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(Circulation. 1997;95:1799-1805.)
© 1997 American Heart Association, Inc.

Articles

Nitroglycerin-Augmented ²⁰¹Tl Reinjection Enhances Detection of Reversible Myocardial Hypoperfusion

A Randomized, Double-Blind, Parallel, Placebo-Controlled Trial

Zuo-Xiang He, MD; Rafael Medrano, MD; John T. Hays, MD; John J. Mahmarian, MD; Mario S. Verani, MD

From the Section of Cardiology, Baylor College of Medicine, and the Methodist Hospital, Houston, Tex.

Correspondence to Mario S. Verani, MD, Baylor College of Medicine and The Methodist Hospital, 6550 Fannin, SM-677, Houston, TX 77030. E-mail mverani{at}bcm.tmc.edu

	Abstract

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Background Recent observations suggest that administration of nitrates before ²⁰¹Tl reinjection enhances the detection of reversible myocardial hypoperfusion.

Methods and Results Ninety-six patients who underwent exercise-redistribution ²⁰¹Tl single photon emission computed tomography (SPECT) and had persistent defects at 4-hour redistribution imaging were prospectively randomized into a double-blind protocol in which they received a reinjection of ²⁰¹Tl (1.0 mCi) 5 minutes after either placebo or 0.8 mg sublingual nitroglycerin administration, followed by repeat SPECT imaging. Of the 69 patients who had coronary angiography, all except one had significant coronary stenoses. The overall extent of perfusion defect and the reversible component assessed by polar maps of the stress-redistribution images were similar in patients who received nitroglycerin or placebo. Among the 66 patients with persistent defects in the redistribution images, 58% of those receiving nitroglycerin showed improved reversibility after reinjection, compared with 33% of patients receiving placebo (P<.05). Among 68 patients with significant coronary stenoses, those who received nitroglycerin and had coronary collateral circulation were more likely to exhibit improved reversibility after reinjection than the remaining patients (50% versus 21%, P<.05). Moreover, the ratio of reversible to total defect in the vascular territories supplied by collaterals was 0.50 after reinjection in 80% of patients who received nitroglycerin (n=20) compared with 40% of the patients who received placebo (n=15) (P<.05).

Conclusions Nitrate-augmented ²⁰¹Tl reinjection significantly, albeit modestly, improves detection of defect reversibility, especially in patients with coronary collateral circulation.

Key Words: coronary disease • nitroglycerin • myocardium • tomography

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Several radionuclide techniques have recently been proposed for evaluating myocardial viability.^{1 2 3 4 5 6 7 8 9 10} Among them, [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) imaging by positron emission tomography (PET) appears to be the most accurate,^{3 5 9 10} but its broader clinical use is hampered by the high cost of this technology, and it is thus unlikely to be widely used in the near future. Single photon emission computed tomography (SPECT) with ²⁰¹Tl is slightly less accurate than imaging with [¹⁸F]FDG for detecting viable myocardium,^{11 12} but it is more widely available and hence has greater potential clinical utility.

Previous studies have shown that reinjection of ²⁰¹Tl can improve detection of myocardial viability.^{13 14 15} Myocardial perfusion defects that improve after reinjection also predict improved wall motion after revascularization,^{13 14 15} thus confirming that these areas contain hypoperfused yet viable myocardium. However, as many as 30% of myocardial segments that fail to improve after ²⁰¹Tl reinjection may also be metabolically active by PET imaging^{16 17 18} and thus still have the potential to improve after revascularization.^{3 5 9 10}

More recent studies have demonstrated that administration of nitrates can improve detection of reversibility by ²⁰¹Tl^{19 20 21} as well as ^99mTc-labeled sestamibi^{22 23 24 25 26} and teboroxime²⁷ SPECT imaging. In two pilot reports, nitrate administration before ²⁰¹Tl reinjection led to improved detection of reversible hypoperfusion compared with reinjection alone.^{19 21} Both of these reports included only a small number of patients, and both used only a visual, qualitative analysis.^{19 21}

The present study was designed to evaluate whether nitroglycerin administration preceding the reinjection of ²⁰¹Tl improves detection of defect reversibility. Moreover, we assessed whether the presence of collateral circulation to hypoperfused myocardium modulates enhanced ²⁰¹Tl uptake after nitroglycerin administration.

	Methods

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Study Protocol
This was a single-center, prospective, randomized, double-blind, parallel, placebo-controlled study. Patients who had a ²⁰¹Tl perfusion defect size 5% of the left ventricle at initial postexercise SPECT and who showed either lack of redistribution or only partial redistribution in the 4-hour redistribution images were included. Patients with significant valvular disease or intolerance to nitrates were excluded.

