Impact of Smoking on Coronary Volume–to–Myocardial Mass Ratio: An ADVANCE Registry Substudy
- Kenneth R. Holmes,
- Gaurav S. Gulsin,
- Timothy A. Fairbairn,
- Lynne Hurwitz-Koweek,
- Hitoshi Matsuo,
- Bjarne L. Nørgaard,
- Jesper M. Jensen,
- Niels-Peter Rønnow Sand,
- Koen Nieman,
- Jeroen J. Bax,
- Gianluca Pontone,
- Kavitha M. Chinnaiyan,
- Mark G. Rabbat,
- Tetsuya Amano,
- Tomohiro Kawasaki,
- Takashi Akasaka,
- Hironori Kitabata,
- Campbell Rogers,
- Manesh R. Patel,
- Geoffrey W. Payne,
- Jonathon A. Leipsic,
- Stephanie L. Sellers
Abstract
Purpose
To examine the relationship between smoking status and coronary volume–to–myocardial mass ratio (V/M) among individuals with coronary artery disease (CAD) undergoing CT fractional flow reserve (CT-FFR) analysis.
Materials and Methods
In this secondary analysis, participants from the ADVANCE registry evaluated for suspected CAD from July 15, 2015, to October 20, 2017, who were found to have coronary stenosis of 30% or greater at coronary CT angiography (CCTA) were included if they had known smoking status and underwent CT-FFR and V/M analysis. CCTA images were segmented to calculate coronary volume and myocardial mass. V/M was compared between smoking groups, and predictors of low V/M were determined.
Results
The sample for analysis included 503 current smokers, 1060 former smokers, and 1311 never-smokers (2874 participants; 1906 male participants). After adjustment for demographic and clinical factors, former smokers had greater coronary volume than never-smokers (former smokers, 3021.7 mm3 ± 934.0 [SD]; never-smokers, 2967.6 mm3 ± 978.0; P = .002), while current smokers had increased myocardial mass compared with never-smokers (current smokers, 127.8 g ± 32.9; never-smokers, 118.0 g ± 32.5; P = .02). However, both current and former smokers had lower V/M than never-smokers (current smokers, 24.1 mm3/g ± 7.9; former smokers, 24.9 mm3/g ± 7.1; never-smokers, 25.8 mm3/g ± 7.4; P < .001 [unadjusted] and P = .002 [unadjusted], respectively). Current smoking status (odds ratio [OR], 0.74 [95% CI: 0.59, 0.93]; P = .009), former smoking status (OR, 0.81 [95% CI: 0.68, 0.97]; P = .02), stenosis of 50% or greater (OR, 0.62 [95% CI: 0.52, 0.74]; P < .001), and diabetes (OR, 0.67 [95% CI: 0.56, 0.82]; P < .001) were independent predictors of low V/M.
Conclusion
Both current and former smoking status were independently associated with low V/M.
Keywords: CT Angiography, Cardiac, Heart, Ischemia/Infarction
Clinical trial registration no. NCT02499679
Supplemental material is available for this article.
© RSNA, 2024
See also commentary by van Assen and Onnis in this issue.
Summary
Both current and former smoking status were independently associated with lower coronary volume–to–myocardial mass ratio in participants from the ADVANCE registry.
Key Points
■ Both current and former smoking were independently associated with lower coronary volume–to–myocardial mass ratio (V/M) in participants with coronary artery disease (ADVANCE registry).
■ When stratified by stenosis severity, the relationship between smoking and low V/M remained significant only in participants with stenosis of 50% or greater.
■ Lower V/M among smokers appeared to be driven by an increase in myocardial mass.
Introduction
Epidemiologic data have identified smoking as an important risk factor for coronary artery disease (CAD), atherosclerotic progression, myocardial infarction, and cardiac death and demonstrate that smoking cessation reduces cardiac risk and mortality (1–3). Furthermore, much of the risk reduction associated with smoking cessation appears to occur in the initial years after quitting (3). A report from the CONFIRM Registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) found that although current and former smokers had a similar extent and severity of CAD, only current smokers had significantly increased rates of major adverse cardiac events compared with never-smokers after 2.8 years of follow-up; this effect could not be explained by age, sex, or other cardiovascular risk factors (4). These findings suggest that the increased cardiovascular risk associated with smoking may not be entirely explained by atherosclerotic burden and may reflect pathology not apparent at standard anatomic imaging, involving endothelial dysfunction, plaque composition, or coronary and myocardial remodeling. This situation highlights the need for a more integrated tool capable of a combined assessment of anatomic CAD, physiologic characteristics, and the myocardium.
