronary computed tomography angiography (CTA) provides a means of mapping inflammatory changes to both epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) as independent markers of coronary risk. Radiodensity or attenuation of PCAT on coronary CTA, notably, provides indirect quantification of coronary inflammation and is emerging as a promising non-invasive imaging implement. An increasing number of observational studies have shown robust associations between PCAT attenuation and major coronary events, including acute coronary syndrome, and 'vulnerable' atherosclerotic plaque phenotypes that are associated with an increased risk of the said events. This review outlines the biological characteristics of both EAT and PCAT and provides an overview of the current literature on PCAT attenuation as a surrogate marker of coronary inflammation.
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http://dx.doi.org/10.3390/cells10051196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153638PMC
May 2021

Multimodality Intravascular Imaging of High-Risk Coronary Plaque.

JACC Cardiovasc Imaging 2022 01 19;15(1):145-159. Epub 2021 May 19.

Adelaide Medical School, University of Adelaide, Adelaide, Australia; Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia; Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, Australia. Electronic address:

The majority of coronary atherothrombotic events presenting as myocardial infarction (MI) occur as a result of plaque rupture or erosion. Understanding the evolution from a stable plaque into a life-threatening, high-risk plaque is required for advancing clinical approaches to predict atherothrombotic events, and better treat coronary atherosclerosis. Unfortunately, none of the coronary imaging approaches used in clinical practice can reliably predict which plaques will cause an MI. Currently used imaging techniques mostly identify morphological features of plaques, but are not capable of detecting essential molecular characteristics known to be important drivers of future risk. To address this challenge, engineers, scientists, and clinicians have been working hand-in-hand to advance a variety of multimodality intravascular imaging techniques, whereby 2 or more complementary modalities are integrated into the same imaging catheter. Some of these have already been tested in early clinical studies, with other next-generation techniques also in development. This review examines these emerging hybrid intracoronary imaging techniques and discusses their strengths, limitations, and potential for clinical translation from both an engineering and clinical perspective.
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http://dx.doi.org/10.1016/j.jcmg.2021.03.028DOI Listing
January 2022

Circadian disruption by short light exposure and a high energy diet impairs glucose tolerance and increases cardiac fibrosis in Psammomys obesus.

Sci Rep 2021 05 6;11(1):9673. Epub 2021 May 6.

South Australian Health & Medical Research Institute, Adelaide, Australia.

Type 2 diabetes mellitus (T2DM) increases cardiac inflammation which promotes the development of cardiac fibrosis. We sought to determine the impact of circadian disruption on the induction of hyperglycaemia, inflammation and cardiac fibrosis.

Methods: Psammomys obesus (P. obesus) were exposed to neutral (12 h light:12 h dark) or short (5 h light:19 h dark) photoperiods and fed a low energy (LE) or high energy (HE) diet for 8 or 20 weeks. To determine daily rhythmicity, P. obesus were euthanised at 2, 8, 14, and 20 h after 'lights on'.

Results: P. obesus exposed to a short photoperiod for 8 and 20 weeks had impaired glucose tolerance following oral glucose tolerance testing, compared to a neutral photoperiod exposure. This occurred with both LE and HE diets but was more pronounced with the HE diet. Short photoperiod exposure also increased myocardial perivascular fibrosis after 20 weeks on LE (51%, P < 0.05) and HE (44%, P < 0.05) diets, when compared to groups with neutral photoperiod exposure. Short photoperiod exposure caused elevations in mRNA levels of hypertrophy gene Nppa (atrial natriuretic peptide) and hypertrophy transcription factors Gata4 and Mef2c in myocardial tissue after 8 weeks.

Conclusion: Exposure to a short photoperiod causes impaired glucose tolerance in P. obesus that is exacerbated with HE diet and is accompanied by an induction in myocardial perivascular fibrosis.
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http://dx.doi.org/10.1038/s41598-021-89191-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102519PMC
May 2021

Surgical and percutaneous management of Aboriginal Australians with rheumatic heart disease: Timeliness and concordance between practice and guidelines.

