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Assessment of coronary flow reserve using digital angiography before and after successful percutaneous transluminal coronary angioplasty
Assessmentof CoronaryFlowReserveUsin Digital Angiography Before and After Successful Percutaneous Transluminal Coronarv Angioulastv JOHN McB. HODGSON, MD, RAYMON S. RILEY, MD, ALBERT S. MOST, MD, and DAVID 0. WILLIAMS, MD
Important alterations of coronary blood flow and coronary flow reserve occur during percutaneous transluminal coronary angioplasty (PTCA). This study evaluated these alterations using digital subtraction angiography. Coronary flow reserve was determined before and after successful PTCA in 20 patients with l-vessel coronary artery disease (CAD). Ten other patients with angiographically normal coronary arteries, normal exercise electrocardiographic responses and normal cardiac structure also were evaluated. Coronary flow reserve was calculated as the ratio of papavarine-induced hyperemit flow to basal flow. Flow reserve for the stenotic artery in patients who underwent PTCA was 1.6 f 0.2 (mean f standard error of the mean) (range 0.9 to 3.9, n = 20). After successful PTCA, flow reserve for this artery increased to 3.1 f 0.2
P
ercutaneous transluminal coronary angioplasty (PTCA) can relieve epicardial coronary artery obstruction and related manifestations of myocardial ischemia.1-4 Patients who undergo successful PTCA provide an excellent model for assessing important alterations of coronary blood flow and coronary flow reserve. The value of coronary flow reserve in assessing the physiologic significance of coronary stenoses is well established.5-10 Digital subtraction imaging performed during coronary angiography before and after intracoronary papavarine administration enables determination of an index that reflects regional coronary flow reserve.11-15 We used digital angiography to investigate coronary flow reserve alterations in 20 paFrom the Division of Cardiology, Rhode Island Hospital and Brown University Program in Medicine, Providence, Rhode Island. Manuscript received January l&1987; revised manuscript received and accepted February 19,1987. Address for reprints: David 0. Williams, MD, Division of Cardiology, Rhode Island Hospital, Providence, Rhode Island 02902.
(range 1.7 to 5.2, n = 20) (p
tients who had clearcut evidence of significant stenoses before PTCA and in whom the procedure was successful, that is, resulted in a final translesional gradient of 16 mm Hg or less, an angiographic stenosis less than 50% in diameter, and absence of stress-induced ischemia.
Methods Patient selection: All patients with l-vessel coronary artery disease [CAD] undergoing PTCA between January and May 1985 were eligible (n”= 45). Coronary flow reserve measurements were routinely attempted in all patients undergoing PTCA unless the patient’s condition was unstable or when logistic constraints existed. In some patients, technical factors (such as atria1 fibrillation, excessive motion and inadequate catheter support) precluded adequate studies. Patients who also met the following criteria were selected for this study: successful PTCA with residual stenosis less than 50% diameter narrowing; electrocardiographic or thallium-201 scintigraphic exercise evaluation before PTCA that was positive for ischemia; exercise evalu-
62
CORONARY
RESERVE
BEFORE
AND AFTER
ANGIOPLASTY
ation after PTCA that was negative for &hernia; and absence of associated valve disease or evidence of left ventricular hypertrophy by electrocardiogram or echocardiogram. Ten patients who met the following criteria were studied as controls: 11) normal epicardial coronary arteries by angiography; (2) normal exercise electrocardiographic response; (3) absence of left ventricular hypertrophy by electrocardiogram or echocardiogram; (4) absence of congenital or acquired structural cardiac abnormalities; (5) normal contrast ventriculographic or radionuclide angiographic findings. All control patients were undergoing clinically indicated diagnostic catheterization for evaluation of chest pain. Coronary flow reserve determinations: Coronary flow reserve was determined using digital angiography as previously described.12*13 Heart rate was controlled by atria1 pacing. Digital images were obtained during precisely timed electrocardiographically gated power injections of meglumine and sodium diatrizoate (Renografin 76@). Image acquisition was programmed to begin precisely at the time of injection and once during each subsequent cardiac cycle for 15 cycles. Radiographic variables were held constant throughout image acquisition. Composite images were constructed that display the progression of radiographic contrast through the coronary circulation using color modulation, and the volume of contrast distribution using intensity modulation. Composite images were produced during baseline flow and during induced hyperemia 30 to 45 seconds after intracoronary injection of papavarine hydrochloride (10 mg for the left coronary, 5 mg for the right coronary). For analysis, regions of interest were operator selected over the distal myocardial perfusion bed of the artery under study. A flow index was calculated for each defined region using both intensity and transit time information. Regional coronary flow reserve was calculated as the ratio of hyperemic to baseline flow indexes. Reproducibility of this technique was assessed by repeated baseline flow determinations in patients with both stenotic and nonstenotic vessels (n = 27). Determinations 1 and 2 differed by an average of 6 f 9% (mean f standard deviation; 95% confidence limits f27%).
