Early detection of obstructive coronary artery disease in the asymptomatic high-risk population: objectives and study design of the EARLY-SYNERGY trial.

BACKGROUND: Coronary artery disease (CAD) burden for society is expected to steeply increase over the next decade. Improved feasibility and efficiency of preventive strategies is necessary to flatten the curve. Acute myocardial infarction (AMI) is the main determinant of CAD-related mortality and morbidity, and predominantly occurs in individuals with more advanced stages of CAD causing subclinical myocardial ischemia (obstructive CAD; OCAD). Unfortunately, OCAD can remain subclinical until its destructive presentation with AMI or sudden death. Current primary preventive strategies are not designed to differentiate between non-OCAD and OCAD and the opportunity is missed to treat individuals with OCAD more aggressively. METHODS: EARLY-SYNERGY is a multicenter, randomized-controlled clinical trial in individuals with coronary artery calcium (CAC) presence to study (1.) the yield of cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) for early OCAD diagnosis and (2) whether early OCAD diagnosis improves outcomes. Individuals with CAC score ≥300 objectified in 2 population-based trials (ROBINSCA; ImaLife) are recruited for study participation. Eligible candidates are randomized 1:1 to cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) or no additional functional imaging. In the CMR-MPI arm, feedback on imaging results is provided to primary care provider and participant in case of guideline-based actionable findings. Participants are followed-up for clinical events, healthcare utilization and quality of life. CONCLUSIONS: EARLY-SYNERGY is the first randomized-controlled clinical trial designed to test the hypothesis that subclinical OCAD is widely present in the general at-risk population and that early differentiation of OCAD from non-OCAD followed by guideline-recommended treatment improves outcomes.

Focal pericoronary adipose tissue attenuation is related to plaque presence, plaque type, and stenosis severity in coronary CTA.

OBJECTIVES: To investigate the association of pericoronary adipose tissue mean attenuation (PCATMA) with coronary artery disease (CAD) characteristics on coronary computed tomography angiography (CCTA). METHODS: We retrospectively investigated 165 symptomatic patients who underwent third-generation dual-source CCTA at 70kVp: 93 with and 72 without CAD (204 arteries with plaque, 291 without plaque). CCTA was evaluated for presence and characteristics of CAD per artery. PCATMA was measured proximally and across the most severe stenosis. Patient-level, proximal PCATMA was defined as the mean of the proximal PCATMA of the three main coronary arteries. Analyses were performed on patient and vessel level. RESULTS: Mean proximal PCATMA was -96.2 ± 7.1 HU and -95.6 ± 7.8HU for patients with and without CAD (p = 0.644). In arteries with plaque, proximal and lesion-specific PCATMA was similar (-96.1 ± 9.6 HU, -95.9 ± 11.2 HU, p = 0.608). Lesion-specific PCATMA of arteries with plaque (-94.7 HU) differed from proximal PCATMA of arteries without plaque (-97.2 HU, p = 0.015). Minimal stenosis showed higher lesion-specific PCATMA (-94.0 HU) than severe stenosis (-98.5 HU, p = 0.030). Lesion-specific PCATMA of non-calcified, mixed, and calcified plaque was -96.5 HU, -94.6 HU, and -89.9 HU (p = 0.004). Vessel-based total plaque, lipid-rich necrotic core, and calcified plaque burden showed a very weak to moderate correlation with proximal PCATMA. CONCLUSIONS: Lesion-specific PCATMA was higher in arteries with plaque than proximal PCATMA in arteries without plaque. Lesion-specific PCATMA was higher in non-calcified and mixed plaques compared to calcified plaques, and in minimal stenosis compared to severe; proximal PCATMA did not show these relationships. This suggests that lesion-specific PCATMA is related to plaque development and vulnerability. KEY POINTS: • In symptomatic patients undergoing CCTA at 70 kVp, PCATMA was higher in coronary arteries with plaque than those without plaque. • PCATMA was higher for non-calcified and mixed plaques compared to calcified plaques, and for minimal stenosis compared to severe stenosis. • In contrast to PCATMA measurement of the proximal vessels, lesion-specific PCATMA showed clear relationships with plaque presence and stenosis degree.

Towards reference values of pericoronary adipose tissue attenuation: impact of coronary artery and tube voltage in coronary computed tomography angiography.

