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(Circulation. 1995;92:342-347.)
© 1995 American Heart Association, Inc.

Articles

Relation Between Diastolic Perfusion Time and Coronary Artery Stenosis During Stress-Induced Myocardial Ischemia

Giuseppe Ferro, MD; Carlo Duilio, MD; Letizia Spinelli, MD; Giovanni Antonio Liucci, MD; Felice Mazza, MD; Ciro Indolfi, MD

From the Department of Internal Medicine, Division of Cardiology, Federico II University, Naples, Italy.

Correspondence to Giuseppe Ferro, MD, Via Pezzullo 30, 80027 Frattamaggiore, Naples, Italy.

	Abstract

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Background Experimental studies have demonstrated that during stress-induced myocardial ischemia, coronary obstruction and diastolic perfusion time are factors that limit subendocardial perfusion and correlate to degree of myocardial dysfunction. The relation between these two factors has not yet been investigated in humans. The aim of the present study was to assess the relation between diastolic perfusion time and degree of coronary stenosis during different types of stress tests.

Methods and Results Nine patients with isolated and proximal stenosis of the left anterior descending coronary artery were selected. Patients underwent three different randomized stress tests (upright, supine bicycle stress test, and transesophageal atrial pacing). Diastolic perfusion time, heart rate (RR interval), and systolic and diastolic pressures were measured during the test and at the ischemic threshold (0.1-mV ST-segment depression). Angiographic measurements of coronary stenosis were evaluated by quantitative coronary angiography. At the ischemic threshold, significant differences among tests were found in heart rate (P<.05), systolic pressure (P<.001), and diastolic pressure (P<.05). In each stress test, diastolic perfusion time at the ischemic threshold was closely correlated with minimal stenosis diameter (r=.97; P<.001) and percent diameter stenosis (r=.92; P<.001) with no difference among the tests. In contrast, heart rate, rate-pressure product, and time to ischemic threshold were not significantly correlated with percent diameter stenosis and minimal stenosis diameter. No significant correlation was observed at the ischemic threshold between diastolic perfusion time and corresponding values of heart rate, despite the close correlation at rest (r=.95; P<.001).

Conclusions Despite differences in associated hemodynamic responses to various stress tests, a close relation exists between stenosis severity and diastolic perfusion time at the onset of stress-induced myocardial ischemia. Therefore, diastolic perfusion time at the ischemic threshold may be an indirect estimate of the hemodynamic significance of coronary stenosis.

Key Words: perfusion • myocardium • stress • stenosis • ischemia

	Introduction

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Coronary obstruction is one factor that limits subendocardial perfusion during stress tests.¹ In experimental models of critical coronary stenosis² or reduced coronary perfusion pressure,³ subendocardial blood flow decreases below the resting value during stress tests. Subepicardial blood flow may increase, whereas transmural blood flow remains unchanged,^{2 3} and regional myocardial function decreases in proportion to the level of subendocardial perfusion.¹ The decrease in subendocardial blood flow and the increase in subepicardial blood flow suggest a retrograde pumping of blood from the deep layer to the superficial layer of the left ventricle.³ This could account for the susceptibility of subendocardium to ischemia compared with subepicardium³ and for ST-segment depression on ECG.⁴

Evidence exists that subendocardial perfusion occurs during the diastolic period.⁵ In the absence of coronary stenosis and myocardial hypertrophy, coronary blood flow increases proportionally as diastolic perfusion time decreases during stress tests.^{6 7 8} This is due primarily to a decrease in coronary vascular resistance,^{6 7} which maintains uniform net transmural perfusion even if a marked reduction in diastolic perfusion time or higher heart rates are achieved.^{3 5} In the presence of coronary artery obstruction, the compensatory mechanism, caused by coronary vasodilation, was observed only at low workload⁷ or in the presence of mild coronary stenosis^{8 9} and may be absent in the presence of severe coronary stenosis.^{8 9 10} Therefore, it is likely that during stress tests, when coronary vasodilation is maximal, myocardial ischemia could depend primarily on a decrease in diastolic perfusion time. In fact, after maximal coronary vasodilation^{5 11} or reduced coronary perfusion pressure,³ a close relation between the decreases in diastolic perfusion time and in subendocardial perfusion was reported.