Catheterization protocol: Patients who underwent PTCA received nitrates, calcium channel blocking drugs, aspirin and dipyridamole for at least 12 hours before PTCA, and were premeditated with diazepam, 10 mg orally and 5 mg intravenously, diphenhydramine, 50 mg orally, and nifedipine, 10 mg orally, at the beginning of the procedure. In control patients all medications were withheld for at least 8 hours before catheterization. Control patients then received premedication of diphenydramine, 50 mg orally, and diazepam, 10 mg orally. Control patients did not receive nifedipine. Cardiac catheterization and coronary angiography were performed using the Judkins technique. Selective angiograms of the coronary arteries were recorded, after which coronary flow reserve was measured as described above using a standard angiograph-
ic catheter. PTCA was then performed. Final translesional gradient was defined as the mean pressure differential across the dilated segment measured at least 10 minutes after the final balloon inflation, At least 20 minutes after the final balloon inflation, postPTCA coronary flow reserve was determined at the same heart rate and using the same radiographic and injection parameters as the pre-PTCA flow reserve determination. When possible (14 of 20 cases], coronary flow reserve was also determined for an adjacent nondilated, nonstenotic coronary artery. No patients received intracoronary vasodilating drugs within 20 minutes of flow reserve determination. Maximal stenoses before and after PTCA were determined by averaging hand-held-caliper-measured percent diameter reduction obtained from at least 2 angiographic projections that clearly displayed the lesion. Minimal luminal diameter in the lesion was compared with that in the normal adjacent proximal segment. Exercise stress evaluation: Sixteen patients underwent pre-PTCA upright treadmill exercise evaluation using either the Bruce or modified Naughton protocols. Exercise electrocardiograms were interpreted by 2 experienced cardiologists and were graded positive or negative for ischemia using the criteria of Ellestad.16 Eight of these patients underwent associated thallium201 scintigraphy immediately after exercise and 3 to 4 hours later. These were interpreted by a blinded, experienced nuclear cardiologist and graded positive for ischemia if they showed a qualitative or quantitative immediate postexercise perfusion defect with partial or complete redistribution on the delayed images. All patients evaluated with exercise testing had either an ischemic electrocardiographic result, an ischemic thallium result or both. Four other patients presented with unstable angina and had reversible electrocardiographic repolarization abnormalities during chest pain. They were considered to have objective evidence of ischemia. All patients underwent post-PTCA upright treadmill exercise evaluation and 4 underwent associated thallium-201 scintigraphy. These examinations were graded as described above and none showed evidence of stress induced ischemia. Thus, all PTCA patients had objective evidence of ischemia before PTCA that was no longer present after the procedure. Control patients all had upright treadmill exercise evaluations. In all cases a pressure-rate product of more than 250,000 was achieved without electrocardiographic evidence of ischemia or angina1 chest pain. Statistical analysis: Paired t tests were used to compare variables before and after PTCA. Unpaired t tests were used to compare PTCA patients and control patients. A p value <&@?I was considered significant. All values are given as mean f standard error of the mean unless otherwise noted.
