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.

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.

Mass cytometry analysis reveals altered immune profiles in patients with coronary artery disease.

Objective: The importance of inflammation in atherosclerosis is well accepted, but the role of the adaptive immune system is not yet fully understood. To further explore this, we assessed the circulating immune cell profile of patients with coronary artery disease (CAD) to identify discriminatory features by mass cytometry. Methods: Mass cytometry was performed on patient samples from the BioHEART-CT study, gated to detect 82 distinct cell subsets. CT coronary angiograms were analysed to categorise patients as having CAD (CAD+) or having normal coronary arteries (CAD-). Results: The discovery cohort included 117 patients (mean age 61 ± 12 years, 49% female); 79 patients (68%) were CAD+. Mass cytometry identified changes in 15 T-cell subsets, with higher numbers of proliferating, highly differentiated and cytotoxic cells and decreases in naïve T cells. Five T-regulatory subsets were related to an age and gender-independent increase in the odds of CAD incidence when expressing CCR2 (OR 1.12), CCR4 (OR 1.08), CD38 and CD45RO (OR 1.13), HLA-DR (OR 1.06) and Ki67 (OR 1.22). Markers of proliferation and differentiation were also increased within B cells, while plasmacytoid dendritic cells were decreased. This combination of changes was assessed using SVM models in discovery and validation cohorts (area under the curve = 0.74 for both), confirming the robust nature of the immune signature detected. Conclusion: We identified differences within immune subpopulations of CAD+ patients which are indicative of a systemic immune response to coronary atherosclerosis. This immune signature needs further study via incorporation into risk scoring tools for the precision diagnosis of CAD.

Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review.

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.

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.

Lipidomics Profiling and Risk of Coronary Artery Disease in the BioHEART-CT Discovery Cohort.

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

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.

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.

Higher mortality in acute coronary syndrome patients without standard modifiable risk factors: Results from a global meta-analysis of 1,285,722 patients.

BACKGROUND: Standard modifiable cardiovascular risk factors (SMuRF), comprising diabetes, hyperlipidemia, hypertension, and smoking, are used for risk stratification in acute coronary syndrome (ACS). Recent studies showed an increasing proportion of SMuRF-less ACS patients. METHODS: Embase, Medline and Pubmed were searched for studies comparing SMuRF-less and SMuRF patients with first presentation of ACS. We conducted single-arm analyses to determine the proportion of SMuRF-less patients in the ACS cohort, and compared the clinical presentation and outcomes of these patients. RESULTS: Of 1,285,722 patients from 15 studies, 11.56% were SMuRF-less. A total of 7.44% of non-ST-segment-elevation ACS patients and 12.87% of ST-segment-elevation myocardial infarction (STEMI) patients were SMuRF-less. The proportion of SMuRF-less patients presenting with STEMI (60.71%) tended to be higher than those with SMuRFs (49.21%). Despite lower body mass index and fewer comorbidities such as chronic kidney disease, peripheral arterial disease, stroke and heart failure, SMuRF-less patients had increased in-hospital mortality (RR:1.57, 95%CI:1.38 to 1.80) and cardiogenic shock (RR:1.39, 95%CI:1.18 to 1.65), but lower risk of heart failure (RR:0.91, 95%CI:0.83 to 0.99). On discharge, SMuRF-less patients were prescribed less statins (RR:0.93, 95%CI:0.91 to 0.95), beta-blockers (RR:0.94, 95%CI:0.92 to 0.96), P2Y12 inhibitors (RR: 0.98, 95%CI: 0.96 to 0.99), and angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker (RR:0.92, 95%CI:0.75 to 0.91). CONCLUSION: In this study level meta-analysis, SMuRF-less ACS patients demonstrate higher mortality compared with patients with at least one traditional atherosclerotic risk factor. Underuse of guideline-directed medical therapy amongst SMuRF-less patients is concerning. Unraveling novel risk factors amongst SMuRF-less individuals is the next important step. SUMMARY: Standard modifiable cardiovascular risk factors (SMuRF), comprising diabetes mellitus, hyperlipidemia, hypertension, and smoking, are often used for risk stratification in acute coronary syndrome (ACS). Recent studies showed an increasing proportion of SMuRF-less ACS patients. Of 1,285,722 ACS patients, 11.56% were SMuRF-less. Despite lower body mass index and fewer comorbidities, SMuRF-less patients had increased in-hospital mortality and cardiogenic shock. However, despite worse outcomes, SMuRF-less patients were prescribed less guideline-directed medical therapies on discharge.