Int J Cardiol 2021 07 18;335:80-84. Epub 2021 Apr 18.

Aboriginal Health Equity Theme, South Australian Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, Australia.

Background: Rheumatic heart disease (RHD) affects over 40 million people globally who are predominantly young and from impoverished communities. The barriers to valvular intervention are complex and contribute to the high morbidity and mortality associated with RHD. The rates of guideline indicated intervention in patients with significant RHD have not yet been reported.

Methods: From 2007 to 2017, we used the Australian Northern Territory Cardiac Database to identify patients with RHD who fulfilled at least one ESC/EACTS guideline indication for mitral valve intervention. Baseline clinical status, comorbidities, echocardiographic parameters, indication for intervention, referral and any interventions were recorded.

Results: 154 patients (mean age 38.5 ± 14.6, 66.1% female) were identified as having a class I or IIa indication for invasive management. Symptoms, atrial fibrillation and pulmonary hypertension were the most common indications for surgery (74.5%, 48.1%, 40.9%). From the onset of a guideline indication the actuarial rates of accepted referral and intervention within two-years were 66.0% ± 4.0% and 53.1% ± 4.4% respectively. Of those who were referred and accepted for intervention, 86% received it within 2 years. The rates of accepted referral for patients with class I indications were 72.5% ± 4.2% while class IIa indications were 42.5% ± 9.0% (p<0.001).

Conclusions: Approximately half of Aboriginal patients with significant rheumatic mitral valve disease who met ESC/EACTS guideline indications for intervention received surgery or valvuloplasty within two-years. A significant difference in referral rates was found between Class I and Class IIa indications for valvular intervention.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.030DOI Listing
July 2021

Omega-3 fatty acids ameliorate vascular inflammation: A rationale for their atheroprotective effects.

Atherosclerosis 2021 05 17;324:27-37. Epub 2021 Mar 17.

Discipline of Medicine, University of Adelaide, Adelaide, Australia; Kolling Institute, University of Sydney, Sydney, Australia. Electronic address:

Background And Aims: Clinical trials have demonstrated reductions in major adverse cardiovascular events with purified high-dose eicosapentaenoic acid (EPA), independent of effects on lipids. We aimed to investigate whether omega-3 fatty acids reduce vascular inflammation, a critical mediator of atherosclerosis, and hypothesised that EPA is superior to docosahexaenoic acid (DHA).

Methods: In a double-blind randomised controlled trial and cell-culture study, 40 healthy volunteers were supplemented with 4 g daily of either EPA, DHA, fish oil (2:1 EPA:DHA), or placebo for 30 days. Serum was incubated with TNF-stimulated human umbilical vein endothelial cells (HUVECs), and markers of acute vascular inflammation (AVI) were measured. The effects of EPA, DHA (600 mg/kg/day), olive oil, or no treatment were also measured in preclinical models of [1] AVI using a periarterial collar (C57Bl/6J; n = 40 mice) and [2] atherosclerosis where ApoE mice (n = 40) were fed a 16-week atherogenic diet.

Results: EPA supplementation reduced expression of C-C motif chemokine ligand 2 (CCL2) by 25% compared to placebo (p = 0.03). In the AVI model, EPA reduced vascular expression of VCAM1 by 43% (p = 0.02) and CCL2 by 41% (p = 0.03). Significant inverse correlations were observed between EPA levels and vascular expression of VCAM1 (r = -0.56, p = 0.001) and CCL2 (r = -0.56, p = 0.001). In ApoE mice, EPA reduced aortic expression of Il1b by 44% (p = 0.04) and Tnf by 49% (p = 0.04), with similar inverse correlations between EPA levels and both Il1b (r = -0.63, p = 0.009) and Tnf (r = -0.50, p = 0.04).

Conclusions: Supplementation with EPA, more so than DHA, ameliorates acute and chronic vascular inflammation, providing a rationale for the cardiovascular benefit observed with high dose omega-3 fatty acid administration.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.003DOI Listing
May 2021

In Vivo Based Fluid-Structure Interaction Biomechanics of the Left Anterior Descending Coronary Artery.