Patients were weaned from any nitrate preparations at least 24 hours before the exercise testing and were then randomized into a double-blind protocol to receive 1 mCi of ²⁰¹Tl 5 minutes after either placebo (two doses 5 minutes apart) or 0.8 mg (0.4 mg followed by 0.4 mg 5 minutes later) sublingual nitroglycerin. The second dose of placebo or nitroglycerin was not given if the heart rate increased by 10 bpm or the blood pressure decreased by 10 mm Hg after the first dose. SPECT imaging was repeated 10 minutes after ²⁰¹Tl reinjection.

Exercise Testing
All patients underwent a symptom-limited treadmill exercise test according to the Bruce protocol. Blood pressure, heart rate, and 12-lead ECG were recorded before and every minute during exercise. ²⁰¹Tl (3.0 mCi) was injected intravenously at peak exercise, and the patients were encouraged to continue to exercise for an additional 60 seconds.

Imaging Acquisition and Reconstruction
Myocardial SPECT was performed according to the technique previously reported from our institution.^{28 29 30} Images were acquired with a large-field-of-view single-crystal rotating gamma camera equipped with a high-resolution, parallel-hole collimator. Projection data containing 32 frames were acquired over a 180° arc from the 45° left posterior oblique view to the 45° right anterior oblique view. Myocardial transaxial tomograms were reconstructed with a filtered backprojection algorithm with a Butterworth filter (cutoff frequency of 0.50 and order 5) and then reoriented into short-axis, horizontal-long-axis, and vertical-long-axis views.

Computer Quantification of Myocardial Tomograms
Extent of stress defects and persistent and reversible fractions. Initial 4-hour redistribution and reinjection polar maps were independently generated and normalized by a circumferential profile technique, as previously described.^{28 29 30} The reversibility polar maps were generated by subtracting the initial polar maps from the 4-hour redistribution and reinjection polar maps on a pixel-by-pixel basis. The raw polar maps for each patient were compared with a normal exercise data bank to determine the total left ventricular perfusion defect size and the extent of persistent and reversible components expressed as a percentage of the left ventricle. The vascular territories of the three major coronary arteries were assigned as previously reported.³⁰ The overall perfusion defect size and the extent of persistent and reversible components on each specific vascular territory were computer-determined. The change in the extent of reversibility from the 4-hour redistribution to the reinjection images was calculated as the absolute difference between the amount of reversibility at reinjection and that in the 4-hour redistribution polar maps.

Ratio of reversible to total defect size. The ratio of reversible to total defect size was calculated in both the 4-hour redistribution and the reinjection polar maps. Defects with a ratio <0.20, between 0.20 and 0.39, between 0.40 and 0.59, between 0.60 and 0.79, and 0.80 were categorized as completely persistent (score 1); predominantly persistent (score 2); with mixed, balanced reversibility (score 3); predominantly reversible (score 4); and totally reversible (score 5), respectively. Defects with 1 grade increase in the reversibility score were designated as improved, whereas those with 1 grade decrease in the reversibility score were designated as worsened.

Coronary Angiography
Selective coronary angiography was performed in standard fashion. The results were reviewed by a single experienced angiographer blinded to the exercise or scan results. Stenoses were measured with the assistance of an electronic caliper. Angiographically significant coronary artery disease refers to 50% diameter luminal narrowing of an epicardial coronary artery. Presence or absence of collateral channels was noted without any attempt to quantify collateral flow.

Statistical Analysis
The differences of continuous variables between the patient groups were tested by unpaired t tests. The Wilcoxon signed-rank test was used to test the changes in tomographic variables from 4-hour redistribution to reinjection imaging for each group. The difference in the change of tomographic variables from 4-hour redistribution to reinjection images between the two patient groups was tested by the Mann-Whitney U test. Categorical data were compared by ² analysis in the two groups of patients. All continuous variables are reported as mean±SEM. A value of P<.05 was considered statistically significant.

	Results

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Demographic Data
A total of 96 patients with known or suspected coronary artery disease were recruited (Table 1). All patients had ²⁰¹Tl perfusion defect with stress images that were persistent or incompletely reversible in the 4-hour redistribution images. Forty-eight patients were randomized to receive nitroglycerin and 48 patients to receive placebo. Sixty-nine patients had coronary angiography within a median of 8 days from the SPECT study, and all except 1 patient had angiographically significant coronary artery disease (Table 1). The mean left ventricular ejection fraction (measured by echocardiography in 52 patients, by contrast angiography in 20 patients, and by radionuclide angiography in 4 patients) was 48±1.5% and was similar for patients who received nitroglycerin or placebo.

