Transesophageal assessment of coronary flow velocity reserve during “regular” and “high”-dose dipyridamole stress testing

transesophageal Assessment of Coronary Flow Velocity Reserve During “Re ular” and “High”Dose Dipyrldamo 4 e Stress testing Stuart J. Hutchison, MD, Albert Shen, MD, Stephen Soldo, MD, Aung Hla, MD, David T. Kawanishi, MD, and P. Anthony N. Chandraratna, MD, FRCP To assess the effect of regular and high-dose dipyridamole on coronary flow velocity in the left anterior descending artery (LAD), and to determine whether assessment of coronary flow velocity reserve (CVFR) is inore sensitive for detection of ischemia than standard echocardiographic criteria, 47 patients were studied prospectively: 16 patients with stenosis of the LAD, 18 patients with angiogmphically normal IADs, and 13 patients with minimal disease. Patients underwent transesophageal echocardiogmphic study of wall motion and IAD flow velocity at baseline and at hyperemia, and for angina and electrocardiographic changes. The mean CFVR values after 0.56 mg/kg and after 0.84 mg/kg of dipyridamole were similar: 2.52 z 0.87 versus 2.62 5 0.90. A CFVR <2.3 (normals mean -2 SDS) was more

sensitive (88% at both doses) for the detection of underlying coronary obstruction than was wall motion monitoring (44% and 75%, respectively). The combination of CFVR <2.3 and wall motion monitoring was more sensitive than either index alone (94% at both 0.56 and 0.84 mg/kg). The rate-pressure product was not significantly different at the two doses of dipyridamole. When flow response is the end point of stress testing, as with transesophageal monitoring, the 0.56 mg/kg dose of dipyridamole is adequate, but when ischemia is the end point (as with wall motion monitoring by 2-dimensional echocardiography), the dose of 0.84 mg/kg is more sensitive. (Am J Cardiol 1996;77:1164-1168)

ipyridamole echocardiographic stress testing is a safe,’ noninvasive modality validated to diagD nose2-9 and prognosticate 9,‘ocoronary artery disease.

emit electrocardiographic changes, and wall motion abnormalities.

Dipyridamole, a fairly specific coronary resistance vessel dilator, l1 increases myocardial perfusion through normal arteries three- to fivefold,‘* but, in the presence of significant stenosis, induces subendocardial “steal,’ ’ I3 which is detected as regional asynergy by 2-dimensional echocardiography. The standard “stress” dose of dipyridamole is 0.56 mgl kg. Picano et al4 reported greater sensitivity with a higher dose of dipyridamole, such as 0.84 mg/kg, without a loss of specificity or an increase in risk. Pulsed-wave Doppler recording of flow in the proximal left anterior descending artery (LAD) by transesophageal echocardiography14 can be used to monitor flow at baseline and hyperemic states and to establish a coronary flow velocity reserve (CFVR). The purposes of this study were ( 1) to record the effects of the 2 doses on flow velocity, and (2) to establish prospectively the value of CFVR (lower limit 2.3) and to compare it with conventional echocardiographic stress-testing indexes of angina, ischFrom the Division of Cardiology, Department of Medicine, Los Angeles County/University of Southern California Medical Center, U.S.C. School of Medicine. Los Anaeles. California. This studv was supported in part by a Trbvelling?ellokhip from the R. Sbmuel McLaughlin Foundation, Toronto, Canada. Manuscript received September 1 1 1995: revised manuscriot received and accented lanuarv I I2, 1996.’ Address for reprints: P. Anthon N. Chandraratna, MD, Division of Cardiology, USC School of Me cl.icrne, 2025 Zonal Avenue, Room 762 1, Los Angeles, California 90033.

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Inc.

