Comparison of regional myocardial blood flow in syndrome X and one-vessel coronary artery disease

Comparison of Regional Myocardial Blood Flow in Syndrome X and One-Vessel Coronary Artery Disease Alfred0 R. Galassi, MD, Filippo Crea, MD, Luis I. Araujo, MD, Adriaan A. Lammertsma, PhD, Giuseppe Pupita, MD, Yusuke Yamamoto, MD, Eldad Rechavia, MD, Terry Jones, DSc, Juan Carlos Kaski, MD, and Attilio Maseri, MD, with the technical assistance of Claire Taylor, DCR(T), and Graham Lewington, DCR(R) large proportion of patients with anginal pain sufficiently severe to justify coronary angiography have normal coronary arteries.Although this is likely to representa rather heterogeneousgroup of patients,’ a reduction in coronary flow reserve was previously reported by most studies.2-7The inconsistencies that have been observedcould be due to the inability to estimate coronary blood flow in ml/g of tissue, a variable distribution of the coronary vascular abnormality in the territory of major coronary arteries,and the inclusion of heterogeneouspatients. We investigated the distribution of regional myocardial perfusion using positron emission tomography with oxygen-B-labeled water, which was shown to provide a reliable method to measure regional myocardial blood flow (MBF).8-t2 We measuredh4BF in myocardial regions of 2.3 cm3 both during baseline conditions and after dipyridamole administration in 13 patients with the syndrome of angina pectoris and normal coronary arteries (syndromeX). We used inclusion criteria stricter than those adoptedin earlier studies2-7to enroll a homogeneousgroup of patients, and selectedonly those characterizedby typical angina pectoris, angiographically normal coronary arteries,positive exercisetest and no detectablecoronary spasm.The value and regional distribution of MBF in patients with syndrome X were compared with those in healthy subjects and patients with coronary stenosis of epicardial coronary arteries.

A

Myocardial blood flow (MBF) was measured using continuous inhalation of oxygen-l&labeled car bon dioxide, and positran emission tomography before and after intravenous dipyridamole in 13 patll with syndrome X (angma pectoris, angb gqlhically normal camnary arterieg positive exerclse test and negative ergonovine test), 7 healthy subjects and 8 patients with l-vessel caronary artery disease (CAD). In patients with syn= drome X, baseline MBF was greater than in healthy subjects and patients with CAD (1.24 -c 0.27 vs 0.87 -c 0.07 and 1.03 f 0.23 ml/g/min, re spectively; p *0.05), and more heterogeneous (34 +7vs28+5and25+-8,respective~p<0.05) as asseswl by the coefficient of variation among myocardial regions 12.3 d. After dipyridamole, MBF in patients with syndrome X was similar to that in healthy subjects (2.95 + 0.75 vs 3.40 + 0.82 ml/g/min; p = NS) and greater than in m tients with CAD (1.78 + 0.78 ml/g/min; p <0.05). However in patients with both syndrome X and CAD, MBF was more heterogeneous than in

hedthysubjects(48~12and48+ll,reqme tively, vs 30 2 I; p *O.Ol). Thus, in patients with syndrome X, MBF is abnormally heterogeneous both at baseline and after dipyridamole. These f%ldhIgs are compatible with the presence of dy namic alterations of small comnaly arteries. Because these atterations appear to be very sparse within the myocardium, they can bs undetectsd when my-al perFusion, function and metab lism are 8888888<1 usCng conventional methods that are unable to detect small myocardial m cons. (Am J Cardid 1993379:~~139)

METHODS

From the Cardiovascular and MRC Cyclotron Units, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom. Manuscript received November 3, 1992; revised manuscript received February l&1993, and accepted February 21. Address for reprints: Alfred0 R. Galassi, MD, Via Antonello da Messina 75, Cannizzaro, Acicastello, 95021 Catania, Italy.

