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.

Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands.

A potential link between mortality, d-dimer values, and a prothrombotic syndrome has been reported in patients with coronavirus disease 2019 (COVID-19) infection. The National Institute for Public Health of the Netherlands asked a group of radiology and vascular medicine experts to provide guidance for the imaging work-up and treatment of these important complications. This report summarizes evidence for thromboembolic disease, potential diagnostic and preventive actions, and recommendations for prophylaxis and treatment of patients with COVID-19 infection.

Early detection of heart function abnormality by native T1: a comparison of two T1 quantification methods.

OBJECTIVE: To compare the robustness of native T1 mapping using mean and median pixel-wise quantification methods. METHODS: Fifty-seven consecutive patients without overt signs of heart failure were examined in clinical routine for suspicion of cardiomyopathy. MRI included the acquisition of native T1 maps by a motion-corrected modified Look-Locker inversion recovery sequence at 1.5 T. Heart function status according to four established volumetric left ventricular (LV) cardio MRI parameter thresholds was used for retrospective separation into subgroups of normal (n = 26) or abnormal heart function (n = 31). Statistical normality of pixel-wise T1 was tested on each myocardial segment and mean and median segmental T1 values were assessed. RESULTS: Segments with normally distributed pixel-wise T1 (57/58%) showed no difference between mean and median quantification in either patient group, while differences were highly significant (p < 0.001) for the respective 43/42% non-normally distributed segments. Heart function differentiation between two patient groups was significant in 14 myocardial segments (p < 0.001-0.040) by median quantification compared with six (p < 0.001-0.042) by using the mean. The differences by median quantification were observed between the native T1 values of the three coronary artery territories of normal heart function patients (p = 0.023) and insignificantly in the abnormal patients (p = 0.053). CONCLUSION: Median quantification increases the robustness of myocardial native T1 definition, regardless of statistical normality of the data. Compared with the currently prevailing method of mean quantification, differentiation between LV segments and coronary artery territories is better and allows for earlier detection of heart function impairment. KEY POINTS: • Median pixel-wise quantification of native T1 maps is robust and can be applied regardless of the statistical distribution of data points. • Median quantification is more sensitive to early heart function abnormality compared with mean quantification. • The new method yields significant native T1 value differentiation between the three coronary artery territories.

Accurate late gadolinium enhancement prediction by early T1- based quantitative synthetic mapping.

OBJECTIVES: Early synthetic gadolinium enhancement (ESGE) imaging from post-contrast T1 mapping after adenosine stress-perfusion cardiac magnetic resonance (CMR) was compared to conventional late gadolinium enhancement (LGE) imaging for assessing myocardial scar. METHODS: Two hundred fourteen consecutive patients suspected of myocardial ischaemia were referred for stress-perfusion CMR. Myocardial infarct volume was quantified on a per-subsegment basis in both synthetic (2-3 min post-gadolinium) and conventional (9 min post-gadolinium) images by two independent observers. Sensitivity, specificity, PPV and NPV were calculated on a per-patient and per-subsegment basis. RESULTS: Both techniques detected 39 gadolinium enhancement areas in 23 patients. The median amount of scar was 2.0 (1.0-3.1) g in ESGE imaging and 2.2 (1.1-3.1) g in LGE imaging (p=0.39). Excellent correlation (r=0.997) and agreement (mean absolute difference: -0.028±0.289 ml) were found between ESGE and LGE images. Sensitivity, specificity, PPV and NPV of ESGE imaging were 96 (78.9-99.9), 99 (97.1-100.0)%, 96 (76.5-99.4) and 99.5 (96.6-99.9) in patient-based and 99 (94.5-100.0), 100 (99.9-100.0)%, 97.0 (91.3-99.0) and 100.0 (99.8-100.0) in subsegment-based analysis. CONCLUSION: ESGE based on post-contrast T1 mapping after adenosine stress-perfusion CMR imaging shows excellent agreement with conventional LGE imaging for assessing myocardial scar, and can substantially shorten clinical acquisition time. KEY POINTS: • Synthetic gadolinium enhancement images can be used for detection of myocardial scar. • Early synthetic gadolinium enhancement images can substantially shorten clinical acquisition time. • ESGE has high diagnostic accuracy as compared to conventional late gadolinium enhancement. • Quantification of myocardial scar with ESGE closely correlates with conventional LGE. • ESGE after stress perfusion CMR avoids need for additional gadolinium administration.

