Introduction and objectives: Left atrial appendage occlusion (LAAO) can be an efficient treatment to prevent strokes in patients who suffer from atrial fibrillation, especially those at risk of bleeding. A non-negligible number of patients treated with LAAO develop device-related thrombosis (DRT) after device implantation. Our study aimed to identify the key blood flow characteristics leading to DRT using patient-specific flow simulations.
Methods: Patients treated with LAAO between 2014 and 2019 at a single center with preoperative and follow-up computerized tomography images and ultrasound imaging (US) were used to create patient-specific flow simulations. Amulet LAAO devices were implanted in the study patients. Flow simulations were blindly assessed to discard the presence of DRT in the follow-up imaging.
Results: A total of 6 patients were processed in this pivotal study, half of them with DRT at the follow-up according to the imaging analysis. After a comprehensive analysis of the simulations, the most relevant in silico indices associated with DRT were the presence of stagnant blood flow, recirculation with low flow velocities (< 0.20 m/s) next to the device surface, and regions with high flow complexity combined with low wall shear stress.
Conclusions: Patient-specific flow simulations of LAAO were successfully used to predict blood flow patterns with different device configurations. The results show the potential of the present modelling and simulation approach to recommend optimal settings capable of minimizing the risk of DRT.
Keywords: Device-related thrombosis. Flow simulation. Left atrial appendage occlusion. Patient-specific.
Introducción y objetivos: El cierre de la orejuela izquierda (COI) puede ser una alternativa de tratamiento eficaz para prevenir eventos cardiovasculares en pacientes con fibrilación auricular, en especial en aquellos con alto riesgo de sangrado. Sin embargo, algunos de estos pacientes en los que se realiza COI desarrollan trombosis relacionada con el dispositivo (TRD). Este estudio presenta las características del flujo sanguíneo que son clave en la formación de TDR, a partir de simulaciones personalizadas para cada paciente.
Métodos: Para crear las simulaciones personalizadas se incluyeron en el estudio pacientes intervenidos de COI entre 2014 y 2019 en un único centro, de quienes se disponía de imágenes de tomografía computarizada previas al procedimiento y de seguimiento, así como de control ecocardiográfico. Para el COI se utilizaron los dispositivos Amulet. Las simulaciones se analizaron de forma ciega al diagnóstico de TRD.
Resultados: En total se estudiaron 6 pacientes, de los que la mitad presentaban TRD según las imágenes del seguimiento clínico. Tras analizar los resultados de las simulaciones, los índices hemodinámicos asociados con TRD fueron la presencia de flujo estancado, las recirculaciones de sangre a velocidades bajas (< 0,20 m/s) cerca de la superficie del dispositivo y las regiones con alta complejidad de flujo y baja tensión de cizallamiento en la pared.
Conclusiones: Las simulaciones de flujo personalizadas en pacientes con COI predijeron correctamente el diagnóstico clínico de TRD en todos los casos analizados. Los resultados obtenidos demuestran el potencial de los modelos personalizados para recomendar configuraciones óptimas del dispositivo y minimizar el riesgo de TRD.
Palabras clave: Trombosis relacionada con el dispositivo. Simulaciones de flujo. Cierre de la orejuela izquierda. Personalización del paciente.
Abbreviations AF: atrial fibrillation. CT: computed tomography. DRT: device-related thrombosis. ECAP: endothelial cell activation potential. LAAO: left atrial appendage occlusion.
Former randomized trials have shown that percutaneous left atrial appendage occlusion (LAAO) can be an efficient strategy to predict cardioembolic events in selected patients with non-valvular atrial fibrillation (AF) as an alternative to lifelong oral anticoagulation (OAC).1,2 However, device-related thrombosis (DRT) has become a major concern due to its incidence rate (2% to 5%)3 and the increased rate of associated strokes.4 Despite the use of different antithrombotic therapies, the rate of DRT has not changed.5 Arguably, adding or intensifying anticoagulant therapy has proven to be capable of reducing effectively the thrombotic burden in patients diagnosed with DRT.6 However, in these high-risk patients, intensive antithrombotic therapies may translate into a higher risk of bleeding. Therefore, identifying the predictors of DRT appears to be essential to individualize suitable antithrombotic treatments post-LAAO and identify those patients who would need a closer follow-up.
Several clinical variables (age, AF at time of implantation, congestive heart failure, CHA2DS2-VASc score) have been associated with a higher risk of DRT mainly due to their impact on hypercoagulability.7 Other factors such as peri-device leaks and uncovered pulmonary venous ridge have been suggested as potential factors for DRT, although the data published on this regard are still controversial.8 Remarkably, only scarce data have been reported on the impact of blood stasis around the device, although the characteristics of blood flow largely influence thrombus formation.9-11
Acquiring reliable imaging data characterizing the complex 4D behaviour of blood flow patterns in the left atrium is a challenge. However, patient-specific computational models of the heart, also known as ‘Digital Twin’ models are emerging as a valuable technology in clinics to back up clinical decisions and contribute to interventional planning, diagnosis, and device optimization.12-14 Several studies analysing blood flow patterns in the LA and LAA with flow-related computational models have been proposed,15,16 but most of them have been applied to a very limited set of patient-specific clinical data without follow-up. Furthermore, only a couple of studies have considered LAAO implantation.11,17 As a matter of fact, only 1 study has analyzed the direct impact of flow dynamics on the generation of DRT with computational models.11
This manuscript is a proof-of-concept study that describes our early experience evaluating a computational workflow to assess the risk of DRT through personalized flow simulations after LAAO implantation. Our objective was to identify patients who would need closer follow-ups after the intervention due to a higher risk of DRT.
We developed a computational methodology to build patient-specific models and drew personalized in silico indices from clinical data standardly available in patients treated with LAAO implantation. Figure 1 shows a scheme of the proposed methodological workflow. To test this workflow, a retrospective, single-centre study was performed including 6 patients (3 with DRT, and 3 without DRT, respectively) referred for LAAO implantation, post-implantation cardiac computerized tomographic (CT) imaging of the whole atrium, and ultrasound imaging (US) of the mitral valve (MV). The study protocol was approved by the Hospital de la Santa Creu i Sant Pau ethics committee, and all patients gave their informed consent.
CT images were acquired at least twice between months 1 and 3, and between months 3 and 6, respectively after LAAO implantation. A prospective cardiac-gated computed tomography angiography was performed with a Phillips Brilliance iCT scanner (Philips Healthcare, The Netherlands). A biphasic contrast injection protocol was used: 40 cc of iodinated material (Iomeprol 350 mg/mL, Bracco, Italy) were infused through an 18-gauge cubital catheter at a rate of 5 mL/s followed by a saline flush of 40 mL.
The bolus-tracking method was used for the arterial phase images being the region of interest on the ascending aorta with a 100 HU threshold. A volumetric scan from heart to diaphragm (14 cm to 16 cm) was acquired. Cardiac phase reconstruction was performed at 30% to 40% of the interval between the QRS complex. Digital image post-processing and reconstruction were performed using the Brilliance Workstation to assess the LAAO device positioning and presence/location of the DRT (defined as a CT hypodensity on the device left atrial extremity): a) unexplained by imaging artefacts, b) inconsistent with normal healing, c) visible in multiple CT planes, and d) in contact with the device. Patient data were anonymized prior to any computational processing. None of the patients showed leaks after assessing the CT following the methodology and the definition provided by Linder et al.18
A 2D Doppler echocardiography was performed within 7 days from CT follow-up acquisition. Transmitral flow velocities as seen on the pulsed-wave Doppler echocardiography were recorded from the apical 4-chamber view with the Doppler samples placed between the tips of the mitral leaflets. Four out of the 6 patients were diagnosed with permanent AF and 2 with paroxysmal AF. One patient from the latter group was in sinus rhythm when the US images were acquired. Since these patients did not have A waves, the measurement of velocity curves corresponded to the mean of the measurements of their E waves over 3 or 5 beats.
3D model construction and simulation experiments
A personalized geometrical model of the whole left atrium was constructed for each patient from the CT images through semi-automatic segmentation. The Slicer 4.10.1 software was used. The geometry and position of the LAAO device implanted were also extracted from the post-procedural CT scans. The thrombi were segmented as a part of the LA. Therefore, the modeller was blind and did not know whether there was a thrombus when he received the 3D model segmented. The segmented regions were then built on 3D mesh models for computational fluid dynamics simulations. The velocity curves at the mitral valve were obtained from the Doppler ultrasound imposing patient-specific boundary conditions in terms of outflow during the left atria flow simulations. All simulations used a generic pressure wave from a patient with AF at pulmonary vein level. The movement of the mitral valve annular plane was defined according to the medical literature available,19 and distributed through the whole LA thanks to a dynamic mesh approach. Flow simulations were performed using the computational fluid dynamics solver Ansys Fluent 19 R3 (ANSYS Inc, United States). Post-processing and visualization of simulation results were performed using ParaView 5.4.1 (Sandia National Laboratories, Kitware Inc., Los Alamos National Laboratory, United States). More details on the 3D construction modelling and computer simulation pipeline are shown on the supplementary data.