I.34

THE AMERICANJOURNALOF CARDIOLOGY VOLUME72

Study group: Thirteen patients (2 men and 11women; age range 43 to 67 years, mean 54), diagnosedwith syndrome X on the basis of history of typical exertional angina, angiographically completely normal epicardial coronary arteries (absenceof detectablestenosesby visual analysis of a standardcoronary angiogram using 24 projections for the left coronary artery, and 22 for the right coronary artery), positive exercisetest (21 mm horizontal or downsloping ST-segmentdepressionand angina) and negative ergonovine test (maximal dose 675 kg), were included in the study, No patient had cardiomyopathy, congestive cardiac failure, valvular heart disease(including mitral valve prolapse), diabetes mellitus, history of systemic hypertension, left ventricular hypertrophy assessedby 2-dimensional echocardiography,myocardial infarction or chest wall syndrome.The baseline 1Zlead electrocardiogramwas normal in 11patients and showed nonspecific ST-T-wave abnormalities in the remaining 2.

JULY 15,1993

TABLE I Hemodynamic Findings Dipyridamole

Baseline Systolic BP

HR (beats/min) Syndrome X Healthy volunteers Coronary artery disease *p co.05

(mm Hg)

HR x BP (beats/mln x mm Hg)

HR (beats/min)

Systolic BP (mm Hg)

HR x BP (beats/min x mm Hg)

108 + 21t

135 2 17’

14,590 f 3,579* 10,696 + 1,959 12,216 ? 1,817

742 11

127 2 15

9,331 k 1,797

69k

117 k 10

8,140

138 + 14*

9,352 + 1,490

12

68 2 7

versus healthy volunteers; tp co.05 BP = blood pressure; HR = heart rate.

wsus

2 1,711

94 + 14

114-c

14

89 2 8

138 2 23*

coronary artery disease.

Seven healthy volunteers (all men, age range 21 to 31 years, mean 30) with a negative exercise test, and 8 patients (3 men and 5 women; age range 47 to 70 years, mean 60) with coronary artery disease(CAD) were also studied. Among patients with CAD, only those with lvessel CAD (270% internal diameter reduction) were enrolled. The stenotic vessel was the left anterior descending artery in 6 patients, the right coronary artery in 1, and the circurntlex artery in 1. No patient with CAD had clinical, electrocardiographic or angiographic signs of myocardial infarction. All antianginal medications were withdrawn 23 days before the study. Subjectswere requestedto refrain from oral intake of methylxanthines (including caffeine) in the 24 hours before the study to avoid attenuation of the effects of dipyridamole. I3 The study protocol was approved by the Hammersmith Hospital ResearchEthics Committee and the Administration of Radioactive Substances Advisory Committee; the nature of the study was explained to each subject before obtaining written consent. Fusihnemiss&n --aand data analysis: Positron emissiontomography scanning was performed with a multislice ECAT 931/08-12 tomograph(CTI, Knoxville, Tennessee)14 within 2 weeks of noninvasive tests and within 6 months of coronary angiography. Fifteen-plane image acquisition in a 10.5 cm axial sample distance enabled data acquisition from the whole heart. Subjectswere initially positioned within the scanner for a short rectilinear transmission scan to enable positioning of the heart at the center of the field of view of the camera. A transaxial transmission scan of the chest was obtained with an external ring of germanium-68 to correct for tissue photon attenuation of all subsequentemission scans.This was followed by a 150-labeled carbon monoxide (C150) blood volume scan. Each subject inhaled Cl50 at a radioactive concentration of 3 MBq/ml for 4 minutes. A 6minute data acquisition commenced 1 minute after the end of Cl50 delivery when the Cl50 had equilibrated in the blood pool.I5 The emission blood pool scan is reliant on in vivo binding and labeling of red blood cells by the inhaled carbon monoxide. Venous blood samples were periodically obtained for counting Cl50 blood activity in a sodium iodide, well counter calibrated with the scanner. After a 15minute interval to allow for decay of tracer activity, a continuous inhalation of 150-labeledcarbon dioxide (C1502) was administered for a period of 3.5 minutes (3 to 5 MBq/min at an air flow of 500 ml/min).