Results Clinical characteristics: Twenty patients who underwent PTCA were identified who met criteria for
duly 1, 1987
TABLE
I
Catheterization
Results
Before
and
After
THE AMERICAN
JOURNAL
Translesional Gradient (mm Hg)
% Stenosis Pt
1 LAD 2 LAD 3 LAD 4 LAD 5 LAD 6 LAD 7 LAD 8 LAD 9 LAD IO LAD 11 LAD 12 LAD 13 LAD 14 LAD 15 LAD 16 OM 17 OM 18 Right 19 Right 20 Right Mean i SEM
Prior AMI
-
+ + -
+ + -
Dilated
Pre
Post
Pre
Post
76 85 57 78 73 95 75 78 80 95 50 77 67 a4 57 68 83 81 94 58 76 i 3
33 41
67 65 81 63 55 58 68 52 59 71 56 64 37 67 61 40 51 65 60 60 60 rt 2
13 4 14 13 4
1.4 1.2 1.8 1.3 3.9 0.9 1.0 1.7 1.2 1.4 1.5 1.9 2.3 1.2 1.2 2.1 2.6 0.9 0.9 1.8 1.6 f 0.2
3.4 2.4 3.7 2.2 3.3 1.7 3.9 3.3 5.2 3.0 1.8 2.8 1.7 2.2 3.6 2.8 3.0 1.7 3.4 3.4 3.1 f 0.2
AMI = prior non-Q-wave infarction; CA = coronary marginal artery; SEM = standard error of the mean.
artery;
inclusion in this study. The dilated artery was the left anterior descending in 15 cases, a major obtuse marginal in 2 and the right coronary in 3. In 4 patients the dilated artery supplied a myocardial region with previous non-Q-wave infarction; these 4 patients had normal motion or mild hypokinesia of the infarct region on contrast ventriculography. Catheterization results: Catheterization results are summarized in Table I. The nondilated arteries were free of discrete stenoses. Many, however, had intimal irregularities. Mean coronary flow reserve for the dilated artery increased from 1.6 f 0.2 to 3.1 f 0.2 (p
53
Vessel
Post
a
60
Flow Reserve
Pre
40 18 26 38 18 10 10 40 40 22 25 8 0 0 15 38 0 22 f 3
Volume
Successful Coronary
CA Dilated
OF CARDIOLOGY
’ 1. 10
a a 15 12 11 9 11 8 4 16 15 5 10 1oi
1
LAD = left anterior
descending
artery;
Nondilated Vessel 2.1 3.3 1.8 2.3 4.5 2.6
2.8 2.8 1.4 3.1 3.4 3.9 2.7
1.6
2.6 f
0.2
QM = obtuse
i
Pre
i
Post
Diluted Vessel FIGURE 1. Coronary flow reserve values for the dilated artery before and after successful percutaneous transluminal coronary angioplasty. Before and after values for individual patients are connected. The mean value after was significantly greater than that before (p
64
CORONARY
RESERVE
BEFORE
AND AFTER
ANGIOPLASTY
lished for this technique in the 10 control patients, Their average age was 45 years (range 31 to 58). Average flow reserve for arteries in these patients was 4.8 f 0.6 (n = 22; range 2.3 to 12.6). This value is similar to that found in humans by other investigators using Doppler velocity probesI or xenon washout techniques.18 Our patients who underwent PTCA had significantly lower flow reserve values in both successfully dilated (3.1 f 0.2; n = 20, range: 1.7 to 5.2, p
Discussion The most important finding of this study is that digital angiographic determination of coronary flow reserve provides information indicative of the physiologic significance of individual coronary stenoses. This study was designed to evaluate the ability of this technique to detect important changes in coronary flow reserve. Accordingly, we measured flow reserve in patients with l-vessel CAD who showed a physiologically significant coronary stenosis before PTCA and no significant stenosis after PTCA. Specifically, each patient had conversion from a positive exercise stress evaluation [or unstable angina] to a negative evaluation, a final stenosis of less than 50% and a final translesional gradient of 16 mm Hg or less. These anatomic and functional factors taken together provided convincing evidence that PTCA was successful in abolishing the physiologic abnormalities associated with the dilated stenoses. The changes in coronary flow reserve determined by digital angiographic techniques in this “best case” situation indicate a nearly uniform increase in the flow reserve after PTCA, with two-thirds of the patients increasing it 85% or more. The considerable overlap evident between patients indicates that the greatest value of individual coronary flow reserve determinations is for within subject rather than between subject comparisons. Compared with flow reserve values determined for adjacent nonstenotic arteries, values in the dilated artery increased in all but 1 patient. Several factors may influence the immediate postPTCA measurement of coronary flow reserve. The