Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

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

Incorporating a polygenic risk score-triaged coronary calcium score into cardiovascular disease examinations to identify subclinical coronary artery disease (ESCALATE): Protocol for a prospective, nonrandomized implementation trial.

BACKGROUND: Identifying and targeting established modifiable risk factors has been a successful strategy for reducing the burden of coronary artery disease (CAD) at the population-level. However, up to 1-in-4 patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. Polygenic risk scores (PRS) have demonstrated an ability to improve risk prediction models independent of traditional risk factors and self-reported family history, but a pathway for implementation has yet to be clearly identified. The aim of this study is to examine the utility of a CAD PRS to identify individuals with subclinical CAD via a novel clinical pathway, triaging low or intermediate absolute risk individuals for noninvasive coronary imaging, and examining the impact on shared treatment decisions and participant experience. TRIAL DESIGN: The ESCALATE study is a 12-month, prospective, multicenter implementation study incorporating PRS into otherwise standard primary care CVD risk assessments, to identify patients at increased lifetime CAD risk for noninvasive coronary imaging. One-thousand eligible participants aged 45 to 65 years old will enter the study, which applies PRS to those considered low or moderate 5-year absolute CVD risk and triages those with CAD PRS ≥80% for a coronary calcium scan. The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) >0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sex-matched percentile, the use and intensity of lipid- and blood pressure-lowering therapeutics, cholesterol and blood pressure levels, and health-related quality of life (HRQOL). CONCLUSION: This novel trial will generate evidence on the ability of a PRS-triaged CACS to identify subclinical CAD, as well as subsequent differences in traditional risk factor medical management, pharmacotherapy utilization, and participant experience. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12622000436774. Trial was prospectively registered on March 18, 2022. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383134.

Immunoglobulin E Sensitization to Mammalian Oligosaccharide Galactose-α-1,3 (α-Gal) Is Associated With Noncalcified Plaque, Obstructive Coronary Artery Disease, and ST-Segment-Elevated Myocardial Infarction.

BACKGROUND: Treating known risk factors for coronary artery disease (CAD) has substantially reduced CAD morbidity and mortality. However, a significant burden of CAD remains unexplained. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal) was recently associated with CAD in a small observational study. We sought to confirm that α-Gal sensitization is associated with CAD burden, in particular noncalcified plaque. Additionally, we sort to assess whether that α-Gal sensitization is associated with ST-segment-elevated myocardial infarction (STEMI) Methods: We performed a cross-sectional analysis of participants enrolled in the BioHEART cohort study. We measured α-Gal specific-immunoglobulin E antibodies in serum of 1056 patients referred for CT coronary angiography for suspected CAD and 100 selected patients presenting with STEMI, enriched for patients without standard modifiable risk factors. CT coronary angiograms were assessed using coronary artery calcium scores and segmental plaque scores. RESULTS: α-Gal sensitization was associated with presence of noncalcified plaque (odds ratio, 1.62 [95% CI, 1.04-2.53], P=0.03) and obstructive CAD (odds ratio, 2.05 [95% CI, 1.29-3.25], P=0.002), independent of age, sex, and traditional risk factors. The α-Gal sensitization rate was 12.8-fold higher in patients with STEMI compared with matched healthy controls and 2.2-fold higher in the patients with STEMI compared with matched stable CAD patients (17% versus 1.3%, P=0.01 and 20% versus 9%, P=0.03, respectively). CONCLUSIONS: α-Gal sensitization is independently associated with noncalcified plaque burden and obstructive CAD and occurs at higher frequency in patients with STEMI than those with stable or no CAD. These findings may have implications for individuals exposed to ticks, as well as public health policy. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12618001322224.

High-Throughput Measure of Mitochondrial Superoxide Levels as a Marker of Coronary Artery Disease to Accelerate Drug Translation in Patient-Derived Endothelial Cells Using Opera Phenix® Technology.