METHODS Between September 1, 1992 and July 15, 1993, 55 patients agreed to undergo transesophageal echocardiographic stress testing and assessmentof CFVR by receiving dipyridamole 0.56 mg/kg. The test was not performed in 8 patients because of hypotension (n= 1) , hypertension (n= 1) , angina within 48 hours (n=2), inability to pass the transesophageal probe (n= l), probe intolerance (n=l), and inability to record coronary flow (n=2). Four patients with significant coronary disease had positive test results after a dose of 0.56 mg/kg dipyridamole, and were not given the additional dose of 0.28 mg/kg. The study protocol was approved by the institutional review board, and all patients gave written informed consent. All patients had calcium channel blocker, p blocker, and nitrate medications discontinued for 18 to 24 hours before the study. Patients with routine contraindications to transesophageal echocardiography and to stress testing were excluded. There were no complications. Patients with valvular heart disease, left ventricular dysfunction, congestive heart failure, and diastolic blood pressure >95 mm Hg were excluded from this study, as such patients could have had abnormal flow reserve.15-19Patients were studied in the conscious state and in a fasting state. Patient groups: Group 1 consisted of significant ( >70%) stenosis of the LAD (n= 16); group 2 consisted of normal LAD (n= 18) ; group 3 patients had 0002-9149/96/s PII 50002.9149(96)

15.00 00156-7

minimal disease (<30% stenosis) of the LAD (n=13). A 5 MHz biplane probe (model 2 1363A) with a Sonos HP-1500 Hewlett-Packard (Palo Alto, California) platform was used. Oropharyngeal anesthesia was obtained with topical spray, and light sedation was given with intravenous midazolam in 0.5 mg intravenous boluses. With the horizontal-plane transducer in the midesophageal position, the proximal left coronary artery system was imaged. The LAD was identified as the vessel with anterior continuation from the left main coronary artery after bifurcation. The pulsed-wave sample volume was placed over the proximal portion of the LAD. After recording baseline flow, we infused dipyridamole 0.56 mg/ kg over 4 minutes. Two minutes after the end of the infusion, spectral profiles were recorded. Dipyridamole 0.28 mg/kg was then infused over 2 minutes, and flow velocity was recorded. Images were recorded for playback analysis and were measured offline later. The dose of 0.28 mg/kg of dipyridamole was not given if there was clear evidence of a wall motion abnormality or significant ST depression. The ratio of peak hyperemic diastolic flow velocity to peak baseline diastolic flow velocity was used as an index of coronary flow reserve and was referred to as the coronary flow velocity ratio. Horizontal- and vertical-plane images of the septum and anterior wall (LAD territory) were recorded at baseline, after 0.56 mg/kg of dipyridamole, and after the additional 0.28 mg/kg of dipyridamole. Transient wall motion asynergy (greater than mild hypokinesia, akinesia, or dyskinesia) was considered to be a positive test result consistent with ischemia. The reader was blinded to the coronary anatomy of the patient. Questionable wall motion abnormalities were resolved by a second reader. We performed continuous transcutaneous oximetric and electrocardiographic monitoring as well as frequent blood pressure monitoring before, during, and after the study. Heart rate was noted from 12-lead electrocardiograms. Greater than 1 mm of transient ST-segment depression or a worsening of ST depression by > 1 mm was considered a positive test result. Blood pressure was taken by automatic self-inflating cuff. Throughout the study, patients were asked if they had chest pain. Chest pain consistent with ischemia was noted and considered a positive test result if the quality and location of the pain were typical of angina. Patients who had positive exams after a dose of 0.56 mg/kg dipyridamole and who did not receive a second dose were considered to have positivity at the higher dose. Coronary arteriography was performed with Judkins catheters using standard views. Stenosis severity was measuredby calipers. All TEE studies were performed within 1 week of arteriography. All patients had undergone coronary arteriography for clinical reasons. Statistical analysis was performed using commercially available software, Primer of Biostatistics, and Microsoft Excel (Redmond, Washington), version 4.0. Data are expressed as mean t SD and were

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I

T

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Dipyridamole FIGURE 1. Coronary 0.84 mg/kg (mean nary artery.

.........