OBJECTIVES: To determine normal pericoronary adipose tissue mean attenuation (PCATMA) values for left the anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) in patients without plaques on coronary CT angiography (cCTA), taking into account tube voltage influence. METHODS: This retrospective study included 192 patients (76 (39.6%) men; median age 49 years (range, 19-79)) who underwent cCTA with third-generation dual-source CT for the suspicion of CAD between 2015 and 2017. We selected patients without plaque on cCTA. PCATMA was measured semi-automatically on cCTA images in the proximal segment of the three main coronary arteries with 10 mm length. Paired t-testing was used to compare PCATMA between combinations of two coronary arteries within each patient, and one-way ANOVA testing was used to compare PCATMA in different kV groups. RESULTS: The overall mean ± standard deviation (SD) PCATMA was - 90.3 ± 11.1 HU. PCATMA in men was higher than that in women: - 88.5 ± 10.5 HU versus - 91.5 ± 11.3 HU (p = 0.001). PCATMA of LAD, LCX, and RCA was - 92.4 ± 11.6 HU, - 88.4 ± 9.9 HU, and - 90.2 ± 11.4 HU, respectively. Pairwise comparison of the arteries showed significant difference in PCATMA: LAD and LCX (p < 0.001), LAD and RCA (p = 0.009), LCX and RCA (p = 0.033). PCATMA of the 70 kV, 80 kV, 90 kV, 100 kV, and 120 kV groups was - 95.6 ± 9.6 HU, - 90.2 ± 11.5 HU, - 87.3 ± 9.9 HU, - 82.7 ± 6.2 HU, and - 79.3 ± 6.8 HU, respectively (p < 0.001). CONCLUSIONS: In patients without plaque on cCTA, PCATMA varied by tube voltage, with minor differences in PCATMA between coronary arteries (LAD, LCX, RCA). PCATMA values need to be interpreted taking into account tube voltage setting. KEY POINTS: • In patients without plaque on cCTA, PCATMA differs slightly by coronary artery (LAD, LCX, RCA). • Tube voltage of cCTA affects PCATMA measurement, with mean PCATMA increasing linearly with increasing kV. • For longitudinal cCTA analysis of PCATMA , the use of equal kV setting is strongly recommended.

Relationships of pericoronary and epicardial fat measurements in male and female patients with and without coronary artery disease.

INTRODUCTION: Although pericoronary adipose tissue (PCAT) is a component of the epicardial adipose tissue (EAT) depot, they may have different associations to coronary artery disease (CAD). We explored relationships between pericoronary adipose tissue mean attenuation (PCATMA) and EAT measurements in coronary CT angiography (CCTA) in patients with and without CAD. MATERIAL AND METHODS: CCTA scans of 185 non-CAD and 81 CAD patients (86.4% >50% stenosis) were included and retrospectively analyzed. PCATMA and EAT density/volume were measured and analyzed by sex, including associations with age, risk factors and tube voltage using linear regression models. RESULTS: In non-CAD and CAD, mean PCATMA and EAT volume were higher in men than in women (non-CAD: -92.5 ± 10.6HU vs -96.2 ± 8.4HU, and 174.4 ± 69.1 cm3 vs 124.1 ± 57.3 cm3; CAD: -92.2 ± 9.0HU vs -97.4 ± 9.7HU, and 193.6 ± 62.5 cm3 vs 148.5 ± 50.5 cm3 (p < 0.05)). EAT density was slightly lower in men than women in non-CAD (-96.4 ± 6.3HU vs -94.4 ± 5.5HU (p < 0.05)), and similar in CAD (-98.2 ± 5.2HU vs 98.2 ± 6.4HU). There was strong correlation between PCATMA and EAT density (non-CAD: r = 0.725, p < 0.001, CAD: r = 0.686, p < 0.001) but no correlation between PCATMA and EAT volume (non-CAD: r = 0.018, p = 0.81, CAD: r = -0.055, p = 0.63). A weak inverse association was found between EAT density and EAT volume (non-CAD: r = -0.244, p < 0.001, CAD: r = -0.263, p = 0.02). In linear regression models, EAT density was significantly associated with PCATMA in both non-CAD and CAD patients independent of risk factors and tube voltage. CONCLUSION: In CAD and non-CAD patients, EAT density, but not EAT volume, showed significant associations with PCATMA. Compared to women, men had higher PCATMA and EAT volume independently of disease status, but similar or slightly lower EAT density. Differences in trends and relations of PCATMA and EAT by sex could indicate that personalized interpretation and thresholding is needed.

Validation and comparison of 28 risk prediction models for coronary artery disease.

