EDITORIAL COMMENT
Do we have agold standard yet?*
Julien I. E. Hoffman, MD, FACC ,*
Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco, California, USA
* Reprint requests and correspondence: Dr. Julien I. E. Hoffman, Box 0544, Room M 1331, University of California, 505 Parnassus Avenue, San Francisco, California 94143, USA.
jhoffman{at}pedcard.ucsf.edu
Coronary angiography can show arterial abnormalities in children who have had an arterial switch operation or Kawasaki disease, but deciding whether these abnormalities are severe enough to cause myocardial ischemia that could be reversed by revascularization is as difficult in children as in adults with a stenosis of intermediate severity. The decision is critical because coronary perfusion will be needed for a lifetime.
Measurement of the arterial stenosis to determine the percentage of narrowing is standard in adults, but it is not ideal, because many stenoses are irregular and long, the relationship of stenosis geometry to flow is non-linear, different methods of quantitative coronary angiography give different results, and the unstenotic portion of the artery used for comparison may be abnormal (1–8). These problems might be worse in children with small coronary arteries. Furthermore, discrepancies between anatomic and physiologic measures of stenosis make judgment even harder (2,9,10).
Investigators have therefore sought functional methods of assessing reversible myocardial ischemia. The first of these was the translesional pressure drop that increases with stenosis severity. However, the relationship of pressure drop to flow is non-linear and varies with flow and microvascular resistance. Furthermore, it is distal flow and not pressure that determines regional ischemia (11). Finally, it is flow during maximal coronary vasodilatation that is important; quite severe stenoses usually allow sufficient flow at rest to prevent ischemia.
Gould and Lipscomb (12) used maximal flows to demonstrate the relationship of stenosis severity to absolute coronary flow reserve (maximal flow/resting flow). Normally, maximal flow is three to six times that of resting flow, and as the stenosis diameter decreases below 85% of normal (or even less for a long stenosis), the absolute coronary flow reserve decreases. Because absolute flow reserve varies with blood pressure, heart rate, neural influences, and degree of hypertrophy, Gould and Lipscomb defined relative flow reserve as maximal flow with stenosis divided by maximal flow without stenosis; the index was independent of external variables but required the rest of the coronary tree to be normal. In patients, Gould et al. (13) measured regional flows with positron emission tomography, but this technique is not always available and is time consuming. A simpler method for measuring flows was performed by using a Doppler tipped wire (FloWire, Cardiometrics Inc., Mountain View, California) passed through a catheter in the coronary artery (10,14,15). The procedure is relatively safe (16) but requires fairly sophisticated data processing (17,18). In addition, it is not always possible to obtain adequate flow recordings. Finally, the wire measures absolute rather than relative flow reserve.
To meet these objections, Pijls and De Bruyne (8,19–23) developed the concept of fractional flow reserve (maximal myocardial flow with stenosis/maximal flow without stenosis) determined from pressure measurements obtained with a thin sensor-tipped pressure wire. Fractional flow reserve: (FFRmyo) = (Pd – Pv)/(Pa – Pv), where Pa = mean aortic pressure, Pd = mean distal coronary pressure, and Pv = mean coronary venous pressure, all measured during maximal coronary vasodilatation. Why these pressure drops are related to flows is discussed in their publications. Any value <0.75 indicates that the stenosis is severe enough to cause ischemia and that revascularization should ameliorate ischemic dysfunction. Important assumptions include a low and constant distal (microvascular) myocardial vascular resistance during maximal vasodilation and no significant ventricular hypertrophy.
Until the study by Ogawa et al. (24) in this issue of the Journal, the concepts of coronary flow reserve (CFR) and FFRmyo had not been applied to children. In a study in children with Kawasaki disease, Ogawa et al. compared 174 normal coronary arteries (normal group), 51 arteries with <75% stenosis (intermediate group), and 47 arteries with >75% stenosis (ischemic group) and found that almost all the arteries in the ischemic group had values for CFR or FFRmyo more than two standard deviations below the corresponding mean values for the normal group with little overlap. The adult cut-off values of 2.0 for CFR and 0.75 for FFRmyo could be applied to children with very high sensitivity (94% CFR, 95.7% FFRmyo) and specificity (98.5% for CFR and 99.1% FFRmyo). The procedures had no morbidity or complications and were successful in almost every child. They repeated the measurements in 20 patients after successful balloon angioplasty or bypass surgery; the CRF in all those with angioplasty and FFRmyo in all patients returned to normal values. Their data therefore show that CRF and FFRmyo may be used to diagnose reversible myocardial ischemia in children and that criteria used in adults can be applied to children.
The crucial question is how do the authors and we know that these criteria are correct? After all, if there is a gold standard for judging myocardial ischemia, why do we need this method? And if there is no such gold standard, what is to say that these criteria are accurate?
Existing non-invasive methods for determining reversible ischemia include electrocardiography, scintigraphy, positron emission tomography, and echocardiography, all supplemented by stress testing with exercise, dobutamine infusion, or vasodilators. These methods have only moderate sensitivity and specificity, especially with lesions of intermediate severity, with atypical symptoms, and in children (25–28). To handle these problems, Pijls and De Bruyne (23) combined several of these measures sequentially to produce a "gold standard" for ischemia with a diagnostic accuracy of almost 100% and used this standard to verify the critical value of FFRmyo. They postulated that "functionally significant disease (corresponding to inducible myocardial ischemia) was present if and only if at least one of the non-invasive tests yielded a clearly positive result and reverted to negative after successful coronary angioplasty or bypass surgery." The downside to this approach is that lesions with FFRmyo deemed not severe enough to warrant revascularization procedures cannot be verified as not causing ischemia, that is, false negatives are harder to validate.
In the study by Ogawa et al., we should ask whether the functional results were any better than the quantitative morphology because the groups were classified by the degree of anatomic stenosis. The answer to this comes in part from a study of the intermediate group. In their study, for those arteries with intermediate stenosis, there were four false positives based on a coronary reserve <2, and two of these were also false positives based on FFRmyo <0.75; false positives were defined as having a CFR <2 or FFRmyo <0.75 but a normal thallium scan at rest and after dobutamine stimulation. Of interest, three of these four false positives had echocardiographic signs of dyskinesis that returned to normal after successful percutaneous transluminal coronary angioplasty or coronary artery bypass graft. In the future, more attention needs to be paid to those with stenoses between 65% and 85%. After all, it is possible to obtain exquisite sensitivity and specificity by merely comparing normal arteries with those having anatomically very severe stenosis. In addition, even if sensitivity and specificity are very high, they do not tell the whole story. If disease prevalence is low, then even a very high sensitivity and specificity cannot yield a high positive predictive accuracy, because the small percentage of false positives produces a large absolute number of false-positive results and the ratio of true to false positives (positive predictive accuracy) will be low (29). It is high positive predictive accuracy that any one patient needs for accurate clinical assessment, and the study to provide these data still needs to be conducted. The present study is a useful stepping-stone toward this goal, but we are not there yet.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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