0.56 mgikg

:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:. .......................... ........................................................................................................ .................................................... :.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:,~~:, .......................... .................................................... .................................................... :.:.:_:.:.:.~:.:.:.~:.:.:.:.:.:.:.:.:.:.:.:.:.,.~ .......................... .................... .:.. :::. ;,.,., ............

Dipyridamoie

0.84 mgkg

flow velocity after dipyridamole 0.56 versus -t SD). lAD=left anterior descending coro-

compared by analysis of variance and post hoc Student-Newman-Keuls testing. The null hypothesis was rejected at p <0.05.

RESULTS The CFVR of group 1 was significantly different from that of groups 2 and 3. The CFVR values of group 2 and 3 were significantly different. For each of the 3 groups, the CFVR was not significantly different after 0.84 mg/kg dipyridamole compared with that after 0.56 mg/kg dipyridamole. The mean CFVR -2 SDS for the normal group was 2.3 (Table I). The peak diastolic flow velocity after 0.84 mg/ kg dipyridamole versus after 0.56 mg/kg dipyridamole (Figure 1) was not significantly different for any of the 3 patient groups. For the 3 patient groups, the peak diastolic flow velocities after 0.56 and 0.84 mg/kg dipyridamole were significantly greater than those at baseline (Table II). Neither the heart rate, blood pressure, nor ratepressure product were different at the 2 doses of dipyridamole for any of the 3 patient groups. Similarly, the rate-pressure product and blood pressure were not significantly different from baseline at either dose of dipyridamole. By standard echocardiographic stress-testing indexes, there was greater sensitivity at the higher dose of dipyridamole (angina, 25% vs 56%; electrocardiographic changes, 31% vs 56%; development of wall motion abnormalities, 44% vs 75%). CFVR <2.3 was the most sensitive single index for the detection of significant underlying coronary artery disease. The combination of CFVR <2.3 and wall motion monitoring was more sensitive than either index alone (94% at both 0.56 and 0.84 mg/kg dipyridamole). With use of both development of new wall motion abnormalities and CFVR <2.3 was the most specific index for the detection of underlying significant coronary artery disease (Table III).

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TABLE I Patient Data Intravenous

Heart Rote (beots/min)

Diameter Stenosis

Rest

Dipyridamole

(mm hi Rest

Dip.

+SD

80 -t-l1

61

79

96

93

2 8.7

+ 17

2 18

2 14

1: left Anterior

87 2 14

0.60 t 0.36

Group 2: Normal Mean +SD

52 ?lO

t

75 18

93 + 18

t

95 14

90 + 14

Group 3: Minimal Meon ?SD

62 211

BP = blood

t

76 12

pressure;

CFVR = coronary

TABLE II Coronary

Flow Reserve

91 ? 14

flow velocity

reserve;

LAD = left anterior

0.61 0.90 0.93

descending

coronary

79 + 17

Descending 3.25 + 0.49

f

2.25 20.59

1.10

t 0.44

Dip. = dipyridamole

Dip.

Mean BP (mm l-44

0.84

mg/kg

Peak Diastolic Velocity km/s)

Rest

Dip.

Rest

Dip.

CFVR

101 2 18

93 2 14

84 ‘- 14

0.60 20.36

0.93 + 0.37

1.77 + 0.66

95 + 14

88 + 15

0.46 20.30

1.16 ~0.26

3.38 kO.53

0.56 t 0.24

1.15 + 0.45

2.36 10.62

Artery 75 18

Artery Disease of the Left Anterior 76 2 12

98 ? 17

Descending 97 + 13

89 2 17

Artery 84 2 10

infusion.