Improved human-relevant preclinical models of coronary artery disease (CAD) are needed to improve translational research and drug discovery. Mitochondrial dysfunction and associated oxidative stress contribute to endothelial dysfunction and are a significant factor in the development and progression of CAD. Endothelial colony-forming cells (ECFCs) can be derived from peripheral blood mononuclear cells (PBMCs) and offer a unique potentially personalised means for investigating new potential therapies targeting important components of vascular function. We describe the application of the high-throughput and confocal Opera Phenix® High-Content Screening System to examine mitochondrial superoxide (mROS) levels, mitochondrial membrane potential, and mitochondrial area in both established cell lines and patient-derived ECFCs simultaneously. Unlike traditional plate readers, the Opera Phenix® is an imaging system that integrates automated confocal microscopy, precise fluorescent detection, and multi-parameter algorithms to visualize and precisely quantify targeted biological processes at a cellular level. In this study, we measured mROS production in human umbilical vein endothelial cells (HUVECs) and patient-derived ECFCs using the mROS production probe, MitoSOXTM Red. HUVECs exposed to oxidized low-density lipoprotein (oxLDL) increased mROS levels by 47.7% (p < 0.0001). A pooled group of patient-derived ECFCs from participants with CAD (n = 14) exhibited 30.9% higher mROS levels compared to patients with no CAD when stimulated with oxLDL (n = 14; p < 0.05). When tested against a small group of candidate compounds, this signal was attenuated by PKT-100 (36.22% reduction, p = 0.03), a novel P2X7 receptor antagonist. This suggests the P2X7 receptor as a valid target against excess mROS levels. As such, these findings highlight the potential of the MitoSOX-Opera Phenix technique to be used for drug discovery efforts in CAD.

Mortality in STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data.

BACKGROUND: In cardiovascular disease, prevention strategies targeting standard modifiable cardiovascular risk factors (SMuRFs; hypertension, diabetes, hypercholesterolaemia, and smoking) are crucial; however, myocardial infarction in the absence of SMuRFs is not infrequent. The outcomes of individuals without SMuRFs are not well known. METHODS: We retrospectively analysed adult patients with first-presentation ST-elevation myocardial infarction (STEMI) using data from the Swedish myocardial infarction registry SWEDEHEART. Clinical characteristics and outcomes of adult patients (age ≥18 years) with and without SMuRFs were examined overall and by sex. Patients with a known history of coronary artery disease were excluded. The primary outcome was all-cause mortality at 30 days after STEMI presentation. Secondary outcomes included cardiovascular mortality, heart failure, and myocardial infarction at30 days. Endpoints were also examined up to discharge, and to the end of a 12-year follow-up. Multivariable logistic regression models were used to compare in-hospital mortality, and Cox-proportional hazard models and Kaplan-Meier analysis for long-term outcomes. FINDINGS: Between Jan 1, 2005, and May 25, 2018, 9228 (14·9%) of 62 048 patients with STEMI had no SMuRFs reaching diagnostic thresholds. Median age was similar between patients with SMuRFs and patients without SMuRFs (68 years [IQR 59-78]) vs 69 years [60-78], p<0·0001). SMuRF-less patients had a similar rate of percutaneous coronary intervention to those with at least one modifiable risk factor, but were significantly less likely to receive statins, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockade (ARB), or ß-blockers at discharge. By 30 days after presentation, all-cause mortality was significantly higher in SMuRF-less patients (hazard ratio 1·47 [95% CI 1·37-1·57], p<0·0001). SMuRF-less women had the highest 30-day mortality (381 [17·6%] of 2164), followed by women with SMuRFs (2032 [11·1%] of 18 220), SMuRF-less men (660 [9·3%] of 7064), and men with SMuRFs (2117 [6·1%] of 34 600). The increased risk of 30-day all-cause mortality in SMuRF-less patients remained significant after adjusting for age, sex, left ventricular ejection fraction, creatinine, and blood pressure, but was attenuated on inclusion of pharmacotherapy prescription (ACEI or ARB, ß-blocker, or statin) at discharge. Additionally, SMuRF-less patients had a significantly higher rate of in-hospital all-cause mortality than patients with one or more SMuRF (883 [9·6%] vs 3411 [6·5%], p<0·0001). Myocardial infarction and heart failure at 30 days were lower in SMuRF-less patients. All-cause mortality remained increased in the SMuRF-less group for more than 8 years in men and up to the 12-year endpoint in women. INTERPRETATION: Individuals who present with STEMI in the absence of SMuRFs have a significantly increased risk of all-cause mortality, compared with those with at least one SMuRF, which was particularly evident in women. The increased early mortality rates are attenuated after adjustment for use of guideline-indicated treatments, highlighting the need for evidence-based pharmacotherapy during the immediate post-infarct period irrespective of perceived low risk. FUNDING: Swedish Heart and Lung Foundation, National Health and Medical Research Council (Australia).

