Melbourne Medical School Collected Works - Research Publications

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    The Translation and Commercialisation of Biomarkers for Cardiovascular Disease-A Review.
    Saleh, S ; George, J ; Kott, KA ; Meikle, PJ ; Figtree, GA (Frontiers Media SA, 2022)
    As a leading cause of mortality and morbidity worldwide, cardiovascular disease and its diagnosis, quantification, and stratification remain significant health issues. Increasingly, patients present with cardiovascular disease in the absence of known risk factors, suggesting the presence of yet unrecognized pathological processes and disease predispositions. Fortunately, a host of emerging cardiovascular biomarkers characterizing and quantifying ischaemic heart disease have shown great promise in both laboratory settings and clinical trials. These have demonstrated improved predictive value additional to widely accepted biomarkers as well as providing insight into molecular phenotypes beneath the broad umbrella of cardiovascular disease that may allow for further personalized treatment regimens. However, the process of translation into clinical practice - particularly navigating the legal and commercial landscape - poses a number of challenges. Practical and legal barriers to the biomarker translational pipeline must be further considered to develop strategies to bring novel biomarkers into the clinical sphere and apply these advances at the patient bedside. Here we review the progress of emerging biomarkers in the cardiovascular space, with particular focus on those relevant to the unmet needs in ischaemic heart disease.
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    Influence of the Human Lipidome on Epicardial Fat Volume in Mexican American Individuals.
    Leandro, AC ; Michael, LF ; Almeida, M ; Kuokkanen, M ; Huynh, K ; Giles, C ; Duong, T ; Diego, VP ; Duggirala, R ; Clarke, GD ; Blangero, J ; Meikle, PJ ; Curran, JE (Frontiers Media SA, 2022)
    Introduction: Cardiovascular disease (CVD) is the leading cause of mortality worldwide and is the leading cause of death in the US. Lipid dysregulation is a well-known precursor to metabolic diseases, including CVD. There is a growing body of literature that suggests MRI-derived epicardial fat volume, or epicardial adipose tissue (EAT) volume, is linked to the development of coronary artery disease. Interestingly, epicardial fat is also actively involved in lipid and energy homeostasis, with epicardial adipose tissue having a greater capacity for release and uptake of free fatty acids. However, there is a scarcity of knowledge on the influence of plasma lipids on EAT volume. Aim: The focus of this study is on the identification of novel lipidomic species associated with CMRI-derived measures of epicardial fat in Mexican American individuals. Methods: We performed lipidomic profiling on 200 Mexican American individuals. High-throughput mass spectrometry enabled rapid capture of precise lipidomic profiles, providing measures of 799 unique species from circulating plasma samples. Because of our extended pedigree design, we utilized a standard quantitative genetic linear mixed model analysis to determine whether lipids were correlated with EAT by formally testing for association between each lipid species and the CMRI epicardial fat phenotype. Results: After correction for multiple testing using the FDR approach, we identified 135 lipid species showing significant association with epicardial fat. Of those, 131 lipid species were positively correlated with EAT, where increased circulating lipid levels were correlated with increased epicardial fat. Interestingly, the top 10 lipid species associated with an increased epicardial fat volume were from the deoxyceramide (Cer(m)) and triacylglycerol (TG) families. Deoxyceramides are atypical and neurotoxic sphingolipids. Triacylglycerols are an abundant lipid class and comprise the bulk of storage fat in tissues. Pathologically elevated TG and Cer(m) levels are related to CVD risk and, in our study, to EAT volume. Conclusion: Our results indicate that specific lipid abnormalities such as enriched saturated triacylglycerols and the presence of toxic ceramides Cer(m) in plasma of our individuals could precede CVD with increased EAT volume.
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    Association between arthritis and cardiovascular risk factors in community-based adults: an opportunity to target cardiovascular risk.