Responses Group 2: Normal LAD (n = 18)

2 0.38 t 0.30 k 0.37

1.72 t 0.66 1.77 + 0.66

7,490 8,225 8,565

Rest

Dipyridamole

Artery Stenosis

1.70 kO.62

1.14 20.27

Group 1: LAD Stenosis (n = 16)

Peak diastolic velocity (m/s) Rest IV dypyridamole 0.56 mg/kg IV dypyridamole 0.84 mg/kg Coronary flow velocity reserve IV dypyridamole 0.56 mg/kg IV dypyridamole 0.84 mg/kg Rotepressure product (beats x mm Hg/min) Rest IV dypyridomole 0.56 mg/kg IV dypyridomole 0.84 mg/kg

CFVR

Descending

Left Anterior

0.56 + 0.24

and Hemodynamic

Index

IV = intravenous;

87 2 10

Heart Rote (beats/min)

0.88 + 0.30

0.46 20.30

Coronary

89 2 17

Intravenous

Dip.

Rest

Group Meon

mg/kg

Peak Diastolic Velocity b/s)

Mean BP

Dip.

0.56

? 2,612 f 2,225 + 2,480

Group 3: Minimal LAD Stenosis (n = 13)

All Patients (n = 47)

0.46 + 0.30 1.14 + 0.27 1.16 + 0.26

0.56

+ 0.24 0.44 1.15 f 0.45

0.53 + 0.31 1.06 + 0.36 1.09 2 0.36

3.25 3.38

2.25 2.36

2.52 2.62

7,209 8,385 8,652

l.lO?

r 0.49 2 0.53

2 2,191 2 2,203 2 2,288

6,785 7,874 8,221

+ 0.59 t 0.62

2 1,994 + 1,356 + 1,686

t 0.87 t 0.90

7,165 2 2,219 8,163? 1,968 8,511 ? 2,146

artery.

combination was CFVR <2.3 and new regional asynergy (94%). There was a small, statistically nonsignificant increase in CFVR and in peak diaCoronory Flow stolic flow velocity in the LAD after dipyridamole Reserve < 2.3 0.84 versus 0.56 mg/kg. However, myocardial oxCoronary Flow ond Wall Motion ygen demand, as estimated by rate-pressure product, Reserve < 2.3 Abnormality did not differ between the doses of dipyridamole, Dose hxdkgl 0.56 0.84 0.56 0.84 suggesting greater coronary “steal” as the mechaSensitivity (%) 88 88 94 94 nism of increased ischemia induced by the higher Specificity (%) 94 100 100 100 Positive predictive value 93 100 100 dose of dipyridamole. 100 Negative predictive value 89 90 100 100 The sensitivity for the detection of underlying significant coronary artery disease by development of regional asynergy in this study was 44% after a dose of 0.56 mg/kg dipyridamole, and 75% after a DISCUSSION In this study, the feasibility of assessing coronary dose of 0.84 mg/kg. These figures are consistent flow reserve by transesophageal-dipyridamole stress with published data describing a sensitivity for deechocardiography was 85%, and the feasibility of tecting coronary artery disease ( >70% stenosis) of wall motion analysis by transesophageal-dipyrida- about 75% for dipyridamole stress echocardiogramole stress echocardiography was 100%. CFVR My- 5*20The mean stenosis severity in this study was ~2.3 was the most sensitive single index (88%) for 80% t 11% diameter stenosis, which would be exthe detection of underlying, angiographically signif- pected to limit maximal but not resting flo~.“-~*~l-~~ icant coronary artery disease, and the most sensitive The specificity of regional asynergy as indicative of TABLE Ill Sensitivity, Specificity, Impaired Flow Reserve