Comparison of guidelines for diagnosing suspected stable angina and the additional value of the calcium score.

Background The performance of current diagnostic algorithms of the American College of Cardiology/American Heart Association (ACC/AHA), National Institute for Health and Care Excellence (NICE) and European Society of Cardiology (ESC) in patients with stable chest pain and coronary artery calcium (CAC) remains a matter of debate. We compared their merits in patients with CAC and investigated the additional value of the CAC score to improve diagnostic accuracy and risk stratification. Methods and results Patient data were obtained from a prospective registry of 642 consecutive patients. Mean age 63 (SD 11) years, 50% male. According to the guidelines, low and intermediate/high pre-test probability groups were constructed. Patients were reclassified based on their CAC score. Obstructive coronary artery disease (CAD) was observed in 14%. All models performed modestly in accurately predicting CAD (c-statistic <0.65). After addition of the CAC score, the c-statistic of the NICE model increased to 0.75 (95% confidence interval (CI) 0.73-0.78) which was just non-significant compared to the ESC model (0.71 95% CI 0.67-0.74) and performed significantly better than ACC/AHA (0.68 (95% CI 0.64-0.72)). After reclassification more than 50% of patients were classified low risk in NICE and ESC, while the prevalence of obstructive CAD (4.8% and 5.2% respectively) did not increase. Conclusions Addition of the CAC score to the studied models improved the ability to safely rule-out obstructive CAD and identified other patients at high risk for future coronary artery events. These results suggest that incorporating CAC score will lead to substantially less downstream testing and lower costs.

Caseous calcification of the mitral annulus assessed by multimodality imaging.

Physicians may not be familiar with caseous calcification of the mitral annulus. It can therefore easily be mistaken for other conditions including tumors. In the appropriate clinical context, by using multimodality imaging, a correct diagnosis can be made, and patient concern or even unnecessary surgery can be avoided.

The vascular nature of COVID-19.

A potential link between mortality, D-dimer values and a prothrombotic syndrome has been reported in COVID-19 patients. The National Institute for Public Health of the Netherlands published a report for guidance on diagnosis, prevention and treatment of thromboembolic complications in COVID-19 with a new vascular disease concept. The analysis of all available current medical, laboratory and imaging data on COVID-19 confirms that symptoms and diagnostic tests can not be explained by impaired pulmonary ventilation. Further imaging and pathological investigations confirm that the COVID-19 syndrome is explained by perfusion disturbances first in the lung, but consecutively in all organs of the body. Damage of the microvasculature by SARS 1 and SARS 2 (COVID-19) viruses causes microthrombotic changes in the pulmonary capillaries and organs leading to macrothrombosis and emboli. Therefore anticoagulant profylaxis, close lab and CT imaging monitoring and early anticoagulant therapy are indicated.

Stress-Only Adenosine CMR Improves Diagnostic Yield in Stable Symptomatic Patients With Coronary Artery Calcium.

OBJECTIVES: This study assessed whether adenosine stress-only perfusion cardiac magnetic resonance (CMR) following a positive coronary artery calcium (CAC) score improved the diagnostic yield of invasive coronary angiography (CAG) in patients with stable chest pain. The study also established the association between positive CAC scores and stress-induced myocardial ischemia. BACKGROUND: The diagnostic yield of catheterization among patients with suspected coronary artery disease (CAD) is low. Improved patient selection and diagnostic testing are necessary. The CAC score can minimize unnecessary diagnostic testing, and in low-risk patients, normal CMR results have a high negative predictive value. Less comprehensive protocols may be sufficient to guide further work-up. METHODS: A total of 642 consecutive patients (mean age: 63 years; 50% women) with stable chest pain and CAC scores of >0 who were referred for CMR were enrolled. Patients with a perfusion defect were subsequently examined by CAG. Patients were followed up for 1 year. Outcome was obstructive CAD. RESULTS: Obstructive CAD was present in 12% of patients. For CAD diagnosis, the sensitivity of adenosine CMR was 90.9% (95% confidence interval [CI]: 88.7 to 93.1), specificity was 98.7% (95% CI: 97.9 to 99.6), positive predictive value was 92.0% (95% CI: 89.8 to 94.1), and negative predictive value was 98.6% (95% CI: 97.6 to 99.5). A CAC score between 0.1 and 100 without typical angina was associated with obstructive CAD in only 3% of patients. Patients with nonanginal chest pain and a CAC score ≥400 had obstructive CAD (16%). CONCLUSIONS: Stress-only adenosine CMR had high diagnostic accuracy and served as an efficient gatekeeper to CAG in stable patients with a CAC score >0. Patients with CAC scores between 0.1 and 100 could be deferred from further testing in the absence of clinical features that suggested high risk. However, in patients with CAC score ≥400, functional testing should be indicated, regardless of the type of chest pain.

