RPS 2403 - Cardiac imaging: insights from trials

Author Block: B. Bogner, M. Jung, M. Reisert, J. Maushagen, S. Rospleszcz, C. L. Schlett, F. Bamberg, J. Weiß, J. Taron; Freiburg/DE
Purpose: To evaluate the association between metabolic phenotypes, MRI-derived cardiac function, major adverse cardiovascular events (MACE), and all-cause mortality.
Methods or Background: We analyzed 22,348 UK Biobank (UKBB) participants who underwent cardiac MRI. Obesity was defined as BMI ≥30kg/m²; metabolically unhealthy as the presence of >=1 metabolic syndrome components or diabetes resulting in four phenotypes: metabolically healthy non-obese (MHN), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUN), metabolically unhealthy obese (MUO). Associations between MRI-derived left ventricular ejection fraction (LVEF, %), cardiac index (cardiac output/body surface area [L/min/m2]), MACE, and all-cause mortality were investigated using uni-/multivariable linear and Cox regression analyses adjusted for age, sex, and smoking status.
Results or Findings: Among 22,348 UKBB participants (mean age 64.1±7.5 years, 48.8% male), 45.4% were MHN, 6.0% MHO, 36.5% MUN and 12.1% MUO. Over a median follow-up of 5.2 years, 52 MACE events and 371 deaths occurred. Compared to MHN, both obese phenotypes showed a significant negative association with LVEF whereas a positive association was found for MUN (p<=0.02). For cardiac index, only MUO showed a significant positive association compared to MHN (p=0.03). Cox regression revealed a >5-fold higher risk of MACE for both obese phenotypes (MHO (HR 5.53 [95% CI 2.10-14.58], p<0.001; MUO (HR 5.24 [95% CI 2.37-11.57], p<0.001) compared to MHN. A similar pattern was seen for all-cause mortality (MHO (1.57 [1.04, 2.36], p=0.03; MUO (1.61 [1.20, 2.17]; p=0.001).
Conclusion: Alterations in metabolic health are linked to differences in cardiac function, MACE and all-cause mortality risk independent of age, sex, and smoking. This suggests distinct mechanisms affecting cardiac health and emphasizes the need to consider both metabolic health and obesity for personalized risk assessment.
Limitations: Findings may not be generalizable to non-UK populations or ethnic groups underrepresented in the UKBB.
Funding for this study: None
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Approved by the UK Biobank.

Author Block: B. J. Kerber¹, T. Küstner², S. Gatidis³; ¹Zurich/CH, ²Tübingen/DE, ³Stanford, CA/US
Purpose: Exploring the relationship between demographic factors and quantitative imaging phenotypes based on cardiac MR (CMR) in the NAKO population study to provide insights into the aging heart and advance the understanding of cardiovascular disease.
Methods or Background: Steady-state free precession short-axis CMR full-cycle sequences from 29,104 participants of the NAKO study, aged 19 to 74 years (16,201 male and 12,903 female, aged 47.9 +/- 12.4, resp. 48.7 +/- 12.2 years), were analyzed. A custom-trained nnU-Net model was used to segment images into left ventricle (LV), leftventricular myocardium, and right ventricle (RV). From these segmentations, key cardiac metrics including LV mass (LVM), LV and RV end-diastolic and end-systolic volumes (LVEDV/RVEDV/LVESV/RVESV), ejection fractions (LVEF/RVEF), stroke volumes (LVSV/RVSV) and cardiac output (LVCO) were calculated. Correlation analysis and group comparisons were performed to examine associations between the participants' demographic and quantitative imaging phenotypes.
Results or Findings: In this study, LVEDV/RVEDV (r=-0.22/r=-0.23), LVESV/RVESV (r=-0.17/r=-0.19), LVSV/RVSV, (r=-0.21/r=-0.20) and LVCO (r=-0.19) significantly decreased with age, with males showing a higher baseline and steeper decline. LVM and LVEF were nearly stable (r=0.01/r=0.01). LVEF was consistently higher in females (p<0.001). RVEF increased with age for females and decreased for males (r=0.07, r=-0.02). Hypertension, diabetes, smoking and high blood lipids were associated with significantly higher LVM and lower LVEF/RVEF (p<0.001), while high HDL was negatively correlated with LVM (r=-0.36), LVEDV/RVEDV (r=-0.20/r=-0.22) and positively with LVEF/RVEF (r=0.08/r=0.14).
Conclusion: A CMR full-cycle segmentation model was developed and applied to a large population study spanning a broad age range. The resulting imaging phenotypes revealed strong associations with age, disease, and demographic factors.
Limitations: The analysis was performed automatically using only basic quality control.
Funding for this study: No specific funding.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study protocol, participant information, and consent forms for the NAKO study were reviewed by all local ethics committees of the participating institutions.

