ABSTRACT
Introduction and objectives: The use of coronary physiology is essential to guide revascularization in patients with stable coronary artery disease. However, some patients without significant angiographic coronary artery disease will experience cardiovascular events at the follow-up. This study aims to determine the prognostic value of the global plaque volume (GPV) in patients with stable coronary artery disease without functionally significant lesions at a 5-year follow-up.
Methods: We conducted a multicenter, observational, and retrospective cohort study with a 5-year follow-up. A total of 277 patients without significant coronary artery disease treated with coronary angiography in 2015 due to suspected stable coronary artery disease were included in the study. The 3 coronary territories were assessed using quantitative flow ratio, calculating the GPV by determining the difference between the luminal volume and the vessel theoretical reference volume.
Results: The mean GPV was 170.5 mm3. A total of 116 patients (42.7%) experienced major adverse cardiovascular events (MACE) at the follow-up, including cardiac death (11%), myocardial infarction (2.6%), and unexpected hospital admissions (38.1%). Patients with MACE had a significantly higher GPV (231.6 mm3 vs 111.8 mm3; P < .001). The optimal GPV cut-off point for predicting events was 44 mm3. Furthermore, in the multivariate analysis conducted, plaque volume, diabetes, hypertension, age, dyslipidemia, smoking, age, and GPV > 44 mm3 turned out to be independent predictors of MACE.
Conclusions: GPV, calculated from the three-dimensional reconstruction of the coronary tree, is an independent predictor of events in patients with stable coronary artery disease without significant lesions. A GPV > 44 mm3 is an optimal cut-off point for predicting events.
Keywords: Coronary artery disease. Coronary atherosclerosis. Coronary angiography. Global plaque volume. Coronary physiology. Quantitative flow ratio.
RESUMEN
Introducción y objetivos: La fisiología coronaria es fundamental para guiar la revascularización en los pacientes con enfermedad coronaria estable. Sin embargo, algunos pacientes sin enfermedad coronaria significativa en la angiografía presentarán eventos cardiovasculares posteriormente. Este estudio pretende determinar el valor pronóstico del volumen global de placa (VGP) en pacientes con enfermedad coronaria estable sin lesiones funcionalmente significativas durante 5 años de seguimiento.
Métodos: Se realizó un estudio observacional multicéntrico de cohortes retrospectivo con seguimiento a 5 años, que incluyó 277 pacientes sin enfermedad coronaria significativa intervenidos mediante coronariografía en 2015 por sospecha de enfermedad coronaria estable. Se evaluaron los 3 territorios coronarios mediante el cociente de flujo cuantitativo, calculando el VGP como la diferencia entre el volumen luminal y el volumen teórico de referencia del vaso.
Resultados: El VGP medio fue de 170,5 mm3. Durante el seguimiento, 116 pacientes (42,7%) presentaron eventos cardiovasculares mayores (MACE), que incluyeron muerte de causa cardiaca (11%), infarto de miocardio (2,6%) y hospitalizaciones no programadas (38,1%). Los pacientes con MACE tenían un VGP significativamente mayor (231,6 frente a 111,8 mm3, p < 0,001). El punto de corte óptimo del VGP para predecir eventos fue de 44 mm3. En el análisis multivariado, que consideró volumen de placa, diabetes, hipertensión, edad, dislipemia y tabaquismo, la edad y un VGP > 44 mm3 fueron predictores independientes de MACE.
Conclusiones: El VGP calculado mediante reconstrucción tridimensional del árbol coronario es un predictor independiente de eventos en pacientes con enfermedad coronaria estable sin lesiones significativas. Un VGP > 44 mm3 es el punto de corte óptimo para predecir eventos.
Palabras clave: Enfermedad coronaria. Ateroesclerosis coronaria. Angiografía coronaria. Volumen global de placa. Fisiología coronaria. Cociente de flujo cuantitativo.
Abbreviations
GPV: global plaque volume. MACE: major adverse cardiovascular events. QFR: quantitative flow ratio. ROC: receiver operating characteristic curve.
INTRODUCTION
Coronary artery disease is the leading cause of mortality worldwide.1 Despite the safety involved in deferring invasive treatment in patients with stable coronary artery disease without functionally significant lesions,2 a percentage of patients experience cardiovascular events at the long-term follow-up.3 It has been reported that cardiovascular events not only depend on the degree of coronary obstruction assessed by intracoronary physiology4-5 but also on the global atherosclerotic burden and its vulnerability assessed by intracoronary imaging modalities.6-8
The new era of coronary physiology is based on predicting fractional flow reserve by reconstructing the coronary tree using angiography and computational fluid dynamics.9-10 Estimating quantitative flow ratio (QFR) is the most validated method of the ones currently available.