Patient-specific flow simulations allowed the local analyses of the following in silico indices: a) the presence of swirling flows (eg, eddies) or stagnated flow next to the device surface; b) the velocity magnitude averaged over the whole cardiac cycle within the area outlined between the pulmonary ridge and the device surface (see figure 2); low velocity values (< 0.20 m/s) were defined as a strong indicator of thrombus formation20; and c) regions with complex flow patterns and low wall shear stress were characterized using the endothelial cell activation potential (ECAP) index21 (ECAP > 0.5).
Six patients treated with LAAO with the Amulet device were selected from the overall LAAO database based on the availability of complete CT imaging at the follow-up including the whole atrium anatomy and an echocardiography study with mitral flow analysis. Three cases with diagnosed DRT and 3 controls (without DRT) were included for patient-specific computational fluid dynamics analyses.
The indication for LAA closure was motivated by a history of major bleeding in 5 patients and high bleeding risk in the remaining one. The patients’ baseline characteristics are shown on table 1 and table 2 (DRT and control groups, respectively). Antithrombotic treatment post-LAAO was prescribed for a minimum of 3 months (table 1 and table 2). No cardioembolic strokes occurred during a minimum clinical follow-up of 12 months.
|Patient #1||Patient #2||Patient #3|
|Indication for LAAO||Intracranial bleeding||GI bleeding||High bleeding risk|
|History of stroke/TIA||Yes||No||No|
|Device size, mm||31||28||22|
|Time after LAAO, CT thrombus detection, in weeks||12||22||15|
|Therapy at time of thrombus detection||Clopidogrel||No treatment||No treatment|
CHA2DS2VASc score (congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65 74, sex); CT, computerized tomography; GI, gastrointestinal; HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly); LAAO, left atrial appendage occlusion; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack.
|Patient #4||Patient #5||Patient #6|
|Indication for LAAO||GI bleeding||GI bleeding||GI bleeding|
|History of stroke/TIA||No||No||No|
|Device size, mm||28||28||22|
|Time after LAAO, CT performed in weeks||25||5||38|
|Therapy at time of thrombus detection||DAPT||Acenocumarol||Acetylsalicylic acid|
CHA2DS2VASc score (congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65 74, sex); CT, computerized tomography; GI, gastrointestinal; HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly); LAAO, left atrial appendage occlusion; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack.
Analysis of the simulated flows to predict the risk of DRT
Swirling flows or eddies (figure 3, column 2, red markers) due to blood stagnation and recirculation near the LAAO device surface were found in all patients except for patient #5. The areas with flow recirculation in the simulations matched exactly the location where thrombi were found in the post-CT follow-ups (figure 3, column 1) of patients with DRT. In addition, the magnitude of blood velocities near the device surface, averaged over the whole beat, were different in the DRT group compared to the control cases: around 0.15 m/s for the DRT group, and > 0.20 m/s for the control cases. Table 3 shows the estimate average blood velocities at systole, diastole, and over the whole cardiac cycle. These velocities were generally higher during ventricular diastole. Remarkably, patient #5 who suffered severe mitral regurgitation had particularly high flow velocities (2-3 m/s during the E wave), according to simulations (0.87 m/s on average) in the LAAO region and Doppler data. On the contrary, patient #2 had the smallest average velocity value at 0.10 m/s.
|Vel-syst (m/s)||Vel-diast (m/s)||Vel-whole (m/s)||Max-ECAP (Pa–1)||Mean-ECAP (Pa–1)|
|Patient #1 (DRT)||0.07 ± 0.02||0.27 ± 0.08||0.16 ± 0.11*||1.23*||0.23 ± 0.14|
|Patient #2 (DRT)||0.11 ± 0.03||0.09 ± 0.02||0.10 ± 0.03*||1.50*||0.24 ± 0.26|
|Patient #3 (DRT)||0.10 ± 0.03||0.19 ± 0.07||0.14 ± 0.07*||0.61*||0.25 ± 0.11|
|Patient #4 (control)||0.13 ± 0.03||0.24 ± 0.13||0.20 ± 0.12||0.45||0.10 ± 0.08|
|Patient #5 (control)||0.28 ± 0.10||1.6 ± 0.77||0.87 ± 0.83||0.07||0.01 ± 0.01|
|Patient #6 (control)||0.08 ± 0.02||0.37 ± 0.17||0.29 ± 0.19||0.30||0.03 ± 0.04|
diast, diastole; ECAP, endothelial cell activation potential; max, maximum; syst, systole; vel, velocity (average ± standard deviation); whole, whole cardiac cycle.
* Velocity values averaged across the whole cardiac cycle < 0.20 m/s and ECAP values were > 0.5 since they are indicators of high risk of device-related thrombogenesis.
ECAP values ≥ 0.5 Pa–1 were found near the device surface in all patients with DRT (see table 3 for peak and average ECAP values). The peak ECAP values in patients #1 and #2 (figure 3, column 3, red areas) allowed us to clearly locate the specific areas where simulations predicted the formation of DRT, which was later compared to the post-CT imaging analyses. For instance, the spatial location of the ECAP highest values in patient #2 (figure 3, row 2) on the device upper region next to the pulmonary ridge matches the location of the thrombus in the follow-up images. However, the ECAP map of patient #1 suggested an inferior thrombogenic area whereas the real thrombus also formed on the device upper region. In patient #3, ECAP values were more homogeneously distributed over the entire device surface, yet the peak values were still found where the thrombus was formed (lower device region). Regarding the control group, ECAP results were very low except for those of patient #4. In any case, the threshold of 0.5 was not reached, and the follow-up confirmed that this patient did not develop DRT.
Early diagnosis, and even prediction, of DRT seems essential to reduce further complications after LAAO implantation like stroke or systemic embolism. It would also contribute to individualize optimal antithrombotic therapies, on which there is still not consensus in the medical community. In this study, the combination of several in silico indices successfully predicted the presence or lack of DRT in all simulated cases (3 controls and 3 patients with DRT diagnosed with follow-up CT imaging). The computational pipeline developed basically required the 3D reconstruction of the whole LA anatomy, obtained with regular cardiac CT imaging acquisition plus a standard US study, already routinely acquired for LAAO candidates, which allowed us to define patient-specific boundary conditions (such as the mitral flow velocity profile from Doppler data). Each patient-specific simulation extended for 48 hours on average. These requirements make the proposed tool particularly suitable for clinical use, and the estimates indicated that an early diagnosis of DRT within 72 hours following device implantation is possible.
This is the first study to validate the ECAP index with a clear clinical endpoint and assess its performance in patients treated with LAAO. The ECAP index could differentiate between DRT and non-DRT cases based on the characteristics of flow complexity. However, it could not robustly predict the exact location of thrombus formation in all of the cases as it wrongly suggested the formation of an inferior thrombus in patient #1 in whom a superior thrombus was identified clinically. Even though the cohort was small, the results suggested that if thrombotic risk after LAAO needs to be studied, the ECAP index alone is not enough, and needs to be combined with other variables.
The velocity results obtained in our in silico analysis are consistent with studies on low velocities with thrombus formation since they could favour the stagnation of flow and consequently trigger the inflammatory process.11,20 Velocity results during systole were more similar among the patients compared to results during diastole that varied more. Point velocity measurement was allocated near the device surface, and it was very close to the MV. Therefore, in general, during ventricular systole when the valve is closed, the velocities in that region tend to be low and differences are difficult to see. Once the MV is open the velocities increase. Also, the mean velocity of the entire cardiac cycle (table 3, column 3) showed that patients who developed DRT had lower velocities in all the beats compared to the control group. However, the process through which blood stasis triggers the inflammatory cascade is not fully understood. For instance, the spatial proximity of the left atrial appendage to the MV makes blood flow into the LAA be quite dependent on the dynamics of the MV as it occurred with patient #5. The unusual hemodynamic behaviour of this patient (eg, very high blood velocities) was due to mitral regurgitation, an effect that was captured by the simulations thanks to the patient-specific US-based boundary conditions. Remarkably, these observations are consistent with studies that hypothesize about a certain degree of protection against flow stagnation and thrombus formation in patients with mitral regurgitation due to a better blood washout of the LAA.22
The areas of flow recirculation at low velocities could indicate potential regions with risk of thrombus formation, but its precise localization depends on the patient’s LA anatomy and the LAAO device final deployment. Our flow simulations revealed the device upper region with an uncovered pulmonary ridge (PR) as the preferred area for eddies as shown on figure 3. This finding was consistent with the literature available on pulmonary ridge uncovering and a higher risk of DRT: 82% of DRT cases with uncovered left upper pulmonary venous ridge.4,8,11 However, we showed that pulmonary ridge uncovering could increase the risk of DRT only if flow velocities are low and the whole pulmonary ridge area cannot be properly washed out. Therefore, covering the pulmonary ridge, which is often not possible due to anatomical constraints (eg, proximity of a circumflex to other structures) would only be critical if blood flow velocities are not high enough.