Screening for cardiovascular disease risk using traditional risk factor assessment or coronary artery calcium scoring: the ROBINSCA trial.

AIMS: Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease-related morbidity and mortality. ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) is a population-based randomized controlled screening trial that investigates the effectiveness of CVD screening in asymptomatic participants using the Systematic COronary Risk Evaluation (SCORE) model or coronary artery calcium (CAC) scoring. This study describes the distributions in risk and treatment in the ROBINSCA trial. METHODS AND RESULTS: Individuals at expected elevated CVD risk were randomized into screening arm A (n = 14 478; SCORE, 10-year fatal and non-fatal risk); or screening arm B (n = 14 450; CAC scoring). Preventive treatment was largely advised according to current Dutch guidelines. Risk and treatment differences between the screening arms were analysed. A total of 12 185 participants (84.2%) in arm A and 12 950 (89.6%) in arm B were screened. In total, 48.7% were women, and median age was 62 (interquartile range 10) years. SCORE screening identified 45.1% at low risk (SCORE < 10%), 26.5% at intermediate risk (SCORE 10-20%), and 28.4% at high risk (SCORE ≥ 20%). According to CAC screening, 76.0% were at low risk (Agatston < 100), 15.1% at high risk (Agatston 100-399), and 8.9% at very high risk (Agatston ≥ 400). CAC scoring significantly reduced the number of individuals indicated for preventive treatment compared to SCORE (relative reduction women: 37.2%; men: 28.8%). CONCLUSION: We showed that compared to risk stratification based on SCORE, CAC scoring classified significantly fewer men and women at increased risk, and less preventive treatment was indicated. TRIAL REGISTRATION NUMBER: NTR6471.

T1 reactivity as an imaging biomarker in myocardial tissue characterization discriminating normal, ischemic and infarcted myocardium.

To demonstrate the potential for differentiating normal and diseased myocardium without Gadolinium using rest and stress T1-mapping. Patients undergoing 1.5T magnetic resonance imaging (MRI) as part of clinical work-up due to suspicion of coronary artery disease (CAD) were included. Adenosine stress perfusion MRI and late gadolinium enhancement (LGE) imaging were performed to identify ischemic and infarcted myocardium. Patients were retrospectively categorized into an ischemic, infarct and control group based on conventional acquisitions. Patient with both ischemic and infarcted myocardium were excluded. A total of 64 patients were included: ten with myocardial ischemia, 15 with myocardial infarction, and 39 controls. A native Modified Look-Locker Inversion Recovery (MOLLI) T1-mapping acquisition was performed at rest and stress. Pixel-wise myocardial T1-maps were acquired in short-axis view with inline motion-correction. Short-axis T1-maps were manually contoured using conservative septal sampling. Regions of interest were sampled in ischemic and infarcted areas detected on perfusion and LGE images. T1 reactivity was calculated as the percentage difference in T1 values between rest and stress. Remote myocardium was defined as myocardium without defects in the ischemic and infarcted group whereas normal myocardium is found in the control group only. Native T1-values were significantly higher in infarcted myocardium in rest and stress [median 1044 ms (interquartile range (IQR) 985-1076) and 1053 ms (IQR 989-1088)] compared to ischemic myocardium [median 961 ms (IQR 939-988) and 958 ms (IQR 945-988)]. T1-reactivity was significantly lower in ischemic and infarcted myocardium [median 0.00% (IQR - 0.18 to 0.16) and 0.41% (IQR 0.09-0.86)] compared to remote myocardium [median 3.54% (IQR 1.48-5.78) and 3.21% (IQR 1.95-4.79)]. Rest-stress T1-mapping is able to distinguish between normal, ischemic, infarcted and remote myocardium using native T1-values and T1-reactivity, and holds potential as an imaging biomarker for tissue characterization in MRI.