Author Block: F. Biavati¹, M. Mohamed¹, S. Tsogias¹, B. Föllmer¹, M. Bosserdt¹, J. Dodd², M. Dewey¹; ¹Berlin/DE, ²Dublin/IE
Purpose: To assess the agreement between core laboratory and the clinical centre measurement of coronary artery calcium (CAC) score using the Agatston method.
Methods or Background: At each of the 26 clinical centres across 16 European countries [NCT02400229], radiologists measured the patients’ CAC score based on noncontrast coronary computed tomography (CT). Two readers measured the CAC score at the core laboratory blinded to the clinical centre reading. Bland-Altman analysis of the CAC scores values and Cohen’s kappa of the CAC score risk categories (I: 0, II: 1-400, III: >400) was performed.
Results or Findings: 1550 patients (mean age, 59 years ± 10 [SD], 56.3% women) were included. The Bland-Altman analysis showed a mean absolute difference of 2.0 and limits of agreement of ± 93.3 between the core laboratory and the clinical centres. There was agreement in the CAC score risk categories in 96.6% (1498 of 1550) of patients between the core laboratory and the clinical centre reading. Discrepancies between CAC score risk categories occurred mostly between categories I and II (88.5%, 46 of 52). Agreement according to Cohen’s kappa was excellent (0.94, 95% CI: 0.93, 0.96; p<.001). Most disagreements in the assignment of risk categories were between category I and II (88.5%).
Conclusion: CAC score measurements had good agreement between the core laboratory and clinical centres in a Pan-European multicentre trial suggesting that CAC score measurements can be widely implemented as part of cardiac CT based on its reproducibility.
Limitations: Our study has limitations. It included only stable chest pain patients. The population was from 26 European centres, limiting global applicability. Some CT scans were excluded due to missing data or non-matching reconstruction parameters, and only filtered back projection reconstruction was used.
Funding for this study: Funding was provided by grants from the EU-FP7 Framework Program (FP 2007-2013, EC-GA 603266).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by The German Federal Office for Radiation Protection and the local or national authorities at each trial site. The reference number is: EA1/294/13.

Author Block: M. Bosserdt, K. Schulze, M. Mohamed, A-M. Stantien, M. Dewey, E. Schöneberger; Berlin/DE
Purpose: Patient preference between coronary computed tomography (CT) and invasive coronary angiography (ICA) in a multicentre analysis in Europe is unknown. Therefore, we compare patient preference for CT and ICA in a European multicentre randomised controlled trial.
Methods or Background: A total of 3561 patients with a clinical indication for ICA with stable chest pain and an intermediate likelihood of obstructive coronary artery disease were analysed in this prespecified secondary analysis from the randomised DISCHARGE trial (NCT02400229) conducted between October 2015 and April 2019 in 26 European centres. Patient preference using a previously validated questionnaire completed at least 24 hours after CT or ICA, including preparation for the tests, anxiety, comfort, level of helplessness, pain, willingness to undergo the tests again, overall satisfaction and preference.
Results or Findings: The questionnaire was completed by 89.7% in the CT group (1622/1808) and 89.4% (1567/1753, P=.75) in the ICA group. Patients reported significantly higher satisfaction with CT (mean (SD): CT: 1.37 (0.53) vs. 1.48 (0.60); score: 1-5; P<.0001), were more willing to undergo CT again (mean (SD): CT: 1404/1622 (86.6%) vs. ICA: 1127/1567 (71.9%); P<.0001), and were better prepared to CT (mean (SD): CT: 1.40 (0.56) vs. 1.49 (0.64); score: 1-5; P=.0005). They were less anxious before CT (mean (SD): CT: 1.07 (1.17) vs. ICA: 1.62 (1.33); score: 1-4; P<.0001), felt less helpless during CT (mean (SD): CT: 0.54 (0.72) vs. ICA: 0.91 (0.90); score: 0-4; P<.0001), and felt more comfortable (mean(SD): CT: 1.64 [0.66] vs. ICA: 1.90 [0.80]; score: 1-5; P<.0001).
Conclusion: In this multicentre, randomised trial of patients referred for ICA with stable chest pain and an intermediate likelihood of obstructive coronary artery disease, patient preference was in favour of coronary CT angiography.
Limitations: Not applicable.
Funding for this study: This study was funded by grants from the EU-FP7 Framework Program (FP 2007-2013, EC-GA 603266).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by ethics committee at Charité (EA1/294/13).