AIMS: Risk prediction models (RPMs) for coronary artery disease (CAD), using variables to calculate CAD risk, are potentially valuable tools in prevention strategies. However, their use in the clinical practice is limited by a lack of poor model description, external validation, and head-to-head comparisons. METHODS AND RESULTS: CAD RPMs were identified through Tufts PACE CPM Registry and a systematic PubMed search. Every RPM was externally validated in the three cohorts (the UK Biobank, LifeLines, and PREVEND studies) for the primary endpoint myocardial infarction (MI) and secondary endpoint CAD, consisting of MI, percutaneous coronary intervention, and coronary artery bypass grafting. Model discrimination (C-index), calibration (intercept and regression slope), and accuracy (Brier score) were assessed and compared head-to-head between RPMs. Linear regression analysis was performed to evaluate predictive factors to estimate calibration ability of an RPM. Eleven articles containing 28 CAD RPMs were included. No single best-performing RPM could be identified across all cohorts and outcomes. Most RPMs yielded fair discrimination ability: mean C-index of RPMs was 0.706 ± 0.049, 0.778 ± 0.097, and 0.729 ± 0.074 (P < 0.01) for prediction of MI in UK Biobank, LifeLines, and PREVEND, respectively. Endpoint incidence in the original development cohorts was identified as a significant predictor for external validation performance. CONCLUSION: Performance of CAD RPMs was comparable upon validation in three large cohorts, based on which no specific RPM can be recommended for predicting CAD risk.

What really matters: a patient-centered instrument to evaluate health-related quality of life in cardiovascular disease.

AIMS: Patient-reported outcome measures (PROMs) to assess health-related quality of life (HRQoL) are increasingly used to guide decision-making in cardiovascular care. However, many of the existing PROMs are developed with limited patient involvement and overlook personal health preferences. We aim to develop a cardiovascular disease (CVD)-specific patient-centred preference-based PROM to assess and monitor HRQoL in CVD patients. METHODS AND RESULTS: A mixed-methods study consisting of several phases was conducted to identify important health items: (i) a scoping literature review, (ii) first- and second-round expert group meetings, (iii) interviews with CVD patients, and (iv) an online survey asking CVD patients to indicate from a large set those health items that are considered the most important. The literature review, expert group meetings, and patient interviews resulted in a list of 55 items potentially important to CVD patients. In total, 666 CVD patients responded to the survey. The following nine items were considered the most important by CVD patients: mobility, activities, self-reliance, fatigue, shortness of breath, chest pain, palpitations, anxiety/worrying, and sexual limitations. An electronic preference-based PROM consisting of these nine items was developed within a cloud-based environment for clinical implementation. CONCLUSION: Nine items considered the most important for health by CVD patients were identified and included in a new preference-based patient-centred PROM. This new CVD-specific PROM can be easily implemented using the electronic application and has the potential to improve quality of care for CVD patients.

Pre-screening to guide coronary artery calcium scoring for early identification of high-risk individuals in the general population.

AIMS: To evaluate the ability of Systematic COronary Risk Estimation 2 (SCORE2) and other pre-screening methods to identify individuals with high coronary artery calcium score (CACS) in the general population. METHODS AND RESULTS: Computed tomography-based CACS quantification was performed in 6530 individuals aged 45 years or older from the general population. Various pre-screening methods to guide referral for CACS were evaluated. Miss rates for high CACS (CACS ≥300 and ≥100) were evaluated for various pre-screening methods: moderate (≥5%) and high (≥10%) SCORE2 risk, any traditional coronary artery disease (CAD) risk factor, any Risk Or Benefit IN Screening for CArdiovascular Disease (ROBINSCA) risk factor, and moderately (>3 mg/24 h) increased urine albumin excretion (UAE). Out of 6530 participants, 643 (9.8%) had CACS ≥300 and 1236 (18.9%) had CACS ≥100. For CACS ≥300 and CACS ≥100, miss rate was 32 and 41% for pre-screening by moderate (≥5%) SCORE2 risk and 81 and 87% for high (≥10%) SCORE2 risk, respectively. For CACS ≥300 and CACS ≥100, miss rate was 8 and 11% for pre-screening by at least one CAD risk factor, 24 and 25% for at least one ROBINSCA risk factor, and 67 and 67% for moderately increased UAE, respectively. CONCLUSION: Many individuals with high CACS in the general population are left unidentified when only performing CACS in case of at least moderate (≥5%) SCORE2, which closely resembles current clinical practice. Less stringent pre-screening by presence of at least one CAD risk factor to guide CACS identifies more individuals with high CACS and could improve CAD prevention.

Association of epicardial adipose tissue with different stages of coronary artery disease: A cross-sectional UK Biobank cardiovascular magnetic resonance imaging substudy.