Combining structured and unstructured data in EMRs to create clinically-defined EMR-derived cohorts.

BACKGROUND: There have been few studies describing how production EMR systems can be systematically queried to identify clinically-defined populations and limited studies utilising free-text in this process. The aim of this study is to provide a generalisable methodology for constructing clinically-defined EMR-derived patient cohorts using structured and unstructured data in EMRs. METHODS: Patients with possible acute coronary syndrome (ACS) were used as an exemplar. Cardiologists defined clinical criteria for patients presenting with possible ACS. These were mapped to data tables within the production EMR system creating seven inclusion criteria comprised of structured data fields (orders and investigations, procedures, scanned electrocardiogram (ECG) images, and diagnostic codes) and unstructured clinical documentation. Data were extracted from two local health districts (LHD) in Sydney, Australia. Outcome measures included examination of the relative contribution of individual inclusion criteria to the identification of eligible encounters, comparisons between inclusion criterion and evaluation of consistency of data extracts across years and LHDs. RESULTS: Among 802,742 encounters in a 5 year dataset (1/1/13-30/12/17), the presence of an ECG image (54.8% of encounters) and symptoms and keywords in clinical documentation (41.4-64.0%) were used most often to identify presentations of possible ACS. Orders and investigations (27.3%) and procedures (1.4%), were less often present for identified presentations. Relevant ICD-10/SNOMED CT codes were present for 3.7% of identified encounters. Similar trends were seen when the two LHDs were examined separately, and across years. CONCLUSIONS: Clinically-defined EMR-derived cohorts combining structured and unstructured data during cohort identification is a necessary prerequisite for critical validation work required for development of real-time clinical decision support and learning health systems.

Utilizing state-of-the-art "omics" technology and bioinformatics to identify new biological mechanisms and biomarkers for coronary artery disease.

Identification of the four standard modifiable cardiovascular risk factors (SMuRFs)-diabetes mellitus, hyperlipidaemia, hypertension, and cigarette smoking-has allowed the development of risk scores. These have been used in conjunction with primary and secondary prevention strategies targeting SMuRFs to reduce the burden of CAD. Recent studies show that up to 25% of ACS patients do not have any SMuRFs. Thus, SMuRFs do not explain the entire burden of CAD. There appears to be variation at the individual level rendering some individuals relatively susceptible or resilient to developing atherosclerosis. Important disease pathways remain to be discovered, and there is renewed enthusiasm to discover novel biomarkers, biological mechanisms, and therapeutic targets for atherosclerosis. Two broad approaches are being taken: traditional approaches investigating known candidate pathways and unbiased omics approaches. We review recent progress in the field and discuss opportunities made possible by technological and data science advances. Developments in network analytics and machine learning algorithms used in conjunction with large-scale multi-omic platforms have the potential to uncover biological networks that may not have been identifiable using traditional approaches. These approaches are useful for both biomedical research and precision medicine strategies.

Metabolites downstream of predicted loss-of-function variants inform relationship to disease.