Author Block: A-M. Stantien¹, F. Biavati¹, A-C. Stahl¹, S. Chimed¹, M. Mohamed¹, L. M. Serna Higuita², M. Bosserdt¹, M. Dewey¹; ¹Berlin/DE, ²Tübingen/DE
Purpose: To investigate major adverse cardiovascular events (MACE) after 10 years of follow-up in patients with an intermediate probability of coronary artery disease (CAD) undergoing computed tomography (CT) or invasive coronary angiography (ICA).
Methods or Background: This is the 10-year long-term clinical follow-up of the single centre randomised CAD-Man (Coronary Artery Disease Management) trial comparing CT with ICA in patients with atypical angina or chest pain clinically referred for ICA. Clinical follow-up was done by interviewing patients using questionnaires asking about MACE (myocardial infarction, stroke, unstable angina, (surgical) re-/revascularization, cardiac death) in the past 10 years. Additionally, every patient was offered a cardiac CT scan and blood samples were taken. The association between randomisation group and MACE was assessed using a multivariate Cox proportional hazards model.
Results or Findings: Out of 329 patients included in CAD-Man 106 patients completed the clinical long-term follow-up resulting in a total median follow-up of 4.9 years. Additional 18 MACE cases occurred, 7/49 (14%) of which in the CT group and 11/57 (19%) in the ICA group. There was no statistically significant difference in MACE between the two randomisation arms. The HR was 0.86 (95% CI 0.42–1.74) in the CT group.
Conclusion: After 10 years of follow-up, the survival and the occurrence of MACE was similar in the CT group compared to the ICA group for patients referred for ICA because of atypical angina or stable chest pain and an intermediate pretest probability of CAD.
Limitations: The limitations of the study are the single centre design and the low number of MACE, limiting the generalisability of our findings.
Funding for this study: This study was funded by a grant of the Heisenberg programme.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by ethics committee at Charité (EA1/124/23).

Author Block: M. Mohamed¹, M. Dewey¹, V. Wieske¹, P. Schlattmann², R. Haase¹, J. Dodd³; ¹Berlin/DE, ²Jena/DE, ³Dublin/IE
Purpose: To evaluate the accuracy of pretest probability (PTP) calculations alone and in combination with computed tomography angiography (CTA) results for the diagnosis of CAD in stable chest pain.
Methods or Background: Individual patient data (IPD) meta-analysis of 65 prospective diagnostic accuracy studies of patients clinically referred to invasive coronary angiography (ICA) with stable chest pain in 22 countries. Three clinical probability models a PTP model based on age, sex and chest pain type (termed the updated DISCHARGE trial PTP calculator), a CTA alone model and the updated DISCHARGE Trial PTP calculator and CTA model combined were constructed. The models were built by multivariable logistic regressions with a dataset-specific random intercept and were compared using the area under the receiver-operating-characteristic curve (AUC) and the decision curve analysis (DCA).
Results or Findings: 5332 stable chest pain patients with clinically indicated ICA were included. The updated DISCHARGE pretest probability calculator was more accurate than the original Diamond-Forrester model (AUC: 0.68, 95% CI: 0.66-0.69 versus 0.63, 95% CI: 0.62-0.65). The combination of DISCHARGE pretest probability calculator with CTA findings significantly improved accuracy compared with either model alone (AUC: 0.86, 95% CI: 0.85-0.87 versus 0.81, 95% CI: 0.80-0.82). The improved prediction of CAD by combining CTA with the updated DISCHARGE Trial PTP calculator prediction model was consistent in the DCA with an increased net benefit for all chest pain types and was almost equally seen in patients with typical or atypical angina (0.85, 95% CI: 0.84-0.86) and nonanginal or other chest discomfort (0.88, 95% CI: 0.86-0.89).
Conclusion: Combining the updated DISCHARGE trial PTP calculator with CTA provides more accurate prediction than CTA alone for the diagnosis of obstructive CAD.
Limitations: The ICA indication resulted in a relatively high CAD prevalence of 48.3%.
Funding for this study: The COME-CCT Consortium is funded by a joint program of the German Research Foundation and the German Federal Ministry of Education and Research (01KG1110) and the Digital Health Accelerator of the Berlin Institute of Health to Marc Dewey. All researchers are independent of the funding bodies. The funding bodies had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This study was approved by the local research ethics committee of Charité (EA-1-080-08) and the German Federal Office for Radiation Protection (Z5-22462/2-2008-048). All patients gave written informed consent before randomisation.

