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Circulation. 1995;92:39-46

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(Circulation. 1995;92:39-46.)
© 1995 American Heart Association, Inc.

Articles

Relation Between Myocardial Fractional Flow Reserve Calculated From Coronary Pressure Measurements and Exercise-Induced Myocardial Ischemia

Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.

Bernard De Bruyne, MD; Jozef Bartunek, MD; Stanislas U. Sys, MD, PhD; Guy R. Heyndrickx, MD, PhD

From the Cardiovascular Center, Aalst, Belgium.

Correspondence to Bernard De Bruyne, MD, Cardiovascular Center, Aalst, O.L.V. Hospital, Moorselbaan, 164, B-9300 Aalst, Belgium.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background Myocardial fractional flow reserve (FFRmyo) is a functional index of stenosis severity that can be derived from intracoronary pressure measurements performed during maximal vasodilatation. It is defined as the maximal myocardial perfusion during hyperemia in the presence of a stenosis in the epicardial artery expressed as a fraction of its normal maximal expected value. To determine threshold values of FFRmyo, of hyperemic translesional pressure gradient ({Delta}Pmax), and of resting translesional pressure gradient ({Delta}Prest) that are uniformly associated with exercise-induced ischemia, we studied the relation between these pressure-derived indexes and the results of exercise ECG.

Methods and Results We studied 60 patients with an isolated lesion in one major epicardial coronary artery, normal left ventricular function, and no left ventricular hypertrophy. Maximal exercise ECG (off anti-ischemic medication) was performed within 6 hours before catheterization. Intracoronary pressure measurements were taken at rest and during hyperemia with a pressure monitoring guide wire. ST-segment depressions at peak exercise (considered abnormal when >=0.1 mV) were compared with FFRmyo, {Delta}Pmax, and {Delta}Prest. Thirty-seven patients had an abnormal and 23 patients a normal exercise ECG. A significant linear correlation was found between the magnitude of ST-segment depressions and both FFRmyo and {Delta}Pmax (r=-.75, SEE=0.53; r=.71, SEE=0.56). A weaker correlation was noted between ST-segment depressions and {Delta}Prest (r=.53, SEE=0.67). Sensitivity and specificity curves were constructed for the prediction of an abnormal exercise ECG for the three pressure-derived indexes. The values that most accurately predicted an abnormal exercise ECG were 66% for FFRmyo, 31 mm Hg for {Delta}Pmax, and 12 mm Hg for {Delta}Prest. No patient with a FFRmyo value >72% showed an abnormal exercise ECG. In addition, receiver operating characteristic curves demonstrated a greater accuracy of FFRmyo and of {Delta}Pmax than of {Delta}Prest for predicting the results of the exercise ECG.

Conclusions In the present study, cutoff values of FFRmyo and translesional pressure gradients are established from the relation between intracoronary pressure–derived indexes and ECG signs of myocardial ischemia during maximal exercise. These values can be helpful for clinical decision making in cases with dubious angiographic results. Furthermore, our data support the concept that stenosis physiology is better reflected by hyperemic than by basal measurements.


Key Words: perfusion • electrocardiography • stenosis • blood flow


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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Coronary angiography remains the cornerstone of diagnosis in patients with coronary artery disease. Presence, location, and extent of disease, as well as the anatomic possibilities for revascularization, can be reliably defined by angiography. Moreover, quantitative coronary angiography can predict the physiological significance of artificial stenoses in animals1 2 3 as well as of discrete coronary narrowings in humans.4 5 6 However, in the majority of patients undergoing angiography or coronary angioplasty, diffuse disease is present. This limits the accuracy of quantitative coronary angiography for functional evaluation of stenoses.7 8 9 Therefore, measurements of coronary vasodilator reserve or maximal hyperemic flow have been proposed10 to quantify physiological effects of the coronary obstruction being examined. Recent development of intracoronary Doppler guide wires11 12 has greatly facilitated the selective assessment of coronary flow reserve in the catheterization laboratory. Yet, coronary flow reserve measurements are hampered by large interstudy variability,13 display hemodynamic dependency on factors such as preload, heart rate, contractility, and driving pressure,14 15 16 and do not take into account collateral perfusion.