first may be responsible for the modest changes in flow reserve observed in patients 13 and 5 in this study. Coronary flow reserve is a relative measurement. Changes in basal blood flow values may markedly influence the reserve ratio. For example, the basal blood flow index (see Methods) in patient 13 doubled, from 0.08 before PTCA to 0.16 after PTCA. Hyperemic flow index, however, also increased after PTCA from 0.19 to 0.27. Thus, although hyperemic flow actually increased, the flow reserve value after PTCA (1.7) was less than that before PTCA (2.3) due to the associated increase in basal blood flow. If the basal flow index before PTCA is used to calculate flow reserve after PTCA, a value of 3.4 is obtained and is compatible with a successful procedure. No consistent, significant change in basal flow index was observed in our 20 patients. The basal flow index after PTCA was unchanged in 10 patients, higher in 6 and lower in 4
compared with the index before PTCA. In comparison, the hyperemic flow index after PTCA was higher than that before PTCA in 18 patients and was unchanged in 2. If all post-PTCA flow reserve values are recalculated using the pre-PTCA basal flow index, the average value is 3.9 f 0.4 (n = 20, range 1.4 to 7.7). Thus, due to changes in basal flow there is a tendency to underestimate flow reserve after PTCA. Although flow reserve was measured at least 20 minutes after final balloon inflation, it is possible that basal flow remained elevated in response to the dilatation process. Pathologic processes other than epicardial coronary stenoses may also influence coronary flow reserve. Myocardial hypertrophy secondary to valvular disease or hypertension,lgJO recurrent ischemia 21 and transmural myocardial infarctior+ may result’in reduced coronary flow reserve. These factors must be taken into account when interpreting flow reserve values. The coronary flow reserve in the nonstenotic neighboring arteries and in the successfully treated post-PTCA arteries was less than in normal patients. This has also been noted after successful coronary bypass surgery.23J4 Identification of factors responsible for this difference was not the objective of this investigation. However, microvascular disease, alterations of vascular regulatory mechanisms or diffuse atherosclerosis of large epicardial arteries without discrete stenoses could be present in patients with CAD. Acknowledgment: We thank Sylvia Berry and Shirley McCray for the preparation of the manuscript and the Cardiac Catheterization Laboratory staff for assistance in obtaining the data.
References 1. Levine E. Ewels CJ, Rosing DR. Kent KM. Coronary angiopfasty: clinical and angiographic follow-up. Am J Cardiol 1985;55:673-676. 2. Kent KM. Bentivoelio LA. Block PC. Bourassa MC. Cowlev MI. Dorros G. Detre KM, Gosselin-AS, G&zig AR, Kelsey SF, Mock MB, Mullin SM; Passamani ER, Myler RK, Simpson 1, Stertzer SH, Van Raden MJ, Williams DO. Long term efficacy of percutaneous transfuminal coronary angiopfasty IPTCAI: renort from the National Heart. Lune.u. and Blood Institute. Am T Cardiol 1984;53:27C-3lC. 3. Mabin TA, Holmes DR Jr, Smith HC, Vliestra RE, Reeder GS, Bresnahan IF, Bove AA. Hammes LN, Elveback LR, Orszulak TA. Follow-up clinical results in patients undergoing percutaneous transluminal coronary angioplasty. Circulation 1985;71:754-760. 4. Okada RD. Lim YL, Boucher CA, Pohost GM, Chesler DA, Block PC. Clinical angiographic, hemodynamic, perfusional and functional changes after one-vessel left anterior descending coronary angioplasty. Am J Cardiol 1985:55:347-356. 5. Klocke FJ. Measurements of coronary blood flow and degree of stenosis: current clinical implications and continuing uncertainties. JACC 1983;1:3141. 6. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Am J Cardiol 1974;33:87-94. 7. Schelbert HR, Wisenberg G, Phelps ME, Gould KL, Henze E, Hoffman E], Gomes A, Kuhl DE. Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilatation. VI. Detection of coronary artery disease in human beings with intravenous N-13 amonia positron computed tomography. Am J Cardiol 1982;49:1197-1207. 8. Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holida MD, Hartley CJ, Armstrong ML, Marcus ML, White CW. Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man. Circulation 1985;72:82-92. 9. Aueron F, Griintzig A, Vogel RA, King S, Douglas J, Meier B, O’Neill WW, Bates E, LeFree M. Effects of successful percutaneous transluminal coronary angioplasty (PTCA] on acute and chronic coronary flow reserve (abstr]. Circulation 1983;68:suppl III:III-31. 10. O’Neill WW, Walton JA, Bates ER, Colfer HT, Aueron FM, LeFree MT,