J Biomech Eng 2021 08;143(8)

Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia 5000, Australia; Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5005, Australia; Department of Cardiology, Central Adelaide Local Health Network, Adelaide, South Australia 5000, Australia.

A fluid-structure interaction-based biomechanical model of the entire left anterior descending coronary artery is developed from in vivo imaging via the finite element method in this paper. Included in this investigation is ventricle contraction, three-dimensional motion, all angiographically visible side branches, hyper/viscoelastic artery layers, non-Newtonian and pulsatile blood flow, and the out-of-phase nature of blood velocity and pressure. The fluid-structure interaction model is based on in vivo angiography of an elite athlete's entire left anterior descending coronary artery where the influence of including all alternating side branches and the dynamical contraction of the ventricle is investigated for the first time. Results show the omission of side branches result in a 350% increase in peak wall shear stress and a 54% decrease in von Mises stress. Peak von Mises stress is underestimated by up to 80% when excluding ventricle contraction and further alterations in oscillatory shear indices are seen, which provide an indication of flow reversal and has been linked to atherosclerosis localization. Animations of key results are also provided within a video abstract. We anticipate that this model and results can be used as a basis for our understanding of the interaction between coronary and myocardium biomechanics. It is hoped that further investigations could include the passive and active components of the myocardium to further replicate in vivo mechanics and lead to an understanding of the influence of cardiac abnormalities, such as arrythmia, on coronary biomechanical responses.
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http://dx.doi.org/10.1115/1.4050540DOI Listing
August 2021

Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study.

Cardiovasc Diagn Ther 2021 Feb;11(1):120-129

Monash Cardiovascular Research Centre, Clayton, Australia.

Background: Technological advances in arterial wall imaging permit the opportunity to visualize coronary atherosclerotic plaque with sufficient resolution to characterize both its burden and compositional phenotype. These modalities have been used extensively in clinical trials to evaluate the impact of lipid lowering therapies on serial changes in disease burden. While the findings have unequivocally established that these interventions have the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved, their impact on plaque phenotype is less certain. More recently optical coherence tomography (OCT) has been employed with a number of studies demonstrating favorable effects on both fibrous cap thickness (FCT) and the size of lipid pools within plaque in response to statin treatment.

Methods: The phase 3, multi-center, double-blind HUYGENS study will assess the impact of incremental lipid lowering with the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab, on plaque features using serial OCT imaging, in statin-treated patients following an acute coronary syndrome (ACS). Subjects with non-ST-elevation ACS (n=150) will be randomized 1:1 into two groups to receive monthly injections of evolocumab 420 mg or placebo.

Results: The primary endpoint is the effect of evolocumab on coronary atherosclerotic plaques will be assessed by OCT at baseline and at week 50.

Conclusions: The HUYGENS study will determine whether intensified lipid lowering therapy with evolocumab in addition to maximally tolerated statin therapy will have incremental benefits on high-risk features of coronary artery plaques.

Trial Registration: This study was registered on Clinicaltrials.gov (NCT03570697).
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http://dx.doi.org/10.21037/cdt-20-684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944215PMC
February 2021

Elevated HDL-bound miR-181c-5p level is associated with diabetic vascular complications in Australian Aboriginal people.

Diabetologia 2021 06 2;64(6):1402-1411. Epub 2021 Mar 2.

South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Aims/hypothesis: Diabetes is a major burden on Australia's Indigenous population, with high rates of disease and vascular complications. Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. MicroRNAs (miRNAs) are key players in the regulation of angiogenesis. HDL-cholesterol (HDL-c) levels are inversely associated with the risk of developing diabetic complications and HDL can carry miRNAs. HDL-miRNA profiles differ in disease states and may present as biomarkers with the capacity to act as bioactive signalling molecules. Recent studies have demonstrated that HDL becomes dysfunctional in a diabetic environment, losing its vasculo-protective effects and becoming more pro-atherogenic. We sought to determine whether HDL-associated miRNA profiles and HDL functionality were predictive of the severity of diabetic vascular complications in Australia's Indigenous population.