Recently, the concept of myocardial fractional flow reserve (FFRmyo) has been introduced.17 It is defined as the ratio of maximal achievable flow in the myocardium supplied by the stenotic vessel to the maximal achievable flow in that same territory in the hypothetical case that the vessel were normal. Stated another way, FFRmyo is the maximal myocardial flow in the presence of a stenosis expressed as a percent of its maximal expected value in the absence of the stenosis. It has been shown that FFRmyo can be derived solely from the ratio of mean distal coronary pressure and aortic pressure during maximal vasodilatation. The accuracy of these measurements has been validated both in animals17 and in humans.18 Measurements of FFRmyo are applicable to patients with three-vessel disease and are insensitive to variations in driving pressure.17 Since all measurements are to be performed during maximal vasodilatation, the calculation of FFRmyo is not affected by conditions known to increase baseline myocardial flow. In addition, FFRmyo takes into account the contribution of collaterals to maximal myocardial perfusion. Therefore, pressure-derived calculation of FFRmyo depicts the functional consequences of an epicardial stenosis for the supplied myocardium even more accurately than functional indexes derived solely from antegrade flow measurements. By definition, each myocardial territory serves as its own control; therefore, the normal value of FFRmyo does not refer to a range of values observed in a series of normal individuals. Instead, the normal value unequivocally equals 100%, whatever the patient and the vessel under study.

Coronary stenoses that induce compensatory arteriolar vasodilatation can be regarded as physiologically significant and will induce a pressure gradient during hyperemia. However, not all lesions responsible for a transstenotic pressure gradient during maximal hyperemia will induce clinical signs of myocardial ischemia during a maximal stress test (diastolic or systolic left ventricular function abnormalities, ECG changes, anginal chest pain).

The purpose of this study was to determine which value of FFRmyo and of resting and hyperemic translesional pressure gradients ({Delta}Prest and {Delta}Pmax, respectively) best predicts the occurrence of exercise-induced myocardial ischemia as assessed by exercise ECG so as to allow the use of these pressure-derived indexes for clinical decision making in the single individual patient.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Patients
The study population consisted of 60 prospectively selected patients referred to us for coronary angioplasty on the basis of a recently performed coronary angiogram and clinical complaints of chest pain suggestive of stable angina. The following inclusion criteria were applied: (1) the presence of an isolated lesion in the proximal or mid left anterior descending coronary artery (LAD) or an isolated lesion in the right coronary artery (RCA) or the left circumflex coronary artery (LCx) with a reference diameter >2.6 mm; (2) no history of myocardial infarction; (3) normal global and regional left ventricular function and normal left ventricular volumes as assessed by biplane left ventricular angiogram; (4) normal resting ECG; (5) normal transthoracic echocardiography (in particular, left ventricular hypertrophy [septal and/or posterior wall thickness >=11 mm] and the presence of a mitral valve prolapse were ruled out); (6) the absence of electrolyte abnormalities; and (7) the physical ability to perform a maximal bicycle stress test. In the absence of obvious signs of myocardial ischemia, a heart rate of at least 85% of the maximal predicted rate was requested. In all patients, cardiac medications (ß-blockers, calcium entry blockers, and long-acting nitrates) were stopped at least 36 hours before the stress test and replaced by aspirin 100 mg/d and molsidomine 4 mg tid.

