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Key Points

Question听 What is the diagnostic value of a coronary artery calcium (CAC) score of 0 to rule out obstructive coronary artery disease (CAD)?

Findings听 In this cohort study of 23 759 symptomatic patients with obstructive CAD, the prevalence of a CAC score of 0 differed markedly by age group and ranged from 58% in patients who were younger than 40 years to 5% among patients who were 70 years or older. The added diagnostic value of a CAC score of 0 was small in younger patients and greater in older patients.

Meaning听 This study found that a sizable proportion of obstructive CAD occurred among younger patients without CAC.

Importance听 The diagnostic value is unclear of a 0 coronary artery calcium (CAC) score to rule out obstructive coronary artery disease (CAD) and near-term clinical events across different age groups.

Objective听 To assess the diagnostic value of a CAC score of 0 for reducing the likelihood of obstructive CAD and to assess the implications of such a CAC score and obstructive CAD across different age groups.

Design, Setting, and Participants听 This cohort study obtained data from the Western Denmark Heart Registry and had a median follow-up time of 4.3 years. Included patients were aged 18 years or older who underwent computed tomography angiography (CTA) between January 1, 2008, and December 31, 2017, because of symptoms that were suggestive of CAD. Data analysis was performed from April 5 to July 7, 2021.

Exposures听 Obstructive CAD, which was defined as 50% or more luminal stenosis.

Main Outcomes and Measures听 Proportion of individuals with obstructive CAD who had a CAC score of 0. Risk-adjusted diagnostic likelihood ratios were used to assess the diagnostic value of a CAC score of 0 for reducing the likelihood of obstructive CAD beyond clinical variables. Risk factors associated with myocardial infarction and death were estimated.

Results听 A total of 23 759 symptomatic patients, of whom 12 771 (54%) had a CAC score of 0, were included. This cohort had a median (IQR) age of 58 (49-65) years and was primarily composed of women (13 160 [55%]). Overall, the prevalence of obstructive CAD was relatively low across all age groups, ranging from 3% (39 of 1278 patients) in those who were younger than 40 years to 8% (52 of 619) among those who were 70 years or older. In patients with obstructive CAD, 14% (725 of 5043) had a CAC score of 0, and the prevalence varied across age groups from 58% (39 of 68) among those who were younger than 40 years, 34% (192 of 562) among those aged 40 to 49 years, 18% (268 of 1486) among those aged 50 to 59 years, 9% (174 of 1963) among those aged 60 to 69 years, to 5% (52 of 964) among those who were 70 years or older. The added diagnostic value of a CAC score of 0 decreased at a younger age, with a risk factor鈥揳djusted diagnostic likelihood ratio of a CAC score of 0 ranging from 0.68 (approximately 32% lower likelihood of obstructive CAD than expected) in those who were younger than 40 years to 0.18 (approximately 82% lower likelihood than expected) in those who were 70 years or older. The presence of obstructive vs nonobstructive CAD among those with a CAC score of 0 was associated with a multivariable adjusted hazard ratio of 1.51 (95% CI, 0.98-2.33) for myocardial infarction and all-cause death; however, this hazard ratio varied from 1.80 (95% CI, 1.02-3.19) in those who were younger than 60 years to 1.24 (95% CI, 0.64-2.39) in those who were 60 years or older.

Conclusions and Relevance听 This cohort study found that the diagnostic value of a CAC score of 0 to rule out obstructive CAD beyond clinical variables was dependent on age, with the added diagnostic value being smaller for younger patients. In symptomatic patients who were younger than 60 years, a sizable proportion of obstructive CAD occurred among those without CAC and was associated with an increased risk of myocardial infarction and all-cause death.