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significant underlying coronary artery disease in this study was 100% at either dose of dipyridamole (0.56 or 0.84 mg/kg). These figures are also consistent with previously published data, 2-8,20*23 which averaged about 95% specificity. Also consistent with previously published data, l1 dipyridamole stress testing in this study had a modest, although statistically significant, effect on myocardial demand: rate-pressure product increases of 13% at dipyridamole 0.56 mg/kg and of 19% at dipyridamole 0.84 mg/kg for the 3 patient groups considered together. The rate-pressure product did not differ between dipyridamole 0.56 and 0.84 mg/kg. As noted previously, ‘I the small decreases in mean blood pressure after dipyridamole were associated with small to moderate increases in heart rate. The changes in heart rate and mean blood pressure in this study were not statistically different between the doses of dipyridamole. Similarly, in this study, the LAD flow did not differ between the doses of dipyridamole. Therefore, it seems unlikely that the higher dose of dipyridamole increases sensitivity through a further increase in myocardial oxygen demand or a reduction in overall supply. The most plausible explanation for the greater sensitivity seen with the higher dose is that greater maldistribution of flow occurred within the LAD territory and greater “steal” occurred. Such maldistribution could occur along the model of ‘ ‘vertical’ ’ / ‘ ‘intramural’ ’ steal or “horizontal” stea1.12,22,24 The technique of transesophageal echocardiography-Doppler can sample flow in only the proximal 1 to 2 cm of the LAD, which in most cases is the total flow through the artery, as it samples flow before the origin of most diagonal and septal branches. In the case of the ostial stenoses, for which the Doppler sampling is likely at or distal to the stenosis (and hence likely to indicate the effect of the stenosis on flow), the peak diastolic flow velocity was greater after dipyridamole 0.84 mg/kg than after 0.56 mg ( 1.28 +- 0.48 m/s vs 1.20 +_0.43 m/s). In the case of the proximal stenoses, for which the sampling is in the vicinity of the stenosis but cannot be shown to be before or after the stenosis by this technique, the peak diastolic flow velocity was greater after dipyridamole 0.84 mg/kg than after 0.56 mg/ kg (0.94 t 0.40 m/s vs 0.92 + 0.39 m/s). Thus, peak coronary flow velocity was not significantly different between the doses for cases of either ostial or proximal stenosis, where Doppler sampling by this technique should sample total flow through the artery. Transesophageal echocardiographic monitoring of flow velocity in the LAD with adenosine stress has been validated as an accurate means of estimating LAD flow reserve. Redberg et a125described an 86% sensitivity and 79% specificity for determining the absence of significant stenosis in the LAD using CFVR ~2.1 with adenosine 0.14 mg/kg/min. Myocardial systolic function is related to coronary flow, and coronary flow is related to coronary stenosis severity. 21Picano et a126described the cor-

onary flow-myocardial function relation during 2dimensional echocardiography dipyridamole stress testing (dose 0.56 mg/kg) by comparing echocardiographic stress indexes with positron emission tomographic estimates of flow. Greater stenosis severity was associated with greater impairment of flow reserve, greater severity of wall motion abnormality, and earlier onset of wall motion abnormality. In this study, LAD flow was not seen to increase at the higher dose of dipyridamole, and the sensitivity of identifying underlying coronary artery disease was similarly unchanged at the higher dose of dipyridamole (88% vs 88%). However, wall motion monitoring was more sensitive at the higher dose (75% vs 44%). Combining flow and function indexes (CFVR <2.3 and wall motion abnormality monitoring) yielded the highest sensitivity (94% at both doses of dipyridamole). Using dipyridamole stress at 0.56 and 0.84 mg/kg, Casanova et a127compared thallium perfusion and 2-dimensional echocardiography for the assessment of coronary artery disease. Thallium perfusion monitoring (an index of flow) was equally sensitive (85%) at both doses of dipyridamole. Wall motion monitoring by echocardiography (an index of function) was more sensitive at the higher dose (53% vs 14%), although it was less sensitive than thallium. Thus, indexes that monitor flow during stress testing, such as flow velocity monitoring or isotope perfusion monitoring, should not have increased sensitivity at the higher dose, but indexes of ischemia/myocardial function, such as angina, electrocardiographic abnormalities, and wall motion monitoring, would be expected to have greater sensitivity at the higher dose, where greater maldistribution of flow induces greater ischemia and myocardial dysfunction. Study limitations: Only the LAD was studied. Some patients in each group had multiple vessel coronary disease, which may complicate the flow characteristics of the LAD complex. Peak flow velocity and flow volume were assumed to be related, as the sampling was performed in the same area of the LAD, as best as could be achieved. Because peak velocity was the easiest to measure, we chose to use it as the flow index. Flow volume is related to flow velocity and cross-sectional area. Although dipyridamole principally dilates resistance vessels, it may dilate epicardial coronary arteries 28as well, which would reduce the closeness of the relation between flow velocity and flow volume, but would maintain the direction of the relation. CFVR was assessedin a select group of patients who did not have recognized disease states that may reduce flow reserve, such as hypertension-hypertrophy, l9 dilated cardiomyopathy, l7 or significant aortic valvular disease.‘5*16,1s Thus, the results of this study cannot be applied to wider, more pathophysiologitally heterogeneous populations. The specificity of coronary flow velocity would be expected to be lower in a general population of patients, whereas patients with some of the above intercurrent abnor-

