Clinical Utility of a Precision Medicine Test Evaluating Outpatients with Suspected Obstructive Coronary Artery Disease

Background Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography. Surprisingly, despite well-established clinical indications, up to 40% of the one million invasive cardiac catheterizations return a result of ‘no blockage’. The present studies employed RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. Methods Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by single-molecule sequencing of RNA (RNAseq) to identify transcripts associated with CAD (TRACs) in a discovery group of 96 patients presenting for elective coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs). Results Surprisingly, 98% of DEGs/TRACs were down-regulated ~ 1.7-fold in patients with mild to severe CAD (> 20% stenosis). The TRACs were independent of comorbid risk factors for CAD, such as sex, hypertension, and smoking. Bioinformatic analysis identified an enrichment in transcripts such as FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A that are likely markers of regulatory T cells (Treg), consistent with known reductions in Tregs in CAD. A validation cohort of 80 patients confirmed the overall pattern (92% down-regulation) and supported many of the Treg-related changes. TRACs were enriched for transcripts associated with stress granules, which sequester RNAs, and ciliary and synaptic transcripts, possibly consistent with changes in the immune synapse of developing T cells. Conclusions These studies identify a novel mRNA signature of a Treg-like defect in CAD patients and provides a blueprint for a diagnostic test for CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.

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“…S3). This impact of age is consistent with the use of age and sex in other gene expression models of CAD [ 22 ].…”

Section: Resultssupporting

confidence: 86%

RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance

et al. 2021

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“…877 Patients with scores in this range showed no abnormal findings on subsequent stress tests or coronary angiography, and had a low rate of coronary revascularization or major cardiovascular events during 1-year follow-up (1.2% in the ASGES ≤15 group vs. 4.5% in the ASGES >15 group; P=0.03). 878 The odds ratio for coronary heart disease in the ASGES >15 group compared with the ASGES ≤15 group was 2.5 (95% CI: 1.6-3.8, P<0.001), and the incidence of a composite endpoint of major cardiovascular events was also higher in the former group (adjusted hazard ratio: 1.70; 95% CI: 1.10-2.64, P=0.017). 879 Thus, ASGES is a useful prognostic indicator for prediction of coronary heart disease and cardiovascular events, and is expected to be used clinically as a convenient diagnostic method for coronary heart disease.…”