The main limitations of our study were the reduced number of patients to confirm our simulation-based factors, the different anticoagulant therapies used in the DRT group, the differences reported between the acquisition time of the follow-up CT imaging among the different patients, the lack of a unified protocol at the follow-up, and the differences seen between the stroke risk stratification scores. The need for follow-up CT images of the entire left atria and patient-specific MV velocity profiles as seen on the echocardiography, both essential to run flow simulations, confirmed that only a few patients were eligible for this study. Hence, our computational fluid dynamics-based descriptors for DRT prediction should be viewed as novel potential biomarker candidates accessible through digital twin technologies. Fortunately, CT imaging is increasingly becoming accepted as a key technology for LAAO planning and follow-up analysis,23 thus facilitating more extensive studies in the next future. More specifically, the requirement of having a whole LA CT image at the follow-up for the computational model would not substantially change the clinical protocol in centers with access to this imaging technique. Also, the examination can be performed within 72 hours after LAAO implantation. Additionally, in the near future, the constant improvements in spatial and temporal resolution of echocardiographies would make it possible to build patient-specific models based on 3D reconstructions of the LA anatomy from these images. Hence, achieving a larger cohort of prospective cases is possible and will allow more rigorous analyses and validations of the candidate factors and thresholds (in both velocities and the ECAP index) to confirm the performance of the proposed in silico indices to predict the risk of DRT after LAAO implantation.
There is not a clear consensus on the optimal boundary conditions to model LA hemodynamics in a realistic way. On the one hand, we used a velocity profile as outlet in the mitral valve since such profile can be obtained from standard echocardiography images routinely acquired on LAAO candidates. On the other hand, a generic pressure waveform of a patient with AF from a former study was applied in the pulmonary veins as an inlet model while coping with the fact that patient-specific pressure measurements would require invasive catheterization, which is not usually performed in these patients. Similarly, in our study, the movement of the LA wall was extrapolated from the passive movement of the mitral valve annular plane, imposed by the left ventricle, which was extracted from the medical literature available. Whereas our patient-specific approximations of the boundary conditions uniquely allowed simulating mitral regurgitation effects, a more realistic left atrial wall dynamics may be extracted from temporal imaging sequences.
Simplifications are intrinsically associated with the concept of modelling, which was applied in the present study. Still, the integration of relevant patient-specific structural and functional information in our modelling and simulation workflow provided boundary conditions that were realistic enough to achieve accurate estimations of the risk of DRT after LAAO implantation.
In this proof-of-concept study we present a description of an in silico modelling workflow capable of integrating patient-specific data and simulating hemodynamics within the LA while predicting the risk of DRT after LAAO device implantation. The model was used to study 6 patients retrospectively: 3 patients with DRT and patients 3 without DRT. The simulations reproduced the flow dynamics inside the LA and showed that patients with DRT had low velocity blood flow recirculation with complex patterns next to the device surface. The combination of several in silico indices representing pro-thrombotic factors that cannot be measured in situ, in clinics, could detect differences and distinguish patients with DRT from those of the control group. Here we showed a first proof-of-concept study with in silico indices from personalized models capable of identifying potential complications of LAAO device implantation and individualizing follow-up therapies to minimize the rate of unfavorable clinical outcomes. Nevertheless, future studies should focus on validating the computational workflow developed in a larger cohort of cases.
This work was supported by the Spanish Ministry of Science, Innovation and Universities under the Retos I+D (RTI2018-101193-B-I00), the Maria de Maeztu Units of Excellence (MDM-2015-0502), the Formation of Doctors (PRE2018-084062) and the Recruitment of Talents (RYC-2015-18888) programmes.
J. Mill: study idea, methodology, investigation, and writing; V. Agudelo: study idea, methodology, and investigation; C. H. Li: data curation; J. Noailly: formal analysis, supervision, and methodology; X. Freixa, and D. Arzamendi: study idea, supervision, and validation; O. Camara: supervision, writing, validation, and study idea.
CONFLICTS OF INTEREST
D. Arzamendi has received personal grants for proctoring for Abbott, and Boston Scientific. X. Freixa has received personal grants for proctoring for Abbott, and Lifetech. The remaining authors have not declared any other conflicts of interest.
WHAT IS KNOWN ABOUT THE TOPIC?
- DRT has become a major concern, because of its incidence rate (2% to 5%) and the increased rate of associated strokes. Despite the use of different antithrombotic therapies, the rate of DRT has not changed.
- Following Virchow’s triad, 3 factors are thought to contribute to thrombus formation: hypercoagulability, endothelial injury, and blood stasis.
- Factors such as peri-device leaks and uncovered pulmonary venous ridge have been suggested as potential factors for DRT, but the data published are still controversial.
WHAT DOES THIS STUDY ADD?
- Patient-specific flow models correctly predicted the formation or lack of device-related thrombus after LAAO implantation in all studied cases.
- The most relevant in silico indices to predict DRT after LAAO implantation were the presence of flow stagnation, low velocity values next to the device surface, and the ratio between (high) flow complexity and (low) wall shear stress.
- Patients treated with LAAO implantation could have more individualized DRT risk assessments and follow-up antithrombotic therapies using personalized simulations built from the patient’s postoperative CT scans and ultrasound imaging.
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* Corresponding author: Departamento de Cardiología, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
E-mail address: email@example.com (D. Arzamendi).
Introduction and objectives: The final diagnosis of a myocardial infarction with non-obstructive coronary arteries (MINOCA) is often hard to achieve. Angiographic findings may be suggestive of the presence of unstable plaques although it is common to discharge patients without an etiologic diagnosis. The high spatial resolution provided by the optical coherence tomography (OCT) allows the detection of vulnerable and unstable coronary plaques that are prone to rupture, erosion, and thrombi which may lead to more targeted individual therapies. The objective of this study is to assess the utility of OCT when achieving an etiologic diagnosis in selected patients with MINOCA and high clinical suspicion of atherosclerotic etiology.
Methods: Registry of 27 patients recruited between September 2015 and January 2020 admitted to a single tertiary hospital with acute coronary syndrome and non-significant stenosis in the coronary angiography who underwent OCT. The baseline data of the study population, the angiographic and OCT findings, treatment and follow-up information were all collected.
Results: The OCT imaging showed evidence of unstable plaques (thrombus, plaque erosion or plaque rupture) in 78% of patients, which lead to an etiologic diagnosis of MINOCA. Patients were predominantly males (89%), smokers (63%), middle-aged (median 53 years old) and with a low cardiovascular risk burden. The left anterior descending coronary artery was the most frequently compromised vessel (74%) and 95% of patients ended up receiving coronary stents. The mid-term follow-up was excellent.
Conclusions: In our study, OCT imaging proved to be a valuable tool to achieve an etiologic diagnosis in a large proportion of selected patients with MINOCA which, as a result could lead to more specific and individualized treatments.
Keywords: Optical coherence tomography. Myocardial infarction with non-obstructive coronary arteries. Unstable plaque. Vulnerable plaque.
Introducción y objetivos: A menudo resulta complejo diagnosticar a pacientes con infarto agudo de miocardio y estenosis coronarias no significativas en la coronariografía (MINOCA). En ocasiones, la angiografía muestra datos sugestivos de placa inestable, aunque no es infrecuente que estos pacientes acaben sin un diagnóstico etiológico. La tomografía de coherencia óptica (OCT) permite detectar placas vulnerables e inestables con rotura, erosión o trombo gracias a su elevada resolución espacial, lo que podría implicar un cambio en el manejo de estos pacientes. El objetivo de este estudio es valorar la utilidad de la OCT para alcanzar un diagnóstico final en casos seleccionados de MINOCA con alta sospecha de etiología ateroesclerótica.
Métodos: Registro de 27 pacientes desde septiembre de 2015 hasta enero de 2020 en los que se indica OCT en el contexto de síndrome coronario agudo y estenosis < 50% en la angiografía. Se describen las características de la población, los hallazgos en la angiografía y la OCT, la actitud terapéutica y la evolución.
Resultados: La OCT evidenció la presencia de placa inestable con trombo, rotura de placa o erosión de placa en el 78% de los pacientes como causa del MINOCA. Los pacientes fueron predominantemente varones (89%), fumadores (63%), de mediana edad (53 años de mediana), con poca carga de factores de riesgo y afectación principalmente de la descendente anterior (74%). El 95% de los casos en que se detectó placa inestable fueron tratados con stent. La evolución a medio plazo fue excelente.
Conclusiones: En nuestra serie de pacientes con MINOCA y alta sospecha de causa ateroesclerótica, la OCT resultó ser una técnica útil para identificar la etiología de la mayoría de ellos, lo que permitió adoptar una estrategia terapéutica más específica.