Methods: HDL was isolated from plasma samples from Indigenous participants without diabetes ('Healthy'), with type 2 diabetes mellitus ('T2DM') and with diabetes-associated macrovascular complications (specifically peripheral artery disease, 'T2DM+Comp'). To assess HDL angiogenic capacity, human coronary artery endothelial cells were treated with PBS, reconstituted HDL (rHDL, positive control) or isolated HDL and then exposed to high-glucose (25 mmol/l) conditions. The expression levels of two anti-angiogenic miRNAs (miR-181c-5p and miR-223-3p) and one pro-angiogenic miRNA (miR-27b-3p) were measured in the HDL fraction, plasma and treated human coronary artery endothelial cells by quantitative real-time PCR. In vitro endothelial tubule formation was assessed using the Matrigel tubulogenesis assay.

Results: Strikingly, we found that the levels of the anti-angiogenic miRNA miR-181c-5p were 14-fold higher (1454 ± 1346%) in the HDL from Aboriginal people with diabetic complications compared with both the Healthy (100 ± 121%, p < 0.05) and T2DM (82 ± 77%, p < 0.05) groups. Interestingly, we observed a positive correlation between HDL-associated miR-181c-5p levels and disease severity (p = 0.0020). Under high-glucose conditions, cells treated with rHDL, Healthy HDL and T2DM HDL had increased numbers of tubules (rHDL: 136 ± 8%, p < 0.01; Healthy HDL: 128 ± 6%, p < 0.01; T2DM HDL: 124 ± 5%, p < 0.05) and branch points (rHDL: 138 ± 8%, p < 0.001; Healthy HDL: 128 ± 6%, p < 0.01; T2DM HDL: 127 ± 5%, p < 0.01) concomitant with elevations in mRNA levels of the key hypoxia angiogenic transcription factor HIF1A (rHDL: 140 ± 10%, p < 0.01; Healthy HDL: 136 ± 8%, p < 0.01; T2DM HDL: 133 ± 9%, p < 0.05). However, this increase in angiogenic capacity was not observed in cells treated with T2DM + Comp HDL (tubule numbers: 113 ± 6%, p = 0.32; branch points: 113 ± 5%, p = 0.28; HIF1A: 117 ± 6%, p = 0.43), which could be attributed to the increase in cellular miR-181c-5p levels (T2DM + Comp HDL: 136 ± 7% vs PBS: 100 ± 9%, p < 0.05).

Conclusions/interpretation: In conclusion, HDL from Aboriginal people with diabetic complications had reduced angiogenic capacity. This impairment is associated with an increase in the expression of anti-angiogenic miR-181c-5p. These findings provide the rationale for a new way to better inform clinical diagnosis of disease severity with the potential to incorporate targeted, personalised HDL-miRNA intervention therapies to prevent further development of, or to reverse, diabetic vascular complications in Australian Aboriginal people.
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http://dx.doi.org/10.1007/s00125-021-05414-6DOI Listing
June 2021

Long-term outcomes following endovascular and surgical revascularization for peripheral artery disease: a propensity score-matched analysis.

Eur Heart J 2021 12;43(1):32-40

School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia.

Aims: Peripheral artery disease (PAD) revascularization can be performed by either endovascular or open surgical approach. Despite increasing use of endovascular revascularization, it is still uncertain which strategy yields better long-term outcomes.