This gas is transformed almost instantaneously to 150 water by the enzyme carbonic anhydrase in the lung capillaries,l6 and as a result, radiolabeled water is delivered into arterial blood. I50 water is freely diffusible through the myocardium17and is unaffected by the tissue metabolic state or flow rate.8A dynamic scan protocol (25 scans obtained over 7 minutes, covering the inhalation period and 3 minutes after inhalation) was used to enableconstruction of time-activity curves of the radiolabeled tracer in tissue and arterial compartments, as previously described.l2 Fifteen minutes after completion of data collection at baseline conditions, dipyridamole was administered intravenously to all patients and healthy subjects at a dosageof 0.56 mg/kg over 4 minutes. After an interval of 2 minutes to enable development of peak flow responsesto dipyridamole,l8 the Cl502 inhalation procedure was repeated.During the procedure, the 3 electrocardiographic leads that showed the most marked changesduring exercise stresstesting were continuously monitored. A 1Zlead electrocardiogramwas obtained before and every minute after beginning the intravenous infusion for 10 minutes. Blood pressure was recorded each minute with a cuff sphygmomanometer.Aminophylline (240 mg), which promptly reversesthe effect of dipyridamole, was available. All patients underwent 21 baseline scan and 1 scan after dipyridamole infusion. Six of 13 patients with syndrome X were studied on 2 different occasions, 1 week apart. In 2 patients, the scan was performed at baseline conditions only; in the remaining 4, it was performed also after dipyridamole infusion. Measurementsof MBF were performed, positioning a total of 25 to 32 tissue regions of interest with a volume 12.3 cm3 detined on 6 to 8 cross-sectionalimages for the whole myocardium and generatingan averagetissue time-activity curve for each anatomic region (anterior, lateral, inferoposterior and septal), as previously reported.‘* Tissue time-activity curves were also generated for each tissue region of interest. In patients with syndrome X and in healthy subjects, MBF was expressedas the mean of the flows in all anatomic regions and tissue regions of interest. In patients with CAD, MBF was calculated separately in regions supplied by normal arteries and the stenotic artery. The coefficient of variation of MBF (SD/mean X 100) among the anatomic regions or tissue regions of interest was also calculated for each scan. Furthermore, to establish the spatial distribution of tissue regions of interest with an abnormal flow, polar maps were manually constructed for MYOCARDIAL PERFUSION IN SYNDROME X

135

each study. Clusters of 23 adjacenttissue regions of interest (on a tridimensional orientation) with flows 21 SD greater or less than the mean h4BF were identified in each map. Finally, myocardial perfusion reserve was defined as the ratio of mean values of MBF using tissue regions of interest after dipyridamole infusion to those at baseline. The values of mean MBF, coefficient of variation of h4BF and myocardial perfusion reserve were compared in the 3 groups of subjectsusing l-way analysis of variance; if there was a signiticant difference,pairwise comparisons were performed using Scheffe’s test. For the 6 patients who underwent a repeat study,the results of the first study only were used in the analysis of variance. Regression analysis was used to assessreproducibility of mean MBF measurement.A p value co.05 was considered statisticahy signihcant. Results are expressedas mean + 1 SD.

RESULTS Clinkal

1

3 Syndrome X

Healthy Volunteers

Normal Stenosed Coronary artery disease 4

FlwREl.Myoclvdblblwd6ow(M6F)msasuNdusl~ra ghSOfllWRStcontdlllllgDlyocalldVOlUmSIZ.3d

dudng basdlns &pen banj and after dllwidmok tHlth(dared&WSj.-=~SUpp6SdbyllOIWlSl MtOlWStSlWSd=~SUPPllSdby~rrterkr.

abnink

5

*p co.05 versus other @aups during basdlne; tp 40.06 VWsusoulwgroupsaftw~. 6

Resting

136

resporrcre~dlwrMa

Syndrome X PBtlem No.