The value of coronary computed tomography angiography (CTA) is unmatched for the noninvasive assessment of coronary luminal stenosis and atherosclerotic plaque. Coronary artery calcium (CAC) that is assessed by computed tomography is reliable in evaluating the future risk in both asymptomatic and symptomatic patients with stable coronary artery disease (CAD).^1,2 In general, patients with a 0 CAC score are estimated to have favorable outcomes, with a low risk for cardiovascular events and all-cause death.^3-5 Furthermore, a CAC score of 0 can help rule out obstructive CAD in a large proportion of symptomatic patients given that obstructive CAD has been reported to be present in less than 5% of symptomatic patients with a CAC score of 0.^6-8 Therefore, further downstream testing, including CTA, may be avoided in this patient category. For example, the 2019 European Society of Cardiology guidelines on the management of patients with chronic coronary syndromes indicated that absence of CAC is associated with a low prevalence of obstructive CAD and recommended that CAC be considered in the diagnostic workup of patients with symptoms that are suggestive of CAD.⁹ These guidelines, however, also stated that more information is needed to understand the optimal use of CAC in clinical practice given that a CAC score of 0 does not exclude coronary atherosclerosis.⁹ Although several studies have reported an overall low prevalence of obstructive CAD in symptomatic patients without CAC,^6-8 it is unknown whether this finding is true across all age groups and in men and women separately. Because early atherosclerotic lesions are often noncalcified, the ability of CAC to rule out obstructive CAD may be dependent on age.¹⁰ Such information would help in understanding the appropriate use of CAC in the diagnostic workup of symptomatic patients.

In this study, we aimed to investigate the diagnostic value of a CAC score of 0 for reducing (and clinically ruling out) the likelihood of obstructive CAD and to assess the implications of a CAC score of 0 and obstructive CAD across different age groups. We used a cohort of consecutive real-world patients who had symptoms that were suggestive of CAD and underwent coronary CTA according to societal guidelines.

The Western Denmark Heart Registry provided data for this cohort study,^11,12 and this data source has been validated.¹³ This study was approved by the Danish Data Protection Agency. According to Danish regulations, observational, registry-based studies from clinical databases do not require approval from ethics committees or informed consent from patients.

In Western Denmark, CTA is the first-line diagnostic test for nonemergency patients with symptoms that are suggestive of CAD.¹⁴ This study included all patients 18 years of age or older who underwent CTA between January 1, 2008, and December 31, 2017, in Western Denmark because of symptoms that were suggestive of CAD. Data on race and ethnicity were not included in the Western Denmark Heart Registry. The exclusion criteria were inconclusive test results, known CAD (previous myocardial infarction [MI] or coronary revascularization), or missing CAC or coronary CTA results. If a patient had more than 1 coronary CTA examination, only the first was included in the analysis.

Symptoms were classified as typical, atypical, or nonanginal chest pain. The pretest likelihood of obstructive CAD was computed according to the updated Diamond-Forrester risk algorithm. Data on clinical outcomes were obtained from the Danish National Patient Register, which is a record of discharge diagnosis as well as dates of admission to and discharge from all Danish hospitals, emergency departments, and outpatient clinics, and the Danish Civil Registration System, which contains complete data on mortality.

Patients were referred to undergo coronary CTA at cardiology departments, outpatient clinics, and private cardiologist practices across Western Denmark. Coronary CTA was performed using computed tomography scanners with 64-slice or more detector rows. Contraindications were renal insufficiency, pregnancy, or allergy to contrast. Patient preparation, coronary CTA data acquisition, and data reporting were done according to Society of Cardiovascular Computed Tomography guidelines.

Local cardiologists performed the readings and reported the results to the Western Denmark Heart Registry. Severity of CAD was categorized as no CAD (0% luminal stenosis and Agatston score of 0), nonobstructive CAD (1% to 49% luminal stenosis), or obstructive CAD (鈮�50% luminal stenosis).

The end point was a composite of MI and all-cause death. The study outcomes were identified through a linkage among the national registries covering all Danish hospitals.¹⁵ Myocardial infarctions that occurred within 90 days of coronary CTA were excluded to avoid including MIs that were related to initial post-CTA management (ie, procedure-related MIs). Follow-up began at the time of the coronary CTA and ended at the time of an event or the end of the study period (July 6, 2018). There was no loss to follow-up.

Baseline characteristics of the patients included in the study were provided as medians (IQRs). We assessed the prevalence of obstructive CAD among patients with a CAC score of 0 in the overall population and across different age groups: younger than 40 years, 40 to 49 years, 50 to 59 years, 60 to 69 years, and 70 years or older. Likewise, we assessed the prevalence of a 0 CAC score among patients with obstructive CAD in the overall population and in the aforementioned age groups.