Exercise ECG
The exercise test was performed on a bicycle ergometer with the patient seated starting with a workload of 25 W that was increased by 25 W/min. A 12-lead ECG was recorded at rest and continuously during the exercise. The analysis of the tracings was performed by a commercially available computer-assisted exercise system (Case 12, Marquette Electronics) and checked by a cardiologist. The exercise ECG was considered positive when horizontal or downsloping ST-segment depression reached or exceeded 0.1 mV 80 ms after the J point. The exercise was continued until one or more of the following end points were reached: (1) one or more ECG leads demonstrating 0.3 mV horizontal or downsloping ST-segment depression measured 80 ms after the J point (the development of chest pain during exercise was not an indication for termination of the exercise unless accompanied by ST-segment depression >0.3 mV); (2) the inability of the patient to exercise further because of fatigue, unbearable chest pain, or dyspnea; (3) a decrease in systolic blood pressure; or (4) severe arrhythmias. Heart rate, systolic blood pressure, and double product were recorded at rest and at peak exercise. Patients who did not reach 85% of the maximal predicted heart rate at peak exercise were not included in the study unless ST-segment depression >=0.1 mV was present at peak exercise.

Coronary Angiography
Coronary angiography was performed by manual injection of 6 to 8 mL of ioxaglate. To determine the reference diameter of the stenotic vessel, a computer-derived reconstruction of the original arterial dimensions at the site of the obstruction was used to define the interpolated reference diameter. The empty catheter was used as a scaling device. All measurements were performed, without administration of intracoronary nitrates, in at least two projections, and the values reported here represent the average of the various measurements performed.

Pressure Measurements and Calculation of FFRmyo
Catheterization was performed within 6 hours after bicycle ergometry. A 7.5F or 8F introduction sheath was inserted into the femoral artery, and a 7F guiding catheter was used to cannulate the coronary ostium. The side arm of the femoral sheath and the guiding catheter were connected to a Spectranetic P23 Statham pressure transducer. To measure distal coronary pressure, either a fluid-filled 0.015-in pressure monitoring guide wire (Premo wire, Advanced Cardiovascular Systems; n=49) or a 0.018-in high-fidelity pressure monitoring wire (Pressure Wire, Radi Medical; n=11) was used. The characteristics of both pressure wires have been described in detail previously.19 20 The pressure monitoring guide wire was first advanced up to the tip of the guiding catheter, where mean and phasic pressures were recorded simultaneously to verify equality of pressures. Thereafter, the pressure monitoring guide wire was advanced through the stenotic segment. Mean aortic pressure and mean distal coronary pressure were recorded at rest and during maximal hyperemia induced either by papaverine (12 mg in the left coronary artery and 8 mg in the RCA) or by adenosine (18 µg in the left and 12 µg in the right coronary arteries). It has been shown that both drugs at the above-mentioned dosages elicit maximal hyperemia in most patients.21 No complications resulted from the study protocol. An example of pressure recording is given in Fig 1Down.



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  		Figure 1. Pressure tracing recorded in a patient with an isolated stenosis in the mid left anterior descending coronary artery. A, Central aortic pressure (Pao) recorded through the guide catheter and distal coronary pressure (Pc) recorded through a high-fidelity 0.018-in pressure monitoring guide wire are measured under baseline conditions. Mean translesional pressure gradient ({Delta}Prest) is 9 mm Hg. Pfem indicates pressure in the femoral artery. B, After intracoronary injection of 18 µg adenosine, distal coronary pressure decreases to 48 mm Hg and translesional pressure gradient ({Delta}Pmax) increases to 40 mm Hg. In this particular case, myocardial fractional flow reserve (FFRmyo{cong}Pc/Pao during hyperemia) reaches 55%.