Methods And Results: This retrospective cohort study evaluated patients hospitalized with PAD in Australia and New Zealand who underwent either endovascular or surgical revascularization between 2008 and 2015, and compared procedures using a propensity score-matched analysis. Hybrid interventions were excluded. The primary endpoint was mortality or major adverse limb events (MALE), defined as a composite endpoint of acute limb ischaemia, urgent surgical or endovascular reintervention, or major amputation, up to 8 years post-hospitalization using time-to-event analyses 75 189 patients fulfilled eligibility (15 239 surgery and 59 950 endovascular), from whom 14 339 matched pairs (mean ± SD age 71 ± 12 years, 73% male) with good covariate balance were identified. Endovascular revascularization was associated with an increase in combined MALE or mortality [hazard ratio (HR) 1.13, 95% confidence interval (CI): 1.09-1.17, P < 0.001]. There was a similar risk of MALE (HR 1.04, 95% CI: 0.99-1.10, P = 0.15), and all-cause urgent rehospitalizations (HR 1.01, 95% CI: 0.98-1.04, P = 0.57), but higher mortality (HR 1.16, 95% CI: 1.11-1.21, P < 0.001) when endovascular repair was compared to surgery. In subgroup analysis, these findings were consistent for both claudication and chronic limb-threatening ischaemia presentations.

Conclusion: Although the long-term risk of MALE was comparable for both approaches, enduring advantages of surgical revascularization included lower long-term mortality. This is at odds with some prior PAD studies and highlights contention in this space.
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http://dx.doi.org/10.1093/eurheartj/ehab116DOI Listing
December 2021

Macrophages in multiple myeloma: key roles and therapeutic strategies.

Cancer Metastasis Rev 2021 03 6;40(1):273-284. Epub 2021 Jan 6.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.

Macrophages are a vital component of the tumour microenvironment and crucial mediators of tumour progression. In the last decade, significant strides have been made in understanding the crucial functional roles played by macrophages in the development of the plasma cell (PC) malignancy, multiple myeloma (MM). Whilst the interaction between MM PC and stromal cells within the bone marrow (BM) microenvironment has been extensively studied, we are only just starting to appreciate the multifaceted roles played by macrophages in disease progression. Accumulating evidence demonstrates that macrophage infiltration is associated with poor overall survival in MM. Indeed, macrophages influence numerous pathways critical for the initiation and progression of MM, including homing of malignant cells to BM, tumour cell growth and survival, drug resistance, angiogenesis and immune suppression. As such, therapeutic strategies aimed at targeting macrophages within the BM niche have promise in the clinical setting. This review will discuss the functions elicited by macrophages throughout different stages of MM and provide a comprehensive evaluation of potential macrophage-targeted therapies.
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http://dx.doi.org/10.1007/s10555-020-09943-1DOI Listing
March 2021

The role of intracoronary imaging in translational research.

Cardiovasc Diagn Ther 2020 Oct;10(5):1480-1507

Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.

Atherosclerotic cardiovascular disease is a key public health concern worldwide and leading cause of morbidity, mortality and health economic costs. Understanding atherosclerotic plaque microstructure in relation to molecular mechanisms that underpin its initiation and progression is needed to provide the best chance of combating this disease. Evolving vessel wall-based, endovascular coronary imaging modalities, including intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS), used in isolation or as hybrid modalities, have been advanced to allow comprehensive visualization of the pathological substrate of coronary atherosclerosis and accurately measure temporal changes in both the vessel wall and plaque characteristics. This has helped further our appreciation of the natural history of coronary artery disease (CAD) and the risk for major adverse cardiovascular events (MACE), evaluate the responsiveness to conventional and experimental therapeutic interventions, and assist in guiding percutaneous coronary intervention (PCI). Here we review the use of different imaging modalities for these purposes and the lessons they have provided thus far.
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http://dx.doi.org/10.21037/cdt-20-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666942PMC
October 2020

Inflammation in Coronary Atherosclerosis and Its Therapeutic Implications.

Cardiovasc Drugs Ther 2022 04 10;36(2):347-362. Epub 2020 Nov 10.

Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.