A small minority (< 3%) of protein-coding genetic variants are predicted to lead to loss of protein function. However, these predicted loss-of-function (pLOF) variants can provide insight into mode of transcriptional effect. To examine how these changes are propagated to phenotype, we determined associations with downstream metabolites. We performed association analyses of 37 pLOF variants - previously reported to be significantly associated with disease in >400,000 subjects in UK Biobank - with metabolites. We conducted these analyses in three community-based cohorts: the Framingham Heart Study (FHS) Offspring Cohort, FHS Generation 3, and the KORA F4 cohort. We identified 19 new low-frequency or rare (minor allele frequency (MAF) <5%) pLOF variant-metabolite associations, and 12 new common (MAF > 5%) pLOF variant-metabolite associations. Rare pLOF variants in the genes BTN3A2, ENPEP, and GEM that have been associated with blood pressure in UK Biobank, were associated with vasoactive metabolites indoxyl sulfate, asymmetric dimethylarginine (ADMA), and with niacinamide, respectively. A common pLOF variant in gene CCHCR1, associated with asthma in UK Biobank, was associated with histamine and niacinamide in FHS Generation 3, both reported to play a role in this disease. Common variants in olfactory receptor gene OX4C11 that associated with blood pressure in UK Biobank were associated with the nicotine metabolite cotinine, suggesting an interaction between altered olfaction, smoking behaviour, and blood pressure. These findings provide biological validity for pLOF variant-disease associations, and point to the effector roles of common metabolites. Such an approach may provide novel disease markers and therapeutic targets.

Associations with Intraocular Pressure in a Large Cohort: Results from the UK Biobank.

PURPOSE: To describe the associations of physical and demographic factors with Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) in a British cohort. DESIGN: Cross-sectional study within the UK Biobank, a large-scale multisite cohort study in the United Kingdom. PARTICIPANTS: We included 110 573 participants from the UK Biobank with intraocular pressure (IOP) measurements available. Their mean age was 57 years (range, 40-69 years); 54% were women, and 90% were white. METHODS: Participants had 1 IOP measurement made on each eye using the Ocular Response Analyzer noncontact tonometer. Linear regression models were used to assess the associations of IOP with physical and demographic factors. MAIN OUTCOME MEASURES: The IOPg and IOPcc. RESULTS: The mean IOPg was 15.72 mmHg (95% confidence interval [CI], 15.70-15.74 mmHg), and the mean IOPcc was 15.95 mmHg (15.92-15.97 mmHg). After adjusting for covariates, IOPg and IOPcc were both significantly associated with older age, male sex, higher systolic blood pressure (SBP), faster heart rate, greater myopia, self-reported glaucoma, and colder season (all P < 0.001). The strongest determinants of both IOPg and IOPcc were SBP (partial R(2): IOPg 2.30%, IOPcc 2.26%), followed by refractive error (IOPg 0.60%, IOPcc 1.04%). The following variables had different directions of association with IOPg and IOPcc: height (-0.77 mmHg/m IOPg; 1.03 mmHg/m IOPcc), smoking (0.19 mmHg IOPg, -0.35 mmHg IOPcc), self-reported diabetes (0.41 mmHg IOPg, -0.05 mmHg IOPcc), and black ethnicity (-0.80 mmHg IOPg, 0.77 mmHg IOPcc). This suggests that height, smoking, diabetes, and ethnicity are related to corneal biomechanical properties. The increase in both IOPg and IOPcc with age was greatest among those of mixed ethnicities, followed by blacks and whites. The same set of covariates explained 7.4% of the variability of IOPcc but only 5.3% of the variability of IOPg. CONCLUSIONS: This analysis of associations with IOP in a large cohort demonstrated that some variables clearly have different associations with IOPg and IOPcc, and that these 2 measurements may reflect different biological characteristics.

Comparison of packing material in an animal model of middle ear trauma.

PURPOSE: To compare the performance of absorbable gelatin sponge (AGS) with polyurethane foam (PUF) as middle ear packing material after mucosal trauma. MATERIALS AND METHODS: Using a randomized, controlled and blinded study design fifteen guinea pigs underwent middle ear surgery with mucosal trauma performed on both ears. One ear was packed with either PUF or AGS while the contralateral ear remained untreated and used as non-packed paired controls. Auditory brainstem response (ABR) thresholds were measured pre-operatively and repeated at 1, 2, and 6weeks postoperatively. Histological analysis of middle ear mucosa was done in each group to evaluate the inflammatory reaction and wound healing. Another eighteen animals underwent middle ear wounding and packing in one ear while the contralateral ear was left undisturbed as control. Twelve guinea pigs were euthanized at 2weeks postoperatively, and six were euthanized at 3days post-operatively. Mucosal samples were collected for analysis of TGF-ß1 levels by enzyme-linked immunosorbent assay. RESULTS: ABR recordings demonstrate that threshold level changes from baseline were minor in PUF packed and control ears. Threshold levels were higher in the AGS packed ears compared with both control and PUF packed ears for low frequency stimuli. Histological analysis showed persistence of packing material at 6weeks postoperatively, inflammation, granulation tissue formation, foreign body reaction and neo-osteogenesis in both AGS and PUF groups. TGF-ß1 protein levels did not differ between groups. CONCLUSION: PUF and AGS packing cause inflammation and neo-osteogenesis in the middle ear following wounding of the mucosa and packing.

