Copyright © 2007, The European Society of Cardiology
Core lab, no core lab or automated LVEF?
Division of Cardiology, Department of Medicine, University of Pennsylvania Medical Center, Room 9017 East Gates Pavilion, 3400 Spruce Street, Philadelphia, PA 19104, USA
Received 6 March 2007; .
suttonm{at}mail.med.upenn.edu
* Corresponding author. Tel./fax: +1 215 349 8190.
Left ventricular ejection fraction (LVEF) is an important tool that enables early risk stratification, and predicts late clinical outcome in a variety of cardiac diseases. In contemporary cardiology practice LVEF is also critically important in clinical decision-making; for example in determining who receives an internal automatic defibrillator, biventricular pacing, or epicardial restraint devices in patients with heart failure. In addition, LVEF is the gate-keeper with regards access to clinical trials for novel pharmacologic and device therapies. Thus, it is of pivotal importance that LVEF be estimated accurately and reproducibly.
LVEF can be assessed by cardiac magnetic resonance (CMR), cardiac computed tomography (CT), nuclear scintigraphy and real-time 3D echocardiography, but in clinical practice, trans-thoracic 2D echocardiography is used most frequently because it is so widely available. There are two echocardiographic methodologies used currently to assess LVEF. The first is visual estimation of LVEF that requires substantial expertise acquired over many years of practice. The second method requires manual tracing of the endocardial contours of the apical four-chamber and/or the apical two chamber views to obtain single plane or biplane LV volumes from which LVEF is derived. This quantitative method is time consuming and requires expertise to identify true endocardial boundaries.
While the prognostic importance of LVEF determined by echocardiography has been established in heart failure, acute myocardial infarction and valvular heart disease, its predictive value for adverse cardiovascular events in patients with chronic stable angina is unknown. In this issue of the journal Dart and colleagues1 compare the predictive values for clinical outcome of LVEF assessed by the "local" investigator sites and assessed by the core echocardiography laboratory in 7016 patients with chronic stable angina enrolled in the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study.2 Adverse cardiovascular events were predefined and included death, myocardial infarction, refractory angina, new onset overt heart failure, disabling stroke, transient ischemic attack, peripheral vascularization, coronary angiography, coronary bypass or percutaneous intervention (PCI). All adverse cardiovascular events were adjudicated by a critical events committee throughout the 4.9 year follow-up.
The authors report that all-cause mortality and development of new onset heart failure were related to LVEF and end-diastolic and end-systolic volumes as determined at the Core Laboratory. The Core Laboratory LVEF was a significant predictor of all predefined adverse events except intractable angina and PCI. In addition, Core Laboratory LVEF was a stronger predictor of all-cause mortality, myocardial infarction, stroke, transient cerebral ischemic attack and new onset heart failure than local LVEF, or Core Lab assessments of end-diastolic or end-systolic volumes. So why the differences in LVEF between the local investigator sites and the Core Laboratory?
There are several potential explanations for the reported discrepancy between LVEF locally and at the Core Lab that included the investigator sites may not have adhered to the American Society of Echocardiography (ASE) recommendations for measurement of LV volumes from which LVEF is derived.3 Alternatively, the site investigators were less experienced at quantifying LV volumes and had difficulties in identifying the LV endocardial boundaries at end-diastole and end-systole. Inter-observer variability was greater at the multiple investigator sites than in the Core Lab where there was only one echo analyst.
Quantification of LV volumes and EF is time consuming and heavily reliant upon good image quality and correct scan plane orientation to avoid foreshortening of the LV. Measurements are made from still frames, so that appropriate gain is essential for optimal endocardial definition. When images are under-gained, there are regions of endocardial drop out and if images are overgained, the endocardium may be obscured. Quantitative echocardiography is also hampered by lack of a consistent method for endocardial recognition especially in the apical images. When the ultrasound beam is parallel to the LV walls in the apical views, the only good reflector points are at the apex and at the insertion points of the mitral valve. These become key points in the recognition of the endocardial silhouette. Papillary muscles and trabecular structures are defined as intracavitary. The points at which these intracavitary structures meet the LV wall are perpendicular to the ultrasound beam and their reflections are small but can be clearly recognized. When a number of these mural reflector points are identified, they are all seen to lie on the same curvilinear line of the endocardium. The LV apex is invariably dome-shaped even in the most distorted ventricles, because the interaction between the distending forces within the cavity and the material properties of the myocardium allow for only a narrow range of ventricle shapes, characterized by walls with smooth curves. This method of endocardial identification results in good inter- and intraobserver agreement and is supported by studies that have used echo contrast agents.
The Core Lab has to analyze echocardiograms that have been recorded already, but can monitor quality control at each investigator site prospectively not only for the initial enrollment phase but also throughout the duration of the study, with constructive bidirectional communication between investigator sites and the Core Lab. The Core Lab can minimize potential differences in LVEF by sending to each investigator site a manual of operations that provides indelibly clear instructions explaining how to optimize the quality of echo recordings such as the degree of gain applied. The Core Lab in turn must adhere strictly to the protocol for data analysis. The Core Lab is similar to the nucleus of a cell, and the investigator sites the cytosolic organelles that can receive and transmit signals but are controlled by the nucleus.
In the ACTION study, which involved a large population of patients with chronic stable symptomatic coronary artery disease, Core Lab estimates of LVEF and LV volumes were powerful predictors of clinical outcome that favorably reflects the meticulous work this Core Lab performed over a 5-year period. Relief from the time-consuming manual tracing of LV endocardial borders may be finally on the way in the form of automated LVEF. Previous attempts to automate calculation of LV volumes and LVEF have not been successful because they have been too dependent on the gain settings or confounded by difficulties with endocardial tracking. New technologies for automatic LVEF are now available that come in three flavors, the first is by velocity vector imaging, the second by speckle tracking and the third uses novel computer algorithms that rely on artificial intelligence and pattern recognition that do not require or advocate human interaction.4 Initial reports of automatic LVEF are encouraging,4 but need to be validated independently by a number of different echocardiographic laboratories. Concordance between several laboratories may necessitate rethinking of the strategy of having a Core Lab for simple measures of LV remodeling, but we are not there yet. We believe that the quality control, standardization of technique for endocardial definition and bidirectional communication of the Core Lab remains of vital importance in large clinical trials using echocardiographic measurements as primary or secondary endpoints.
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- Dart A.M., Otterstad J.E., Kirwan B.-E., Parker J.D., de Brouwer S., Poole-Wilson P.A., et al. Predictive value of local and core laboratory echocardiographic assessment of cardiac function in patients with chronic stable angina: the ACTION study. Eur J Echocardiogr (2007) 8:275–283.
[Abstract/Free Full Text] - Poole-Wilson P.A., Lubsen J., Kirwan B.-A., van Dalen F.J., Wagener G., Danchin N., et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomized controlled trial. Lancet (2004) 364:849–857.[CrossRef][Web of Science][Medline]
- Lang R.M., Bierig M., Devereux R.B., Flachskampf F.A., Foster E., Pellikka P.A., et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr (2005) 18:1440–1463.[CrossRef][Web of Science][Medline]
- Cannesson M., Tanabe M., Suffoletto M.S., McNamara D.M., Madan S., Lacomis J.M., et al. A novel two-dimensional echocardiographic image analysis system using artificial intelligence-learned pattern recognition for rapid automated ejection fraction. J Am Coll Cardiol (2007) 49:217–226.
[Abstract/Free Full Text]
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