Section: ▋ 223 Age-and Sex-specific Gene Expression Scorementioning

confidence: 89%

JCS 2018 Guideline on Diagnosis of Chronic Coronary Heart Diseases

Yamagishi¹,

Tamaki²,

Akasaka³

et al. 2021

Circ J

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ABI ankle-brachial index ACC American College of Cardiology ACS acute coronary syndrome AHA American Heart Association APV averaged peak velocity ARH autosomal recessive hypercholesterolemia AS Agatston score ASO arteriosclerosis obliterans ATP adenosine triphosphate BMIPP β-methyl-p-iodophenyl-pentadecanoic acid BNP B-type natriuretic peptide CABG coronary artery bypass grafting CACS coronary artery calcium score CAD coronary artery disease CANM Canadian Association of Nuclear Medicine CanSCMR Canadian Society of Cardiovascular Magnetic Resonance CAR Canadian Association of Radiologists CCS Canadian Cardiovascular Society CCTA coronary CT angiography CDC Centers for Disease Control and Prevention CFR coronary flow reserve CFVR coronary flow velocity reserve CI confidence interval CKD chronic kidney disease CNCS Canadian Nuclear Cardiology Society CPAP continuous positive airway pressure CT computed tomography CTA computed tomography angiography CTDIvol computed omography dose index volume ▋ 2.2.1 Selection of the Lead System and Recording Time Appropriate ECG recording is essential for making a diagnosis of coronary heart disease. Care should be exercised with regard to selection of the electrodes, leads, paste, and lead system to obtain stable recordings during daily activities. The leads that are most likely to reflect ischemic changes are V5-like leads. In particular, lead CM5 is less affected by body movements and has a good detection rate for ischemic changes. 50 A 2-lead system is commonly used, and the AHA guidelines recommend a combination of leads that approximates leads V1 and V5. 51 For capturing ST elevation in patients with variant angina, vertical leads (II, III, and aVF) and approximations to lead V2 or V3 provide a high diagnostic rate. 52 Both circadian and diurnal (dayto-day) variations may exist in relation to the incidence and duration of myocardial ischemia and the extent of ST changes. However, it is difficult to evaluate the influence of diurnal variation based on 24-hour recording, which means that 48-hour recording is desirable for detecting myocardial ischemia and determining the response to treatment. ▋ 2.2.2 Criteria for ST-Segment Changes The diagnostic significance of persistent ST depression on Holter ECG is not high. Rather, detection and evaluation of transient ST-segment changes is more important. The criteria for ST depression are as follows: (1) horizontal or sagging depression of the ST segment by ≥0.1 mV; (2) reaching maximum ST depression after 1 min; and (3) ST depression of ≥0.1 mV lasting for ≥30-60 s compared with the baseline in a controlled state. 49,53-55 ST depression is measured at 0.08 s after the S or J point, and J-type ST depression is not judged to be ischemic ST depression. 52 When counting the number of ischemic episodes, the definition adopted is that each ischemic interval should last for at least 1 min. 56 The criterion for ST elevation is elevation of the ST segment by ≥0.1 mV lasting for ≥30-60 s in leads without Q waves. 49 In patients with chest pain ...

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“…The study design, participant flow chart, and exclusion criteria have been described in detail ( Figure S1). 19 Of 566 individuals in this PRESET Registry, 176 (31%) were aged 65 and older. The current study focused on subgroup analysis of this elderly population.…”

Section: Study Participantsmentioning

confidence: 99%

Utility of a Precision Medicine Test in Elderly Adults with Symptoms Suggestive of Coronary Artery Disease

Ladapo

Budoff

Sharp³

et al. 2017

J American Geriatrics Society

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BACKGROUND: Diagnosing obstructive coronary artery disease (CAD) is challenging in elderly adults, and current diagnostic approaches for CAD expose these individuals to risks from contrast dye and invasive procedures. DESIGN: A Registry to Evaluate Patterns of Care Associated with the Use of Corus CAD in Real World Clinical Care Settings (PRESET; NCT01677156), pragmatic clinical trial. SETTING: Community, 21 primary care practices. PARTICIPANTS: Of 566 stable, nonacute outpatients presenting with symptoms suggestive of obstructive CAD, the 176 who were aged 65 and older (median age 70, 61% female) were the current study participants. INTERVENTION: Blood-based precision medicine test, incorporating age, sex, and gene expression score (ASGES) to improve clinical decision-making and quality of care. MEASUREMENTS: Information on demographic characteristics, clinical factors, ASGES results (range 1-40; low (≤15), high (>15)), referral patterns to cardiology and advanced cardiac testing, and major adverse cardiac events (MACEs) was collected in a subgroup analysis of elderly adults in the PRESET Registry. Follow-up was for 1 year after ASGES testing. RESULTS: Median ASGES was 25, and 40 (23%) participants had a low score. Clinicians referred 12.5% of participants with a low ASGES and 49.3% with a high ASGES to cardiology or advanced cardiac testing (odds ratio for referral = 0.12, P < .001, adjusted for participants demographics and clinical covariates). Higher scores were associated with greater likelihood of posttest cardiac referral. At 1-year follow-up, the incidence of a MACE or

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Clinical Utility of a Precision Medicine Test Evaluating Outpatients with Suspected Obstructive Coronary Artery Disease

Cited by 13 publications

References 30 publications

RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance

RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance

JCS 2018 Guideline on Diagnosis of Chronic Coronary Heart Diseases

Utility of a Precision Medicine Test in Elderly Adults with Symptoms Suggestive of Coronary Artery Disease

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