We further calculated the diagnostic likelihood ratio (DLR) of a CAC score of 0 to reduce the posttest likelihood of obstructive CAD. The DLR assesses the value of performing a diagnostic test.¹⁶ Thus, we used DLR to compute the change from pretest (based on traditional cardiovascular risk factors alone) to posttest risk that was associated with the results of a subsequent test showing a negative risk marker (ie, a CAC score of 0 in this study). A DLR value greater than 1 specifies that the posttest risk is higher than the pretest risk (ie, tested risk marker is not useful for downgrading risk), whereas a DLR value less than 1 specifies that the posttest risk is lower than the pretest risk (ie, tested risk marker may be useful for downgrading risk). We calculated DLRs as previously done,⁴ comparing coefficients from multivariable adjusted logistic regression models as follows:

Pretest Risk鈥�=鈥塋ogit P (Coronary Heart Disease鈥�=鈥�1 | X)鈥�=鈥壩�_O*鈥�+鈥坝�_X*X

Posttest Risk鈥�=鈥塋ogit P (Coronary Heart Disease鈥�=鈥�1 | X, Y)鈥�=鈥壩�_O鈥�+鈥坝�_XX鈥�+鈥坝�_yY鈥�+鈥坝�_XYXY.

The multivariable adjusted DLR was then calculated by subtracting the pretest risk from the posttest risk as follows:

Log DLR_C(驰)鈥�=鈥�(尾_O鈥夆赌撯赌坝�_O*)鈥�+鈥�(尾_X鈥夆赌撯赌坝�_X*)鈥�+鈥坝�_YY鈥�+鈥坝�_XYXY.

The pretest logistic model contained age, sex, smoking status, diabetes status, and symptom characteristics. The DLR for a given risk marker (ie, CAC score of 0) varies from patient to patient; that is, the value and ability of a negative risk marker to reduce posttest risk depend on the combination of risk factors (ie, age and sex) that are present in the particular patient. Thus, the DLR may be small for some patients even though the odds ratio for the negative risk marker obtained from the logistic regression analyses was large in the overall cohort.

We calculated the MI and death event rate per 1000 person-years among patients with a CAC score of 0 and no or nonobstructive CAD, and then we compared this rate in patients with a CAC score of 0 and obstructive CAD. To assess the independent association (hazard ratio [HR]) between obstructive CAD and a CAC score of 0, we used Cox proportional hazards regression models analyzing time to event. Analyses were adjusted for age and sex (model 1), and adjustments for age, sex, smoking status, diabetes status, and symptom characteristics were also made (model 2). Data analysis was performed from April 5, 2021, to July 7, 2021.

The study cohort comprised 23 759 symptomatic patients, of whom 12 771 (54%) had a CAC score of 0. Baseline characteristics according to CAC and CTA findings are shown in Table 1. The cohort comprised 10 599 men (45%) and 13 160 women (55%) with a median (IQR) age of 58 (49-65) years. A total of 1372 patients (6%) were younger than 40 years and 2691 (11%) were older than 70 years.

Overall, among symptomatic patients with a CAC score of 0, 6% (725 of 12 771) had obstructive CAD (Figure 1A). The prevalence of obstructive CAD was low across all age groups in patients with a CAC score of 0. Among those patients who were younger than 40 years, 3% (39 of 1278) with a CAC score of 0 had obstructive CAD compared with 5% (192 of 3684) of those aged 40 to 49 years, 6% (268 of 4453) of those aged 50 to 59 years, 6% (174 of 2737) of those aged 60 to 69 years, and 8% (52 of 619) of those who were 70 years or older. Similar results were found in men and women separately (eFigures 1A and 2A in the Supplement).

Overall, 14% of patients (725 of 5043) with obstructive CAD had a CAC score of 0 (Figure 1B). The prevalence of a CAC score of 0 among patients with obstructive CAD decreased with age. Thus, among those who were younger than 40 years, 58% (39 of 68) with obstructive CAD had a CAC score of 0 compared with 34% (192 of 562) of those aged 40 to 49 years, 18% (268 of 1486) of those aged 50 to 59 years, 9% (174 of 1963) of those aged 60 to 69 years, and 5% (52 of 964) of those who were 70 years or older. Although similar trends were found in men and women separately, women with obstructive CAD had a CAC score of 0 more often than men (eFigures 1B and 2B in the Supplement). For example, among women with obstructive CAD, 74% (17 of 23) who were younger than 40 years, 48% (90 of 188) aged 40 to 49 years, and 25% (149 of 590) aged 50 to 59 years had a CAC score of 0 (eFigure 2B in the Supplement).