Objective: Increased epicardial adipose tissue (EAT) has been identified as a risk factor for the development of coronary artery disease (CAD). However, the exact role of EAT in the development of CAD is unclear. This study aims to compare EAT volumes between healthy controls and individuals with stable CAD and a history of myocardial infarction (MI). Furthermore, associations between clinical and biochemical parameters with EAT volumes are examined. Methods: This retrospective cross-sectional study included 171 participants from the United Kingdom Biobank (56 healthy controls; 60 stable CAD; 55 post MI), whom were balanced for age, sex and body mass index (BMI). EAT volumes were quantified on end-diastolic cardiac magnetic resonance (CMR) imaging short-axis slices along the left and right ventricle and indexed for body surface area (iEAT) and iEAT volumes were compared between groups. Results: iEAT volumes were comparable between control, CAD and MI cases (median [IQR]: 66.1[54.4-77.0] vs. 70.9[55.8-85.5] vs. 67.6[58.6-82.3] mL/m2, respectively (p > 0.005 for all). Increased HDL-cholesterol was associated with decreased iEAT volume (ß = -14.8, CI = -24.6 to -4.97, p = 0.003) and suggestive associations (P-value < 0.05 and ≥ 0.005) were observed between iEAT and triglycerides (ß = 3.26, CI = 0.42 to 6.09, p = 0.02), Apo-lipoprotein A (ß = -16.3, CI = -30.3 to -2.24, p = 0.02) and LDL-cholesterol (ß = 3.99, CI = -7.15 to -0.84, p = 0.01). Conclusions: No significant differences in iEAT volumes were observed between patients with CAD, MI and healthy controls. Our results indicate the importance of correcting for confounding by CVD risk factors, including circulating lipid levels, when studying the relationship between EAT volume and CAD. Further mechanistic studies on causal pathways and the role of EAT composition are warranted.

Multi-Modality Imaging for Prevention of Coronary Artery Disease and Myocardial Infarction in the General Population: Ready for Prime Time?

Cardiovascular disease (CVD) remains a leading cause of death and disability worldwide. Acute myocardial infarction (AMI) causes irreversible myocardial damage, heart failure, life-threatening arrythmias and sudden cardiac death (SCD), and is a main driver of CVD mortality and morbidity. To control the forecasted increase in CVD burden for both the individual and society, improved strategies for the prevention of AMI and SCD are required. Current prevention of AMI and SCD is directed towards risk-modifying interventions, guided by risk assessment using clinical risk prediction scores (CRPSs) and the coronary artery calcium score (CACS). Early detection of more advanced coronary artery disease (CAD), beyond risk assessment by CRPSs or CACS, is a promising strategy to allow personalized treatment for the improved prevention of AMI and SCD in the general population. We review evidence for further testing, beyond CRPSs and CACS, and therapies focusing on promising targets, including subclinical obstructive CAD, high-risk plaques, and silent myocardial ischemia. We also evaluate the potential of multi-modality imaging to enhance the conduction of adequately powered trials to provide high-quality evidence on the impact of add-on tests and therapies in the prevention of AMI and SCD in asymptomatic individuals. To conclude, we discuss the occurrence of AMI and SCD in individuals currently estimated to be at "low-risk" by the current strategy based on CRPSs, and methods to improve prevention of AMI and SCD in this "low-risk" population.

Genomic insights in ascending aortic size and distensibility.

BACKGROUND: Alterations in the anatomic and biomechanical properties of the ascending aorta (AAo) can give rise to various vascular pathologies. The aim of the current study is to gain additional insights in the biology of the AAo size and function. METHODS: We developed an AI based analysis pipeline for the segmentation of the AAo, and the extraction of AAO parameters. We then performed genome-wide association studies of AAo maximum area, AAo minimum area and AAo distensibility in up to 37,910 individuals from the UK Biobank. Variants that were significantly associated with AAo phenotypes were used as instrumental variables in Mendelian randomization analyses to investigate potential causal relationships with coronary artery disease, myocardial infarction, stroke and aneurysms. FINDINGS: Genome-wide association studies revealed a total of 107 SNPs in 78 loci. We annotated 101 candidate genes involved in various biological processes, including connective tissue development (THSD4 and COL6A3). Mendelian randomization analyses showed a causal association with aneurysm development, but not with other vascular diseases. INTERPRETATION: We identified 78 loci that provide insights into mechanisms underlying AAo size and function in the general population and provide genetic evidence for their role in aortic aneurysm development.

Effects of Caffeine on Myocardial Blood Flow: A Systematic Review.