Calculations of FFRmyo
FFRmyo is defined as the ratio of maximal achievable flow in the myocardium subtended by a stenosed coronary artery to the maximal achievable myocardial flow if the epicardial coronary artery were to be normal. The theoretical and experimental bases of determining maximal coronary, myocardial, and collateral blood flow by pressure measurements have been published recently.17 Based on a schematic representation of the coronary circulation, the FFRmyo can be calculated as


(1)


(2)


(3)


(4)

where {Delta}P is transstenotic pressure gradient, Pao is mean aortic pressure, Pv is mean right atrial pressure, and Pc is mean distal coronary pressure, all pressures being measured during maximal hyperemia. In 24 patients, central venous pressure was measured and FFRmyo was calculated from Equation 1Up, while in 36 patients, central venous pressure was not measured and FFRmyo was calculated from Equation 4Up. We have previously shown that the influence of central venous pressure could be neglected in routine clinical calculation of FFRmyo.18

Statistics
Baseline characteristics (Table 1Down) of the patients with normal and abnormal exercise ECGs were compared by either Fisher's exact test for variables measured on a nominal scale or unpaired two-sample t test for variables measured on an interval scale. For the linear regression relations between either FFRmyo, {Delta}Pmax, or {Delta}Prest and ST-segment depression, the absolute values of the three correlation coefficients were compared, after Fisher's Z transformation, by {chi}2 test followed by a Tukey multiple comparison procedure.22 The area under the receiver operating characteristic (ROC) curves was calculated from the slope and intercept of the linear regression of the original data when plotted on binormal graph paper.23 The associated SEE was obtained from an approximation of the Wilcoxon statistics assuming underlying negative exponential distributions.24 Finally, the areas under the ROC curves, generated from one single set of patients (n=60), were compared according to Hanley and McNeill.25


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  		Table 1. Baseline Characteristics, Angiographic Data, and Hemodynamics of Patients With Normal and Abnormal Exercise ECG


*    Results
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 up arrowMethods
*Results
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Baseline Characteristics of Patients According to the Exercise ECG
Thirty-seven patients had an abnormal and 23 patients a normal exercise ECG. The baseline characteristics, angiographic data, and hemodynamics of patients with positive and negative bicycle ergometry are summarized in Table 1Up. There was no significant difference between the two groups with respect to sex, age, location of the lesion, and size of the diseased vessel. As expected, the duration of exercise, the workload achieved, peak heart rate, and rate-pressure product were significantly higher in patients with normal than in patients with abnormal exercise ECGs. Conversely, systolic pressure, heart rate, and rate-pressure product during adenosine-induced hyperemia were similar in patients with a normal and with an abnormal exercise ECG.

Reasons for Terminating the Exercise
In all patients with a normal bicycle stress test, the exercise was stopped when the patient was unable to continue because of exhaustion or dyspnea. In 5 patients with an abnormal exercise ECG, the test was terminated because of severe angina. All of them showed ST-segment depression >0.1 mV. In 2 patients, the exercise was interrupted because the ST-segment depression reached 0.3 mV. No fall in systolic blood pressure or severe arrhythmia occurred.

Reason for Revascularization
All patients with an abnormal exercise ECG underwent balloon angioplasty (n=34) or stent implantation (n=3) whatever the value of FFRmyo. Three of the 23 patients with a normal exercise ECG underwent a percutaneous revascularization procedure (two balloon angioplasties and one stent implantation). In these patients, the decision was based on concordant clinical and angiographic data and on markedly decreased values of FFRmyo (44%, 50%, and 60%, respectively). The latter 3 patients can be considered as having a false-negative exercise ECG. In 29 of the 37 patients with an abnormal exercise ECG, a maximal bicycle stress test was obtained within 10 days after the procedure. All tests but one were normal. The only patient with an abnormal exercise ECG after the revascularization received a stent in the proximal LAD because of chest pain compatible with angina, ST-segment depression of 0.25 mV in the anterior leads during the exercise test, and the presence of a stenosis in the proximal LAD at coronary angiography. After the procedure, the exercise ECG remained abnormal (ST-segment depression of 0.12 mV), suggesting that in this particular patient, the ECG signs of ischemia could be ascribed, at least in part, to a dysfunction of the resistive vessels.