The added diagnostic value of a CAC score of 0 for ruling out obstructive CAD beyond available clinical data in symptomatic patients varied according to age (eFigures 3 and 4 in the Supplement; Table 2). Overall, the mean (SD) DLR of a CAC score of 0 was 0.38 (0.17), corresponding to approximately 63% lower likelihood than expected for obstructive CAD based on the clinical variables. In different age groups, the mean (SD) DLR was 0.68 (0.05) in patients who were younger than 40 years (approximately 32% lower likelihood than expected), 0.45 (0.10) in those aged 40 to 49 years (approximately 55% lower likelihood than expected), 0.33 (0.07) in those aged 50 to 59 years (approximately 67% lower likelihood than expected), 0.24 (0.05) in those aged 60 to 69 years (approximately 76% lower likelihood than expected), and 0.18 (0.03) in those who were 70 years or older (approximately 82% lower likelihood than expected). Across all patient characteristics, this trend was similar with lower DLR (equal to changing risk more) of a CAC score of 0 in older patients (Table 2). Generally, a CAC score of 0 changed the posttest risk less in women than in men (mean [SD] DLR, 0.40 [0.17] vs 0.33 [0.17]). This result was particularly evident in women younger than 50 years (Table 2).

Figure 2 presents different examples of how a CAC score of 0 will change the likelihood of having obstructive CAD across different age groups and risk factors. A CAC score of 0 reduced the absolute likelihood of obstructive CAD in all age groups but did so more in older than younger individuals. For example, among men without CAC, being a nonsmoker without diabetes and with atypical chest pain, the likelihood of obstructive CAD based on clinical variables alone was 6% vs 4% when a CAC score of 0 was also known (equal to an absolute difference of 2%). In men who were 70 years or older, the corresponding likelihood was 40% with clinical variables alone vs 8% when a CAC score of 0 was known (equal to an absolute difference of 32%).

During a median of 4.3 years of follow-up, 774 first-time MIs or all-cause deaths occurred. Among these events, 241 (31%) occurred in patients with a CAC score of 0, yielding an overall event rate per 1000 person-years of 4.31 (95% CI, 3.79-4.93) in patients without CAC. Among patients with a CAC score of 0 and obstructive CAD, the event rate per 1000 person-years was 7.11 (95% CI, 4.72-10.69) compared with 4.07 (95% CI, 3.56-4.64) in patients with a CAC score of 0 and no or nonobstructive CAD. In comparison, the event rate was 15.00 (95% CI, 13.27-16.90) in those with a CAC score higher than 0 and obstructive CAD (eTable 1 in the Supplement). In all analyses, the event rate was higher in patients who were 60 years or older than in those who were younger than 60 years. In analyses that were adjusted for baseline characteristics, the multivariable adjusted HRs for the presence of obstructive CAD vs no CAD in patients with a CAC score of 0 were 1.51 (95% CI, 0.98-2.33) in the overall population vs 1.80 (95% CI, 1.02-3.19) in those who were younger than 60 years and 1.24 (95% CI, 0.64-2.39) in those who were 60 years or older (Table 3). Similar trends with higher event rates in those with obstructive CAD were found for both MI and death, separately (eTables 2-3 in the Supplement). Post-CTA use of statin and aspirin in patients with a CAC score of 0 is shown in eTable 4 in the Supplement.

In sensitivity analyses, we did not exclude events within 90 days of CTA, yielding a total of 838 events. As shown in eTables 5-6 in the Supplement, the results were similar to those of the main analyses with HRs for the presence of obstructive CAD vs no CAD in patients with a CAC score of 0 of 1.62 (95% CI, 1.06-2.44) in the overall population vs 1.92 (95% CI, 1.12-3.29) in those who were younger than 60 years and 1.31 (95% CI, 0.68-2.53) in those who were 60 years or older.

This cohort study of contemporary consecutive patients who underwent first-line coronary CTA in day-to-day clinical practice for symptoms suggestive of CAD provides new information on the association of age with the diagnostic value of CAC. Although patients with a CAC score of 0 generally had a low prevalence of obstructive CAD, ranging from 3% to 8% across different age groups, a substantial proportion of patients with obstructive CAD at a younger age had a CAC score of 0. The explanation for this apparent paradox is that early atherosclerotic lesions are usually noncalcified. The added diagnostic value of knowing a CAC score of 0 is highly dependent on age, with less value for younger than for older patients. This finding was observed in both men and women separately. However, throughout the age spectrum, a substantially higher proportion of women with obstructive CAD had a CAC score of 0 as compared with men. In younger patients with a CAC score of 0 but obstructive CAD, the multivariable adjusted risk for MI or death during 4.3 years of follow-up was almost double that observed in patients with no or nonobstructive CAD.