The relation between diastolic perfusion time and coronary stenosis has not yet been investigated in humans. The aim of the present study was to assess the relation between diastolic perfusion time at the onset of stress-induced myocardial ischemia and coronary stenosis severity. Stress tests, including atrial pacing and exercise, performed with patients in the supine and upright positions enabled study of influence of different hemodynamic responses on the relation between diastolic perfusion time and stenosis severity.

	Methods

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Patient Selection
Nine selected coronary artery disease patients (eight men, one woman; mean age, 55±5 years) were included in the study. Each patient had to have an isolated proximal to the first septal branch lesion of the left anterior descending coronary artery without visible collateral circulation at coronary angiography. They were selected according to the following criteria: history of stress-induced ischemia, no previous myocardial infarction, significant ST-segment depression (0.1 mV) during the stress test, negative response to the ergonovine test, no valvular disease, and no hypertension or left ventricular hypertrophy. Informed consent was obtained from all patients before study.

Study Protocol
All drugs were withdrawn 1 week before and for the whole period of the study. Only aspirin and sublingual nitroglycerin, when needed, were allowed during the study. Patients underwent three randomized stress tests: upright bicycle exercise, supine bicycle exercise, and atrial pacing. All stress tests were performed in the morning (9 AM to 12 noon) with at least a 3-day interval between different tests. The exercise stress test was begun with an initial workload of 50 W and was increased by 20 W every 2 minutes until ischemic threshold was achieved (0.1-mV ST-segment depression). The atrial pacing test, performed with an electrocatheter in the esophagus, started with an initial rate of 100 beats per minute (bpm) and increased by 10 bpm every 2 minutes until the ischemic threshold was achieved (0.1-mV ST-segment depression). Only one patient started the pacing test at 140 bpm because of emotional high resting heart rate. At rest and during the stress tests, three ECG leads were monitored continuously. A computer-assisted system (CASE Marquette, Marquette Electronics) was used to calculate the ST-segment depression on signals averaged over 12 seconds at 80 milliseconds after the J point. An ECG lead and phonocardiogram (microphone positioned on the centrum cordis) were recorded at a paper speed of 100 mm/s (Irex II system, Irex Medical Systems). The recordings were performed at rest, at each stage of the stress test, and at ischemic threshold. Two observers read the recordings in an independent and blind fashion. The results of these readings were averaged, and mean values were used in the statistical analysis of our data. Blood pressure was measured by a standard cuff sphygmomanometer in patients at rest, at each stage of the stress test, and at ischemic threshold.

Quantitative Coronary Angiography
Coronary angiography was performed with a 6- to 8-mL injection of nonionic contrast medium (Omnipaque 350, Winthrop-Breon Laboratories). Cineangiograms were recorded with a Siemens radiographic system at a rate of 50 frames per second. End-diastolic cine frames were blindly videodigitized and stored in the image analysis system (Mipron, Kontron Electronics) in a 512x512 matrix with 8-bit gray scale with a 12-cm field of view, resulting in a pixel density of 7.3 pixels per square millimeter. Automatic vessel segment contour detection was performed by a geometric edge differentiation technique by use of a previously described method.¹² After interactive determination of a centerline within the vessel, the computer automatically generated a number of scan lines perpendicular to the centerline. The first and second derivative functions of densograms along each scan line were then computed, with the contour point defined as 70% of the distance between the extreme of the first and second derivatives. Using the detection contour points, the computer then automatically generated a refined centerline of the vessel segment, and the edge detection algorithm was repeated. Each individual scan line was smoothed by a second-order polynomial fit. The contour was smoothed by averaging three neighboring scan lines. The diameter of the guiding catheter in the field of view was used to convert imaging data from pixel to millimeters.¹² Quantitative angiographic measurements, ie, minimal stenosis diameter and percent diameter stenosis, were determined from the analysis of cine films of 11 Plexiglas blocks with precision-drilled models of coronary arteries filled with contrast medium. The normal arterial size was obtained on the basis of the computed centerline at the 90th percentile of the diameter values from a first-degree polynomial computed through the diameter values of the proximal and distal portions of the arterial segment followed by a translation to the 80th percentile level. The intraobserver variability of angiographic measurements in our system was determined previously by a pilot study. The mean (±SD) intraobserver variability (determined by repeated analysis of cineangiograms by a single observer) was 2.3±1.8%.¹²

