Postocclusion Hyperemia Provides a Better Estimate of Coronary Reserve than Intracoronary Adenosine in Patients with Coronary Ar

The physiologic effects of the majority of coronary artery stenosis cannot be determined accurately by conventional angiographic approaches.^1,2 Coronary flow reserve^3,4 (CFR), and, more recently, fractional flow reserve⁵ (FFR) have been proposed for assessment of the functional consequence of coronary lesions and evaluation of coronary angioplasty efficiency.^6,7 In addition, CFR is a useful tool for the diagnosis of coronary microvascular disease.^8,9 Because FFR is the ratio of maximal flow in a stenotic vessel to maximal flow without stenosis, and because CFR is the ratio of maximal-to-basal coronary blood flow, it is of crucial importance for the accuracy of these measurements to achieve maximal coronary vasodilation, i.e., maximal coronary blood flow. In the absence of maximal coronary vasodilation, FFR could be overestimated and CFR could be underestimated, leading to erroneous decisions or diagnosis. Many studies have validated adenosine (ADE) for the measurement of FFR and CFR, however, the appropriate dosage of ADE to achieve maximal coronary vasodilation has been frequently revisited. For example, a bolus of 16 μg intracoronary ADE for the left coronary artery has been shown to be unable to ensure maximal flow in many subjects, and higher doses have been suggested.^10,11 Moreover, it has been shown in dogs that hyperemic responses comparable to those obtained by postocclusion hyperemia (PH) could not be obtained by 100 μg intracoronary ADE.¹²

The aim of the present study was to compare hyperemic responses elicited by intracoronary ADE and PH in terms of their ability to induce maximal coronary blood flow.

Methods

Patient selection. The study group consisted of 10 male patients with stable coronary artery disease for whom coronary angioplasty was scheduled. Patients with myocardial infarction and those with abnormal systolic left ventricular function were excluded. All patients with a history and a concurrent myocardial infarction were excluded due to the fact that PH is depressed or abolished in an artery upstream from an infarcted area. Patients with triple-vessel disease, complex stenosis or a stenosis located on a bifurcation were also excluded. The decision for the procedure was made immediately after the coronary stenosis was visually assessed by two reviewers.

The study protocol was approved by the ethics committee of Saint Germain-en-Laye Hospital. Signed informed consent was obtained from all of the patients.

Procedure. After local anesthesia and insertion of an arterial sheath, diagnostic catheterization and coronary angiography were performed. Next, a 6 Fr guiding catheter was positioned into the coronary ostium of the artery to be dilated. Dilatation of the coronary artery was achieved using an intracoronary 1 mg bolus of linsidomine. A 0.014 inch FloWire Doppler flow probe (Volcano Therapeutics, Inc.,Rancho Cordova, California) was advanced across the stenosis into the distal part of the vessel in order to obtain an adequate signal, and an angioplasty catheter was positioned in the coronary artery to be dilated just upstream from the coronary stenosis. The patient’s heart rate and aortic pressures recorded by the guiding catheter were continuously measured.

Coronary flow and resistance reserve. Coronary hyperemia was achieved in each patient by intracoronary injection of a 60 μg bolus of ADE, and PH was obtained by occlusion of the coronary artery for 30 seconds with the angioplasty catheter. Occlusion was obtained by inflating the balloon at 3 bars (~ 3 atm) and verified by the absence of flow detected by the flow probe. Each measurement was made in duplicate and after return of flow velocity to the baseline value, and ADE or PH measurement order was randomized. Measurements were made before and after PTCA (Figure 1).

Coronary flow reserve was calculated as the average peak-to-resting coronary blood flow velocity (each point was the mean of the 2 measures). In order to account for changes in coronary perfusion pressure due to adenosine or coronary occlusion, coronary reserve was also estimated through the coronary resistance reserve (CRR), calculated as [resting mean aortic pressure/coronary flow velocity]/[mean aortic pressure at peak velocity/peak coronary flow velocity].

Statistical analysis. Data are presented as mean ± standard deviation. Statistical analysis was performed using the Student’s paired t-test. ANOVA for repeated measures for experimental condition factor, followed by the Fisher’s protected least-significance difference test, were used for multiple comparisons. Linear regression analysis was used to analyze ADE and PH relationships. Probability values < 0.05 were considered statistically significant.

Results

Clinical characteristics of the 10 patients are presented in Table 1. The procedure was achieved mainly on left anterior descending coronary artery and percent stenosis was ≥ 80% in all patients.