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.

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.

Cardiovascular magnetic resonance characteristics and clinical outcomes of patients with ST-elevation myocardial infarction and no standard modifiable risk factors-A DANAMI-3 substudy.

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

Mortality and Cardiovascular Outcomes in Patients Presenting With Non-ST Elevation Myocardial Infarction Despite No Standard Modifiable Risk Factors: Results From the SWEDEHEART Registry.

Background A significant proportion of patients with ST-segment-elevation myocardial infarction (MI) have no standard modifiable cardiovascular risk factors (SMuRFs) and have unexpected worse 30-day outcomes compared with those with SMuRFs. The aim of this article is to examine outcomes of patients with non-ST-segment-elevation MI in the absence of SMuRFs. Methods and Results Presenting features, management, and outcomes of patients with non-ST-segment-elevation MI without SmuRFs (hypertension, diabetes, hypercholesterolemia, smoking) were compared with those with SmuRFs in the Swedish MI registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies; 2005-2018). Cox proportional hazard models were used. Out of 99 718 patients with non-ST-segment-elevation MI, 11 131 (11.2%) had no SMuRFs. Patients without SMuRFs had higher all-cause and cardiovascular mortality at 30 days (hazard ratio [HR], 1.20 [95% CI, 1.10-1.30], P<0.0001; and HR, 1.25 [95% CI, 1.13-1.38]), a difference that remained after adjustment for age and sex. SMuRF-less patients were less likely to receive secondary prevention statins (76% versus 82%); angiotensin-converting enzyme inhibitors/angiotensin receptor blockade (54% versus 72%); or ß-blockers (81% versus 87%, P for all <0.0001), with lowest rates observed in women without SMuRFs. In patients who survived to 30 days, rates of all-cause and cardiovascular death were lower in patients without SMuRFs compared with those with risk factors, over 12 years. Conclusions One in 10 patients presenting with non-ST-segment-elevation MI present without traditional risk factors. The excess 30-day mortality rate in this group emphasizes the need for both improved population-based strategies for prevention of MI, as well as the need for equitable evidence-based treatment at the time of an MI.

Clinical Outcomes in Patients With ST-Segment Elevation MI and No Standard Modifiable Cardiovascular Risk Factors.

BACKGROUND: The author recently reported ∼50% excess early mortality in patients with first-presentation ST-segment elevation myocardial infarction (STEMI) without standard modifiable cardiovascular risk factors (SMuRFs); the cause of this is not clear. OBJECTIVES: The aim of this study was to examine differences in infarct characteristics and clinical outcomes in patients with versus without SMuRFs (dyslipidemia, hypertension, diabetes mellitus, and smoking). METHODS: Individual-level data were pooled from 10 randomized percutaneous intervention (PCI) trials in which infarct size was measured within 1 month by either cardiac magnetic resonance or technetium-99m sestamibi single-photon emission computed tomography imaging. First-presentation STEMI was classified into 2 groups according to the presence or absence of at least 1 SMuRF. RESULTS: Among 2,862 patients, 524 (18.3%) were SMuRF-less. After adjusting for study effect, SMuRF-less patients had more frequent poor pre-PCI flow Thrombolysis In Myocardial Infarction 0/1 compared with patients with at least 1 SMuRF (72.0% vs 64.1%; OR: 1.35; 95% CI: 1.08-1.70). There were no independent associations between the presence or absence of SMuRFs at baseline and infarct size (estimate = -0.35; 95% CI: -1.93 to 1.23), left ventricular ejection fraction (estimate = -0.06; 95% CI: -1.33 to 1.20), or mortality at 30 days (HR: 0.46; 95% CI: 0.19-1.07) and 1 year (HR: 0.74; 95% CI: 0.43-1.29). CONCLUSIONS: First-presentation STEMI patients with no identifiable baseline SMuRFs had a higher risk of Thrombolysis In Myocardial Infarction flow grade 0/1 pre-PCI. However, after adjustment, there were no significant associations between SMuRF-less status and infarct size, left ventricle ejection fraction, or mortality.

Integrating a Polygenic Risk Score for Coronary Artery Disease as a Risk-Enhancing Factor in the Pooled Cohort Equation: A Cost-Effectiveness Analysis Study.