Data Analysis
Diastolic perfusion time, RR interval, and blood pressures were measured at rest, at each stage of the test, and at 0.1-mV ST-segment depression. Time to ischemic threshold in each stress test was also evaluated. Values of diastolic perfusion time, expressed as seconds per minute, represent the mean of at least five consecutive measurements and were calculated by the formula [(RR)-(S₁-S₂)]xheart rate, where RR represents the interval between two consecutive R waves on the ECG and S₁-S₂ represents the interval between the first high-frequency component of the first heart sound (S₁) and the aortic component of the second heart sound (S₂). Results of these readings were averaged, and the mean values were used in the statistical analysis of our data.

Statistical Analysis
In each stress test, resting and ischemic threshold values of RR interval and systolic and diastolic pressures were compared by use of the paired t test. Comparison among mean values of each parameter at rest and at ischemic threshold during various stress tests was evaluated by one- and two-way ANOVA for independent samples. When a significant overall difference was detected, a Tukey test was used; P<.05 was considered significant.

Ischemic threshold values of RR interval, diastolic perfusion time, systolic and diastolic pressures, rate-pressure product, and time to 0.1-mV ST-segment depression were used as independent variables in a multiple regression analysis, with the percent diameter stenosis or minimal stenosis diameter as the dependent variable. Multiple comparison of the linear regression lines obtained, correlating the diastolic perfusion time versus RR interval, percent diameter stenosis, and minimal stenosis diameter in each stress test, was performed as suggested by Brownlee.¹³

	Results

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Table 1 gives clinical and angiographic data. Values of percent diameter stenosis and minimal stenosis diameter ranged from 40% to 95% and from 0.5 to 1.76 mm, respectively.

View this table: [in this window] [in a new window]   Table 1. Clinical and Angiographic Data of the Patients

Table 2 lists the values of RR interval, diastolic perfusion time, and systolic and diastolic pressures at rest, at each stage of the tests, and at ischemic threshold. At ischemic threshold, the RR interval decreased significantly (P<.001) in all stress tests, with a significant difference (P<.05) between supine exercise and atrial pacing. Systolic and diastolic pressures increased significantly (P<.001) during both exercise tests and were significantly higher than those observed during atrial pacing. No significant changes in blood pressure were observed during atrial pacing tests (Fig 1).

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Data With Patients at Rest, During Tests, and at Ischemic Threshold

View larger version (22K): [in this window] [in a new window]   Figure 1. Bar graphs showing the comparison among RR interval, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in patients at rest and at ischemic threshold during various stress tests. Each value represents the mean±SD. *P<.05, **P<.001 versus pacing; +P<.001 versus rest. Solid bar indicates upright exercise; dotted bar, supine exercise; and stippled bar, atrial pacing.

At the ischemic threshold, the multiple regression analysis performed for each stress test among all the parameters showed that only the diastolic perfusion time was significantly correlated with the degree of coronary stenosis. A close linear relation was found between diastolic perfusion time and minimal stenosis diameter in upright exercise (y=35.6-5x; r=.97; P<.001), supine exercise (y=35.5-5.1x; r=.97; P<.001), and pacing (y=35.3-4.8x; r=.97; P<.001), as well as between diastolic perfusion time and percent diameter stenosis in upright exercise (y=23.4+0.1x; r=.92; P<.001), supine exercise (y=23.3+0.1x; r=.92; P<.001), and pacing (y=23.6+0.1x; r=.93; P<.001) with no difference in tests (Fig 2, bottom). In contrast, in each stress test, RR interval (Fig 2, top), systolic and diastolic pressures, rate-pressure product, and time to 0.1-mV ST-segment depression were not significantly correlated with the degree of coronary stenosis.