QFR—which predicts fractional flow reserve10-11—has proven to be a better tool than angiography alone to guide the need for lesion revascularization12 and shown long-term prognostic value13. Furthermore, it provides quantitative information out of the 3D reconstruction of the coronary tree, including minimum diameter and area, reference diameters, luminal volume, and atherosclerotic plaque volume in the studied vessel. However, the prognostic value of this quantitative analysis has not been sufficiently studied.
The main aim of this study was to determine the prognostic value of global plaque volume (GPV) in patients with stable coronary artery disease without functionally significant lesions at a 5-year follow-up.
METHODS
We conducted a retrospective observational study on a cohort of patients from 6 tertiary referral centers.
Study population
Patients who underwent coronary angiography from January through December 2015 for suspected stable coronary artery disease were included. Each participant center retrospectively enrolled all patients who underwent coronary angiography for suspected stable coronary artery disease and met the inclusion criteria. Patients with chronic total coronary occlusions, prior coronary artery bypass graft surgery, or inadequate angiographic quality for analysis were excluded. Additionally, patients whose angiographic analysis revealed a positive QFR study (< 0.80) in any coronary territory were excluded. The principal investigator conducted a retrospective follow-up at each center within the next 5 years following the index procedure. Baseline and procedural characteristics, and events at the follow-up were collected by local investigators. The study fully complied the good clinical practice principles and regulations set forth in the Declaration of Helsinki for research with human subjects. The study protocol was approved by the ethics committee of the reference hospital (Hospital Clínico Universitario de Valladolid) and the institutional review boards, including informed consent obtained from participants or, alternatively, approval for retrospective data analysis under ethical committee supervision.
Angiographic analysis
A blinded angiographic analysis of diagnostic coronary angiograms was performed by trained analysts at a centralized imaging unit (Icicorelab, Valladolid) using specialized software (QAngio XA 3D QFR, Medis Medical Imaging System, The Netherlands). A 3D reconstruction of the 3 major coronary vessels was performed using 2 different projections with > 25° of separation. For the right and left circumflex coronary arteries, the proximal marker was manually placed at the vessel ostium, while for the left anterior descending coronary artery, it was placed at the left main coronary artery ostium. The distal marker was placed at the end of the coronary artery. Plaque volume was estimated by calculating the difference between the theoretical reference vessel volume in the absence of atherosclerotic disease and the estimated vessel volume in angiography using QFR software via quantitative analysis. Reference diameters, minimum diameter, and minimum area were obtained for each vessel. Considering contrast flow through the coronary tree, QFR was calculated according to FAVOR II standards for the physiological significance of coronary lesions. Patients with functionally significant disease (QFR < 0.80) were excluded.
Statistical analysis
Categorical variables are expressed as totals and percentages, and continuous ones as means and standard deviations. GPV was estimated as the sum of plaque volume across 3 coronary territories.
The primary endpoint—major adverse cardiovascular events (MACE)—was a composite of cardiac death, acute myocardial infarction, or all-cause unplanned hospital admission.
An optimal GPV cutoff as a predictor of MACE was determined using the receiver operating characteristic (ROC) curve as the value with the maximum Youden index. Multivariate logistic regression models were used to calculate the odds ratio and 95% confidence interval as independent predictors for MACE. Variables with P < .20 in the univariate analysis were included in the multivariate model as covariates.
Event-free survival was compared using Kaplan-Meier and Mantel-Haenszel analyses. All probability values were two-tailed, and P < .05 was considered statistically significant. Statistical analysis was performed using Stata (16.1, StataCorp, College Station, United States).
RESULTS
Descriptive population analysis
A total of 803 patients were evaluated for inclusion in the registry, 122 of whom (15.2%) were excluded due to chronic occlusions in ≥ 1 coronary territory, 17 (2.12%) due to previous surgical myocardial revascularization, and 159 (19.2%) due to inadequate angiographic analysis in, at least, 1 coronary territory. Among the remaining patients, 228 (45.1%) had significant coronary artery disease (QFR < 0.80) in, at least, 1 coronary territory, which left a final cohort of 277 patients. Patient flowchart is shown in figure 1.
Figure 1. Flowchart of the patient selection process for inclusion in the study. CABG, coronary artery bypass graft; CTO, chronic total coronary occlusion; QFR, quantitative flow ratio.
The mean age of the population was 65.8 years (most were hypertensive [74.4%] men [66.1%]). Table 1 illustrates the baseline characteristics of the population. The median follow-up was 69 months, during which time 5 patients were lost to follow-up.