BACKGROUND: Caffeine is one of the most widely consumed stimulants worldwide. It is a well-recognized antagonist of adenosine and a potential cause of false-negative functional measurements during vasodilator myocardial perfusion. The aim of this systematic review is to summarize the evidence regarding the effects of caffeine intake on functional measurements of myocardial perfusion in patients with suspected coronary artery disease. Pubmed, Web of Science, and Embase were searched using a predefined electronic search strategy. Participants-healthy subjects or patients with known or suspected CAD. Comparisons-recent caffeine intake versus no caffeine intake. Outcomes-measurements of functional myocardial perfusion. Study design-observational. Fourteen studies were deemed eligible for this systematic review. There was a wide range of variability in study design with varying imaging modalities, vasodilator agents, serum concentrations of caffeine, and primary outcome measurements. The available data indicate a significant influence of recent caffeine intake on cardiac perfusion measurements during adenosine and dipyridamole induced hyperemia. These effects have the potential to affect the clinical decision making by re-classification to different risk-categories.

Influence of hydrostatic pressure on intracoronary indices of stenosis severity in vivo.

BACKGROUND: An influence of hydrostatic pressure on intracoronary indices of stenosis severity in vitro was recently reported. We sought to analyze the influence of hydrostatic pressure, caused by the height difference between the distal and proximal pressure sensor after guidewire positioning in the interrogated vessel, on intracoronary pressure measurements in vivo. METHODS AND RESULTS: In 30 coronary stenoses, intracoronary pressure measurements were performed in supine, left, and right lateral patient position. Height differences between the distal and proximal pressure sensor were measured by blinded observers. Measurement results of the position with the highest ("high") and lowest height difference ("low") were compared. In group "high", all measured indices were higher: mean difference of fractional flow reserve (FFR) 0.045 (SD 0.033, 95% CI 0.033-0.057, p < 0.0001), of instantaneous wave-free ratio (iFR) 0.043 (SD 0.04, 95% CI 0.029-0.057, p < 0.0001), and of resting Pd/Pa 0.037 (SD 0.034, 95% CI 0.025-0.049, p < 0.0001). Addition of the physically expectable hydrostatic pressure to the distal coronary pressures of the control group abolished the differences: corrected ∆FFR - 0.006 (SD 0.027, 95% CI - 0.015 to 0.004, p = 0.26), corrected ∆Pd/Pa - 0.008 (SD 0.03, 95% CI - 0.019 to 0.003, p = 0.18). Adjustment for hydrostatic pressure of FFR values in a standard supine position increased all values in anterior vessels and decreased all values in posterior vessels. The mean changes of FFR due to adjustment were: LAD - 0.048 (SD 0.016), CX 0.02 (SD 0.009), RCA 0.02 (SD 0.021). Dichotomous severity classification changed in 12.9% of stenoses. CONCLUSIONS: The study demonstrates a relevant influence of hydrostatic pressure on intracoronary indices of stenosis severity in vivo, caused by the height differences between distal and proximal pressure sensor.

Computational quantitative flow ratio to assess functional severity of coronary artery stenosis.

Background Computational quantitative flow ratio (QFR) based on 3-dimensional quantitative coronary angiography (3D QCA) analysis offers the opportunity to assess the significance of coronary artery disease (CAD) without using an invasive pressure wire or inducing hyperemia. This study aimed to evaluate the diagnostic performance of QFR compared to wire-based fractional flow reserve (FFR) and to validate the previously reported QFR cut-off value of >0.90 to safely rule out functionally significant CAD. Methods QFR was retrospectively derived from standard-care coronary angiograms. Correlation and agreement of fixed-flow QFR (fQFR) and contrast-flow QFR (cQFR) models with invasive wire-based FFR was calculated. Diagnostic performance of QFR was evaluated at different QFR cut-off values defining significant CAD (FFR ≤ 0.80). Results 101 vessels in 96 patients who underwent FFR were studied. Mean FFR was 0.87 ±â€¯0.08 and 21 of 101 (21%) vessels had an FFR ≤ 0.80. Correlation of fQFR and cQFR with FFR was r = 0.71 (p < 0.001) and r = 0.70 (p < 0.001), respectively. Sensitivity and specificity were 57% and 93% for fQFR and 67% and 96% for cQFR at a QFR cut-off value >0.80 defining non-significant CAD, respectively. fQFR > 0.90 was present in 34 (34%) and cQFR > 0.90 in 39 (39%) vessels. For both QFR models, none of the vessels with QFR > 0.90 had an FFR ≤ 0.80. Conclusions QFR appears to be a safe and effective gatekeeper to wire-based FFR when applying a QFR threshold of >0.90 to rule out significant CAD. Further prospective research is required to establish QFR in the real-life setting of functional CAD assessment in the catheterization laboratory.