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.

Coronary Artery Calcium Imaging in the ROBINSCA Trial: Rationale, Design, and Technical Background.

RATIONALE AND OBJECTIVES: To describe the rationale, design, and technical background of coronary artery calcium (CAC) imaging in the large-scale population-based cardiovascular disease screening trial (Risk Or Benefit IN Screening for CArdiovascular Diseases [ROBINSCA]). MATERIALS AND METHODS: First, literature search was performed to review the logistics, setup, and settings of previously performed CAC imaging studies, and current clinical CAC imaging protocols of participating centers in the ROBINSCA trial were evaluated. A second literature search was performed to evaluate the impact of computed tomography parameter settings on CAC score. RESULTS: Based on literature reviews and experts opinion an imaging protocol accompanied by data management protocol was created for ROBINSCA. The imaging protocol should consist of a fixed tube voltage, individually tailored tube current setting, mid-diastolic electrocardiography-triggering, fixed field-of-view, fixed reconstruction kernel, fixed slice thickness, overlapping reconstruction and without iterative reconstruction. The analysis of scans is performed with one type and version of CAC scoring software, by two dedicated and experienced researchers. The data management protocol describes the organization of data handling between the coordinating center, participating centers, and core analysis center. CONCLUSION: In this paper we describe the rationale and technical considerations to be taken in developing CAC imaging protocol, and we present a detailed protocol that can be implemented for CAC screening purposes.

Disagreement between splenic switch-off and myocardial T1-mapping after caffeine intake.

Caffeine is an adenosine receptor antagonist and a possible cause of inadequate stress perfusion. Splenic switch-off (SSO) and splenic rest-stress T1-mapping have been proposed as indicators of stress adequacy during perfusion cardiac magnetic resonance (CMR). We compared myocardial rest-stress T1-mapping with SSO and splenic rest-stress T1-mapping in patients with and without recent coffee intake. We analyzed 344 consecutive patients suspected of myocardial ischemia with adenosine perfusion CMR. All 146 normal CMR studies with a normal T1-rest of the myocardium, used as standard of reference, were included and divided in two groups. 22 patients accidentally ingested coffee < 4 h before CMR, compared to control group of 124 patients without self-reported coffee intake. Two independent readers graded SSO visually. T1-reactivity (ΔT1) was defined as percentual difference in T1-rest and T1-stress. Follow-up data were extracted from electronic patients records. In patients with recent coffee intake SSO was identified in 96%, which showed no significant difference with SSO in controls (94%, p = 0.835), however event rates were significantly different (13.6 and 0.8%, respectively (p < 0.001), median FU 17 months). Myocardial ΔT1 in the coffee group (- 5.2%) was significantly lower compared to control (+ 4.0%, p < 0.001), in contrast to the splenic ΔT1 (- 3.7 and - 4.0%, p = 0.789). The splenic T1-mapping results failed to predict false negative results. SSO and splenic rest-stress T1-mapping are not reliable indicators of stress adequacy in patients with recent coffee intake. Therefore, the dark spleen sign does not indicate adequate myocardial stress in patients with recent caffeine intake. Myocardial rest-stress T1-mapping is an excellent indicator of stress adequacy during adenosine perfusion CMR.

High-pitch versus sequential mode for coronary calcium in individuals with a high heart rate: Potential for dose reduction.