Atherosclerotic coronary artery disease has a complex pathogenesis which extends beyond cholesterol intimal infiltration. It involves chronic inflammation of the coronary artery wall driven by systemic and local activation of both the adaptive and innate immune systems, which can ultimately result in the rupture or erosion of atherosclerotic plaque, leading to thrombosis and myocardial infarction (MI). Despite current best practice care, including the widespread use of cholesterol-lowering statins, atherothrombotic cardiovascular events recur at alarming rates post-MI. To a large extent, this reflects residual inflammation that is not adequately controlled by contemporary treatment. Consequently, there has been increasing interest in the pharmacological targeting of inflammation to improve outcomes in atherosclerotic cardiovascular disease. This has comprised both novel pathway-specific agents, most notably the anti-interleukin-1 beta monoclonal antibody, canakinumab, and the repurposing of established, broad-acting drugs, such as colchicine, that are already approved for the management of other inflammatory conditions. Here we discuss the importance of inflammation in mediating atherosclerosis and its complications and provide a timely update on "new" and "old" anti-inflammatory therapies currently being investigated to target it.
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http://dx.doi.org/10.1007/s10557-020-07106-6DOI Listing
April 2022

Risk Factors for Delirium and Cognitive Decline Following Coronary Artery Bypass Grafting Surgery: A Systematic Review and Meta-Analysis.

J Am Heart Assoc 2020 11 7;9(22):e017275. Epub 2020 Nov 7.

Cognitive Ageing and Impairment Neurosciences Laboratory, Justice and Society Academic Unit University of South Australia Adelaide Australia.

Background Coronary artery bypass grafting (CABG) is known to improve heart function and quality of life, while rates of surgery-related mortality are low. However, delirium and cognitive decline are common complications. We sought to identify preoperative, intraoperative, and postoperative risk or protective factors associated with delirium and cognitive decline (across time) in patients undergoing CABG. Methods and Results We conducted a systematic search of Medline, PsycINFO, EMBASE, and Cochrane (March 26, 2019) for peer-reviewed, English publications reporting post-CABG delirium or cognitive decline data, for at least one risk factor. Random-effects meta-analyses estimated pooled odds ratio for categorical data and mean difference or standardized mean difference for continuous data. Ninety-seven studies, comprising data from 60 479 patients who underwent CABG, were included. Moderate to large and statistically significant risk factors for delirium were as follows: (1) preoperative cognitive impairment, depression, stroke history, and higher European System for Cardiac Operative Risk Evaluation (EuroSCORE) score, (2) intraoperative increase in intubation time, and (3) postoperative presence of arrythmia and increased days in the intensive care unit; higher preoperative cognitive performance was protective for delirium. Moderate to large and statistically significant risk factors for acute cognitive decline were as follows: (1) preoperative depression and older age, (2) intraoperative increase in intubation time, and (3) postoperative presence of delirium and increased days in the intensive care unit. Presence of depression preoperatively was a moderate risk factor for midterm (1-6 months) post-CABG cognitive decline. Conclusions This meta-analysis identified several key risk factors for delirium and cognitive decline following CABG, most of which are nonmodifiable. Future research should target preoperative risk factors, such as depression or cognitive impairment, which are potentially modifiable. Registration URL: https://www.crd.york.ac.uk/prosp​ero/; Unique identifier: CRD42020149276.
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http://dx.doi.org/10.1161/JAHA.120.017275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763731PMC
November 2020

Cardiovascular bioimaging of nitric oxide: Achievements, challenges, and the future.

Med Res Rev 2021 01 19;41(1):435-463. Epub 2020 Oct 19.

Australian Research Council (ARC), Centre of Excellence for Nanoscale BioPhotonics (CNBP), Adelaide, Australia.