    Sewell, J ; Hussain, SM ; Wang, Y ; Wluka, AE ; Lim, YZ ; Carrington, MJ ; Samaras, K ; Cicuttini, FM (Springer Science and Business Media LLC, 2022-05-19)
    BACKGROUND: Undertreated risk factors are major contributors to the burden of cardiovascular disease (CVD). Those with arthritis have an increased prevalence of CVD risk factors. CVD risk factors are often asymptomatic, which may be a barrier their treatment. Arthritis causes pain and immobility, and is a common reason for individuals to seek healthcare. Our aims were to (1) examine the relationship between arthritis and CVD risk factors in Australian adults, and (2) calculate the proportion of CVD risk factors that could be reduced if individuals with arthritis were targeted. METHODS: This cross-sectional study uses data from the 2017-18 Australian National Health Survey which included 13,776 participants, categorised into young (18-39 years), middle aged (40-64 years) and older (≥ 65 years) adults. Hypertension, height and weight were measured. Arthritis, dyslipidemia and diabetes were self-reported. The associations between arthritis and CVD risk factors were examined using logistic regression, and the population attributable fraction (PAF) of arthritis for each CVD risk factor was calculated. RESULTS: Arthritis was reported by 4.0% of young adults, 28.8% of middle-aged adults and 54.5% of older adults. Those with arthritis were at increased odds of obesity (2.07 fold in young, 1.75 fold in middle-aged and 1.89 fold in older adults), increased odds of diabetes (5.70 fold in young, 1.64 fold in middle-aged and 1.37 fold in older adults), increased odds of hypertension (2.72 fold in young, 1.78 fold in middle-aged and 1.48 fold in older adults) and an increased odds of dyslipidaemia (4.64 fold in young, 2.14 fold in middle-aged and 1.22 fold in older adults) compared to those without arthritis. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. The PAF of the presence of arthritis for having at least one CVD risk factor was 30.7% in middle-aged adults and 70.4% in older adults. CONCLUSION: Australian adults of all ages with arthritis are at increased odds of having CVD risk factors. For young and middle-aged adults, this increased odds remains significant even when adjusted for obesity. Presentation to healthcare practitioners with arthritis is an opportunity to screen for asymptomatic CVD risk factors with the potential of improving outcomes for both diseases. By adopting an approach of managing arthritis and CVD risk factors in parallel, rather than in silos, we could reduce the burden of CVD risk factors by 20-30%.
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    Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease
    Cadby, G ; Giles, C ; Melton, PE ; Huynh, K ; Mellett, NA ; Thy, D ; Anh, N ; Cinel, M ; Smith, A ; Olshansky, G ; Wang, T ; Brozynska, M ; Inouye, M ; McCarthy, NS ; Ariff, A ; Hung, J ; Hui, J ; Beilby, J ; Dube, M-P ; Watts, GF ; Shah, S ; Wray, NR ; Lim, WLF ; Chatterjee, P ; Martins, I ; Laws, SM ; Porter, T ; Vacher, M ; Bush, A ; Rowe, CC ; Villemagne, VL ; Ames, D ; Masters, CL ; Taddei, K ; Arnold, M ; Kastenmueller, G ; Nho, K ; Saykin, AJ ; Han, X ; Kaddurah-Daouk, R ; Martins, RN ; Blangero, J ; Meikle, PJ ; Moses, EK (NATURE PORTFOLIO, 2022-06-06)
    We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
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    Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis
    Lee, MKS ; Cooney, OD ; Lin, X ; Nadarajah, S ; Dragoljevic, D ; Huynh, K ; Onda, D-A ; Galic, S ; Meikle, PJ ; Edlund, T ; Fullerton, MD ; Kemp, BE ; Murphy, AJ ; Loh, K (ELSEVIER, 2022-07-01)
    OBJECTIVES: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. METHODS: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe-/- and Apoe-/-/Hmgcr KI mice. RESULTS: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe-/-/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe-/-/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe-/-/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. CONCLUSIONS: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
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    Roles of nutrition in muscle health of community-dwelling older adults: evidence-based expert consensus from Asian Working Group for Sarcopenia
    Chen, L-K ; Arai, H ; Assantachai, P ; Akishita, M ; Chew, STH ; Dumlao, LC ; Duque, G ; Woo, J (WILEY, 2022-03-20)
    General muscle health declines with age, and in particular, sarcopenia-defined as progressive loss of muscle mass and strength/physical performance-is a growing issue in Asia with a rising population of community-dwelling older adults. Several guidelines have addressed early identification of sarcopenia and management, and although nutrition is central to treatment of sarcopenia, there are currently few guidelines that have examined this specifically in the Asian population. Therefore, the Asian Working Group for Sarcopenia established a special interest group (SIG) comprising seven experts across Asia and one from Australia, to develop an evidence-based expert consensus. A systematic literature search was conducted using MEDLINE on the topic of muscle health, from 2016 (inclusive) to July 2021, in Asia or with relevance to healthy, Asian community-dwelling older adults (≥60 years old). Several key topics were identified: (1) nutritional status: malnutrition and screening; (2) diet and dietary factors; (3) nutritional supplementation; (4) lifestyle interventions plus nutrition; and (5) outcomes and assessment. Clinical questions were developed around these topics, leading to 14 consensus statements. Consensus was achieved using the modified Delphi method with two rounds of voting. Moreover, the consensus addressed the impacts of COVID-19 on nutrition, muscle health, and sarcopenia in Asia. These statements encompass clinical expertise and knowledge across Asia and are aligned with findings in the current literature, to provide a practical framework for addressing muscle health in the community, with the overall aim to encourage and facilitate broader access to equitable care for this target population.