View larger version (23K): [in this window] [in a new window]   Figure 2. Scatterplots showing the relation of diastolic perfusion time and RR interval to minimal stenosis diameter and percent diameter stenosis in patients during upright exercise (), supine exercise (), and atrial pacing test ().

Fig 3 shows the relation between diastolic perfusion time and corresponding values of RR interval at rest and in each stress test. Resting values of diastolic perfusion time in each stress test were closely correlated with the corresponding RR interval (y=23.95+0.014x; r=.95; P<.001). A linear correlation was also found between RR interval and diastolic perfusion time in upright exercise (y=22.1+0.17x; r=.53; P<.01), supine exercise (y=24.8+0.09x; r=.48; P<.05), and pacing (y=17.7+0.27x; r=.73; P<.001). The overall comparison of relation between RR interval and diastolic perfusion time among the different tests showed a significant difference in slope (P<.05). Moreover, ischemic threshold values of diastolic perfusion time were not significantly correlated with the corresponding values of RR interval in each stress test.

View larger version (21K): [in this window] [in a new window]   Figure 3. Scatterplots showing the relation between R-R interval and diastolic perfusion time in patients at rest (top) and during upright exercise (), supine exercise (), and atrial pacing test () (bottom).

	Discussion

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The major finding of the present study is the close relation between diastolic perfusion time at ischemic threshold and degree of coronary stenosis. The associated hemodynamic response to various stresses does not affect the relation between diastolic perfusion time and degree of coronary stenosis but significantly influences the relation between heart rate and diastolic perfusion time in each stress test.

Previous studies demonstrated that the degree of coronary stenosis is related to systolic flow reverse^{14 15 16} and is associated with a drop in diastolic subendocardial flow,^{3 14} according to the theory of systolic-diastolic interaction.¹⁷ This mechanism is enhanced when diastolic time decreases, as during a stress test, and may explain the failure of nitroglycerin to relieve pacing-induced angina.¹⁸ The significance of diastolic perfusion time as a determinant of subendocardial perfusion has been well demonstrated in experimental studies.^{5 19 20}

Our data indicate that diastolic perfusion time and degree of coronary stenosis strictly interact in the complex mechanism underlying stress-induced myocardial ischemia. Diastolic perfusion time at the ischemic threshold is closely correlated with minimal stenosis diameter and percent diameter stenosis, regardless of stress performed. This suggests that during a stress test, when the compensating mechanism caused by coronary vasodilation is exhausted, myocardial ischemia becomes dependent primarily on the interaction between the reduction of diastolic perfusion time and the degree of coronary stenosis. Previous studies demonstrated that during a stress test, the magnitude of the compensating mechanisms^{9 20} and the fall of coronary perfusion pressure throughout the stenosis depend on the severity of stenosis.^{9 10 17 21 22 23} Our results show that in patients with a marked reduction of the coronary lumen diameter (<1 mm), regardless of the type of stress test, a small reduction in diastolic perfusion time can induce the outcome of ECG signs of myocardial ischemia, suggesting that the compensating mechanism of subendocardial perfusion is quickly exhausted. In contrast, in patients with a minor narrowing of the coronary vessel (>1 mm), a large decrease in diastolic perfusion time (<30 s/min) is needed to induce myocardial ischemia, suggesting that the compensating mechanism of the subendocardial perfusion is exhausted later than in patients with reduced coronary lumen diameter. Thus, in our selected population, diastolic perfusion time at the ischemic threshold predicts the hemodynamic significance of the coronary stenosis.