Palabras clave: Infarto de miocardio con arterias coronarias sin estenosis significativas. Placa inestable. Placa vulnerable. Tomografía de coherencia óptica.
MINOCA: myocardial infarction with non-obstructive coronary arteries. OCT: optical coherence tomography. ACS: acute coronary syndrome.
Patients admitted with a diagnosis of acute coronary syndrome (ACS) with coronary arteries without significant angiographic obstructions (considered as angiographic stenoses < 50% of the lumen of a major epicardial vessel) should be reassessed before re-planning their diagnosis.1 In general, differential diagnosis is required with other conditions that may trigger acute myocardial damage without an acute myocardial ischemia as the underlying cause (myocarditis, stress cardiomyopathy or other cardiomyopathies, pulmonary thromboembolism, etc.). Only when these are discarded or unlikely the diagnosis of acute myocardial infarction with non-obstructive coronary arteries, also known as MINOCA, can be established.2
MINOCA amounts to between 5% and 7% of all acute myocardial infarctions, but even in some series its prevalence reaches 15% of the cases.3-5 The causes for MINOCA are varied: atherosclerotic plaque disruption (rupture or erosion), vasospasm, microvascular dysfunction, thrombus or coronary embolism, spontaneous coronary dissection or oxygen supply-demand imbalance (like in the tachyarrhythmia or anemia setting). For this reason, treatment varies significantly depending on each particular case.6 However, some studies have reported that in half of the patients no specific etiological diagnosis was established,7,8 which may lead to inappropriate treatments.
The optical coherence tomography (OCT) is an intravascular imaging modality based on the use of infrared light to acquire images with very good spatial resolution (approximately between 10 µm and 20 µm), even 10 times better resolution compared intravascular ultrasound (IVUS).9 For this reason, the OCT allows the detection of vulnerable plaques (those whose characteristics show a higher risk of destabilization) or findings suggestive that the plaque is already destabilized (table 1).10-12 Therefore, it is a useful imaging modality to establish the etiological diagnosis of MINOCA, especially when there is clinical or electrocardiographic suspicion of ACS due to atherosclerosis and also in cases of spontaneous coronary dissection.
|Vulnerable plaque||Unstable plaque|
|Type of plaque||Thrombus|
|Macrophages||Rupture of plaque|
|Neovessels||Erosion of the plaque|
|Cholesterol microcrystals||Protruding calcium nodule with presence of thrombus or plaque disruption|
The objective of this study was to assess the utility of the OCT to establish the etiological diagnosis of patients with MINOCA and highly suspected ACS due to atherosclerosis, and describe the profile of the population studied.
This was a prospective registry of selected cases of MINOCA in the reference center of an autonomous community between September 2015 and January 2020 with the following characteristics: a) admission with a diagnosis of ACS or recovered sudden death with suspected ACS as the underlying cause; b) angiographic coronary stenoses < 50%, and c) performance of an OCT on the possible culprit artery causing the event due to suspected angiographic imaging or ECG or segmental alterations on the echocardiogram. When in doubt on which the infarct-related culprit artery was, the vessels considered in each case were assessed using the OCT.
Procedure and analysis
The OCT was performed using the Dragonfly Optis catheter (Abbott, United States) over a pullback length of 55 mm or 75 mm in the segment of interest. The OCT study was performed in the same Ilumien Optis OCT console (Abbott). The angiographic study was performed using the Stenosis Analysis 1.6 software package (GE Healthcare, Advantage Workstation 4.5, United States). The offline analyses of the angiographic and OCT findings were performed by the same operator while the interventional procedure was being performed. This operator made the therapeutic decisions too. Afterwards, 2 expert operators performed an independent, thorough, and retrospective analysis of the angiographic and OCT images in a first reading and, simultaneously, in a second reading to achieve consensus when in the presence of suspected cases or possible discrepancies.
The following qualitative analysis were defined according to the methodology described in the OCT consensus document:12 vulnerable plaque, presence of thin-cap fibroatheroma (TCFA), macrophages, neovascularization, presence of thrombus, erosion of the plaque, ruptured plaque, and protruding calcium nodule. Unstable plaque is defined as a plaque with a thrombus, ruptured plaque, erosion of the plaque or protruding calcium nodule with thrombus or plaque disruption as seen on the OCT. Quantitative analysis was performed for every 1 mm interval while the software automatically calculated luminal dimension. The results of patients treated with a stent and those who underwent a new OCT after the implant were confirmed by verifying the adequate position, expansion, and lack of large dissections of the borders of the stent.
Quantitative variables with a normal distribution were expressed as mean and standard deviation. Those without a normal distribution were expressed as median and interquartile range [IQR]. Finally, qualitative variables were expressed using percentages as the frequency measure.
The registry included 27 patients. A total of 28 arteries through 38 OCT pullbacks were studied. Results are shown on table 2.
|Demographic and clinical variables of the patients (n = 27)|
|Female sex||3 (11)|
|Arterial hypertension||10 (37)|
|Diabetes mellitus||1 (4)|
|Indication for coronary angiography:|
|Sudden death with suspected ACS||4 (15)|
|Elevation of high-sensitive troponin I levels||20 (74)|
|LVEF||61 ± 9|
|Findings of the coronary angiography|
|Stenosis as seen on the visual angiographic assessment, %||40 [30-40]|
|Stenosis as seen on the quantitative coronary angiography assessment, %||41.2 [35.5-48.4]|
|Suspected vessels on the coronary angiography|
|Angiographic characteristics of the lesion|
|Irregular lesion||9 (33)|
|Image of an ulcer||3 (11)|
|Calcified lesion||3 (11)|
|Smooth lesion||15 (56)|
|Angiographic thrombus||2 (7)|
|Long lesion||6 (22)|
|Variables of the OCT|
|Minimum lumen area, mm2||3.2 [2.5-4.9]|
|Vulnerable plaque||23 (85)|
|Lipid core > 90% of the vessel area||13 (48)|
|Protruding calcium nodule||2 (7)|
|Measure of the TCFA fibrous layer, µm||63 ± 7|
|Unstable plaque||21 (78)|
|Protruding calcium nodule with thrombus/plaque disruption||2 (7)|
|Variables of the OCT|
|Other causes for MINOCA found on the OCT: hematoma/spontaneous coronary dissection||2 (7)|
|OCT post-stent implantation||15 de 20 casos (75)|
|Dissection of the borders||1 (7)|
|Perform PCI after OCT with findings suggestive of plaque||20 de 21 casos (95)|
|Perform PCI after OCT without findings suggestive of plaque||0 de 6 casos (0)|
|Death during admission||0 (0)|
|Death during follow-up||1 (4)|
|Cardiac death||1 (4)|
|Follow-up, months||4 [1-19]|
ACS, acute coronary syndrome; Cx, circumflex artery; LAD, left anterior descending coronary artery; LVEF, left ventricular ejection fraction; MINOCA, myocardial infarction with non-obstructive coronary arteries; NSTEACS, non-ST-segment elevation acute coronary syndrome; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; RCA, right coronary artery; STEACS, ST-segment elevation acute coronary syndrome; TCFA, thin-cap fibro-atheroma.
Unless specified otherwise, data are expressed as no. (%), mean ± standard deviation or median [interquartile range].
The patients’ mean age was 53 years [45-64]. Most of them were males (89%). Smoking was the main cardiovascular risk factor (63%). The most common indication for the coronary angiography was non-ST-segment elevation ACS (63%).
The median angiographic stenosis obtained through visual analysis was 40% [30-40]. In 5 cases the stenosis assessed through visual estimation was between 50% to 60%; according to the quantitative coronary angiography the median stenosis was 41.2% [35.5-48.8]. The quantitative coronary angiography showed a 50% to 60% stenosis in 2 cases only. In all of the patients the initial TIMI flow was normal (Thrombolysis in Myocardial Infarction [TIMI] grade 3). The vessel most often damaged was the left anterior descending coronary artery (74%). In most patients the angiographic imaging did not show any signs indicative of an unstable plaque. The angiographic imaging was suggestive of a thrombus and an ulcer in 2 and 3 cases, respectively. No thromboaspiration was performed in any of the patients.
Regarding the OCT findings, the median minimum lumen area was 3.2 mm2 [2.5-4.9]. In most of the cases different types of vulnerable plaque were found in the form of a TCFA (67%), macrophages (59%), and neovessels (56%). The OCT showed signs of unstable plaque in 21 cases (78%) with thrombus in 70% of the patients. The erosion of the plaque was the main cause for plaque instability (41%) followed by the rupture of the plaque (30%). A decision was made to implant a stent in 20 of the 21 patients (95%) with data of unstable plaque as seen on the OCT. One patient with plaque erosion received medical therapy. The 6 patients without data of unstable plaque on the OCT received medical therapy too. In 75% of the cases with stenting the outcomes were assessed using the OCT; 5 out of the 20 cases were postdilated and an additional overlapping stent was implanted in 1 out of the 20 cases.