Table 1. Baseline characteristics of the included population
| Variable | n/mean | Proportion/SD |
|---|---|---|
| Female Sex | 94 | 33.9% |
| Hypertension | 206 | 74.3% |
| Diabetes mellitus | 106 | 38.2% |
| Dyslipidemia | 188 | 67.9% |
| Smoking | 121 | 43.7% |
| Chronic kidney disease | 21 | 7.6% |
| Peripheral arterial disease | 14 | 5.1% |
| Previous ischemic heart disease | 105 | 37.9% |
| Age (years) | 65.8 | 12.2 |
| Weight (kg) | 78.0 | 15.0 |
| Height (cm) | 156.2 | 36.8 |
| Left ventricular ejection fraction (%) | 57.4 | 9.3 |
|
SD, standard deviation. |
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Angiographic analysis
Mean plaque volume in the study population was 170.5 mm3 (± 16.5); mean QFR was 0.95. Table 2 illustrates the overall means from the angiographic analysis according to the coronary territory studied. Plaque volume was independently analyzed for each coronary territory and was significantly higher in the right (243 mm3) vs the left anterior descending (161.4 mm3) and left circumflex coronary arteries (172.9 mm3). Data on this analysis by coronary territories are shown in table 1 and figure 1 of the supplementary data.
Table 2. Characteristics of the angiographic analysis performed in the 3 coronary territories using quantitative flow ratio
| Variable | Mean | SD | 95%CI |
|---|---|---|---|
| QFR | 0.95 | 0.37 | 0.95-0.96 |
| Length | 76.99 | 13.21 | 75.22-78.77 |
| Proximal diameter | 3.18 | 0.47 | 3.11-3.24 |
| Distal diameter | 1.99 | 0.34 | 1.95-2.04 |
| Reference diameter | 2.69 | 0.42 | 2.58-2.70 |
| Minimum lumen diameter | 1.76 | 0.34 | 1.72-1.81 |
| Percent diameter stenosis | 33.81 | 6.44 | 32.95-34.68 |
| Stenosis area (%) | 38.72 | 9.59 | 37.43-40.01 |
| Minimum lumen area | 3.53 | 1.30 | 3.35-3.70 |
| Lumen volume | 295.5 | 242.25 | 262.83-328.12 |
| Plaque volume | 170.54 | 240.24 | 138.17-202.91 |
|
SD, standard deviation; 95%CI, 95% confidence interval; QFR, quantitative flow ratio. |
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Prognostic value of global plaque volume
The primary event (MACE) occurred in 116 patients, which amounts to 42.7% of the cohort at the follow-up. Among these patients, 11% died, 2.6% suffered an acute myocardial infarction, and 38.1% required unplanned hospitalization. Patients who developed MACE had a significantly higher GPV (231.6 vs 111.8 mm3; P < .001), as well as those with a higher mortality rate (255.2 mm3 vs 154.3 mm3; P = .04) or unplanned hospitalizations (235.0 mm3 vs 125.4 mm3; P < .001). However, there were no significant differences in patients who experienced acute myocardial infarction (235.1 mm3 vs 169.3 mm3; P = .51).
The optimal GPV cutoff to predict events was set at 44 mm3 based on ROC curve analysis (sensitivity, 64%; specificity, 65.8%; LR+, 1.9; LR–, 0.6).
Table 3 illustrates the study of the main determinants of the primary event. Variables with a significance level of P < .10 were included in the multivariate analysis. In the final model, age and GPV were independent predictors. A GPV > 44 mm3 was associated with a 2.8-fold higher risk of events at the follow-up (figure 2).
Table 3. Uni- and multivariate analysis of determinants of the main event
| Determinants of the main event | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| OR | 95%CI | OR | 95%CI | |
| Sex, female | 1.09 | 0.66-1.81 | ||
| Age* | 1.03 | 1.01-1.10 | 1.03 | 1.00-1.07 |
| Hypertension* | 2.26 | 1.26-4.07 | 1.70 | 0.82-3.53 |
| Diabetes mellitus | 1.18 | 0.72-1.93 | ||
| Dyslipidemia | 1.04 | 0.62-1.73 | ||
| Smoking | 1.01 | 0.72-1.42 | ||
| Chronic kidney disease | 1.00 | 0.41-2.46 | ||
| Peripheral arterial disease | 1.37 | 0.47-4.01 | ||
| Previous ischemic heart disease* | 1.52 | 0.93-2.50 | 1.46 | 0.80-2.68 |
| LVEF | 0.98 | 0.96-1.01 | ||
| GPV (> 44 mm3)* | 1.93 | 1.17-3.18 | 2.80 | 1.51-5.21 |
| Reference vessel diameter* | 2.20 | 1.12-4.35 | 1.62 | 0.75-3.50 |
|
* P values < .10 were included in the multivariate analysis. 95%CI, 95% confidence interval; GPV, global plaque volume; LVEF, left ventricular ejection fraction; OR, odds ratio. |
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Figure 2. Kaplan-Meier curve showing the patients’ event-free survival based on their global plaque volume.