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malities would have a wider range and a lower mean CFVR. Conclusions: Dipyridamole stress testing with transesophageal monitoring is a safe, feasible, and accurate means of identifying underlying coronary artery disease. Monitoring of impaired flow reserve is a sensitive means of identifying an underlying stenosis. LAD flow is similar at the doses of 0.56 and 0.84 mg/kg of dipyridamole. When flow response is the end point of stress testing, as with scintigraphy or transesophageal monitoring, the dose of dipyridamole of 0.56 mg/kg is adequate, but when ischemia is the end point (as with wall motion monitoring by 2-dimensional echocardiography), the dose of 0.84 mg/kg is more sensitive.

1. Picano E, Marini C, Pirelli S, Maffei S, Bolognese L, Chiriatti G, Chiarella F, Orlandini A, Seveso G, Colosso MQ, et al. Safety of intravenous high-dose dipyridamole echocardiography. The Echo-Persantine International Cooperative Study Group. Am J Cardiol 1992;70:252-258. 2. Lattanzi F, Picano E, Frogoli A, Bolognese L, Rossi L, Piccinino C, Lencioni G, Distante A. Oral vs intravenous dipyridamole echocardiography for detecting coronary artery disease. Chest 1992;102:1189-1192. 3. Picano E, di MC, Gigli G, Sclavo MG, Seveso G, d’Urbano M, Gandolfo N, Cabani E, Terre F, Distante A. Dipyridamole-echocardiography in coronary artery disease. Herz 1991;16:379-387. 4. Picano E, Lattanzi F, Masini M, Distante A, L’ Abbate A. Comparison of the high-dose dipyridamole-echocardiography test and exercise two-dimensional echocardiography for diagnosis of coronary artery disease. Am J Cardiol 1987;59:539-542. 5. Picano E, Lattanzi F, Masini M, Distante A, L’Abbate A. High dose dipyridamole echocardiography test in effort angina pectotis. J Am Coil Cardiol 1986;8:848-854. 6. Masini M, Picano E, Lattanzi F, Distante A, L’ Abbate A. High dose dipyridamole-echocardiography test in women: correlation with exercise-electrocardiography test and coronary arteriography. .I Am Coil Cardiol 1988;12:682685. 7. Picano E, Distante A, Masini M, Morales MA, Lattanzi F, L’Abbate A. Dipyridamole-echocardiography test in effort angina pectoris. Am J Cardiol 1985;56:452-456. 8. Mazeika P, Nihoyannopoulos P, Joshi J, Oakley CM. Uses and limitations of high dose dipyridamole stress echocardiography for evaluation of coronary artery disease. Br Heart J 1992;67:144-149. 9. Picano E, Severi S, Michelassi C, Lattanzi F, Masini M, Orsini E, Distante A, L’Abbate A. Prognostic importance of dipyridamole-echocardiography test in coronary artery disease. Circulation 1989;80:450-457. 10. Tischler MD, Lee TH, Hirsch AT, Lord CP, Goldman L, Creager MA, Lee RT. Prediction of major cardiac events after peripheral vascular surgery using dipyridamole echocardiography. Am J Cardiol 1991;68:593-597. 11. van Rugge RF, van der Wall EE, Bruschke AV. New developments in pharmacologic stress imaging. Am Heart J 1992;124:468-485.