View this table: [in this window] [in a new window]   Table 1. Demographic Data

Defect Characteristics in the 4-Hour Redistribution Images
In the patients who received nitroglycerin, defects were completely persistent in 11 patients; predominantly persistent in 22 patients; had mixed, balanced reversibility in 12 patients; and were predominantly reversible in 3 patients. In the placebo group, defects were completely persistent in 2 patients; predominantly persistent in 31 patients; had mixed, balanced reversibility in 10 patients; and were predominantly reversible in 5 patients. The overall extent of perfusion defects and the fraction of defect that was persistent or reversible in the 4-hour redistribution images were similar for the patients who received nitroglycerin or placebo.

Changes in the Extent of Reversible Hypoperfusion After Reinjection
In comparison with the 4-hour redistribution images, the overall extent of defect reversibility after reinjection increased significantly both in the nitroglycerin and in the placebo groups (Table 2).

View this table: [in this window] [in a new window]   Table 2. Extent of Persistent and Reversible Defects (%) at 4-Hour Redistribution and Reinjection Images

Overall, among the 48 patients who received nitroglycerin, 23 (48%) demonstrated additional reversibility, compared with 16 patients (33%) among the 48 patients who received placebo (P=NS). In the 66 patients with defects that were either completely or predominantly persistent in the 4-hour redistribution images, 19 of 33 patients (58%) who received nitroglycerin showed enhanced reversibility (Fig 1); in contrast, only 11 of 33 patients (33%) who received placebo showed further reversibility (P<.05). In the 30 patients with defects that had balanced reversibility/irreversibility or were predominantly reversible in the 4-hour redistribution images, 4 of 15 patients (27%) who received nitroglycerin and 5 of 15 patients (33%) who received placebo showed additional reversibility with reinjection (P=NS).

View larger version (74K): [in this window] [in a new window]   Figure 1. Example of patient who had improved reversibility after nitrate-augmented thallium reinjection. Severe inferoposterior and lateral defects were observed in exercise images that persisted in 4-hour redistribution images but became reversible after thallium reinjection augmented by nitroglycerin.

In the 66 patients with completely or predominantly persistent defects in the 4-hour redistribution images, there was no difference between those who received nitroglycerin or placebo with respect to the frequency of prior myocardial infarction (64% versus 64%), history of angina pectoris (15% versus 18%), chest pain (9% versus 3%), and ST-segment depression (18% versus 27%) during exercise testing (P=NS for all comparisons). Likewise, in the patients randomized to nitroglycerin, there was no difference between those with and those without further reversibility after reinjection with respect to the frequency of prior myocardial infarction (58% versus 71%), history of angina pectoris (21% versus 7%), chest pain (11% versus 7%), and ST-segment depression (21% versus 14%) during exercise testing (P=NS for all comparisons).

The overall changes in the extent of reversibility from the 4-hour redistribution to the reinjection images were similar in the nitroglycerin and placebo groups. The absolute changes in reversible defect size were 2.8±1.0% versus 2.1±1.0%, respectively (P=NS), and the relative percent changes were 26% versus 18% (P=NS). After ²⁰¹Tl reinjection, the extent of reversibility increased by 5% in 18 of 48 patients (38%) who received nitroglycerin and in 10 of 48 patients (21%) who received placebo (P=.073). The ratio of reversible to total defect increased by 0.15±0.03 from the 4-hour redistribution to the reinjection images in the nitroglycerin group, compared with 0.05±0.03 in the placebo group (P=.017).

Relation of Change in Reversibility to Collateral Circulation
In the 68 patients who had angiographically significant coronary artery disease, collateral vessels were present in 35 patients and absent in 33 patients. The patients' clinical characteristics were similar regardless of the presence of collaterals, except that those with collaterals were slightly older than those without collaterals (64±1.2 versus 60±1.8 years, P<.05). The total extent of perfusion defects (32.4±2.8% versus 27.3±2.4%, P=NS) and the defect fraction that was persistent (19.1±1.9% versus 18.0±1.8%, P=NS) or reversible (13.4±1.9% versus 9.3±1.1%, P=NS) in the 4-hour redistribution images were also similar in patients with and without collaterals.

Among patients with documented coronary artery disease, the overall extent of reversible myocardium after ²⁰¹Tl reinjection increased by 2.8±1.3% of the left ventricle (P<.001) compared with the 4-hour redistribution images. When patients were classified according to the presence or absence of collateral circulation, the increase in extent of reversibility after reinjection was significant only in patients who had collateral vessels and received nitroglycerin (Fig 2).