”

and hmodywb

mole te& Baseline values of heart rate-blood pressure product were similar in the 3 groups (Table I). After the dipyridamole test, 8 of 13patients with syndrome X had chest pain that was accompaniedby STsegmentdepression21 mm. The features of chest pain were similar to those of patients’ usual anginal pain, and in 3, it was the most severethey had ever had. Five of 8 patients with CAD complained of chest pain after the dipyridamole test, which was accompaniedby ST-segment depression21 mm in 3 patients. No healthy volunteer had chest pain or ST-segmentdepressionduring the dipyridamole test. The values of rate-pressureproduct after dipyridamole infusion were significantly greater

Dipyridamole

THE AMERICANJOURNALOF CARDIOLOGY VOLUME72 JULY 15, ,993

IP*m

NO.

in patients with syndrome X than in healthy subjects(p ~0.05) (Table I). Baseline myocardial blood flow: MBF calculated using the anatomic regions was greater in patients with syndromeX than in healthy volunteers and patients with CAD, in regions supplied by both normal and stenotic arteries (1.22 f 0.29 vs 0.86 f 0.11, 1.00+ 0.22 and 1.01 f 0.23 ml/g/mm, respectively; p ~0.05); MBF calculated using the tissue regions of interest was also greater in patients with syndrome X than in the remaining groups (1.24 f 0.27 vs 0.87 + 0.07, 1.04k 0.21 and 1.03 f 0.23 ml&&in, respectively; p <0.05) (Figure 1). The coefficient of variation of MBF among the anatomic regions was similar in patients with syndrome X, healthy volunteers and patients with CAD (17 f 7, 13 f 6 and 13 rt 4, respectively); conversely,the coefficient of variation among tissue regions of interest was greater in syndrome X patients than in the remaining groups (34 + 7 vs 26 f 5 and 25 f 6, respectively; p ~0.05) (Figure 2). Eleven of 13 patients with syndrome X, in 15 of 19 scansperformed during baselineconditions, had clusters of tissue regions of interest with greater MBF (Figure 3). Clusters of tissue regions of interest with greater MBF were not observed in any healthy subject or patient with CAD (Figure 4). Myocardial blood flow after dipyMamok: Although patients with syndrome X had a significantly greater heart rate-blood pressure product than did healthy subjects,MBF calculated using the anatomic region was similar to that in healthy subjectsand patients with CAD in regions supplied by normal arteries (3.06 + 1.00, 3.53 f 0.94 and 3.36 + 1.07 ml/dmin, respectively; p = NS) (Figure 1); similar values of MBF were obtained also using tissue regions of interest (2.95 f 0.75, 3.40 f 0.82 and 3.30 + 1.06rnQ$min, respectively; p = NS). In patients with CAD, mean MBF in regions supplied by stenotic arteries (1.81 k 0.76 ml/g/mm using anatomic regions, and 1.78+ 0.76 ml/g/min using tissue regions of interest) was significantly less (p cO.05) than in-the other groups (Figure 1). .