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    Improved sleep efficiency is associated with reduced cardio-metabolic risk: Findings from the MODERN trial
    Yiallourou, SR ; Carrington, MJ (WILEY, 2021-06-02)
    Poor sleep increases cardio-metabolic risk, but limited information on the impact of sleep for the improvement of cardio-metabolic health exists. This analysis examined the impact of sleep on a health and lifestyle modification programme to reduce cardio-metabolic disease risk factors. Secondary analysis of the MODERN randomised controlled trial to reduce cardio-metabolic risk was undertaken at baseline and 24-month follow-up. Participants aged 40-70 years (n = 121) with three or more cardio-metabolic risk factors were randomised to a health and lifestyle modification intervention (n = 59) or usual care (n = 62), and underwent 7 day/night actigraphy to assess total sleep time, sleep efficiency (%), number of awakenings/night and physical activity levels. Blood pressure, blood lipid and glycaemic levels, anthropometric and diet measures were collected. The mean age was 59 ± 7 years and 37% were male. Baseline sleep measures were not different between groups. At the 24-month follow-up, both groups showed improvements in cardio-metabolic risk factors, albeit the change in blood pressure was greater in the intervention compared with the usual care group (systolic blood pressure: -11 versus -4 mmHg, p = .014). There were no differences between groups for diet, physical activity or sleep parameters. An increase in sleep efficiency was independently associated with lower systolic blood pressure (β = -2.117, p = .002) and higher high-density lipoprotein levels (β = 0.040, p = .033); an increase in total sleep time was associated with lower low-density lipoprotein levels (β = -0.003, p = .038) at 24 months. Overall, improvement in sleep quality over time was beneficial to reduce blood pressure and lipid levels. These findings highlight sleep as a potential target to reduce cardio-metabolic risk.
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    Early life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study.
    Mansell, T ; Saffery, R ; Burugupalli, S ; Ponsonby, A-L ; Tang, MLK ; O'Hely, M ; Bekkering, S ; Smith, AAT ; Rowland, R ; Ranganathan, S ; Sly, PD ; Vuillermin, P ; Collier, F ; Meikle, P ; Burgner, D ; Barwon Infant Study Investigator Group, (eLife Sciences Publications, Ltd, 2022-05-10)
    Background: The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation. Methods: Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used. Results: At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1. Conclusions: Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk. Funding: The establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).
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    Peripheral Oxygen Extraction and Exercise Limitation in Asymptomatic Patients with Diabetes Mellitus
    Kobayashi, Y ; Christle, JW ; Contrepois, K ; Nishi, T ; Moneghetti, K ; Cauwenberghs, N ; Myers, J ; Kuznetsova, T ; Palaniappan, L ; Haddad, F (EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2021-06-16)
    Patients with diabetes mellitus (DM) frequently present reduced exercise capacity. We aimed to explore the extent to which peripheral extraction relates to exercise capacity in asymptomatic patients with DM. We prospectively enrolled 98 asymptomatic patients with type-2 DM (mean age of 59 ± 11 years and 56% male sex), and compared with 31 age, sex and body mass index-matched normoglycemic controls. Cardiopulmonary exercise testing with resting followed by stress echocardiography was performed. Exercise response was assessed using peak oxygen uptake (peak VO2) and ventilatory efficiency was measured using the slope of the relationship between minute ventilation and carbon dioxide production (VE/VCO2). Peripheral extraction was calculated as the ratio of VO2 to cardiac output. Cardiac function was evaluated using left ventricular longitudinal strain, E/e', and relative wall thickness. Among patients with DM, 26 patients (27%) presented reduced percent-predicted-peak VO2(<80%) and 18 (18%) presented abnormal VE/VCO2slope (>34). There was no significant difference in peak cardiac output; however, peripheral extraction was lower in patients with DM compared to controls. Higher peak E/e' (beta = -0.24, p = 0.004) was associated with lower peak VO2 along with age, sex and body mass index (R2 = 0.53). A cluster analysis found left ventricular longitudinal strain, E/e', relative wall thickness and peak VO2 in different clusters. In conclusion, impaired peripheral extraction may contribute to reduced peak VO2in asymptomatic patients with DM. Furthermore, a cluster analysis suggests that cardiopulmonary exercise testing and echocardiography may be complementary for defining subclinical heart failure in patients with DM.