BACKGROUND: To determine the impact of high-pitch spiral acquisition on radiation dose and cardiovascular disease (CVD) risk stratification by coronary artery calcium (CAC) assessment with computed tomography in individuals with a high heart rate. METHODS: Of the ROBINSCA trial, 1990 participants with regular rhythm and heart rates >65 beats per minute (bpm) were included. As reference, 390 participants with regular heart rates ≤65 bpm were used. All participants underwent prospectively electrocardiographically(ECG)-triggered imaging of the coronary arteries using dual source CT at 120 kVp, 80 ref mAs using both high-pitch spiral mode and sequential mode. Radiation dose, Agatston score, number of positive scores, as well as median absolute difference of the Agatston score were determined and participants were stratified into CVD risk categories. RESULTS: A similar percentage of participants with low heart rates and high heart rates had a positive CAC score in data sets acquired in high-pitch spiral (low heart rate: 57.7%, high heart rate: 55.8%) and sequential mode (58.0%, 54.7%, p = n.s.). The median absolute difference in Agatston scores between acquisition modes was 14.2% and 9.2%, for the high and low heart rate groups, respectively. Excellent agreement for risk categorization between the two data acquisition modes was found for the high (κ = 0.927) and low (κ = 0.946) heart rate groups. Radiation dose was 48% lower for high-pitch spiral versus sequential acquisitions. CONCLUSION: Radiation dose for the quantification of coronary calcium can be reduced by 48% when using the high-pitch spiral acquisition mode compared to the sequential mode in participants with a regular high heart rate. CVD risk stratification agreement between the two modes of data acquisition is excellent.

Imaging the myocardial ischemic cascade.

Non-invasive imaging plays a growing role in the diagnosis and management of ischemic heart disease from its earliest manifestations of endothelial dysfunction to myocardial infarction along the myocardial ischemic cascade. Experts representing the North American Society for Cardiovascular Imaging and the European Society of Cardiac Radiology have worked together to organize the role of non-invasive imaging along the framework of the ischemic cascade. The current status of non-invasive imaging for ischemic heart disease is reviewed along with the role of imaging for guiding surgical planning. The issue of cost effectiveness is also considered. Preclinical disease is primarily assessed through the coronary artery calcium score and used for risk assessment. Once the patient becomes symptomatic, other imaging tests including echocardiography, CCTA, SPECT, PET and CMR may be useful. CCTA appears to be a cost-effective gatekeeper. Post infarction CMR and PET are the preferred modalities. Imaging is increasingly used for surgical planning of patients who may require coronary artery bypass.

Correction to: Imaging the myocardial ischemic cascade.

In the original publication of the article, the seventh author name "Matthias Gutberlet" has been misspelt.

Caffeine intake inverts the effect of adenosine on myocardial perfusion during stress as measured by T1 mapping.

Caffeine intake before adenosine stress myocardial perfusion imaging may cause false negative findings. We hypothesized that the antagonistic effect of caffeine can be measured by T1 relaxation times in rest and adenosine stress cardiac magnetic resonance imaging (CMR), as T1 mapping techniques are sensitive to changes in myocardial blood volume. We prospectively analyzed 105 consecutive patients with adenosine stress perfusion CMR on a 1.5-T MRI system. Rest and stress T1 mapping was performed using Modified Look-Locker Inversion recovery. T1 reactivity was defined as difference in T1rest and T1stress (∆T1). Fifteen patients drank coffee within 4 h of CMR (<4H caffeine group), and 10 patients had coffee the day before (>8H caffeine group). Comparison was made to patients without self-reported coffee intake: 50 with normal CMR (control group), 18 with myocardial ischemia, and 12 with myocardial infarction. The national review board approved the study; all patients gave written informed consent. The <4H caffeine group showed inverted ∆T1 of -7.8 % (T1rest 975 ± 42 ms, T1stress 898 ± 51 ms, p < 0.0005). The >8H caffeine group showed reduced T1 reactivity (1.8 %; T1rest 979 ms, T1stress 997 ms) compared to the controls (4.3 %; T1rest 977 ± 40 ms, T1stress 1018 ± 40 ms), p < 0.0005. Ischemic and infarcted myocardium showed minimal T1 reactivity (0.2 and 0.3 %, respectively). Caffeine intake inverts the adenosine effect during stress perfusion CMR as measured by T1 mapping. T1 reactivity can assess the adequacy of adenosine-induced stress in perfusion CMR.