In patients with syndrome X, the coefficient of variation of MBF among anatomic regions was significantly greater than in healthy volunteers (19 + 13 vs 9 + 4; p <0.05), but significantly less than in patients with CAD (34 + 9; p ~0.01). However, the coefficient of variation among tissue regions of interest was similar in patients with syndrome X and CAD (48 f 12 vs 48 + 11; p = NS), and in both casessignificantly greater than in healthy volunteers (30 + 7; p ~0.01) (Figure 2). Eleven of 13 patients with syndrome X, in 14 of 17 scansperformed after the dipyridamole test, had clusters of tissue regions of interest with lower MBF that typically occurred in myocardial regions different from those showing clusters of tissue regions of interest with greater MBF at baseline (Figure 3). Clusters of tissue regions of interest with lower MBF were also found in all patients with CAD (Figure 4), but not in any healthy volunteers. Myhal perfusion reserve: Myocardial perfusion reserve in patients with syndrome X was less than in those with CAD in regions supplied by normal arteries (2.5 f 1.07vs 3.3 + 1.05;p = NS); however,it was similar to those with CAD in regions supplied by stenotic arteries (2.5 + 1.07 vs 1.8 + 0.79) and signiticantly less than in healthy volunteers (3.9 zk 0.70; p ~0.05). Furthermore, in patients with syndrome X, no correlation was observedbetween myocardial perfusion reserve and the coefficient of variation of MBF among tissue regions of interest at baseline and after dipyridamole (r = 0.40 and 0.19, respectively; p = NS). In 4 patients with syndrome X who underwent 2 repeat studies after dipyridamole, myocardial perfusion reserve measurements were highly reproducible (r = 0.96; p ~0.05). l?egmddbilityofmyocardialbloodfIowmeawre mentsr In 6 patientswith syndromeX who underwent 2 repeated studies, the mean values of MBF calculated using tissue regions of interest and the coefficients of Flow measurements

reproducibility

6 r

1 r = 0.93

Coronary Artery Disease FIesI

Dipyridamole

Patient NC..

Rest

Dlpyridamole

01 0123456 MBF 1 (ml/g/min)

_.-- - -

FiG~~~5.Wqpnshowii1gcorrelation

measummants of myocdial

~~‘J.Q.~d@Mayofdustamofm&msofia& estwithabaommlllowinpathtswilh aass.Ro duling baadine acal.

cornnay

aatary

dia

between2mpeated blood flaw (MM), avaraging

~OfhtWMttWIhhhgmYocardblVOlUfllaIz.2~~ ~dotrepresenk~MBF/patiantchuingeachsam.In meaWmmentrW-repeatedbOthdUriIlg~ epatienb, line and aftar dipykknok, wharws in ramalaiqg measU~W~~dUlillg-OlltY.Excec kntcuwdathisobsawadbatwaanvaluasofavaragaMtK

2,

duringflrst(MEwi)and!scmlld(MBF2)crtwller. MYOCARDIALPERFUSIONIN SYNDROMEX

137

variation of MBF were highly reproducible (r = 0.93) (Figure 5). In all 6 patients, clusters of tissue regions of interest with higher MBF at baseline or lower MBF after dipyridamole identified during the ftrst study appearedin different myocardial regions during the second study (Figure 3). DISCUSSION This study showsthat patients with syndromeX have an abnormal heterogeneityof MBF both at baseline and during the coronary dilation provoked by dipyridamole. This is due to clusters of myocardial regions with relatively higher flow during baseline and relatively lower flow during dipyridamole infusion. Gpherk et al3 and Cannon et a14,5J8previously observed an impairment of coronary blood flow reserve in patients with syndrome X during dipyridamole administration or atrial pacing, using argon washout or thermodilution, respectively,to measureMBE The presencein our patients of myocardial regions with greater baseline MBF and of regions with impaired coronary vasodilation after dipyridamole suggeststhat the mechanismsof the impairment of coronary flow reservemay be due to: (1) a regional increase of baseline MBF; (2) a regional impairment of coronary dilatory capacity; and (3) both mechanismsoperating in the same or different myocardial regions in the same or different patients. The marked interpatient variability previously observed in patients with syndrome X using thermodihrtion 3-s~18 radioactive gas clearance techniques2~19-21 or thalhum scintigraphy22,23to measure MBF may be related in part to less strict patient inclusion criteria and limitations of the techniques used to measure MBF. In the present study, regional MBF was measured using positron emission tomography and oxygen-1%labeled water. In comparison with tracers such as nitrogen-13 ammonia and rubidium-82 that are affectedby the metabolic stateof the myocardium and are dependenton acoxygen-E-labeled water has the adtive processes,24Js vantage of being metabolically inert and linearly related to myocardial perfusion over a wide range of flows.8912 Previous studies in patients with angina and normal coronary arteries in which MBF was measured using argon washout3or thermodilution4~5~18 did not show alterations of baselineMBF. More recently,however,Geltman et a12’jusing positron emission tomography and oxygen-E-labeled water confirmed our observation of a greater baseline MBF in patients with angina and normal coronary arteriesthan in healthy subjects.In patients with angina and normal coronary arteries,Geltman et al also found lower values of MBF after dipyridamole administration. A similar difference was observed in the present study, but it did not achieve statistical signiticance, probably becausepatients with syndrome X had a greater rate-pressure product than did the control group. Geltman et al, using large tissue regions of interest, did not tind significant differences in the coefficient of variation of MBF between patients and control subjects.The present analysis using a larger number of smaller myocardial regions showed a signiticantly greater heterogeneity in patients with syndrome X than in healthy subjectsand patients with CAD. After dipyri138