CT fractional flow reserve (CT-FFR) analysis has emerged as an accurate noninvasive alternative to invasive fractional flow reserve measurement for the determination of lesion-specific pressure loss and is useful in guiding clinical decision-making (5,6). Through the CT-FFR computational modeling process, an additional measure known as coronary volume–to–myocardial mass ratio (V/M) can be determined and is proposed as a quantitative measure of myocardial supply and demand (7). Based on allometric scaling laws, coronary luminal volume typically exhibits a strong linear relationship with myocardial mass, a relationship that has been confirmed in human studies (8). In turn, V/M is believed to provide insight into cardiovascular characteristics related to coronary and myocardial remodeling. Previous reports found V/M to be reduced in multiple disease states, including microvascular angina and hypertrophic cardiomyopathy; in CAD, low V/M is associated with greater stenosis (9). However, to date, the effect of smoking status on V/M has not been well established in the literature. Therefore, this study examined the relationship between smoking status and V/M among individuals with CAD from the Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care (ADVANCE) registry.
Materials and Methods
Participants
This study was a retrospective analysis of the ADVANCE registry (ClinicalTrials.gov: NCT02499679), a prospective, multicenter registry of participants who underwent coronary CT angiography (CCTA) for suspected CAD at 38 sites across North America, Europe, and Japan from July 15, 2015, to October 20, 2017. Registry design and data management have been previously described (10). All participating sites required institutional review board approval, and all participants provided written informed consent. Participants within the ADVANCE registry were symptomatic but clinically stable at the time of enrollment, with CAD identified at CCTA as stenosis of 30% or greater in one or more vessels. Additional inclusion criteria included being aged 18 years or older, having the ability to provide informed consent, and meeting eligibility criteria for CT-FFR analysis on the basis of CAD severity. Smoking status within the ADVANCE registry was classified as current smoker (individuals who smoked at the time of CCTA or quit <90 days before CCTA), former smoker (individuals who quit smoking ≥90 days before CCTA), or never-smoker.
Individuals were excluded from the ADVANCE registry if they had no evidence of CAD at CCTA, CCTA findings that were uninterpretable or rejected from CT-FFR analysis, life expectancy less than 1 year, or inability to adhere to follow-up requirements. Individuals were also excluded from the current analysis if their smoking history was unknown or if V/M analysis was unavailable; V/M was determined in only a subset of the participants in the ADVANCE registry because of software development during the study period. Analysis was completed using data within the locked 1-year ADVANCE database. All participants from this study have been previously reported on, with the parent study evaluating the relationship between CT-FFR and downstream clinical care and outcomes (11–17).
Demographic and clinical factors were recorded for each participant in accordance with the values reported within the registry. The presence of hypertension requiring treatment, dyslipidemia, and diabetes was recorded. Angina status was categorized as typical angina, atypical angina, dyspnea, noncardiac chest pain, no chest pain, and unknown. Among those with typical angina, severity was graded by Canadian Cardiovascular Society class.
CCTA and CT-FFR
CCTA was recommended to be performed according to Society of Cardiovascular Computed Tomography guidelines (18). Across all participating sites, CCTA was performed using scanners with at least 64 detector rows after administration of sublingual nitroglycerin (3–5 minutes before scanning); the target heart rate was below 60 beats per minute, with β-blockers given at the discretion of the supervising physician. The presence of coronary stenosis was then visually assessed in all vessels measuring at least 2 mm in diameter. The location of highest-grade stenosis was recorded, and stenosis severity was categorized as 0% (no stenosis), less than 50%, 50% or greater, and 70% or greater. The number of epicardial vessels affected by at least 50% stenosis was also recorded.