Systemic and coronary hemodynamics. Heart rate and aortic pressures were not significantly modified either by intracoronaryADE or during PH (Table 2). Despite the fact that after PTCA, baseline average peak velocity was increased and baseline coronary resistance was reduced, there were no significant differences between baseline pre-ADE and precoronary occlusion values before or after PTCA (Table 2).

Average flow velocity at peak hyperemia before PTCA was comparable with ADE and with PH; minimal coronary resistance at peak hyperemia was also comparable (Table 2). After PTCA, average peak velocity at peak hyperemia was significantly higher and minimal coronary resistance was significantly lower after coronary occlusion compared to after intracoronary ADE (Table 2). We did not observed anystatistical differences between PH and ADE responses between the left anterior descending and circumflex coronary arteries possibly because there were only 7 left anterior descending and 3 circumflex coronary arteries assessed in this study. However, we have always observed that flow is higher after PH than after ADE.

Coronary flow reserve and coronary resistance reserve. Before PTCA, CFR was higher with PH than with ADE in only 4/10 patients, and although there was a trend for CFR to be lower after intracoronary ADE than after coronary occlusion (-8 ± 13%), values were not statistically different (Figure 2). On the contrary, CRR was higher with PH than with ADE in 9/10 patients, and CRR was significantly higher with PH than with ADE (Figure 2), which underestimated CRR by 16 ± 13%. The differences were dramatically increased after PTCA (Figure 2), CFR being underestimated by 23 ± 10% and CRR being underestimated by 24 ± 10% with ADE, and both CFR and CRR were higher in all the patients with PH. Although there was a good correlation between the values obtained by intracoronary adenosine and coronary occlusion for CFR and CRR (Figure 3), the greater the CFR and CRR, the greater the differences between the values (Figure 3). Thus, the mean difference between the two methods for CFR (ADE-PH) was -0.16 ± 0.26 before PTCA (range -0.58 to +0.15), and -0.78 ± 0.36 after PTCA (range - 1.35 to +0.25). For CRR, the mean difference between the two methods was -0.40 ± 0.40 before PTCA (range -1.17 to +0.14), and –0.88 ± 0.51 after PTCA (range -0.41 to 1.96).

Discussion

This is the first study comparing the effects of intracoronary adenosine and complete coronary occlusion for theinduction of coronary hyperemia in CFR and CRR evaluation in humans with coronary artery stenosis. The results show that intracoronary ADE administered at a dose of 60 μg is less efficient than 30-second coronary occlusion at increasing coronary blood flow. These results suggest that the use of ADE, even at a high dosage, might lead to underestimation of coronary stenosis severity and misinterpretation of the results of coronary interventions.

Intracoronary adenosine versus postocclusion hyperemia for coronary vascular reserve evaluation. Adenosine is currently used for the evaluation of coronary vasodilator reserve^10,13 and FFR.^5,14 Coronary vasodilation obtained by this compound has been demonstrated to be as potent as intracoronary papaverine.^10,13,14 However, the accuracy of the results depends on the ability of ADE to elicit maximal vasodilation and it has been shown that the first tested doses of ADE (12 μg for the right coronary artery, and 16 μg for the left coronary artery) result in less dilation than intracoronary papaverine.¹⁰ Thus, it has been suggested that to ensure maximal vasodilation, the doses should be doubled.¹¹ Recently, it has been shown that 40 μg intracoronary ADE provided similar coronary vasodilation to 20 mg of intracoronary papaverine¹⁵ and it has been suggested that in patients with coronary artery disease, a decreased sensibility of the vessels to ADE could minimize the vasodilator effect. Lastly, increasing the dosage of ADE may have side effects, the most severe of which is atrioventricular block, especially when ADE is injected into the right coronary artery.¹⁶

It is well known that coronary occlusion is followed by a reactive hyperemia³ that is maximal after 15-second occlusionin humans.¹⁷ A recent study in dogs demonstrated that 30- second coronary occlusion yielded a better hyperemic response than high doses intracoronary of adenosine triphosphate or ADE (100 μg). These results suggest that even very high doses of ADE may not be able to maximally dilate the coronary circulation.¹² In another study conducted on 6 anesthetized minipigs (unpublished data), we found that a minimum of 300 μg intracoronary adenosine was able to produce minimal coronary resistance and CFR comparable to PH. Our results are in accordance with the fact that high doses of intracoronary ADE are less efficient than coronary occlusion in producing maximal hyperemia. These differences between ADE and coronary occlusion could not result from differences in pressure changes during hyperemia, pressure drop being comparable with ADE and with PH (Table 2). Moreover CRR, which takes into account pressure changes, show that underestimation of coronary reserve with ADE is independent of pressure changes.