THE AMERICANJOURNALOF CARDIOLOGY VOLUME72

damole infusion, the heterogeneity of MBF was quantitatively similar to patients with CAD, although the distribution of this heterogeneitywas substantially different in the 2 groups of patients. In patients with syndrome X, clusters of lesser increase of flow were patchily distributed in all anatomic regions, whereas in those with CAD, the tissue regions of interest with lesser increase in flow were all grouped in the anatomic regions supplied by the stenotic artery. The heterogeneity of MBF observed in patients with syndrome X in regions of 2.3 cm3 may be due to clustering of alterations in even smaller myocardial regions. If this is the case, it may represent an amplification of the temporal and spatial heterogeneity of MBF observedby Austin and Coggins et a127,28 in dogs under physiologic conditions. They found that coronary flow reserve among small myocardial regions (mean weight 106 mg) ranged between 1.75 and 21.9. In their study, the marked variability of coronary flow reserve was accompaniedby a substantial absence of correlation between baseline and maximal MBF, similar to the present study. The presencein our patients of small regions with abnormal MBF patchily distributed in the myocardium may explain why myocardial perfusion, metabolism and function are fiequently found within normal limits when assessedusing conventional diagnostic techniques that can only detect abnormalities occurring in large myocardial regions. The present results do not provide information regarding the causesresponsible for the regional impairment of coronary dilatory capacity after dipyridamole infusion in patients with syndrome X. A possible explanation may be a patchily distributed increase of coronary tone in the small arteriesproximal to those responsible for the metabolic regulation of MEW.The reduction of distending pressuredue to dipyridamole-induced arteriolar dilation combined with the presenceof an abnormal increase in vascular tone may cause a reduction and perhaps occlusion of the lumen of the most constricted vessels.29This hypothesis could also explain the patchy increase of baseline MBF observed in patients with syndromeX. The increasedresistanceat the site of small coronary arteries is likely to result in an increase of adenosinereleaseto preservebaseline MBE30 However, because of the patchy nature of vascular abnormalities, the interface with normal myocardial regions is probably much greater than in patients with stenosesof large epicardial arteries, thus resulting in a substantial spillover of adenosineto the surrounding myocardial regions supplied by normal coronary branches. This, in turn, may cause an increase of baseline MBF in these regions. Alternatively, the high baseline MBF may be due to an impairment of myocardial oxygen consumption secondary to myocardial metabolic derangement, which was observed in some previous studies.2,31,32 However, this pathogenetic mechanism would not explain the abnormalities of coronary vasodilatoty capacity observedafter dipyridamole. The high values of baseline MESFobserved in the present study are in agreement with the findings of earlier studies in which MBF was measured using xenon clearance,2 but not with those of other investigations.s-5J9-21In patients with syndrome X, the increasein heart rate and rate-pressure