Finally, no sudden deaths were reported during the index event. At the median 4-month follow-up only 1 death due to cardiovascular causes was reported.
In some series of patients with MINOCA it has been reported that in up to 50% to 70% of the cases no etiological diagnosis is established. This means that these patients may end up receiving unspecific treatment for their MINOCA.7,8 For this reason, diagnostic algorithms have been designed by expert consensus including intravascular imaging techniques as useful tools to establish the etiological diagnosis of MINOCA.2,12,13 Regarding the use of the OCT specifically for these patients, the studies have proven its capacity to detect the mechanism of the infarction in some of MINOCAs.14,15 However, although its use has been reported in some series of patients with MINOCA7,8,16 it is still scare (only 0.08% in some registries.)16 This may be due to the fact that its wide use in this type of patients has not been fully established or to the different availability and training capabilities of each center.
According to different expert consensuses2,12,13 in our center OCTs are performed on this type of patients (suspected atherosclerotic cause). This registry was started back in 2015 to later study and assess the utility of OCT in these cases since scientific evidence available on this regard is scarce in part due to its low use. Also, it would be advisable to establish a protocol to perform OCTs in most cases of MINOCA even in the absence of suspected atherosclerotic etiology; thanks to its high spatial resolution, the OCT also allows us to detect other causes for MINOCA like thromboembolisms, vasospasms or spontaneous coronary dissections.12 This was also confirmed by our study that identified 2 cases of hematoma/spontaneous coronary dissection (table 2, figure 3).12
The characteristics of this registry were those of a young population of patients (median age, 53 years), which is consistent with what has been reported by former studies. However, most of the patients included were males (89%), which varies significantly from other previous registries or reviews where over half of the patients with MINOCA were women.3,7,8,15,16 Our interpretation of these data is that our registry studied highly selected cases of MINOCA with a high clinical suspicion of atherosclerotic ACS due, which is more common in males. This would be consistent with the characteristics of the series of ACS previously reported.17 Also, when the different causes for MINOCA were analyzed, some studies have reported that when it is due to the disruption of the plaque there is a higher prevalence of male sex. However, in the occurrence of MINOCAs due to other causes, female sex is still predominant.15
According to several studies, the main clinical presentation of these patients was non-ST-elevation ACS (63%). However, there was a larger number of sudden deaths with MINOCA as the early presentation, which would be indicative of the utility of OCT for the etiological study of recovered sudden death.7,8,16
Regarding the coronary angiography findings, although the atherosclerotic cause for MINOCA was suspected, the angiography imaging were inconclusive (non-significant stenosis and scarce cases of images suggestive of plaque instability). This totally justified performing the OCT in all of the cases. The left anterior descending coronary artery was the vessel more commonly damaged, which is consistent with the results reported by other studies.15
The OCT findings show that the median minimum lumen area of the patients was 3.2 mm2. Former studies conducted with IVUS have reported on the minimum lumen area as suggestive of non-significant stenosis for which medical therapy is, therefore, preferred.18 The study conducted by Gonzalo et al.,19 that studied the value of OCT to establish the severity of intermediate angiographic stenoses (40% to 70% as seen on the quantitative coronary angiography) in patients with stable coronary artery disease revealed that the minimum lumen area as seen on the OCT to establish the concept of a functionally significant stenosis (fractional flow reserve ≤ 0.80) was 1.95 mm2. Therefore, our patients showed stenoses on the OCT without compromised coronary flows, which is consistent with the angiographic results that showed non-significant stenoses (median of 40% by visual estimation and 41.2% on the quantitative coronary angiography). However, the OCT detected the instability of the plaque in 78% of registry patients, which is why although no significant stenosis was seen (on the angiography or OCT) a decision was made to implant a stent in 95% of the cases with an unstable plaque as seen on the OCT. There is not enough evidence to support this therapeutic strategy over pharmacological treatment only.2,6,13,20-22 The EROSION trial21,22 studied conservative management (pharmacological) in cases of ACS with residual angiographic stenosis < 70% after the aspiration of a thrombus and the erosion of the plaque as the infarction mechanism. At the 1-year follow-up, 92.5% of the patients were still free from any major cardiovascular events. Therefore, conservative treatment may have been an option for a larger percentage of patients from our series. We should mention that the OCT avoided stent implantation in 6 patients in whom no unstable plaque was detected or in whom a different cause for MINOCA was found (hematoma/coronary dissection). It would be advisable to conduct randomized, prospective clinical trials to assess the possible benefit of percutaneous coronary intervention compared to pharmacological medical therapy for the management of patients with plaque disruption as the cause for MINOCA.
Mid-term patient progression was good and consistent with what has been reported by registries.7 Only 1 patient died of cardiovascular causes at the follow-up (a patient with multiple comorbidities and of an older age compared to the study median age, that is, a patient different from the population studied).
On the other hand, although this trial basically tries to identify the presence of unstable plaques on the OCT, the presence of vulnerable plaques was also studied since they are indicative of high cardiovascular risk. Thus, in most of the patients studied vulnerable plaques were found and they were often thin-cap fibroatheromas. TCFAs are considered as some of the most vulnerable plaques of all because they are made up of a lipid core (also known as lipid-rich necrotic core) covered by a very thin fibrous cap (< 65 µm) that makes them more prone to destabilization. Plaques with calcium nodules protruding towards the vessel lumen also have a higher risk of destabilization due to prospective plaque disruption, but in general they are less common. As a matter of fact, only 2 cases were found in our registry. Other findings of vulnerable plaque are the presence of macrophages (indicative of plaque inflammation), neovessels (they are immature, they can break, and cause intraplaque hemorrhage), and the size of the lipid core. all of these findings were present in over half of the study patients. Findings that are consistent with those reported by former studies.10,11,14,15
Finally, we should mention that the registry included very few patients (27) over a 4.5-year period. The largest number of patients included happened over the last 2 years. This is due to the few OCTs performed in our center to this profile of patients at the beginning of the registry with a wider use of this imaging modality after its great utility was confirmed in selected cases (figure 1 of supplementary data ). The follow-up of patient was short (median follow-up, 4 months) because over the last 6 months of the registry up to 9 patients (33%) were included and because 7 patients (26%) had a different nationality and were followed in their home countries; overall this amounts to 59% of the patients with a limited follow-up period.
The OCT is an intravascular imaging modality to establish etiological diagnosis in a large number of patients with MINOCA, which can lead to a better decision-making process with each particular case. Our study confirms the great accuracy of this imaging modality for the detection of unstable atherosclerotic plaques. Yet despite its proven utility and recommendation from expert consensuses, the use of this imaging modality in this type of patients is still scarce. This means that it will be necessary to establish algorithm of common actions in patients with MINOCA to avoid misdiagnosing its different etiologies.
CONFLICTS OF INTEREST
WHAT IS KNOWN ABOUT THE TOPIC?
- MINOCAs amount to 5% to 7% of all myocardial infarctions. Different causes can trigger MINOCAs and treatment is different in each of them.
- Although there are different imaging modalities available (magnetic resonance imaging, OCT, IVUS, etc.) and their utility has been proven in the diagnosis of MINOCA, in over half of the patients the etiological diagnosis is never established.
- In part this is due to a scarce use of these imaging modalities, although expert consensuses recommend their use.
WHAT DOES THIS STUDY ADD?
- This study shows the utility of OCT to establish the etiological diagnosis of MINOCA, which reinforces the idea of a wider use of this imaging modality.
- We should mention that OCT findings can change the therapeutic approach.
- The need to conduct more specific studies to assess the best therapeutic strategy for the management of patients with MINOCA and plaque disruption.
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3. Pasupathy S, Air T, Dreyer RP, Tavella R, Bertrame JF. Systematic Review of Patients Presenting With Suspected Myocardial Infarction and Nonobstructive Coronary Arteries. Circulation. 2015;131:861-870.
4. Bainey KR, Welsh RC, Alemayehu W, et al. Population-level incidence and outcomes of myocardial infarction with non-obstructive coronary arteries (MINOCA):Insights from the Alberta contemporary acute coronary syndrome patients invasive treatment strategies (COAPT) study. Int J Cardiol. 2018;264:12-17.
5. Barr PR, Harrison W, Smyth D, Flynn C, Lee M, Kerr AJ. Myocardial Infarction Without Obstructive Coronary Artery Disease is Not a Benign Condition (ANZACS-QI 10). Heart Lung Circ. 2018;27:165-174.
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7. Abdu FA, Liu L, Mohammed AQ, et al. Myocardial infarction with non-obstructive coronary arteries (MINOCA) in Chinese patients:Clinical features, treatment and 1 year follow-up. Int J Cardiol. 2019;287:27-31.