Author Block: M. C. Langenbach¹, I. Hadzic¹, T. Mayrhofer¹, J. Karady¹, S. Shah², M. T. Lu¹, M. Ferencik¹, P. Douglas², B. Foldyna¹; ¹Boston, MA/US, ²Durham/US
Purpose: Pericoronary adipose tissue (PCAT) is related to pericoronary inflammation and contributes to atherogenesis and adverse outcomes. We investigated the association between PCAT and advanced plaque characteristics in patients with stable chest pain.
Methods or Background: PCAT was quantified around all three major epicardial vessels on non-contrast CT images from the PROMISE trial using a validated deep-learning algorithm. Quantitative coronary plaque metrics included total plaque volume and burden (TPV, mm³; TPB, %), and plaque composition (calcified plaque (CP), non-calcified plaque (NCP), and low-density NCP (LD-NCP; <30HU). Multivariable linear regression analyses related global PCAT density (per 10HU) and BSA-indexed PCAT volume (per 10 cm³/m²) to plaque metrics (per 10mm³/1%), adjusted for signal-to-noise ratio, tube voltage, risk score, and BMI.
Results or Findings: In 3,620 participants (age: 60±8 years; women: 1,945(51.2%), mean total heart PCAT volume and density were 12.9±3.1cm³/m² and -81.4±6.4HU. Greater PCAT volume related to higher CP volume (Coef. 2.24, 95%CI:0.40–4.08, p=0.017), LD-NCP volume (Coef. 0.28, 95%CI:0.05–0.52, p=0.018), and TPV (Coef. 3.84, 95%CI:-0.21–7.88, p=0.06). A 10 cm³/m² increase in PCAT volume was associated with a 7% higher TPB (Coef. 6.93, 95%CI:3.58–10.28, p<0.001), 4% higher CP burden (Coef. 3.97, 95%CI:2.42–5.51, p<0.001), 3% higher NCP burden (Coef. 2.96, 95%CI:0.33–5.59, p=0.027), and 1% higher LD-NCP burden (Coef. 0.68, 95%CI:0.34–1.01, p<0.001). PCAT density showed no significant association with plaque volume and burden including composition.
Conclusion: PCAT volume is associated with plaque volume, burden, and composition suggesting a relationship with both atherogenesis and plaque architecture. In contrast, PCAT density, a known measure of inflammation, was not associated with either. These findings emphasize the complex physiology of pericoronary fat and underscore the need to further investigate PCAT’s potential role as a target for treatment interventions.
Limitations: Secondary analysis
Funding for this study: DFG (project number: 502109212)
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Massachusetts General Hospital (2009P002231)

Author Block: M. Bosserdt¹, M. Mohamed¹, M. C. Williams², M. Dewey¹, J. Knape¹; ¹Berlin/DE, ²Edinburgh/UK
Purpose: To assess 3.5 years of cumulative radiation doses of cardiovascular imaging to participants undergoing computed tomography (CT) or invasive coronary angiography (ICA) for suspected coronary artery disease.
Methods or Background: This is a prespecified analysis of a multicentre, randomised DISCHARGE trial involving 3561 participants with stable chest and who were referred for ICA, conducted between October 2015 and April 2019 in 26 European centres. Participants were randomised to either CT (1808) or ICA (1753). Radiation dose from CT (dose-length product), SPECT (injected activity), PET-CT (injected activity) and ICA (kern-area product) was assessed for 3.5 years after randomisation. Effective dose was calculated using conversion factors appropriate for the imaging modality. Missing data were imputed using the mean. Wilcoxon rank sum test was used to assess group differences.
Results or Findings: Over a median follow-up period of 3.5 years, a total of 1845 (CT: 1796 vs. ICA: 49) CT scans, 1939 (CT: 344 vs. ICA: 1595) ICA without PCI, 584 (CT: 269 vs. ICA: 315) ICA with PCI, 75 (CT: 46 vs. ICA: 29) SPECT and 81 (CT: 66 vs. ICA: 15) PET-CT were performed. Total per-participant cumulative dose was higher in the CT group (median, 6.1 mSv; IQR, 3.9-10.3 mSv) compared with ICA group (median, 4.4 mSv; IQR, 2.2-9.1 mSv, P<0.001). The cumulative dose varied across participating centre, with a mean 9-fold for CT-group and 4-fold for ICA-group variation between the highest and lowest dose.
Conclusion: The cumulative radiation dose over 3.5 years was higher in the CT group compared to the ICA group. However, the total radiation dose for the CT and ICA group differed greatly among the participating centres.
Limitations: At a follow-up radiation dose was not available for all procedures
Funding for this study: This study was funded by grants from the EU-FP7 Framework Program (FP 2007-2013, EC-GA 603266)
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by ethics committee at Charité (EA1/294/13)).