CT-FFR analysis of CCTA images was performed using HeartFlow, version 2 (HeartFlow), as previously described (19). Minimum CT-FFR was recorded with both nadir and poststenosis CT-FFR values. Nadir CT-FFR values represent the lowest CT-FFR value in each of the epicardial systems for the left anterior descending, left circumflex, and right coronary arteries, as well as the overall lowest CT-FFR value across all territories. The poststenosis CT-FFR value represents the value 2 cm distal to the greatest stenosis across all epicardial vessels. In the event of stenoses of equal severity, poststenosis CT-FFR value was preferentially selected from the left anterior descending artery, followed by the left circumflex artery. The Duke Clinical Research Institute (Durham, North Carolina) acted as the core laboratory analyzing all CCTA and CT-FFR data in a blinded fashion.
Computation of V/M
V/M derived from CT-FFR analysis represents the ratio between total coronary luminal volume (in cubic millimeters) and left ventricular (LV) mass (in grams) and is proposed as a quantitative metric of myocardial supply relative to demand (7). V/M was calculated as previously described (15). In brief, epicardial coronary arteries (>1 mm) were segmented from the three-dimensional anatomic model generated from the imaging data and used to calculate total coronary volume. The volume of the LV myocardium was calculated using semiautomated image segmentation during the cardiac phase that best visualized the ventricular lumen. This value was then multiplied by a value estimating myocardial tissue density (1.05 g/mL) to determine LV myocardial mass. Finally, V/M was computed as the ratio of total coronary luminal volume to LV myocardial mass.
Statistical Analysis
Clinical, CCTA, CT-FFR, and V/M data are presented as counts and percentages for categorical variables and means and SDs for continuous variables. Categorical variables were compared using the χ2 test, and continuous variables were compared using an analysis of variance model followed by a t test in a pairwise fashion. Additionally, an analysis of covariance model was used to assess differences in total coronary volume and myocardial mass between smoking groups while correcting for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), and presence of other cardiovascular risk factors. Predictors of low V/M were determined using a multivariable logistic regression analysis. High and low V/M were defined using the sample median V/M as the threshold. Data were analyzed by combining all variables of interest, including age, sex, symptoms, stenosis severity, and cardiovascular risk factors, in a single multivariable logistic model to determine independent predictors of V/M. P < .05 was considered to indicate a statistically significant difference. All study data were controlled and verified by two study authors (K.R.H. and S.L.S.) and an independent study statistician (Nicholas Ng), with statistical analyses completed using SAS software, version 9.2 (SAS Institute).
Results
Participant Characteristics
Of the 5083 participants recruited into the ADVANCE trial, 4737 participants (93.2%) had diagnostic CCTA examinations eligible for CT-FFR analysis (Fig 1). Of these, 3110 participants (65.7%) underwent assessment of V/M; 1627 participants (34.3%) were excluded because their CT-FFR analysis was completed before the development of the V/M software plug-in and reprocessing was not feasible. Among those with calculated V/M, 2874 (92.4%) participants had known smoking status and made up the final study sample for analysis. The study sample consisted of 503 current smokers (17.5%), 1060 former smokers (36.9%), and 1311 never-smokers (45.6%).
Figure 1: Flow diagram outlines participant inclusion in the study. ADVANCE = Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care, CCTA = coronary CT angiography, CT-FFR = CT fractional flow reserve, V/M = coronary volume–to–myocardial mass ratio.
Participant demographic characteristics by smoking group are outlined in Table 1. Among the total 2874 participants, 1906 (66.3%) were male and 968 (33.7%) were female, with the current smoker and former smoker groups having a higher proportion of male participants compared with the never-smoker group (current smokers, 364 of 503 [72.4%]; former smokers, 818 of 1060 [77.2%]; never-smokers, 724 of 1311 [55.2%]). Current smokers were younger than former and never-smokers (mean age: current smokers, 62 years ± 10 [SD]; former smokers, 68 years ± 10; never-smokers, 67 years ± 11). Former smokers had higher mean body mass index than current and never-smokers (current smokers, 26.1 ± 4.9; former smokers, 26.7 ± 4.8; never-smokers, 26.2 ± 4.9). Former smokers had a higher rate of dyslipidemia than never-smokers (former smokers, 665 of 1060 [62.7%]; never-smokers, 790 of 1311 [60.3%]), and current smokers had a higher rate of diabetes than never-smokers (current smokers, 134 of 503 [26.6%]; never-smokers, 269 of 1311 [20.5%]). Angina status also differed between groups, with both current and former smokers more frequently exhibiting typical angina (current smokers, 105 of 503 [20.9%]; former smokers, 215 of 1060 [20.3%]; never-smokers, 236 of 1311 [18.0%]). Among participants with typical angina, there was no evidence of a difference in Canadian Cardiovascular Society class between groups.