Short-term effect of diode laser cyclophotocoagulation on intraocular pressure: a prospective study.

BACKGROUND: This aims to determine the immediate and short-term risk of intraocular pressure spikes following diode laser cyclophotocoagulation. DESIGN: This study is a prospective, consecutive cohort study in a UK teaching hospital. PARTICIPANTS: Fifty-three consecutive patients undergoing cyclophotocoagulation were invited to participate in this study. METHODS: Intraocular pressure (IOP) measurements were taken immediately prior to cyclodiode laser, hourly for the first 3 h after laser, on the first and seventh postoperative days, and at three months following laser. MAIN OUTCOME MEASURES: Eyes experiencing intraocular pressure elevation defined at two levels (≥3 mm Hg and ≥10 mm Hg from the pretreatment level) were identified. RESULTS: Seventeen eyes (34%) had an elevation in intraocular pressure (≥3 mmHg) during the first 3 h postoperatively with a mean increase of 10.3 mmHg. No preoperative or perioperative associations were found for a postcyclodiode spike within the first 3 postoperative hours.No association was found between pressure spikes and visual acuity, reduction of glaucoma medication or final postoperative intraocular pressure at 3 months. Eyes that did not have an IOP spike during the first 3 h postoperatively had a greater reduction in IOP at 3 months (15.2 mmHg vs. 10.2 mmHg; P = 0.184). CONCLUSION: IOP spikes are common in the immediate period after cyclophotocoagulation. An elevation in IOP is noted after the first hour in the vast majority who experience a spike in the first 3 h post-procedure.

Construction and optimization of multi-platform precision pathways for precision medicine.

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

Prevalence and Associations of Epiretinal Membranes in an Elderly English Population: The Bridlington Eye Assessment Project.

Purpose: To determine the prevalence and risk factors of epiretinal membranes (ERMs) in an adult English population. Methods: The Bridlington Eye Assessment Project is a population-based study of eye disease among residents aged 65 years or older. Comprehensive interviews and ophthalmic examinations were conducted to assess potential risk factors. Digital mydriatic nonstereoscopic 30° colour fundus photography (CFP) was performed. ERMs were classified as primary/idiopathic or secondary on the basis of findings from the ocular examination and the structured questionnaire. Logistic regression models were used to determine the independence of potential risk factors for idiopathic ERMs. Results: In a comprehensive screening of 3588 patients aged over 65, we identified an eye-based prevalence of ERMs of 4.26% and a subject-based prevalence of ERMs of 6.88%. The majority of these cases were idiopathic in nature (90.7%), while 9.3% were secondary ERMs; predominantly, there was a history of cataract surgery (43.5%). No significant correlation between idiopathic ERMs and factors such as age, gender, diabetes, hypertension, a history of stroke, or the presence of AMD was found. Conclusions: The prevalence of ERMs in an elderly English population and the proportion of idiopathic and secondary ERMs are similar to previous reports. However, in elderly patients aged over 65 years, age is not a risk factor for the presence of idiopathic ERMs. The presence of diabetes, hypertension, a history of stroke, and AMD of any grade was not associated with ERMs.

Vascular Cytokines and Atherosclerosis: Differential Serum Levels of TRAIL, IL-18, and OPG in Obstructive Coronary Artery Disease.

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

Health economic analysis of polygenic risk score use in primary prevention of coronary artery disease - A system dynamics model.

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

Lipidomic Risk Score to Enhance Cardiovascular Risk Stratification for Primary Prevention.