DISCUSSION
The main finding of this study is that GPV quantification emerged as an independent prognostic factor in patients without functionally significant coronary artery disease, which demonstrated that those with a higher GPV experienced more events at the follow-up. The optimal GPV cutoff for event prediction was set at 44 mm3. This study emphasizes the importance of anatomically characterizing coronary arteries without significant lesions.
Despite the absence of significant coronary artery obstructions, some patients still experience events during follow-up.14 In patients with a negative QFR functional study, it has been reported that the 5-year rate of events—cardiac death, target vessel myocardial infarction—is 11.6%,3 similar to our findings, where mortality rate was 11% and acute myocardial infarction occurred in 2.6% of patients. Determining the difference between the actual vessel diameter and the estimated diameter obtained through 3D reconstruction from QFR-based angiography has been used in other studies.15 This estimation—previously derived from coronary computed tomography16-17—has demonstrated the prognostic significance of plaque volume differences between normal and non-obstructive coronary arteries. These differences have also been confirmed using invasive imaging modalities such as intravascular ultrasound.18 Although angiography-derived percent luminal stenosis shows poor concordance with myocardial ischemia,19 a greater degree of coronary stenosis (percent diameter stenosis > 50%) is associated with a higher event rate at the 2-year follow-up in patients without functionally significant coronary lesions.20 The present study takes a step further into the minimally invasive characterization of atherosclerotic burden using easy-to-implement 3D coronary tree reconstruction technology as an independent prognostic factor in patients without functionally significant coronary lesions. In this regard, this study is consistent with recent studies which demonstrated that subclinical atherosclerosis burden—measured by vascular ultrasound for carotid plaque quantification and computed tomography for coronary calcium scoring—in asymptomatic individuals is independently associated with all-cause mortality.21
Based on these findings, GPV measurement enables the identification of patients who, despite having no significant coronary lesions, are at risk of developing events within the next 5 years, allowing for intensified treatment and cardiovascular risk factor control. However, this study has limitations, including its retrospective design for patient inclusion and recruitment, the use of indirect methods—such as QFR—to estimate plaque volume, and the inability of this method to describe plaque characteristics, or potential lipid plaque vulnerability. Of note, the estimated plaque volume in each coronary artery was not specifically correlated with events in that territory but rather with overall adverse cardiovascular events. Therefore, further studies are needed to confirm or refute this hypothesis.
CONCLUSIONS
Plaque volume, calculated by 3D coronary tree reconstruction, is an independent predictor of events in patients with suspected stable ischemic heart disease without significant coronary artery disease. The optimal GPV cutoff for event prediction is 44 mm3.
FUNDING
C. Cortés received funding through the Río Hortega contract CM22/00168 and Miguel Servet CP24/00128 from Instituto de Salud Carlos III (Madrid, Spain).
ETHICAL CONSIDERATIONS
The present study was conducted in full compliance with clinical practice guidelines set forth in the Declaration of Helsinki for clinical research and was approved by the ethics committees of the reference hospital (Hospital Clínico Universitario de Valladolid) and other participant centers. Possible sex- and gender-related biases were also considered.
DECLARATION ON THE USE OF ARTIFICIAL INTELLIGENCE
No artificial intelligence was used in the writing of this text.
AUTHORS’ CONTRIBUTIONS
C. Cortés and J. Ruiz-Ruiz participated in study design, data analysis, manuscript drafting, and critical review. C. Fernández and M. García participated in data collection and result analysis. F. Rivero and R. López-Palop assisted in data collection. S. Blasco and A. Freites contributed to statistical analysis. L. Scorpiglione and M. Rosario Ortas Nadal collaborated in data interpretation. O. Jiménez participated in manuscript preparation and initial review. J.A. San Román Calvar and I.J. Amat-Santos conducted the final review and approved the version for publication.
CONFLICTS OF INTEREST
None declared.
WHAT IS KNOWN ABOUT THE TOPIC?
- Global plaque volume has already been identified as an independent risk factor for the occurrence of new coronary events at the follow-up of patients without significant coronary lesions. However, this risk was determined using coronary computed tomography and imaging modalities such as intravascular ultrasound.
WHAT DOES THIS STUDY ADD?
- This article is the first study to only use the patient’s own angiography and minimally invasive coronary physiology techniques, such as quantitative flow ratio to determine plaque volume and its relationship with major cardiovascular events at a 5-year follow-up in patients without significant coronary artery disease. This approach simplifies the implementation of this technique and enhances prevention strategies for patients at higher risk of cardiovascular events.
SUPPLEMENTARY DATA
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* Corresponding author.
E-mail address: carlos.cortes.villar@gmail.com (C. Cortés).