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At CCTA, current but not former smokers were more likely than never-smokers to have stenosis of 50% or greater (current smokers, 391 of 503 [77.7%]; never-smokers, 909 of 1311 [69.3%]) and stenosis of 70% or greater (current smokers, 193 of 503 [38.4%]; never-smokers, 390 of 1311 [29.7%]) (Table S1). Similarly, current smokers had a higher prevalence of stenosis of 50% or greater affecting multiple vessels than did never-smokers. When stratified by epicardial vessel, never-smokers were more likely than current smokers to have their highest-grade stenosis involve the left anterior descending artery (current smokers, 302 of 503 [60.0%]; never-smokers, 967 of 1311 [73.8%]), while both current and former smokers showed higher rates of their highest-grade stenosis affecting the right coronary artery than did never-smokers (current smokers, 171 of 503 [34.0%]; former smokers, 350 of 1060 [33.0%]; never-smokers, 321 of 1311 [24.5%]).
Evaluation of coronary stenosis with CT-FFR demonstrated that current but not former smokers had lower mean nadir CT-FFR value (current smokers, 0.71 ± 0.12; never-smokers, 0.73 ± 0.11) and lower mean poststenotic CT-FFR value (current smokers, 0.74 ± 0.12; never-smokers, 0.76 ± 0.12) compared with never-smokers. Table S1 shows a detailed analysis of coronary stenosis and CT-FFR by smoking status.
Analysis of V/M
Analysis of total coronary volume, myocardial mass, and V/M is outlined in Tables 2 and 3. In the unadjusted analysis, there was no evidence of a difference in total coronary volume between groups, but both former and current smokers had higher myocardial mass than never-smokers (current smokers, 127.8 g ± 32.9; former smokers, 124.6 g ± 31.4; never-smokers, 118.0 g ± 32.5; P < .001 for both comparisons). After adjustment for participant factors, former but not current smokers had greater total coronary volume than never-smokers (former smokers, 3021.7 mm3 ± 934.0; current smokers, 2997.9 mm3 ± 1005.8; never-smokers; 2967.6 mm3 ± 978.0; P = .002 and .15, respectively), while current but not former smokers had increased myocardial mass compared with never-smokers (P = .02 and .36, respectively). Both current and former smokers had a lower V/M than never-smokers (current smokers, 24.1 mm3/g ± 7.9; former smokers, 24.9 mm3/g ± 7.1; never-smokers, 25.8 mm3/g ± 7.4; unadjusted P < .001 and P = .002, respectively; adjusted P = .005 for both). Current and former smoking status were also associated with a decreased likelihood of having a V/M value above the sample median of 24.70 mm3/g compared with never-smoker status (current smokers, 212 of 503 [42.1%]; former smokers, 507 of 1060 [47.8%]; never-smokers, 705 of 1311 [53.8%]; P < .001 and P = .004, respectively).
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In a two-way groupwise analysis, both smoking status and the presence of stenosis of 50% or greater were associated with significant between-group differences in V/M (P < .001 for both); however, there was no interaction between smoking status and stenosis severity with respect to V/M (P > .99). Nonetheless, after stratification by stenosis severity, V/M differed between smoking groups among participants with stenosis of 50% or greater, with a graded reduction in V/M observed from never- to former to current smokers (current smokers, 23.8 mm3/g ± 7.6; former smokers, 24.1 mm3/g ± 6.9; never-smokers, 25.2 mm3/g ± 7.2; P = .001), while V/M did not appear to differ between groups among participants with maximum stenosis less than 50% (current smokers, 25.4 mm3/g ± 8.6; former smokers, 26.9 mm3/g ± 7.1; never-smokers, 27.2 mm3/g ± 7.6; P = .09) (Table 3). Representative images of CT-FFR–derived V/M models are shown in Figure 2, and the relationship between smoking status and V/M is shown in Figure 3.
Figure 2: Sample CT fractional flow reserve models and calculated coronary volume–to–myocardial mass ratio (V/M, in cubic millimeters per gram) in current smokers and never-smokers demonstrate low and high V/M, respectively.