8. Reparelli V, Elharram M, Shimony A, Eisenberg MJ, Cheema AN, Pilote L. Myocardial Infarction With No Obstructive Coronary Artery Disease:Angiographic and Clinical Insights in Patients With Premature Presentation. Can J Cardiol. 2018;34:468-476.
9. Herrero-Garibi J, Cruz-González I, Parejo-Díaz P, Jang IK. Optical Coherence Tomography:Its Value in Intravascular Diagnosis Today. Rev Esp Cardiol. 2010;63:951-962.
10. Uemura S, Soeda T, Sugawara Y, Ueda T, Watanabe M, Saito Y. Assessment of Coronary Plaque Vulnerability with Optical Coherence Tomography. Acta Cardiol Sin. 2014;30:1-9.
11. Sinclair H, Bourantas C, Bagnall A, Mintz GS, Kunadian V. OCT for the identification of vulnerable plaque in acute coronary syndrome. JACC Cardiovasc Imaging. 2015;8:198-209.
12. Johnson TW, Räber L, di Mario C, et al. Clinical use of intracoronary imaging. Part 2:acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making:an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J. 2019;40:2566-2584.
13. Agewal S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J. 2017;38:143-153.
14. Bogale N, Lempereur M, Sheikh I, Wood D, Saw J, Fung A. Optical coherence tomography (OCT) evaluation of intermediate coronary lesions in patients with NSTEMI. Cardiovasc Revasc Med. 2016;17:113-118.
15. Opolski MP, Spiewak M, Marczak M, et al. Mechanisms of Myocardial Infarction in Patients With Nonobstructive Coronary Artery Disease:Results From the Optical Coherence Tomography Study. JACC Cardiovasc Imaging. 2019;12:2210-2221.
16. Rakowski T, De Luca G, Siudak Z, et al. Characteristics of patients presenting with myocardial infarction with non-obstructive coronary arteries (MINOCA) in Poland:data from the ORPKI national registry. J Thromb Thrombolysis. 2019;47:462-466.
17. EUGenMed Cardiovascular Clinical Study Group, Regitz-Zagrosek V, Oertelt- Prigione S, et al. Gender in cardiovascular diseases:impact on clinical manifestations, management, and outcomes. Eur Heart J. 2016;37:24-34.
18. de la Torre Hernandez JM, Hernández Hernandez F, Alfonso F, et al. Prospective application of pre-defined intravascular ultrasound criteria for assessment of intermediate left main coronary artery lesions results from the multicenter LITRO study. J Am Coll Cardiol. 2011;58:351-358.
19. Gonzalo N, Escaned J, Alfonso F, et al. Morphometric assessment of coronary stenosis relevance with optical coherence tomography:a comparison with fractional flow reserve and intravascular ultrasound. J Am Coll Cardiol. 2012;59:1080-1089.
20. Lindahl B, Baron T, Erlinge D, et al. Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease. Circulation. 2107;135:1481-1489.
21. Jia H, Dai J, Hou J, et al. Effective anti-thrombotic therapy without stenting:intravascular optical coherence tomography-based management in plaque erosion (the EROSION study). Eur Heart J. 2017;38:792-800.
22. Xing L, Yamamoto E, Sugiyama T, et al. EROSION Study (effective Anti-Thrombotic Therapy Without Stenting:Intravascular Optical Coherence Tomography-Based Management in Plaque Erosion):A 1-Year Follow-Up Report. Circ Cardiovasc Interv. 2017;10:e005860.
Corresponding author: Camí de Ciutat Vell 15, 07630 Campos, Islas Baleares, Spain.
E-mail address: firstname.lastname@example.org (C. Mas Lladó).
Introduction and objectives: Complete revascularization is recommended for the management of ST-segment elevation myocardial infarctions (STEMI). Although physiological evaluation is recommended for the assessment of nonculprit lesions, in this context, the use of fractional flow reserve (FFR) is limited. The quantitative flow ratio (QFR) is a new angiography-based tool for the assessment of functional severity. We evaluated the functional changes occurring in nonculprit lesions after the acute phase and the QFR/FFR correlation in non-infarct-related arteries.
Methods: We recruited all patients with multivessel disease admitted to our institution due to STEMI from January 2016 through December 2017 who underwent staged interventions for the management of nonculprit lesions. We conducted a retrospective QFR assessment at both the index and the staged procedures and drew a comparison. Also, the QFR/FFR concordance and agreement were prospectively evaluated between January and May 2018 in a cohort of patients with STEMI and multivessel disease.
Results: We analyzed a total of 131 lesions in 88 patients. During the initial procedure, 93.1% of the lesions were considered significant based on the angiography compared to only 56.3% studied through QFR (P ≤ .001). The QFR reassessment during the staged intervention brought this percentage down to 32.1%. All patients with QFR values ≥ 0.82 during the index procedure remained nonsignificant at the staged assessment. Both the FFR and the QFR were compared in 12 patients showing good agreement and a mean difference of 0.015 ± 0.02 (P > .1).
Conclusions: The QFR-based physiological assessment of nonculprit lesions in STEMI patients led us to consider nonsignificant 40% of the lesions classified as significant by the angiography. Also, the QFR significantly increased from the acute phase to the staged procedure, indicative that in patients with QFR ≥ 0.82 in the acute phase a new coronary angiography procedure may be unnecessary.
Keywords: Fractional flow reserve. Quantitative flow ratio. Non-infarct-related artery. STEMI.
Introducción y objetivos: En pacientes con infarto agudo de miocardio con elevación del segmento ST y enfermedad multivaso se recomienda la revascularización completa. La evaluación funcional con reserva fraccional de flujo (RFF) de las arterias no culpables del infarto es limitada. El quantitative flow ratio (QFR) es una herramienta basada en la angiografía para valorar la gravedad funcional de las lesiones. Se analizaron la evolución funcional de las arterias no culpables del infarto tras la fase aguda y la correlación QFR/RFF en este contexto.
Métodos: Se incluyeron pacientes ingresados con infarto agudo de miocardio con elevación del segmento ST entre enero de 2016 y diciembre de 2017, con enfermedad multivaso y revascularización diferida de lesiones no culpables. Se evaluaron retrospectivamente con QFR durante el procedimiento índice y el diferido, y se evaluó la concordancia QFR/RFF de manera prospectiva entre enero y mayo de 2018.
Resultados: Se incluyeron 131 lesiones de 88 pacientes. Durante el procedimiento índice, el 93,1% de las lesiones se consideraron significativas de acuerdo con la angiografía, pero solo el 56,3% cuando se evaluaron con QFR (p < 0,001). El QFR del procedimiento diferido demostró una mayor reducción, con solo el 32,1% de las lesiones significativas. Todos los pacientes con QFR ≥ 0,82 durante el procedimiento índice continuaron con estenosis no significativas en la evaluación diferida. La comparación del QFR y la RFF en este contexto demostró buen acuerdo, con una diferencia media de 0,015 ± 0,02 (p > 0,1).
Conclusiones: La evaluación fisiológica mediante QFR de las lesiones en arterias no culpables del infarto descartó la significación en el 40% de las consideradas significativas por angiografía. El valor de QFR se incrementó significativamente del procedimiento índice al diferido, lo que sugiere que en pacientes con QFR ≥ 0,82 en la fase aguda podrían evitarse procedimientos diferidos innecesarios.
Palabras clave: Reserva fraccional de flujo. Quantitative flow ratio. Arteria no culpable. IAMCEST.
Abbreviations: FFR: fractional flow reserve. IRA: infarct-related artery. PCI: percutaneous coronary intervention. QFR: quantitative flow ratio. STEMI: ST-segment elevation myocardial infarction.
Up to 50% of the patients admitted with ST-elevated acute myocardial infarction (STEMI) show multivessel disease1. Currently, complete revascularization is recommended before hospital discharge but the benefits of non-infarct-related artery (non-IRA) revascularization during primary percutaneous coronary interventions (PCI) or subsequent procedures is still controversial1. As a matter of fact, the strategy for the management of non-IRA has widely varied across landmark studies2-4.
The lack of consensus can be partially explained by the inaccuracy of angiography when assessing the severity of stenosis in non-IRA, with less than 30% to 50% of the lesions initially considered eligible for revascularization finally confirmed when assessed using the fractional flow reserve (FFR) 3-4. In particular, the severity of non‐IRA stenosis is more frequently overestimated during primary PCIs due to the hemodynamic conditions5.However, also in this context, the FFR measurements are usually invalid due to altered micro and macrovascular tone or microvascular flow obstruction3,6.Also, little has been said on the variability of FFR results over time in non‐culprit lesions. All these factors probably explain why most interventional cardiologists still use angiography as the only tool when it comes to deciding whether or not to treat nonculprit lesions7. The quantitative flow ratio (QFR) is a new tool to assess the severity of coronary stenosis based on computational fluids dynamics and the three-dimensional reconstruction of coronary angiography without a wire or the need for inducing hyperemia, which favorably correlates with FFR in stable coronary disease8-10. On the other hand, and although good agreement between FFR and QFR has also been suggested in the acute phase of myocardial infarctions11 it is widely known that the presence of microvascular dysfunction is associated with a worse correlation12.