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12. Fang AY, Gallagher KP, Buda AJ. The physiologic basis of dobutamine as compared with dipyridamole stress interventions in the assessment of critical coronary stenosis. Circtdation 1987;76:943-951. 13. picano E, Lattanzi F. Dipyridamole echocardiography. A new diagnostic window on coronary artery disease. Circulation 1991;83 (suppl III):III-19-111. 26. 14. Iliceto S, Marangelli V, Memmola C, Rizzon P. Transesophageal Doppler echocardiography evaluation of coronary blood flow velocity in baseline conditions and during dipyridamole-induced coronary vasodilation. Circulation 1991;83:61-69. 15. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries. N Engl J Med 1982;307: 13621366. 16. Eberli FR, Ritter M, Schwitter J, Bortone A, Schneider J, Hess OM, Krayenbuehl HP. Coronary reserve in patients with aortic valve disease before and after successful aortic valve replacement. Eur Heart J 1991;12:127-128. 17. Nitenberg A, Foult JM, Blanchet F, Zouioueche S. Multifactorial determinants of reduced coronary flow reserve after dipyridamole in dilated cardiomyopathy. Am J Cardiol 1985;55:748-754. 18. Nitenberg A, Fault JM, Antony I, Blanchet F, Rahali M. Coronary flow and resistance reserve in patients with chronic aortic regurgitation, angina pectoris and normal coronary arteries. JAm Coil Cardiol 1988;11:478-486. 19. Vogt M, Motz W, Strauer BE. Coronary haemodynamics in hypertensive heart disease. Eur Heart J 1992;13:44-49. 20. Severi S, Picano E, Michelassi C, Lattanzi F, Landi P, Distante A, L’Abbate A. Diagnostic and prognostic value of dipyridamole echocardiography in patients with suspected coronary artery disease. Comparison with exercise electrocardiography. Circulation 1994;89:1160-1173. 21. 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. 22. Klein LW, Askenase AD, Weintraub WS, Akaishi M, Mercier RJ, Schneider RM, Agarwal JB, Helfant RH. Absence of coronary vascular reserve in myocardium distal to a fixed coronary stenosis. Cardiovasc Res 1987;21:99-106. 23. Previtali M, Lanzarini L, Ferrario M, Tortorici M, Mussini A, Montemartini C. Dobutamine versus dipyridamole echocardiography in coronary artery disease. Circulation 1991;83 (suppl III):III-27-111-31. 24. Picano E, Simonetti I, Masini M, Ma&Ii M, Lattanzi F, Distante A, De NM, L’Abbate A. Transient myocardial dysfunction during pharmacologic vasodilation as an index of reduced coronary reserve: a coronary hemodynamic and echocardiographic study. JAm Coil Cardiol 1986;8:84-90. 25. Redberg RF, Sob01 Y, Chou TM, Malloy M, Kumar S, Botvinick E, Kane J. Adenosine-induced coronaq vasodilation during tramesophageal Doppler echocardiography. Rapid and safe measurement of coronary flow reserve ratio can predict significant left anterior descending coronary stenosis. Circulation 1995;92:190-196. 26. Picano E, Parodi 0, Lattanzi F, Sambuceti G, Andrade MJ, Marzullo P, Giorgetti A, Salvadori P, Marzilli M, Distante A. Assessment of anatomic and physiological severity of single-vessel coronary artery lesions by dipyridamole echocardiography. Comparison with positron emission tomography and quantitative arteriography. Circulation 1994;89:753-761. 27. Casanova R, Patroncini A, Guidalotti PL, Capacci PF, Jacopi F, Fabbri M, Maresta A. Dose and test for dipyridamole infusion and cardiac imaging early after uncomplicated acute myocardial infarction. Am J Cardiol 1992;70:14021406. 28. Hintze TH, Vatner SF. Dipyridamole dilates large coronary arteries in conscious dogs. Circulation 1983;68:1321-1327.

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