Nitric oxide (NO) is a ubiquitous, volatile, cellular signaling molecule that operates across a wide physiological concentration range (pM-µM) in different tissues. It is a highly diffusible messenger and intermediate in various metabolic pathways. NO plays a pivotal role in maintaining optimum cardiovascular function, particularly by regulating vascular tone and blood flow. This review highlights the need for accurate, real-time bioimaging of NO in clinical diagnostic, therapeutic, monitoring, and theranostic applications within the cardiovascular system. We summarize electrochemical, optical, and nanoscale sensors that allow measurement and imaging of NO, both directly and indirectly via surrogate measurements. The physical properties of NO render it difficult to accurately measure in tissues using direct methods. There are also significant limitations associated with the NO metabolites used as surrogates to indirectly estimate NO levels. All these factors added to significant variability in the measurement of NO using available methodology have led to a lack of sensors and imaging techniques of clinical applicability in relevant vascular pathologies such as atherosclerosis and ischemic heart disease. Challenges in applying current methods to biomedical and clinical translational research, including the wide physiological range of NO and limitations due to the characteristics and toxicity of the sensors are discussed, as are potential targets and modifications for future studies. The development of biocompatible nanoscale sensors for use in combination with existing clinical imaging modalities provides a feasible opportunity for bioimaging NO within the cardiovascular system.
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http://dx.doi.org/10.1002/med.21736DOI Listing
January 2021

Investigating how electroencephalogram measures associate with delirium: A systematic review.

Clin Neurophysiol 2021 01 1;132(1):246-257. Epub 2020 Oct 1.

Cognitive Ageing and Impairment Neurosciences Laboratory, Justice and Society, University of South Australia, Adelaide, Australia.

Delirium is a common neurocognitive disorder in hospital settings, characterised by fluctuating impairments in attention and arousal following an acute precipitant. Electroencephalography (EEG) is a useful method to understand delirium pathophysiology. We performed a systematic review to investigate associations between delirium and EEG measures recorded prior, during, and after delirium. A total of 1,655 articles were identified using PsycINFO, Embase and MEDLINE, 31 of which satisfied inclusion criteria. Methodological quality assessment was undertaken, resulting in a mean quality score of 4 out of a maximum of 5. Qualitative synthesis revealed EEG slowing and reduced functional connectivity discriminated between those with and without delirium (i.e. EEG during delirium); the opposite pattern was apparent in children, with cortical hyperexcitability. EEG appears to have utility in differentiating those with and without delirium, but delirium vulnerability and the long-term effects on brain function require further investigation. Findings provide empirical support for the theory that delirium is a disorder of reduced functional brain integration.
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http://dx.doi.org/10.1016/j.clinph.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410607PMC
January 2021

Systematic review and meta-analysis of the clinical characteristics and outcomes of spontanous coronary artery dissection.

Int J Cardiol 2021 01 28;322:34-39. Epub 2020 Aug 28.

The University of Adelaide Medical School, Adelaide, Australia; Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia. Electronic address:

Background: Spontaneous coronary artery dissection (SCAD) is an uncommon, non-iatrogenic, non-atherosclerotic cause of acute coronary syndrome. A lack of large prospective cohort studies and randomised controlled trials means that important questions about clinical characteristics and outcomes of patients with SCAD are yet to be fully answered.

Method: A literature search of PUBMED, EMBASE and SCOPUS was undertaken up to and including the 23 January 2020. Studies reporting any cohort of 10 or more SCAD patients presenting with acute coronary syndrome, with appropriate clinical follow-up data were included in the analysis. Incidences of major adverse cardiovascular events (MACE), myocardial infarction and SCAD recurrence were meta-analysed using Poisson regression.

Results: 19 studies, totalling p=2,172 patients, were included in the analysis. There was significant heterogeneity across the studies in all baseline characteristics and clinical outcomes. Prevalence of traditional cardiovascular risk factors was low; however, hypertension had a prevalence of 45% (95% CI; [35-54]) and fibromuscular dysplasia (FMD) was present in 68% (95% CI; [61-74]). Across all cohorts, the incidence of MACE in patients with SCAD was 7.80 per 100 person years (n=19, p=2172, 95% CI; [4.50-13.54]) and SCAD recurrence was 5.49 per 100 person years (n=13, p=1408, 95% CI; [3.75-8.02]).

Conclusions: This meta-analysis confirms that SCAD is not an inconsequential cause of acute coronary syndrome and heralds the need for further prospective research to identify predictors of recurrent events and therapies to prevent them.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.076DOI Listing
January 2021
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