These results showed that the diagnostic value of a CAC score of 0 beyond clinical variables in symptomatic patients was not uniform across age groups. To identify obstructive CAD in symptomatic younger patients and in women, an approach involving coronary CTA is needed despite a CAC score of 0.

Numerous studies from both the United States and Europe have demonstrated the ability of CAC to provide valuable information for asymptomatic individuals or to improve the evaluation of risks beyond the traditional risk factors.^17-20 For example, absence of CAC (known as the power of 0) is associated with an excellent outcome for up to 15 years, whereas the risk in patients with a CAC score higher than 300 may be comparable to that of patients under secondary prevention treatments.^21,22 Information on CAC can guide the allocation of preventive therapies to those who are most likely to benefit while withholding such therapies in patients with limited or no CAC who would likely derive little or no net benefit.^23-25

The role of CAC as a diagnostic tool for ruling in or ruling out obstructive CAD, however, has not been examined. Both the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines underscore that additional evidence from large cohorts is warranted to better identify the potential value of CAC in this setting.⁹ Specifically, the European Society of Cardiology guidelines state that 鈥渢he absence of coronary calcium (Agatston score鈥�=鈥�0) is associated with a low prevalence of obstructive CAD (<5%), and low risk of death or nonfatal MI (<1% annual risk). However, it should be noted that coronary calcium imaging does not exclude coronary stenosis caused by a noncalcified atherosclerotic lesion.鈥�^9(p422) Smaller studies, including those involving 125 to 5100 patients with a CAC score of 0, have found an association between the prevalence of obstructive CAD ranging from 2% to 7% with a good outcome during follow-up.^6,7,26-31 For example, in the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) Registry, the prevalence of obstructive CAD among 5128 patients with a CAC score of 0 was 3.5%, and only 0.9% of these patients experienced MI, all-cause death, or revascularization after 2.1 years of follow-up.⁶ Among 1457 patients with a CAC score of 0 in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), the prevalence of obstructive CAD was 2%.⁷ During 2.2 years of follow-up, 1.4% of the patients experienced an event (MI, all-cause death, or unstable angina).⁷ The highest prevalence of obstructive CAD in patients with a CAC score of 0 was reported in the Coronary Artery Evaluation Using 64-Row Multi-Detector Spiral Computed Tomography Angiography (CorE-64) study in which 19% of the 72 patients with a CAC score of 0 had obstructive CAD.²⁷ However, 39% of patients in the CorE-64 study presented with acute symptoms; thus, this finding is not generalizable to patients with stable CAD.²⁷

To our knowledge, the present European all-comer cohort of symptomatic patients who underwent European Society of Cardiology guideline鈥揹irected first-line CTA used 1 of the largest data sets (including 12 341 patients with a CAC score of 0) to date on the prevalence of obstructive CAD in patients with a CAC score of 0. In this study, the overall prevalence of obstructive CAD among symptomatic patients with a CAC score of 0 was 6%, and not less than 5% as suggested by the European Society of Cardiology guidelines. Prevalence ranged from 3% in patients who were younger than 40 years to 8% in patients who were older than 70 years. Moreover, the results showed that the prevalence of a CAC score of 0 among patients with obstructive CAD was not fixed but was highly dependent on age and sex, with a substantial proportion of patients with obstructive CAD at a younger age having no coronary calcification (ie, 1 of 3 with obstructive CAD at 40 to 49 years of age had a CAC score of 0). Furthermore, women with obstructive CAD more often had noncalcified plaque compared with men. Thus, a strategy that uses a CAC score of 0 to rule out obstructive CAD in all symptomatic patients will likely miss a sizable proportion of younger patients and women with obstructive CAD. Our analyses showed that the added independent diagnostic value of a CAC score of 0 to change the posttest likelihood of obstructive CAD varied substantially with age; that is, a CAC score of 0 was associated with a smaller decrease in the likelihood of obstructive CAD in younger patients and a greater decrease in older patients. A similar result regarding the value of a CAC score of 0 was observed in the primary prevention setting, in which the added value of a CAC score of 0 to reduce risk was dependent on age.