FFRmyo and Translesional Pressure Gradients in Relation to Exercise ECG
In the study population as a whole, FFRmyo varied from 28% to 94% (mean, 60±18%), {Delta}Pmax from 5 to 80 mm Hg (mean, 37±19 mm Hg), and {Delta}Prest from 0 to 73 mm Hg (mean, 23±21 mm Hg). FFRmyo was significantly lower (50±12% versus 77±13%, P<.01, Fig 2Down) and both {Delta}Pmax and {Delta}Prest were significantly higher in patients with a positive exercise ECG compared with patients with a negative exercise ECG (47±14 versus 20±13 mm Hg and 31±20 versus 11±14 mm Hg, respectively; both P<.01). Fig 3Down depicts the relation between pressure-derived indexes and the magnitude of ST-segment depression reached at the time of peak exercise. FFRmyo correlated well with the magnitude of ST-segment depression during peak exercise (y=-0.032x+3.15; r=-.75, SEE=0.53; P<.01). Similarly, {Delta}Pmax correlated well with the magnitude of ST-segment depression on the exercise ECG (y=0.030x+0.11; r=.71, SEE=0.56; P<.01). However, the correlation between {Delta}Prest and the extent of ST-segment depression (y=0.020x+0.74; r=.53, SEE=0.67; P<.01) was significantly weaker (P<.001 versus both FFRmyo and {Delta}Pmax).



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  		Figure 2. Scatterplots showing values of myocardial fractional flow reserve (FFRmyo), hyperemic translesional pressure gradient ({Delta}Pmax), and resting translesional pressure gradient ({Delta}Prest) associated with normal (<0.1 mV ST-segment depression) and abnormal (>=0.1 mV ST-segment depression) exercise ECG.



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  		Figure 3. Scatterplots showing relation between myocardial fractional flow reserve, hyperemic translesional pressure gradient, and resting translesional pressure gradient and the magnitude of ST-T depression during peak exercise.

Among the patients who developed significant ST-segment depression during exercise, weak but significant correlations were observed between heart rate at the initial occurrence of 0.1 mV ST-segment depression and FFRmyo (r=.39, P<.05), {Delta}Pmax (r=-.36, P<.05), and {Delta}Prest (r=-.41, P<.05).

Value of the Different Indexes in Predicting a Positive Exercise ECG
Percent correct classification for an abnormal stress test (sensitivity) and percent correct classification for a normal test (specificity) as a function of the values of FFRmyo, {Delta}Pmax, and {Delta}Prest are given in Fig 4Down and Table 2Down. The point of intersection of the sensitivity and specificity curves corresponds to the value (on the x axis) for which diagnostic accuracy is optimal (ie, the point of best compromise between sensitivity and specificity). The intersection point of the sensitivity and specificity curves of FFRmyo occurred at the level of 87% (95% CI, 74% to 94%) and corresponded to a FFRmyo of 66%. The intersection point of the sensitivity and specificity curves of {Delta}Pmax occurred at the level of 83% (95% CI, 71% to 92%) and corresponded to a {Delta}Pmax value of 32 mm Hg. {Delta}Prest performed less favorably, with a sensitivity and specificity both equal to 75% (95% CI, 62% to 85%) for a {Delta}Prest value of 12 mm Hg. The value of FFRmyo above which the exercise ECG was uniformly normal (100% sensitivity level) was 72%. The values of {Delta}Pmax and of {Delta}Prest under which the exercise ECG were uniformly normal were 21 mm Hg and 2 mm Hg, respectively. To compare the diagnostic accuracy of the different indexes for predicting the results of the exercise ECG, ROC curves were constructed (Fig 5Down). The diagnostic accuracies of FFRmyo and {Delta}Pmax were similar, since the two ROC curves were almost superimposed. The areas under the ROC curves were 91.7% (SEE=4.4%) and 90.3% (SEE=4.7%), respectively (P=NS). In contrast, a significantly weaker diagnostic accuracy was found for {Delta}Prest, whose area under the ROC curve was only 81.2% (SEE=6.6%; P=.006 versus FFRmyo and P=.015 versus {Delta}Pmax).