Another important finding from our data is that the greater the coronary reserve, the greater the difference between ADE and PH, both for CFR and CRR. Before PTCA, coronary reserve was higher with PH than with ADE only when changes in aortic pressures were taken into account, showing that CRR was a more sensitive method for evaluation of coronary reserve than CFR. After PTCA, both CFR and CRR were significantly lower with ADE than with PH.

Study Limitations

Although we used higher doses of ADE in this study than those currently recommended, it is still possible that a 60 μg bolus is not sufficient to maximally vasodilate the coronary microcirculation. Whether higher doses of adenosine could produce more vasodilation, like in dogs or in pigs, without any complication in humans, is unknown. On the other hand, PH can be achieved only in patients for whom a coronary angioplasty is scheduled. For ethical considerations, this technique cannot be used to explore coronary microvascular diseases such as arterial hypertension or diabetes.

Inflation of a balloon in a coronary artery, even at low pressure, could induce transient endothelial dysfunction. The possibility exists that this maneuver could result in endothelial damage, as well as the progression of the guidewire and the angioplasty catheter sliding into the coronary artery. Despite this possibility, no stent coverage for the ballooned segment was considered, and no long-term complications were observed.

Summary and Clinical Implications

In humans, coronary reserve evaluated either by CFR or CRR seems to be higher with PH than with ADE, even when high doses of ADE are used. This could represent a potential source of error in the coronary reserve measurements, resulting in an underestimation of the consequences of a coronary stenosis on myocardial perfusion, especially those of moderate coronary artery stenoses. Moreover, the greater the maximal coronary blood flow, the greater the underestimation with ADE. Thus, post-PTCA evaluation could miss residual stenosis in some patients, and a “normal” FFR after angioplasty might not actually be “normal” if maximal flow is not reached. Because PH produces higher flow than intracoronary ADE, it could improve the sensitivity of assessing and detecting the hemodynamic consequence of a coronary stenosis on maximal coronary blood flow. However, further studies are needed to examine whether higher doses of intracoronary adenosine could provide higher values of maximal coronary flow and be safely used in humans.

References

1. White CW, Wright CB, Doty DB, et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984;310:819–824.

2. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995;92:2333–2342.

3. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:87-94.

4. Wilson RF, Johnson MR, Marcus ML, et al. The effect of coronary angioplasty on coronary flow reserve. Circulation 1988;77:873–885.

5. Pijls NH, Van Gelder B, Van der Voort P, et al. Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92:3183–3193.

6. Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous coronary angioplasty. Circulation 1993;87:1354–1367.

7. Pijls NHJ, Klauss V, Siebert U, et al. Coronary pressure measurement after stenting predicts adverse events at follow-up: A multicenter registry. Circulation 2002;105:2950–2954.

8. Hoffman JIE. Maximal coronary flow and the concept of coronary vascular reserve. Circulation 1984;70:153–159.

9. Nitenberg A, Antony I. Coronary vascular reserve in humans: A critical review of methods and of interpretation of the results. Eur Heart J 1995;16(Suppl I):7–21.

10. Wilson RF, Wyche K, Christensen BV, et al. Effects of adenosine on coronary arterial circulation. Circulation 1990;82:1595–1606.

11. Marzili M, Klassen GA, Maraccini P, et al. Coronary effects of adenosine in conscious man. Eur Heart J 1989;10F:78–81.

12. Jeremias A, Filardo SD, Witbourn RJ, et al. Effects of intravenous and intracoronary adenosine 5’-triphosphate as compared with adenosine on coronary flow and pressure dynamics. Circulation 2000;101:318–323.

13. Kern MJ, Deligonul U, Tatieni S, et al. Intravenous adenosine: Continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease. J Am Coll Cardiol 1991;18:718–729.

14. van der Voort PH, van Hagen E, Hendrix G, et al. Comparison of intravenous adenosine to intracoronary papaverine for calculation of pressure-derived fractional flow reserve. Cathet Cardiovasc Diagn 1996;39:120–125.

15. De Bruyne B, Pijls NHJ, Barbato E, et al. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877–1883.

16. Cerqueira MD, Verani MS, Schwaiger, et al. Safety profile of adenosine stress perfusion imaging: Results from the Adenoscan Multicenter Trial Registry. J Am Coll Cardiol 1994;23:384–389.

17. Marcus M, Wright C, Doty D, et al. Measurements of coronary velocity and reactive hyperemia in the coronary circulation in humans. Circ Res 1981;49:877–891.