View larger version (30K): [in this window] [in a new window]   Figure 2. Changes in the extent of defect reversibility (%LV) from 4-hour redistribution to reinjection imaging among patients with no collateral who received nitroglycerin (C-N+) or placebo (C-N-) and patients with collateral who received nitroglycerin (C+N+) or placebo (C+N-). Statistically significant increase in extent of defect reversibility (4.0±1.4, P<.05) was noted only in C+N+ group.

Among the patients without collaterals, 22% of patients who received nitroglycerin and 21% of patients who received placebo had more reversibility after reinjection. Among patients with collaterals, 50% of those who received nitroglycerin and 20% of those who received placebo had improved reversibility after reinjection (Table 3). Although improved reversibility was noted after reinjection irrespective of the presence of collateral circulation and nitroglycerin administration, patients with collaterals who received nitroglycerin were more likely to exhibit enhanced reversibility after reinjection than the remaining patients (50% versus 21%, P<.05).

View this table: [in this window] [in a new window]   Table 3. Changes in Perfusion Defects After 201Tl Reinjection

The ratio of reversible to total defect after reinjection was 0.54±0.05 in the patients who had collateral circulation and received nitroglycerin, compared with 0.42±0.04 in the remaining patients (P=.05). Moreover, the ratio of reversible to total defect size in the vascular territories supplied by collaterals was 0.50 after reinjection in 16 of 20 patients (80%) who received nitroglycerin, compared with 6 of 15 patients (40%) who received placebo (P<.05).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Differentiation between infarcted and ischemic but viable myocardium is of critical importance in patients with coronary artery disease and left ventricular dysfunction.³¹ PET with [¹⁸F]FDG has been considered the "gold standard" for evaluation of myocardial viability,^{3 5 9 10} but the limited availability of this technology precludes its widespread clinical use. Other techniques, such as ²⁰¹Tl SPECT,^{1 3 5 6 7 13 14} dobutamine echocardiography,^{32 33} and dobutamine cardiac MRI,³⁴ are also useful in predicting recovery of regional function in hibernating myocardium.

²⁰¹Tl Reinjection for Detection of Reversible Hypoperfusion
Previous studies have shown that stress-redistribution ²⁰¹Tl imaging significantly underestimates the occurrence of hypoperfused yet viable myocardium.^{2 4} Reinjection imaging significantly improves detection of defect reversibility, thereby enhancing detection of viable myocardium.^{13 14 15} Thus, ²⁰¹Tl myocardial imaging after ²⁰¹Tl reinjection is a significant advance in the clinical detection of myocardial viability, but it still underestimates the extent of myocardial viability compared with [¹⁸F]FDG metabolic imaging.^{16 17 18}

He et al¹⁹ recently reported a group of 20 patients in which 26% of the segments showing persistent defects after ²⁰¹Tl reinjection became reversible after nitrate-augmented reinjection. Miyagawa et al²¹ studied 80 patients with coronary artery disease with stress-redistribution ²⁰¹Tl SPECT followed by reinjection either preceded or not preceded by administration of nitroglycerin (0.6 mg sublingually). In patients who received nitroglycerin, 42% of defects that persisted and 50% of defects that had incomplete redistribution in the 4-hour redistribution images became reversible after ²⁰¹Tl reinjection, compared with 31% and 41%, respectively, in patients who did not receive nitroglycerin. These two studies concordantly demonstrated that nitrate-augmented ²⁰¹Tl reinjection moderately improves the detection of reversible hypoperfusion compared with reinjection alone.

Present Study
In the present study, 48% of the 48 patients who received nitroglycerin had enhanced reversibility, compared with 33% of the 48 patients who received placebo. Among patients showing completely or predominantly persistent defects in the 4-hour redistribution images, 58% of those who received nitroglycerin had greater reversibility, compared with only 33% of the patients who received placebo (P<.05). In the present study, patients were weaned from any nitrate medications at least 24 hours before the exercise testing. Our results are consistent with the two previously mentioned studies^{19 21} and further demonstrate that nitrate-augmented ²⁰¹Tl reinjection enhances the detection of defect reversibility compared with reinjection alone.