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  		Figure 4. Graphs showing percent correct classification of an abnormal exercise ECG (sensitivity, %) and percent correct classification of normal exercise ECG (specificity, %) as a function of the different pressure-derived indexes (myocardial fractional flow reserve, %, hyperemic translesional pressure gradient, mm Hg, and resting translesional pressure gradient, mm Hg). The cutoff value of the different indexes providing the highest diagnostic accuracy is located at the point of intersection of the two curves. The corresponding value is indicated above this point of intersection.


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  		Table 2. Parameters of Sensitivity and Specificity Curves for the Prediction of the Results of Exercise ECG



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  		Figure 5. Receiver operating characteristic curves for comparison of the diagnostic accuracy of myocardial fractional flow reserve (FFR), hyperemic translesional pressure gradient, and resting translesional pressure gradient for predicting the results of the exercise ECG.


*    Discussion
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 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
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{Delta}Prest, {Delta}Pmax, and FFRmyo can be measured in the setting of percutaneous transluminal coronary angioplasty to assess the result of the intervention and in the setting of diagnostic coronary angiography to evaluate the physiological significance of a coronary narrowing. It has been shown that transstenotic coronary pressure gradients can be determined easily and accurately with pressure monitoring guide wires20 26 and that it is possible to calculate FFRmyo from distal coronary and aortic pressures recorded during maximal hyperemia.17 18 FFRmyo is the ratio of myocardial perfusion reached during maximal vasodilatation in the presence of an epicardial coronary stenosis to the myocardial perfusion that would have been reached in the hypothetical case that the epicardial vessel were normal. Practical guidelines for the use of these pressure-derived indexes for clinical decision making have not yet been proposed. The present study establishes threshold values of FFRmyo, {Delta}Pmax, and {Delta}Prest that best predict an abnormal exercise ECG as well as the values of these pressure-derived indexes, which are uniformly associated with the absence of ECG signs of myocardial ischemia during exercise. For FFRmyo, 66% is the value with the highest diagnostic accuracy, ie, the value that provides the best compromise between sensitivity and specificity for predicting an abnormal exercise ECG. More importantly for clinical decision making, no patients were found to have an abnormal exercise ECG when the FFRmyo was >72%. The corresponding values were 31 and 21 mm Hg for {Delta}Pmax and 12 and 2 mm Hg for {Delta}Prest. Our results are consistent with data obtained by Doppler flow velocity measurements. In 20 patients with normal coronary arteries, McGinn et al27 found an average coronary flow reserve value of 4.8, with 3.5 as lowest value (which represents 73%). Similarly, in patients with isolated one-vessel disease, Wilson et al28 found the coronary flow reserve value of 3.5 to best discriminate between patients with a normal and an abnormal exercise ECG.

In addition, the present study also demonstrates that FFRmyo and {Delta}Pmax better predict the results of exercise ECG than merely {Delta}Prest.

Methodological Considerations
Some potential limitations must be considered when interpreting these data. First, pressure-derived indexes were compared with ST-segment changes during exercise ECG as a marker of myocardial ischemia. This may represent a potential limitation, since sensitivity and specificity of exercise ECG for detecting the presence of significant angiographic coronary artery narrowings were found to vary widely,29 reflecting variations in patient selection and exercise test methodology. However, despite these limitations, the provocation of ST-segment depression in response to increased cardiac work is the simplest and most widely accepted test for the documentation of myocardial ischemia in routine clinical practice.30 31 Moreover, the finding of a coronary narrowing at angiography in a patient with chest pain will most often trigger a revascularization procedure if ST-segment depressions are documented during exercise. Therefore, the comparison of transstenotic pressure gradients and of FFRmyo with the occurrence of ST-segment depression during exercise sounds clinically relevant.