JULY 15,1993

product causedby dipyridamole was greater than that in healthy subjects,thus enhancing the imbalance between myocardial demandand supply. A similar, abrupt, hemodynamic response to the stress of exercise was previously described in some patients with syndrome X.33 It remains to be established whether the reasons for this enhancedhemodynamic responseare the sameones responsible for the regional impairment of MBE 1. Syndrome X. Lancer 1987;2:1247-1248. 2. Korhola 0, Valle M, Frick MH, Wiijasalo M, Riibimaki E. Regional mycardial perfusion abnormalities on xenon-133 imaging in patients with angina pectw ris and normal coronary ateries. Am J Cardiol 197739355-359. 3. Opherk D, Z&e H, W&e E, Mall G, Dun C, Gravert B, M&me1 HC, Schwarz F, Kubler W. Reduced coronary dilatory capacity and ultmstmchual changes of the myocmiium in patients with angina pectmis but normal coronary arteriogmms. Circulation 1981;63:817-825. 4. Cannon RO III, Watson RM, Rosing DR, Epstein SE. Angina caused by reduced vawdilator reserve of the small coronary arteries. J Am CoN Cardiol 1983;l: 359-373. 5. Cannon RO III, Bonow RO, Bacharach SL, Green MV, Rosing DR. Leon MB, Watson RM, Epstein SE. Left ventricular dysfunction in patients with angina pettoris, normal epicardial coronary arteries, and abnormal vascdilator reserve. Circulation 1985;71:218-226. 5. Legrand V, Hodgwn JM, Bates ER, Aueron FM, Man&i GBJ, Smith JS, Gross MD, Vogel RA. Abnormal coronary flow resave and abnormal radionuclide exercise test results in patients with normal coronary angiograms. .I Am Co11 Cardiol 1985;6:1245-1253. 7. Greenberg MA, Grose RM, Neubwger N, Silverman R, Strain JE, Cohen MV. Impaired coronary vascdilator responsiveness as a cause of lactate production dw ing pacing-induced ischemia in patients with angina pectoris and normal coronay arteries. J Am CON Cardiol 1987;9:743-751. 8. Bergmann SR, Fox KA, Rand AL, McElvany KD, Welch MJ, Markham J, Sobel BE. Quantification of regional myocardial blood flow in viva with oxygen-15 and positron emission tomography. Circulation 1984;70:724-733. 9. Knabb RM, Fox KA, Sobe1 RA, Bergmann SR. Characterization of the functional significance of subcritical coronary stenoses with Hz150 and positron emission tomography. Circulation 1985;77:1271-1278. 10. Iida H, Kanno I, T&h&i A, Miura S, Murakami M, T&ah&i MS, One Y, Shishido F, lnugami A, Tomum N, Higano S, Fujita H, Sasaki H, Nakamichi H, Mizusawa S, Kondo Y, Uemura K. Measurement of absolute myocaniial blood flow with H2150 and dynamic positron emission tomography. Suategy for quantification in relation to the partial-volume effect. Circulation 1988;78: 10&l 15. 11. Bergmann SR, Herrem P, Markham J, Weinheimer CJ, Walsh MN. Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15. labelled water and positron emission tomography. J Am Co/l Cardiol 1989;14: 63%652. 12. Amujo LI, Lammertsma AA, Rhodes CG, McFalls EO, Iida H, Rechavia E, Galassi AR, De Silva R, Jones T, Masai A. Noninvasive quantification of regional myocardial blood flow in comnaty artery disease with oxygen-15.labeled carbon dioxide inhalation and positron emission tomography. Circulation 1991;83:875-885. la. D&y PJ, Mann TH, Zielonka JS, Kmbsack AJ, Akhtar R, Bamrah VS. Ef-