Among those with a CAC score of 0, the presence of obstructive CAD was associated with a higher risk for MI or death during follow-up. However, the annual risk remained less than 1% in those with a CAC score of 0 regardless of whether they had obstructive CAD. This finding suggests that the value of CAC as a strong outcome indicator is not restricted to asymptomatic patients but extends to symptomatic patients with both nonobstructive and obstructive CAD. In support of the estimated good outcome among symptomatic patients with a CAC score of 0, the Calcium Imaging and Selective CT Angiography in Comparison to Functional Testing for Suspected Coronary Artery Disease (CRESCENT) randomized trial, which compared a tiered coronary CTA approach with functional testing, showed that no adverse events occurred among the 39% of patients who deferred undergoing a coronary CTA because of a CAC score of 0.³⁰ Given that the intensity of preventive interventions should be guided by absolute risk for events, the absence of coronary calcification can help identify patients with CAD who would have limited benefit from intensified secondary prevention therapies (ie, PCSK9 [proprotein convertase subtilsin/kexin type 9] inhibitors).

This study has several limitations. First, the observational multicenter design of the study was potentially affected by referral and selection bias. Second, the European patient population had a low risk for CAD, and thus the results may not be applicable to populations with higher background risk. However, this real-world study population comprised all-comer, consecutive symptomatic patients with baseline characteristics who were comparable to samples in other studies and were representative of everyday practice. Third, we did not adjust the estimates for the potential implications of post-CTA management. However, as demonstrated by the increased uptake of statin and aspirin after CTA among patients who had obstructive CAD despite a CAC score of 0 vs patients with a CAC score of 0 without obstructive CAD, we may have underestimated the association of obstructive CAD with the risk for MI and death.

This cohort study found that the incremental diagnostic value of a CAC score of 0 to rule out obstructive CAD was highly dependent on age. Although a CAC score of 0 was associated with a substantial reduction in the likelihood of obstructive CAD in older patients, the diagnostic value of a CAC score of 0 was smaller in younger patients. In patients who were younger than 60 years, a sizable proportion of obstructive CAD was observed among patients without CAC and separately in men and women; however, a higher proportion of women with obstructive CAD have a CAC score of 0 as compared with men. The annual event rate of MI or death remained less than 1% in patients with a CAC score of 0, regardless of the presence of obstructive CAD, suggesting a favorable future outcome in patients without coronary calcification. These results may help to inform future guidelines on the differential value of CAC in the workup of patients with symptoms suggestive of CAD.

Accepted for Publication: August 18, 2021.

Published Online: October 27, 2021. doi:10.1001/jamacardio.2021.4406

Corresponding Author: Martin B酶dtker Mortensen, MD, PhD, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard, 8200 Aarhus N, Denmark (martin.bodtker.mortensen@clin.au.dk).

Author Contributions: Dr Mortensen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mortensen, Gaur, B酶tker, Steffensen, Kanstrup, Blaha, Dzaye, N酶rgaard.

Acquisition, analysis, or interpretation of data: Mortensen, Gaur, Frimmer, S酶rensen, Kragholm, Niels Peter, R. V. Jensen, M忙ng, Shaw, Dzaye, Leipsic, N酶rgaard, J. M. Jensen.

Drafting of the manuscript: Mortensen, Gaur, Frimmer, Shaw, Dzaye.

Critical revision of the manuscript for important intellectual content: Gaur, B酶tker, S酶rensen, Kragholm, Niels Peter, Steffensen, R. V. Jensen, M忙ng, Kanstrup, Blaha, Dzaye, Leipsic, N酶rgaard, J. M. Jensen.

Statistical analysis: Mortensen, Gaur, Frimmer, Dzaye.

Obtained funding: Mortensen.

Administrative, technical, or material support: Mortensen, Gaur, Frimmer, B酶tker, Niels Peter, Steffensen.

Supervision: Gaur, B酶tker, S酶rensen, Kanstrup, Blaha, Shaw, N酶rgaard, J. Jensen.

Conflict of Interest Disclosures: Dr Kragholm reported receiving personal fees from Novartis outside the submitted work. Dr M忙ng reported receiving personal fees from Novo Nordisk outside the submitted work. Dr Blaha reported receiving grants from the National Institutes of Health, US Food and Drug Administration, American Heart Association, Aetna Foundation, Amgen Foundation, and Novo Nordisk; and personal fees from Sanofi, Regeneron, Novartis, Bayer, Akcea, 89Bio, Kaleido, Inozyme, Kowa, Roche, and VoxelCloud outside the submitted work. Dr Leipsic reported serving as a consultant to and holding stock options in Circle CVI and HeartFlow; speaking fees from Philips; and an institutional grant from GE Healthcare. Dr N酶rgaard reported receiving grants from HeartFlow outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by public funding from Aarhus University Hospital.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.