Factors such as systemic arterial pressures^{24 25} and ventricular diastolic pressure²⁶ could play a role in the mechanisms underlying stress-induced myocardial ischemia. The end-diastolic left ventricular pressure, which varies according to the type of stress,^{27 28 29} may affect subendocardial perfusion.²⁶ However, during exercise-induced myocardial ischemia³⁰ or resting myocardial ischemia,³¹ an increase in subendocardial perfusion was observed, despite an elevated end-diastolic ventricular pressure. Changes in systemic arterial pressure may also influence the outcome of myocardial ischemia.^{24 25} Nevertheless, it has been demonstrated that the sudden increase in mean arterial pressure does not affect coronary flow reserve.^{32 33} The fact that the type of stress test does not affect the relation between diastolic perfusion time and the degree of coronary stenosis, despite the differences in hemodynamic responses to exercise tests and atrial pacing, suggests that these factors may have a slight influence on the mechanisms underlying stress-induced myocardial ischemia.

Our results also show that there is not a significant correlation between heart rate at the ischemic threshold and the degree of coronary stenosis. A previous study from our laboratory demonstrated that diastolic perfusion time correlates with signs of stress-induced myocardial ischemia better than heart rate in patients with coronary artery disease.³⁴ Similar data were observed in exercising dogs.³⁵ The close correlation of diastolic perfusion time, despite the insignificant correlation of heart rate, to the degree of coronary obstruction is not surprising. Two factors determine the value of diastolic time: heart rate and systole duration. A close relation between heart rate and diastolic perfusion time was found at rest,³⁶ indicating that the at-rest heart rate is the main determinant of diastolic duration. Our data demonstrated a close correlation between heart rate and diastolic perfusion time during rest, a weak correlation during stress tests, and no correlation at the ischemic threshold. Moreover, it should be pointed out that for a given heart rate, the decrease in diastolic perfusion time is more marked in supine than in upright exercise and even more notable in exercise than in atrial pacing. This significant difference results because left ventricular loading conditions and sympathetic nervous system activity differ considerably in the various stress tests.^{27 28 29 37} These factors, operating on systole duration, change the relation between diastolic perfusion time and heart rate considerably during various stress tests, primarily at the ischemic threshold. In fact, it has been demonstrated that not only heart rate but also age,³⁸ sex,³⁹ preload,⁴⁰ afterload,⁴¹ myocardial inotropism,⁴⁰ and catecholamines⁴² can produce changes in systolic duration and consequently in diastolic perfusion time. This explains why, during the various stress tests, heart rate does not reflect actual values of diastolic perfusion time in our selected population. The primary role of diastolic perfusion time in determining stress-induced myocardial ischemia^{34 35} and in predicting the hemodynamic significance of coronary stenosis may depend on the fact that this parameter, expressed as seconds per minute, indicates the total amount of diastole (ie, supply) relative to that of systole (ie, demand) in a minute. Thus, diastolic perfusion time could address not only the supply side but also the demand side in a minute.

Contrary to the common belief that angiographic stenosis of coronary arteries is well correlated with functional capacity,⁴³ the rate-pressure product and time to ischemic threshold did not correlate with the degree of coronary obstruction in our patients. A recent study also demonstrated that in a large population of patients with single-vessel coronary disease, exercise duration and the rate-pressure product were poorly correlated with minimum lumen diameter and percent diameter stenosis.⁴⁴

Study Limitations and Advantages
This study was designed to assess the relation between two important determinants of stress-induced myocardial ischemia. The measurements of subendocardial blood flow and coronary pressure gradient distal to the stenosis would be desirable in evaluations of the precise mechanisms operating during stress-induced myocardial ischemia. However, the technique used to measure subendocardial blood flow is not yet available in humans; the technique to measure coronary perfusion pressure is available but not applicable during exercise in humans. The traditional visual criteria for determining severity of coronary artery disease suffer from considerable interobserver and intraobserver variability.^{45 46} In contrast, the assessment of coronary stenosis with a computerized quantitative technique may provide a reliable method of assessing the degree of coronary stenosis,¹² particularly the minimal lumen diameter, that correlates with coronary flow reserve.⁴⁷ Finally, the measurement of diastolic perfusion time by phonomechanocardiographic recordings is a reliable noninvasive technique³⁶ that also can be used during exercise.³⁴

Received October 19, 1994; revision received January 4, 1995; accepted January 17, 1995.

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