fect of maintenance oral theophylline on dipyridamole-thallium-201 myocardial imaging using SPECI and dipyridamole-induced hemodynamics changes. Am Heart J 1988;115:1185-1192. 14. Spinks TJ, Jones T, Gilardi MC, Heather JD. Physical performance of the latest generation of commercial positron scanner. Trams Nucl Sci 1988;35:721-725. 15. Matin WRW, Powers WJ, Raichle ME. Cerebral blood volume measured with inhaled Cl5 0 and positron emission tomography. J Cereb Blood Flow Metab 1987; 7:421-426. 15. West JB, Dallery CL. Uptake of oxygen-15.lab&d CO2 compared with carbon-l 1-labelled CO2 in the lung. J Appl Physiol 1962;17:%13. 17. Yipintsoi T, Bassingthwaite JB. Circulatory transport of iodoantpy?ine and water in the isolated dog heart. Circ Res 1970;27:461-477. 19. Cannon RO ill, Schenke WH, Leon MB, Rosing DR. Urquart J, Epstein SE. Limited camnay flow reserve after dipyridamole in patients with ergonovine-induced coronary vascconshiction. Circulation 1987;75: 163-174. 19. Berland J, Cribier A, Cazor JL, Letac B. Angina pectoris with angiographially normal coronary arteries: a clinical, hemodynamic and metabolic study. C/in Cardiol 1984,7:485492. 20. Vi&men KS. Evidence of myccardial ischemia in patients with chest pain syndmmes and normal cmonaxy angiograms. Acto Med Scond 1984$94z58-68. 21. Green LH, Cohn PF, Holman L, Adams DF, Markis JE. Regional myocardial blood flow in patients with chest pain syndromes and normal coronary arteriograms. Br Heart J 1978;40:242-249. 22. MeUer J, Goldsmith SJ, Rudin A, Pichard AD, Gorlin R, Teichholz LE, Herman IvfV. Speztmm of exercise thallium-201 myocadial perfusion imaging in patients with chest pain and normal coronary angiogmms. Am J Cm&l 1979;43: 717-723. 23. Kaul S, Newell JB, Chesler DA, Pohost GM, Okada RD, Boucher CA. Quantitative thallium imaging fmdings in patients with normal coronary angiogmphic findings and in clinically normal subjects. Am J Cardiol 1986;57:509-512. 24. Krivokapich J, Huang SC, Phelps MB, MacDonald NS, Shine KI. Dependence of 13NH3 myocardial extraction and clearance on flow and metabolism. Am J Physiol 1982;242:H53&H544. 26. Amujo LI, Schelbert HR. Rubidium 82: dynamic positron emission tomogmphy imaging in ischemic heart disease. Am J Cardiac Imag 1987;1:117-123. 25. G&man EH, Henes CG, Senneff MJ, S&e1 BE, Bergmann SR. Increased mycxxdid perfusion at reSt and dished perfusion reserve in patients with angina and angiogmphically normal coronary arteries. J Am CON Cardiol 1990,16:586-595. 27. Austin RJ?, Aldea GS, Coggins DL, Flynn AE, Hoffman JlE. Profound spatial heterogeneity of coronary reserve. Discordance between patterns of resting and maximal myocardial blood flow. Circ Res 1990,67:31%331. 29. Coggins DL, Flynn AE, Austin RE Jr, Aldea GS, Muehrcke D, Goto M, Hoffman JIE. Nonuniform loss of regional flow reserve during myocardial ischemia in dogs. Circ Res 1990,67:253-264. 29. Masai A, Crea F, K&i JC, Cmke T. Mechanisms of angina pectmis in syndrome X. J Am Coil Cardiol 1991;17:499-506. MO. Olsson RA, Snow JA, Gentry MK. Adenosine metabolism in canine myccardial reactive hyperemia. Circ Res 1978;42:358-366. 31. Richardson PJ, Livesley B, Oram S. Angina pectmis with normal cornnary arteries; transvenous myccardial biopsy in diagnosis. Loncet 1974;2:677680. 32. Camici P, Marmcini P, Lorenmni R, Buzzigoli G, Perissinotto A, Fenanini E, L’Abbate A, Mazilli M. Comnary hemodynamics and myocadial metabolism in patients with syndmme X: response to pacing stress. J Am CoN Cardiol 1991;17: 1461-1470. 93. Romeo F, Gaspardone A, Ciavolella M, Gioff& PA, Reale A. Verapamil vs acebutolol for syndrome X. Am J Cardiol 1988;62:312-313.

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