Although the overall extent of additional reversibility after reinjection in the present study was relatively small (2.8±1.0% in the nitroglycerin group and 2.1±1.0% in the placebo group, or relative increases of 26% and 18%, respectively), this is not surprising. One possible explanation is that we assessed the extent of additional reversibility after reinjection only in the segments with persistent defects in the 4-hour redistribution images, rather than in the segments that had already had some reversibility; the latter segments might also have improved further after reinjection.²¹ In fact, in another study, reinjection alone did not yield an appreciable increase in defect reversibility over that determined solely from quantitative analysis of the 4-hour redistribution images,³⁵ as shown in the present study. Another possible explanation is that our patients may not have had very extensive regions of ischemic but viable (hibernating) myocardium, judging from the relatively small impairment of their global ejection fractions. Alternatively, one could question whether some of our patients might have developed nitrate tolerance because of chronic nitrate usage. This, however, is unlikely, because we discontinued nitrates 24 hours before initiating our protocol.

The results from the present and previous studies using different types of nitrate administration were quite consistent regardless of the tracer used (²⁰¹Tl or ^99mTc sestamibi).^{19 20 21 22 23 24 25 26} It seems that any type of nitrate delivery (sublingual, buccal, intravenous, topical, oral, etc) will have the same effect in terms of perfusion/viability imaging. Simultaneous evaluation of left ventricular myocardial perfusion and wall thickening during nitrate administration can be performed with a ^99mTc-labeled agent and gated SPECT, which may further improve assessment of myocardial viability.

Mechanism of Nitrate-Augmented Defect Reversibility
Nitrates are unique vasodilators in that they not only dilate the arteries and arterioles but also selectively induce venous dilation and therefore reduce both afterload and preload.³⁶ Their effects on large arteries are most profound in the coronary vessels, especially at sites of stenosis.³⁷ In addition, nitrates may alleviate myocardial ischemia by enhancing collateral flow distal to an occluded coronary artery³⁸ and by lowering left ventricular end-diastolic pressure, thereby decreasing the subendocardial compressive forces and improving subendocardial perfusion. The administration of nitrates improves regional myocardial perfusion at rest^{39 40} and during exercise,^{38 41} as well as global and regional left ventricular function.^{42 43 44} The estimation of contractile reserve after nitrate administration was at one time used to predict improvement of left ventricular function after coronary artery bypass graft surgery.^{45 46}

Administration of nitrates may enhance tracer uptake in hypoperfused areas with viable myocardium by enhancing coronary flow, either by directly dilating the stenotic areas or through an increase in collateral blood flow. In the present study, although reversibility was improved after reinjection irrespective of collaterals and nitroglycerin administration, patients who had collaterals and received nitroglycerin were more likely to show 5% increase in the extent of defect reversibility after ²⁰¹Tl reinjection than the remaining patients (50% versus 21%, P<.05). Furthermore, in the myocardial segments supplied by collaterals, the ratio of reversible to total defect size in the reinjection images was 0.50 in 16 of 20 patients (80%) who received nitroglycerin, compared with 8 of 15 patients (40%) who did not (P<.05). These results suggest that administration of nitroglycerin before ²⁰¹Tl reinjection enhances detection of reversibility and that this effect is probably modulated by the presence of collaterals.

Nonetheless, nitrates may also theoretically produce an apparent improvement in perfusion defects by modifying left ventricular geometry (decreased diastolic and systolic volumes) and improving regional ventricular wall thickening, thereby leading to a reduction in partial-volume effect.

Clinical Implications
The predictive accuracy of nitrate-augmented ²⁰¹Tl scintigraphy for recovery of left ventricular dysfunction after coronary revascularization was recently evaluated by Senior et al.⁴⁷ These authors reported a sensitivity and specificity of nitrate-augmented ²⁰¹Tl SPECT of 92% and 78%, respectively, for prediction of left ventricular wall motion improvement after revascularization in a group of 45 patients with severe ischemic left ventricular dysfunction. Furthermore, Basu et al,⁴⁸ in a preliminary report, indicated that nitrate-augmented rest ²⁰¹Tl imaging in patients who had a myocardial infarction and were treated with thrombolytic drugs allowed better risk stratification than standard redistribution ²⁰¹Tl imaging.

Conclusions
Nitrate-augmented ²⁰¹Tl reinjection significantly, albeit modestly, improves detection of defect reversibility. On the basis of our results, it appears appropriate to recommend nitrate-augmented ²⁰¹Tl reinjection imaging only in patients with persistent defects but not in those who already show clear-cut reversibility on the 4-hour redistribution images. This approach will allow identification of myocardial viability in 25% more patients among those with persistent perfusion defects on standard ²⁰¹Tl imaging.

	Acknowledgments

 
The authors are grateful to Anna Bravo for expert secretarial assistance.

	Footnotes

 
Guest editor for this article was Barry L. Zaret, MD, Yale University School of Medicine, New Haven, Conn.

Received August 22, 1996; revision received November 26, 1996; accepted December 2, 1996.

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