Figure 3: Graph shows mean (± SD) coronary volume–to–myocardial mass ratio (V/M) according to smoking status across all participants and stratified by stenosis severity.
Predictors of V/M
Multiple regression analysis demonstrated both current and former smoking status to be independent predictors of a V/M value below the sample median (current smokers, odds ratio [OR] = 0.74 [95% CI: 0.59, 0.93], P = .009; former smokers, OR = 0.81 [95% CI: 0.68, 0.97], P = .02). Presence of stenosis of 50% or greater (OR = 0.62 [95% CI: 0.52, 0.74]; P < .001), diabetes (OR = 0.67 [95% CI: 0.56, 0.82]; P < .001), typical angina (OR = 0.65 [95% CI: 0.51, 0.81]; P < .001), and dyspnea (OR = 0.63 [95% CI: 0.48, 0.84]; P = .001) were also independent predictors of low V/M, while age 65 years or older (OR = 1.60 [95% CI: 1.35, 1.88]; P < .001) and female sex (OR = 1.39 [95% CI: 1.17, 1.66]; P < .001) predicted higher V/M (Fig 4).
Figure 4: Forest plot shows multivariable analysis for the prediction of coronary volume–to–myocardial mass ratio (V/M) above or below the sample median.
Discussion
In this large, multicenter, international sample of individuals with stable CAD who underwent CT-FFR analysis, current and former smoking status were associated with reduced V/M compared with never-smoking status (current smokers, 24.1 mm3/g ± 7.9; former smokers, 24.9 mm3/g ± 7.1; never-smokers, 25.8 mm3/g ± 7.4) and were independent predictors of having lower V/M in a multivariable analysis (current smoking, OR = 0.74 [95% CI: 0.59, 0.93]; former smoking, OR = 0.81 [95% CI: 0.68, 0.96]). Of note, when participants were stratified by stenosis severity, differences in V/M between smoking groups remained significant only among participants with stenosis of 50% or greater, suggesting that a deleterious effect of smoking on coronary supply-demand balance may be more prominent in persons with more advanced luminal narrowing.
The reduction in V/M observed in current and former smokers appeared to be driven by greater myocardial mass among current and former smokers. However, after adjustment for participant and clinical factors, only current smokers demonstrated increased myocardial mass compared with never-smokers. Although experience with V/M in patients with elevated myocardial mass is limited, a previous analysis demonstrated reduced V/M despite preserved coronary volume among patients with hypertrophic cardiomyopathy (20). Remodeling of the LV may be a similarly important contributor to myocardial supply-demand mismatch and potentially elevated cardiovascular risk in those who smoke. Alternatively, the relatively similar coronary volume between smoking groups may reflect a failure to compensate for increased myocardial mass in smoking, suggesting that impaired vasomotor function or vascular remodeling may also underpin reduced V/M among current and former smokers.
Smoking is a recognized risk factor for CAD, myocardial infarction, and death. The mechanism of action is multifaceted, including oxidative stress, inflammation, lipid modification, prothrombosis, and vasomotor dysfunction (21–23). Smoking-associated hypertension is a proposed mechanism that could explain our observations; however, there was no evidence of a difference in hypertension requiring treatment between current or former smokers and never-smokers, and hypertension itself was not an independent predictor of lower V/M.
Other studies have shown smoking to be independently associated with LV mass; the LARGE Heart study (24) found smoking to be an independent predictor of increased LV mass during exercise training in young people, and this finding is consistent with studies showing an association of increased LV mass and smoking in older populations (25–28). Although these studies relied on clinical imaging and patient history to document changes in LV mass associated with smoking, mechanisms associated with smoking not appreciable in our study may explain increased myocardial mass with a history of smoking. Smoking causes oxidative stress owing to the generation and inhalation of reactive oxygen species as well as expression of inflammatory and fibrotic signaling markers and may contribute to myocardial hypertrophy, based on translational studies (29,30). Nicotine has been shown to activate similar proteins as angiotensin II (including extracellular signal–regulated kinase, mitogen-activated protein kinase, and AMPa2), leading to tissue remodeling, including activation of mitogen responses in vascular smooth muscle cells and fibroblasts (31,32). Moreover, both nicotine and reactive oxygen species are associated with insulin resistance in cardiomyocytes, and insulin resistance molecular pathways are linked to cardiomyocyte growth and cardiac hypertrophy (33,34).