BACKGROUND: Accurate risk stratification is vital for primary prevention of cardiovascular disease (CVD). However, traditional tools such as the Framingham Risk Score (FRS) may underperform within the diverse intermediate-risk group, which includes individuals requiring distinct management strategies. OBJECTIVES: This study aimed to develop a lipidomic-enhanced risk score (LRS), specifically targeting risk prediction and reclassification within the intermediate group, benchmarked against the FRS. METHODS: The LRS was developed via a machine learning workflow using ridge regression on the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab; n = 10,339). It was externally validated with the Busselton Health Study (n = 4,492), and its predictive utility for coronary artery calcium scoring (CACS)-based outcomes was independently validated in the BioHEART cohort (n = 994). RESULTS: LRS significantly improved discrimination metrics for the intermediate-risk group in both AusDiab and Busselton Health Study cohorts (all P < 0.001), increasing the area under the curve for CVD events by 0.114 (95% CI: 0.1123-0.1157) and 0.077 (95% CI: 0.0755-0.0785), with a net reclassification improvement of 0.36 (95% CI: 0.21-0.51) and 0.33 (95% CI: 0.15-0.49), respectively. For CACS-based outcomes in BioHEART, LRS achieved a significant area under the curve improvement of 0.02 over the FRS (0.76 vs 0.74; P < 1.0 × 10-5). A simplified, clinically applicable version of LRS was also created that had comparable performance to the original LRS. CONCLUSIONS: LRS, augmenting the FRS, presents potential to improve intermediate-risk stratification and to predict atherosclerotic markers using a simple blood test, suitable for clinical application. This could facilitate the triage of individuals for noninvasive imaging such as CACS, fostering precision medicine in CVD prevention and management.

Repeatability of ocular response analyzer metrics: a gender-based study.

PURPOSE: To assess the repeatability of Goldmann-correlated intraocular pressure (IOPG), corneal-compensated IOP (IOPCC), corneal hysteresis (CH), and the corneal resistance factor (CRF) obtained with the Ocular Response Analyzer (ORA) in normal eyes and to determine whether any differences in corneal biomechanical parameters or their repeatability exist between the sexes. METHODS: A prospective observational study assessing 100 normal adults (50 men and 50 women; median age, 54.5 years). Comparison of ORA parameters measured in both eyes in three sets of four consecutive readings by one examiner within a 30-minute period. RESULTS: The mean values of the ORA parameters assessed, the intraclass correlation coefficient (ICC) and the coefficient of repeatability (CR), were as follows for the right eye (n = 100): IOPG, 16.2 ± 3.3 mm Hg (ICC, 0.96; CR, 6.37); IOPCC, 16.2 ± 3.2 (ICC, 0.94; CR, 6.29); CRF, 10.9 ± 1.9 (ICC, 0.91; CR, 3.62); CH, 10.6 ± 1.7 (ICC, 0.94; CR, 3.37). The ICC between the readings was excellent (>0.9) for all the ORA parameters in both sexes, with the exception of one group (female CRF ICC, 0.86). Coefficient of repeatability of the instrument satisfies the British Standards Institution criteria for repeatability. There were no significant differences between corneal biomechanical factors and IOP results for men and women. CONCLUSIONS: Corneal biomechanical parameters measured by the ORA provide repeatable results in normal eyes, with no significant difference between the sexes.

Overcoming cohort heterogeneity for the prediction of subclinical cardiovascular disease risk.

Cardiovascular disease remains a leading cause of mortality with an estimated half a billion people affected in 2019. However, detecting signals between specific pathophysiology and coronary plaque phenotypes using complex multi-omic discovery datasets remains challenging due to the diversity of individuals and their risk factors. Given the complex cohort heterogeneity present in those with coronary artery disease (CAD), we illustrate several different methods, both knowledge-guided and data-driven approaches, for identifying subcohorts of individuals with subclinical CAD and distinct metabolomic signatures. We then demonstrate that utilizing these subcohorts can improve the prediction of subclinical CAD and can facilitate the discovery of novel biomarkers of subclinical disease. Analyses acknowledging cohort heterogeneity through identifying and utilizing these subcohorts may be able to advance our understanding of CVD and provide more effective preventative treatments to reduce the burden of this disease in individuals and in society as a whole.

Serum Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor-1 (sLOX-1) Is Associated with Atherosclerosis Severity in Coronary Artery Disease.

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