Although ST-segment depression on stress ECG reflects the electrical manifestation of ischemia, its specificity could be clouded by the development of similar ECG patterns with nonischemic process. Therefore, in the present study, patients were carefully selected to avoid as many confounding factors as possible, such as left ventricular hypertrophy, influence of digitalis, resting repolarization abnormalities, electrolyte abnormalities, and intraventricular conduction disturbances, all of which are known to affect the specificity of the exercise ECG.29

Likewise, the sensitivity of the exercise ECG can be reported to be lowered by several factors. The intake of antianginal medications is often reported as a factor that lowers the sensitivity of exercise ECG. In the present study, ß-blocking agents, calcium entry blockers, and long-acting nitrates were stopped at least 36 hours before the exercise test. Several authors have emphasized the influence of the extent of coronary artery disease on diagnostic accuracy of noninvasive testing in predicting the presence of coronary artery disease.32 33 34 35 36 In the present study, we restricted ourselves, by design, to patients with single-vessel, single-lesion disease. Only one lesion could, therefore, be held responsible for an abnormal exercise ECG, although in multivessel disease, the lesion responsible for exercise-induced ischemia is often difficult to identify. To minimize this potential selection-induced decrease in sensitivity, only patients with a reference diameter of the LCx or RCA >2.6 mm were studied. This size corresponds to the upper half of a recently reported large cohort of patients undergoing coronary angioplasty.37 Since a clear relation between vessel size and myocardial mass supplied by the artery has been shown,38 the area at risk for exercise-induced ischemia was large enough in the patients of the present study to compensate for the selection of patients with one-vessel disease.

In addition, to limit the number of false-negative exercise ECGs as much as possible, all patients with equivocal results as well as the patients who had a normal exercise ECG but did not reach 85% of the maximal predicted heart rate at peak exercise were excluded from the study. Therefore, because of the rigorous screening of the patients, we believe that in the present study, ST-segment changes occurring during peak exercise can be considered both very sensitive and specific for myocardial ischemia.

Second, the concept of fractional flow reserve assumes that during maximal vasodilatation, myocardial resistance is minimal compared with the resistance related to the epicardial stenosis. This could not be the case in patients with significant impairment of vasodilator capacity. In the latter patients, microvascular disease rather than the epicardial stenosis can be responsible for ST-segment depression during exercise. In this study, the presence of patients with significant dysfunction of the resistive vessels was limited by careful selection of patients with a discrete coronary artery narrowing. However, their presence cannot be excluded, since flow or flow velocities were not measured.

Third, molsidomine was given to all patients to avoid vasospasm during guide-wire manipulations and to standardize the conditions of the stress test and of the pressure measurements as much as possible. Yet, molsidomine could also offset the exercise-induced vasoconstriction.39 Therefore, lesions deemed to be insignificant in the study might become quite significant during exercise without nitrates.

Transmural Flow Reserve Versus Subendocardial Ischemia
ST-segment depression reflects changes in the polarity of myocardial segments based on ischemia-induced disturbances in the electrical state of individual myocytes40 and depends to some extent on the location and the magnitude of abnormal myocardial perfusion.41 Animal experiments have demonstrated that ST-segment elevation occurs only when the flow is reduced by at least 50% and that a general correlation exists between the ST-segment changes and both the magnitude of the flow deprivation and the intramyocardial gas tension, even though wide scatter is observed.42 43 44 45 Ruffy et al46 reported a similar relation between myocardial blood flow and epicardial or endocardial electrogram. Ischemia produced by increased demand was evaluated by pacing tachycardia after ameroïd constriction. A linear relation was found between the magnitude of ST-segment depression and the endocardial/epicardial flow ratio.47 In the present study also, as illustrated in Fig 3Up, a similar correlation was observed between ST-segment depression and pressure-derived indexes. These findings suggest that the intensity of ischemia (rather than the extent of ischemia in terms of area at risk) within a given vascular bed plays a major role in producing the clinical range of ST-segment depression.