Smoking-induced endothelial dysfunction and reduced coronary vasomotion reduce coronary hyperemic response during cold pressor testing among smokers with normal resting coronary flow (35). This phenomenon may also be appreciable in our study as a relative reduction in coronary volume at CCTA. Although total coronary volume did not significantly differ between groups in our study, calculation of V/M may allow interrogation of coronary vascular reserve in smokers through quantification of the supply-demand balance. In addition, the ability to achieve adequate hyperemic response among smokers when acquiring CCTA data suggests that alterations in V/M may represent a fixed supply-demand mismatch.
Aside from smoking, the presence of diabetes was also an independent predictor of low V/M in our sample. Previous studies have demonstrated reduced coronary vascular reserve in patients with diabetes and marked coronary microvascular dysfunction in response to both endothelium-dependent and -independent vasodilatory stimuli (36). In addition, coronary microvascular dysfunction has been independently linked to increased cardiac mortality in this population (37), warranting further investigation into the potential use of V/M to assess microvascular function among patients with diabetes. Conversely, age 65 years or older and female sex were predictors of higher V/M, with the observed relationship between sex and V/M consistent with previous reports from the ADVANCE registry (15).
Our study had important limitations. It was a post hoc analysis of participants enrolled in the ADVANCE registry, which was designed to assess the real-world utility of CT-FFR in the evaluation of stable, symptomatic CAD; therefore, we cannot rule out the possibility that referral bias affected our study sample. The analysis was also limited to participants with greater than 30% stenosis at CCTA, limiting generalizability to populations without CAD. Among former smokers, information on time since last smoking was not collected, resulting in potentially inappreciable differences between current and former smokers if mean time elapsed since quitting was inadequate to allow sufficient cardiovascular remodeling. Similarly, information on duration and intensity of smoking was not available; this prevented comparison of total smoking exposure between groups. Participant groups also differed with respect to baseline demographic characteristics and severity of atherosclerotic disease. This was addressed by including these variables as covariates in our statistical analysis; however, the potential for residual confounding remains. Some potentially important clinical factors were also not available for analysis, including lifestyle factors (such as alcohol use), use of cardiovascular medication, presence of dilated or hypertrophic cardiomyopathy, and quantified atherosclerotic burden. Because of the relatively low event rates in the ADVANCE cohort, it was also not statistically feasible to evaluate the relationship between V/M and clinical outcomes across smoking groups, representing a notable limitation and an important avenue of future investigation.
In conclusion, history of smoking (current or former smoking status) was an independent predictor of low V/M derived from CT-FFR. Mechanisms driving low V/M in smokers and the potential use of V/M as a surrogate marker of vascular health and predictor of downstream clinical outcomes require further study.
Acknowledgments
We would like to thank Nicholas Ng, BS, of HeartFlow for his assistance with the statistical analysis of this study. Requests for data should be directed to [email protected].
Author Contributions
Author contributions: Guarantors of integrity of entire study, K.R.H., J.J.B., S.L.S.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agree to ensure any questions related to the work are appropriately resolved, all authors; literature research, K.R.H., G.S.G., B.L.N., K.N., J.J.B., G.P., M.G.R., T.K., C.R., M.R.P., G.W.P., J.A.L., S.L.S.; clinical studies, T.A.F., H.M., B.L.N., J.M.J., K.N., G.P., T. Amano, T.K., T. Akasaka, H.K., C.R., M.R.P., J.A.L., S.L.S.; statistical analysis, K.R.H., G.S.G., T.K., G.W.P.; and manuscript editing, K.R.H., G.S.G., T.A.F., L.H.K., B.L.N., J.M.J., N.P.R.S., K.N., J.J.B., G.P., K.M.C., M.G.R., T.K., H.K., C.R., M.R.P., G.W.P., J.A.L., S.L.S.
The ADVANCE registry was funded by HeartFlow via individual clinical study agreements with each enrolling institution and with the Duke Clinical Research Institute Core Laboratory and Clinical Event Committee.
Data sharing: Requests for data should be directed to the provider indicated in the Acknowledgments.
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Article History
Received: Sept 17 2022Revision requested: Nov 15 2022
Revision received: Oct 30 2023
Accepted: Jan 26 2024
Published online: Mar 14 2024