We conducted one pilot study to conduct physiological assessments of the severity of non-IRA lesions based on the QFR during primary PCIs and in staged angiographies. Also, the FFR and QFR correlation was explored in this context.
Single-centre retrospective and observational study conducted in full compliance with the Declaration of Helsinki and after approval from the local ethics committee. All the patients included in this research provided informed consent for the anonymous use of their clinical and imaging data with scientific purposes only.
The study included consecutive patients of ≥ 18 years of age admitted to our institution due to STEMI between January 2016 and December 2017 with > 50% diameter coronary stenosis in nonculprit arteries after angiographic assessment. A two‐procedure strategy to achieve complete revascularization was decided in these patients during the index procedure. The staged procedure to treat the nonculprit lesions was conducted before hospital discharge as the standard care in this setting and according to the actual recommendations1. Consecutive patients with ≥ 18 years of age admitted to our institution due to STEMI between January 2018 and May 2018 with coronary stenosis after coronary angiographic assessment in non‐IRA lesions were prospectively included in our study to evaluate the concordance between the QFR and the FFR. The decision to conduct FFR assessments in these patients was made at operator’s discretion based on interventional and clinical criteria. The level of concordance and agreement between the FFR and the QFR were established here.
Exclusion criteria included inability to provide informed consent, lack of adequate coronary angiographic images for valid QFR analysis, presence of normal coronary arteries in the index procedure, surgical revascularization, and death or presence of other conditions precluding revascularization during the index procedure or contraindicating the staged procedure within the same admission.
Angiographic and physiological assessments
Standardized angiographic projections were performed in both procedures following the center acquisition protocol. The computation of the QFR was performed offline using specific software (QAngio XA 3D prototype, Medis Medical Imaging System, Leiden, the Netherlands). Details from the QFR assessment have been previously reported elsewhere13. In short, two projections > 25º apart recorded at 15 frames per second were used for the threedimensional reconstruction of the target non-IRA. The diameter stenosis, area stenosis, minimal luminal area, maximal, minimal and reference vessel diameters were estimated. The QFR values were obtained by applying computational principles of fluid dynamics to the aforementioned software. The modeled virtual hyperemic flow velocity derived from contrast flow (contrast QFR, cQFR) without adenosine was implemented. Two independent certified software users blinded to the visual assessment of the severity of stenosis and the QFR value obtained during the first or staged procedure, respectively, conducted the offline assessment in a core laboratory14. The inter- and intra-observer variability were examined in 20 lesions through repeated measurements conducted by both certified software users (10 lesions to determine the intra-observer variability and 10 lesions to asses the interobserver variability).
Finally, the correlation between the FFR and the QFR values was estimated in the prospective group of patients during the index or staged procedures. The FFR measurements were performed using the Aeris device (St. Jude Medical, St. Paul, MN, United States). Maximal hyperemia was induced through the continuous IV infusion of adenosine (140-μg/kg/min) that was maintained for 2 minutes or until symptom onset. The QFR analysis was conducted in a blind fashion with respect to the FFR values. Values ≤ 0.8 were considered significant stenosis for both the QFR and the FFR.
The qualitative variables are expressed as absolute frequencies and percentages. The quantitative ones as mean ± standard deviation. The normal distribution of the quantitative variables was determined using the Kolmogorov-Smirnov test and Q-Q plots. Data were analyzed on a per-patient basis for the clinical characteristics and on a per-vessel basis for the quantitative coronary angiography and QFR values. The agreement between the FFR and the QFR was determined using the Bland-Altman plot method and the intraclass correlation coefficient. The paired sample t-test was used to determine the evolution of measurements between the index and the staged procedures. The receiver operating characteristic curve was analyzed to assess the capacity of the QFR at the index procedure to predict the QFR at the staged procedure. Finally, both the intra- and inter-observer variability were determined using the intraclass correlation coefficient for these measurements with repeated analysis 1-month apart in 20% of the lesions. All analyses were conducted using the statistical package SPSS, version 24.0 (Armonk, NY: IBM Corp) and R 3.4.3.
A total of 828 patients were admitted or transferred to our department with suspected STEMI between January 2016 and December 2017. The diagnosis was confirmed in 455 patients of which 196 (43.1%) showed multivessel disease. Among them, 31 patients (15.8%) underwent complete revascularization during the index procedure and in 165 patients (84.2%) the operation on the nonculprit lesions was postponed or never conducted. Finally, 46 patients with multivessel disease and staged procedure were excluded due to suboptimal angiographic images precluding an adequate QFR analysis during the primary (13 patients) or staged (33 patients) procedure. The study population included 88 patients with a total of 131 lesions in nonculprit arteries. The main characteristics of the overall population are shown on table 1. Most patients were males (86.4%) with inferior or anterior STEMI in 57.9% and 37.5%, respectively, and admitted due to primary PC n 64.8% of the cases. The culprit artery Thrombolysis in Myocardial Infarction flow grade was 0-1 in 51.1%, and 4.5% were in shock. The left anterior descending artery was the most common non-IRA (50%). Following the index procedure, the staged revascularization of 1 (56.8%), 2 (38.7%), or more arteries (4.5%) was performed during the hospital stay for an average 5 days [interquartile range, 2-6]. Successful revascularization of the IRA and complete revascularization were achieved in 100% and 76% of the patients, respectively.
|Variables||Retrospective sample N = 88||Prospective sample N = 12|
|Age (y)||67.8 ± 11.2||70.1 ± 9.3|
|Gender (male) (%)||86.4||75|
|Height (cm)||167.8 ± 8.2||164.9 ± 7.8|
|Weight (kg)||79.5 ± 10.6||78.3 ± 8.9|
|Chronic kidney disease (%)||3.4||0|
|STEMI main features|
|AMI Killip I (%)||85.2||100.0|
|AMI Killip II (%)||10.4||0|
|AMI Killip III (%)||0||0|
|AMI Killip IV (%)||4.5||0|
|Radial access (%)||95.3||83.3|
|Primary PCI (%)||64.8||100.0|
|Post thrombolysis routine PCI (%)||25||0|
|Rescue PCI (%)||10.2||0|
|IRA LAD (%)||40.9||50.0|
|IRA RCA (%)||47.8||16.7|
|IRA Cx (%)||11.3||33.3|
|TIMI grade-0 flow IRA (%)||44.3||41.7|
|TIMI grade-1 flow IRA (%)||6.8||25.0|
|TIMI grade-2 flow IRA (%)||3.4||0.0|
|TIMI grade-3 flow IRA (%)||45.5||33.3|
|Time to staged procedure (d)||5.8 ± 3.6||N/A|
Data are expressed as no. (%) or mean ± standard deviation.
AMI, acute myocardial infarction; Cx, circumflex artery; IRA, infarct related artery; LAD, left anterior descending; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.
Validation of QFR assessment in nonculprit lesions
The prospective assessment of the correlation between the QFR and the FFR was conducted in 12 patients (15 lesions) of the study population following the protocol described elsewhere11. The main characteristics of this validation sample were similar to those of the QFR cohort as shown on table 1. No complications followed the use of pressure wires. The mean FFR value was 0.87 ± 0.06 and the mean difference compared to the QFR was0.017 ± 0.02. One paradigmatic example of a lesion assessed through FFR and QFR is showed on figure 1. The intraclass correlation coefficient was 0.959 (95% confidence interval, 0.882- 0.986). In 4 lesions (26.7%) the FFR was performed during the first procedure after the revascularization of the culprit lesion. No difference was found on the diagnostic accuracy of the QFR between the first and the staged procedures in this sample (relative mean difference 0.0346 ± 0.29 and 0.114 ± 0.10, P = .214); The Bland Altman plot used to see the degree of agreement between these measures and the correlation according to the procedure is shown on figure 2.