Background Cardiovascular diseases are the leading cause of death in the United States, yet a significant proportion of adults at high risk remain undetected by standard screening practices. Polygenic risk score for coronary artery disease (CAD-PRS) improves precision in determining the 10-year risk of atherosclerotic cardiovascular disease but health benefits and health care costs associated with CAD-PRS are unknown. We examined the cost-effectiveness of including CAD-PRS as a risk-enhancing factor in the pooled cohort equation (PCE)-the standard of care for determining the risk of atherosclerotic cardiovascular disease-versus PCE alone. Methods and Results We applied a Markov model on a cohort of 40-year-old individuals with borderline or intermediate 10-year risk (5% to <20%) for atherosclerotic cardiovascular disease to identify those in the top quintile of the CAD-PRS distribution who are at high risk and eligible for statin prevention therapy. Health outcomes examined included coronary artery disease (CAD; ie, myocardial infarction) and ischemic stroke. The model projected medical costs (2019 US$) of screening for CAD, statin prevention therapy, treatment, and monitoring patients living with CAD or ischemic stroke and quality-adjusted life-years for PCE+CAD-PRS versus PCE alone. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed to examine uncertainty in parameter inputs. PCE+CAD-PRS was dominant compared with PCE alone in the 5- and 10-year time horizons. We found that, respectively, PCE+CAD-PRS had 0.003 and 0.011 higher mean quality-adjusted life-years and $40 and $181 lower mean costs per person screened, with 29 and 50 fewer events of CAD and ischemic stroke in a cohort of 10 000 individuals compared with PCE alone. The risk of developing CAD, the effectiveness of statin prevention therapy, and the cost of treating CAD had the largest impact on the cost per quality-adjusted life-year gained. However, this cost remained below the $50 000 willingness-to-pay threshold except when the annual risk of developing CAD was <0.006 in the 5-year time horizon. Results from Monte Carlo simulation indicated that PCE+CAD-PRS would be cost-effective. with the probability of 94% and 99% at $50 000 willingness-to-pay threshold in the 5- and 10-year time horizon, respectively. Conclusions Implementing CAD-PRS as a risk-enhancing factor in the PCE to determine the risk of atherosclerotic cardiovascular disease reduced the mean cost per individual, improved quality-adjusted life-years, and averted future events of CAD and ischemic stroke when compared with PCE alone.

Biomarker Development in Cardiology: Reviewing the Past to Inform the Future.

Cardiac biomarkers have become pivotal to the clinical practice of cardiology, but there remains much to discover that could benefit cardiology patients. We review the discovery of key protein biomarkers in the fields of acute coronary syndrome, heart failure, and atherosclerosis, giving an overview of the populations they were studied in and the statistics that were used to validate them. We review statistical approaches that are currently in use to assess new biomarkers and overview a framework for biomarker discovery and evaluation that could be incorporated into clinical trials to evaluate cardiovascular outcomes in the future.

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.

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

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

Association of Global Coagulation Profiles With Cardiovascular Risk Factors and Atherosclerosis: A Sex Disaggregated Analysis From the BioHEART-CT Study.

Background Although the association between dysregulated coagulation and atherosclerosis is well recognized, individual assays have been of minimal value in understanding disease susceptibility. Here we investigated the association of global coagulation profiles with coronary artery disease with consideration of sex differences. Methods and Results The study included patients from the BioHEART-CT (The BioHEART Study: Assessing Patients With Suspected Cardiovascular Disease for New Disease Markers and Risk Factors) biobank who had computed tomography coronary angiograms scored for coronary artery calcium score (CACS) and Gensini score. The cohort included 206 adult patients who were referred for clinically indicated computed tomography coronary angiography and had a median of 2 major cardiac risk factors; 50% were women and the average age was 62.6 years (±9.9 years). The overall hemostatic potential (OHP) and calibrated automated thrombography generation assays were performed on platelet-poor plasma. CACS and Gensini score in men were significantly correlated in bivariate analysis with measures from the OHP assay, and regression models predicting disease severity by CACS or Gensini score were improved by adding the OHP assay variables in men but not in women. The calibrated automated thrombography generation assay demonstrated a more hypercoagulable profile in women than in men. The OHP assay showed hypercoagulable profiles in women with hyperlipidemia and men with obesity. Conclusions The OHP assay identified hypercoagulable profiles associated with different risk factors for each sex and was associated with CACS and Gensini score severity in men, emphasizing the associations between increased fibrin generation and reduced fibrinolysis with cardiac risk factors and early atherosclerosis. Registration Information www.anzctr.org.au. Identifier: ACTRN12618001322224.