Diagnostic Importance of Hyperemic Versus Resting Measurements
Fig 2Up shows a larger overlap between positive and negative exercise ECG as predicted by the {Delta}Prest than by the {Delta}Pmax or by FFRmyo. As illustrated in Fig 5Up, the discriminatory power of FFRmyo and {Delta}Pmax (both obtained during maximal vasodilatation) in predicting the results of the exercise ECG was significantly larger than that of {Delta}Prest. These results emphasize the importance of hyperemic measurements to evaluate the functional repercussions of a coronary stenosis on the underlying myocardium. Under normal circumstances, myocardial resistance and blood flow are fitted to metabolic demand by coronary autoregulation. At rest, the coronary vascular system behaves as a low-flow, high-resistance system in which flow is determined by the peripheral resistance. During maximal exercise or during pharmacological vasodilatation, peripheral resistances in normal individuals decrease by a of factor four to five. In case of epicardial narrowing, flow is determined by resistances in series: the resistance of the coronary stenosis and the resistance of the coronary vascular bed. At rest, the proximal stenosis has to be severe before its resistance exceeds that of the resting coronary vascular bed. Resting blood flow will not be hampered by the narrowing until the lesion reaches approximately 80% diameter stenosis.10 48 In contrast, during maximal vasodilatation, the peripheral resistances are minimal and hyperemic flow is determined mainly by the severity of the narrowing. Accordingly, measurements performed under conditions of resting flow are less sensitive measures of stenosis severity. Since translesional pressure gradient is highly dependent on blood flow, {Delta}Prest is expected to correlate less closely with indexes of exercise-induced ischemia than {Delta}Pmax and FFRmyo, which are both obtained under conditions of minimal myocardial resistance (conditions that are also supposed to prevail during maximal exercise). In addition, from a clinical point of view, making functional measurements of stenosis severity from {Delta}Pmax rather than {Delta}Prest is intuitively reasonable, since the functional capacity and the complaints of patients with ischemic heart disease are determined mainly by the maximal achievable myocardial blood flow rather than by the resting flow.

Clinical Implications
The conclusions of the present study should be limited to patients without left ventricular hypertrophy and with normal systolic function of the territory supplied by the stenosed vessel. In patients with a partially infarcted area, the relation between FFRmyo as derived from pressure measurements and residual reversible myocardial ischemia still needs to be investigated. Nevertheless, the present data obtained in patients with isolated coronary artery stenoses with a broad range of severities establish the values of FFRmyo and of {Delta}Pmax and {Delta}Prest that best discriminate between a normal and an abnormal exercise ECG. In addition, we determined values of FFRmyo and of translesional pressure gradients that are uniformly associated with a normal exercise ECG. The latter is the most widely used diagnostic test to detect myocardial ischemia and to guide the therapeutic choice in a patient with coronary narrowings proven at angiography. Both in the setting of interventional cardiology and in the setting of diagnostic coronary angiography, these cutoff values of pressure-derived indexes should help clinical decision making in cases with questionable angiographic findings. Therefore, coronary pressure measurements during maximal hyperemia could be proposed to warrant coronary interventions when an objective proof of reversible myocardial ischemia is lacking.49 Conversely, the finding of a FFRmyo >72% (or a {Delta}Pmax <21 mm Hg) could avoid unnecessary coronary interventions.


*    Acknowledgments
 
This work was supported by a grant from the Bekales Foundation.

Received September 13, 1994; revision received December 29, 1994; accepted January 9, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Kirkeeide RL, Gould KL, Parsel L. Assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic vasodilation, VII: validation of coronary flow reserve as a single integrated functional measure of stenosis severity reflecting all its geometric dimensions. J Am Coll Cardiol. 1986;7:103-113. [Abstract]
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