QFR changes across index and staged procedures
One hundred and twenty-two (93.1%) of the 131 lesions in non- culprit vessels were considered eligible for scheduled percutaneous revascularizations according to the angiography visual assessment. Among them, only 56.3% showed QFR values ≤ 0.80 in the index procedure when assessed retrospectively(figure 3). A statistically nonsignificant decrease of the QFR values was confirmed between the index and the staged procedure in patients with initial QFR values > 0.80; however, 2 patients with initial nonsignificant QFR values showed a drop < 0.80 in the staged angiography assess-ment. All patients with initial values > 0.82 showed non-significant stenosis in the second procedure. On the other hand, 45.9% of the lesions with significant QFR values were considered non-significant when assessed during the second procedure, with larger mean diame-ters and stenotic areas (P < .001 for both) as shown on table 2. The main changes seen between both proceedures are shown on figure 4 and one paradigmatic example is shown on figure 5. The sensitivity and specificity of QFRs > 0.82 during the index procedure to predict significant stenosis (QFR < 0.80) during the staged procedure were 84% and 58.7%, respectively, with a positive predictive value of 52.5% and a neg-ative predictive value of 87% (figure 6). The therapeutic strategy was implemented regardless of the findings from the QFR assess-ment since it was estimated retrospectively. This allowed us to compare the strategy based on the angiography visual assessment interpretation and posterior QRF findings leading to a total of 46 lesions treated with stents despite showing nonsignificant QFRs.
|Total: 131 no-ARI||Procedimiento índice||Segundo procedimiento||p*|
|Diámetro de estenosis (%)||58,9 ± 12,0||51,15 ± 10,6||< 0,001|
|Área estenótica (%)||70,1 ± 15,1||63,9 ± 15,1||< 0,001|
|Diámetro máximo del vaso proximal (mm)||2,7 ± 0,6||2,8 ± 0,6||0,182|
|Diámetro mínimo del vaso proximal (mm)||2,4 ± 0,5||2,5 ± 0,6||0,231|
|Diámetro máximo del vaso distal (mm)||2,6 ± 0,7||2,6 ± 0,6||0,850|
|Diámetro mínimo del vaso distal (mm)||2,3 ± 0,6||2,3 ± 0,5||0,751|
|Diámetro del vaso de referencia (mm)||2,5 ± 0,7||2,5 ± 0,6||0,295|
|Diámetro luminal mínimo (mm)||1,0 ± 0,3||1,2 ± 0,4||< 0,001|
|Ratio de flujo cuantitativo||0,76 ± 0,14||0,82 ± 0,12||< 0,001|
ARI: arteria responsable del infarto.
* Valores p significativos en negrita.
Intra- and inter-observer variability
Also, the optimal intra- and interobserver variability for measur-ing the QFR were confirmed by intraclass correlation coefficients of 0.958 (95% confidence interval, 0.877-0.984) and 0.991 (95% confidence interval, 0.960-0.997), respectively.
It is well known that the visual assessment of coronary stenosis usually overestimates its severity5, but operators are often reluc-tant to conduct functional assessments of nonculprit lesions inthis context due to potential risks associated with the FFR and the altered physiology of this condition. The QFR value for the assessment of nonculprit lesions in STEMI patients was already investigated in a small pilot study8 and offers potential advantages mainly based on its quick application and no need for wiring coronary arteries or administering adenosine. The main findings of our study are: a) The QFR has a good correlation with both the FFR and the optimal intra- and inter-observer variability in trained operators in the assessment of functional severity in coronary lesions, suggestive that this may be an excellent tool also in STEMis; b) The severity of stenosis in nonculprit lesions is higher in the acute phase of STEMis, which is mainly confirmed by the angiography but also by the QFR; c) The functional assessment of nonculprit lesions through the QFR may be useful in the acute phase of STEMis. On the one hand, stenoses with QFR values > 0.82 remained nonsignificant in the follow-up in all cases, which may lead to avoiding staged procedures and stenting in up to 1/3 of these patients; on the other hand, significant QFR values during the index procedure should not lead to treating the lesion in the same intervention since, according to the QFR, 45.9% of significant lesions became nonsignificant during the staged assessment.
Differences in anatomical and physiological assessments
The growing evidence that places physiology above anatomy in the field of coronary disease deserves its own research when it comes to STEMI patients in order to reduce the rates of overtreatment. Overestimation when decisions are made based on angiographies5 and underestimation when based on FFR have been reported in this context6. In the COMPARE-ACUTE trial, the physiological assessment of non-IRA was conducted during the index procedure and showed that only half of the lesions angiographically considered significant were confirmed through the FFR3. On the contrary, in the DANAMI-3-PRIMULTI trial, the assessment of nonculprit lesions was conducted during staged procedures rising the percentage of lesions with FFR < 0.80 to almost 70%4. The changes in the macrovascular tone or the obstruction of microvascular flow during the acute phase of myocardial infarctions may partially explain these findings in large trials. This difference when estimating severity between both procedures both through quantitative coronary angiography and QFR should be taken into consideration to avoid treating non-IRA lesions during primary PCIs. This is especially important even when only the angiographic assess-ment is taken into account since the need for complete revascu-larization is under discussion and still not recommended by the actual guidelines.
Potential new contributions of QFR in STEMI patients
The QFR can be safely conducted during primary percutaneous coronary interventions. A cut-off value of 0.82 helped to identify the patients who were not eligible for sequential revascularization. The QFR assessment in the staged procedure showed no significant differences compared to the acute phase probably due to the limited sample size. However, a trend towards higher QFR values in the staged procedure–similar to that of FFR–was ob-served. This may be explained by the presence of microvascular dysfunction in the acute phase12, though the quality of coronary angiography may have had an influence here. Nevertheless, the potential of QFR in non-IRAs to identify lesions that should not be treated and, therefore, avoid unnecessary staged procedures is very interesting. From this perspective, the QFR may be that long-awaited tool to help determine what the best strategy is when making the complex decision of treating multivessel disease in STEMI patients. Ongoing studies that are putting this hypothesis to the test while assessing the need for urgent revascularization during follow-up with this new strategy will determine the clini-cal relevance of QFR.
The main limitations of this study are its retrospective nature and limited sample size. The QFR assessment requires good quality from the angiographic assessment and, although a standard protocol was routinely performed for coronary angiographies, several studies had to be excluded due to their inadequate quality, which may be a bias that should be analyzed by future prospective studies. Also, the limited sample size may have associated limited power in the diagnostic accuracy of the QFR in certain subgroups of patients and in terms of validating the QFR compared to the FFR.
In sum, coronary functional assessments based on the QFR of non-culprit lesions after an acute myocardial infarction showed a high percentage of angiographic overestimation in the severity of stenoses (> 40%). QFRs > 0.82 during the index procedure accurately identified those nonculprit lesions that are no flow-limiting and nonculprit lesions and QFR values below this threshold triggered re-assessments before recommending the angioplasty procedure. The prospective validation of this hypothesis is totally justified.
This project, code: GRS1728/A/18, has been financed by the Gerencia Regional de Salud de la Junta de Castilla y León, Spain.
Conflicts of interests
There is no conflict of interest to declare.
Whait is known about the topic?
- Over half of the patients admitted due to STEMI show multivessel disease, which is why complete revascularization is recommended.
- The functional assessment of nonculprit lesions after STEMI has proven useful when establishing the revascularization strategy to be followed; how-ever, most interventional cardiologists base their decision on the angiography because of the challen-ges and limitations of FFR in this context.
- The QFR is a new functional index based on the three-dimensional reconstruction of the coronary anatomy and computational fluid dynamics while keeping a good correlation with the FFR and without having to wire the coronary arteries.
What does this study add?
- Good degree of agreement between the QFR and the FFR confirmed for nonculprit lesions in STEMI patients.
- The QFR values in the acute phase of STEMI suggested greater severity compared to deferred assessments. QFR thresholds = 0.82 in the acute phase better identified patients threshold who may not need deferred procedures for new functional assessments or angioplasties in nonculprit lesions, thus reducing risks and unnecessary costs.
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2. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: The CvLPRIT trial. J Am Coll Cardiol. 2015;65:963-972.
3. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional Flow Reserve–Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med. 2017;376:1234-1244.
4. Engstrøm T, Kelbæk H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386:665-671.
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8. Tu S, Westra J, Yang J, et al. Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography. JACC Cardiovasc Interv. 2016;9:2024-2035.
9. Yazaki K, Otsuka M, Kataoka S, et al. Applicability of 3-Dimensional Quantitative Coronary Angiography-Derived Computed Fractional Flow Reserve for Intermediate Coronary Stenosis. Circ J. 2017;81:988-992.
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11. Spitaleri G, Tebaldi M, Biscaglia S, et al. Quantitative Flow Ratio Identifies Nonculprit Coronary Lesions Requiring Revascularization in Patients With ST-Segment-Elevation Myocardial Infarction and Multivessel Disease. Circ Cardiovasc Interv. 2018;11:e006023.
12. Mejía-Rentería H, Lee JM, Lauri F, et al. Influence of Microcirculatory Dysfunction on Angiography-Based Functional Assessment of Coronary Stenoses. JACC Cardiovasc Interv. 2018;11:741-753.
13. Tu S, Barbato E, Yang J, Li Y, Rusinaru D, Reiber JHC. Fractional Flow Reserve Calculation From 3-Dimensional Quantitative Coronary Angiography and TIMI Frame Count. JACC Cardiovasc Interv. 2014;7:768-777.14. Instituto de Ciencias del Corazón. Disponible en: http://icicorelab.es. Consultado 14 Jul 2018.
E-mail address: email@example.com (I.J. Amat-Santos).
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José Miguel Blanco Borreguero, Inmaculada Guillén Rodríguez, et al.