Pitt B, Vogel RA. Criteria for successful coronary angioplasty as assessed by alterations in coronary vasodilatory reserve. JACC 1984;3:1362-1390. 11. Foerster JM, Link DP, Lantz MT, Lee G, Holcroft JW, Mason DT. Measurement of coronary reactive hyperemia during clinical angiography by video dilution technique. Acta Radio1 Diog 1981;22:209-216. 12. Vogel R, Lefree M, Bates E, O’Neill WW, Foster R, Kirlin P, Smith D, Pitt B. Application of digital techniques to selective coronary arteriography: use of myocardial contrast appearance time to measure coronary flow reserve, Am Heart J 1984;107:353-164. 13. Hodgson JMcB, Legrand V. Bates ER, Mancini GBJ, Aueron FM, O’Neill WW, Simon SB, Beauman GJ, LeFree MT, Vogel RA. Validation in dogs of a rapid digital angiographic technique to measure relative coronary blood flow during routine cardiac catheterization. Am J Cardiol 1985;55:188-193. 14. Nissen SE, Elion IL, Booth DC, Evans J, DeMaria AN. Value and Jimitations of computer analysis of digital subtraction angiography in the assessment of coronary flow reserve. Circulation 1986;73:562-571, 18. Whiting JG, Drury JK, Pfaff JM, Chang BL, Eigler NL, Meerbaum S, Corday E, Nivatpumin T, Forrester JG, Swan HJC. Digital angiographic measurement of radiographic contrast material kinetics for estimation ofmyocardial perfusion. Circulation 1986;73:789-798. 16. Ellestad MH. Stress Testing. Philadelphia: F.A. Davis, 1975:207-211. 17. Wilson RF, White CW. Introcoronary papavarine: an ideal coronary
vasodilator for studies of the coronary circuiation in conscious humans. Circulation 1986;73:444-451. 18. Scheibel RL, Moore R, Korbuly D, Ovitt TW, Payne JT, Tuna N, Ampiatz K. Regional myocardial blood flow measurements in the evaluation of patients with coronary artery disease. Radiology 1975;115:379-386. 19. Marcus ML, Doty DB, Hiratza 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;307:1362-1367. 20. Wangler RD, Peters KG, Marcus ML, Tomanek RJ. Effects of duration and severity of arterial hypertension and cardiac hypertrophy on coronary vasodilator reserve. Circ Res 1982;51:10-18. 21. Nicklas JM, Gips S, Van Heyningen CA. Decreased flow reserve following transient myocardial ischemia [abstr.] JACC 1984;3:546. 22. Klein LW, Agarwal JB, Schneider RM, Hermann G, Weintraub WS, Helfant RH. Effects of previous myocardial infarction on measurement of reactive hyperemia and the coronary vascular reserve. JACC 1986;8:357-363. 23. Parker PR, Bashour FA, Downey HF, Boutros IS. Coronary reperfusion: effects of vasodilators (papavarine and adenosine]. Am Heart J 1977;93:66-72. 24. Bates ER, Aueron FM, LeFree MT, LeGrand V, Mancini GBJ, Hodgson JMcB, Vogel RA. Comparative effects of coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty on chronic regional coronary flow reserve. Circulation 1985:72:833-839.
Important alterations of coronary blood flow and coronary flow reserve occur during percutaneous transluminal coronary angioplasty (PTCA). This study evaluated these alterations using digital subtraction angiography. Coronary flow reserve was determined before and after successful PTCA in 20 patients with l-vessel coronary artery disease (CAD). Ten other patients with angiographically normal coronary arteries, normal exercise electrocardiographic responses and normal cardiac structure also were evaluated. Coronary flow reserve was calculated as the ratio of papavarine-induced hyperemit flow to basal flow. Flow reserve for the stenotic artery in patients who underwent PTCA was 1.6 f 0.2 (mean f standard error of the mean) (range 0.9 to 3.9, n = 20). After successful PTCA, flow reserve for this artery increased to 3.1 f 0.2
P
ercutaneous transluminal coronary angioplasty (PTCA) can relieve epicardial coronary artery obstruction and related manifestations of myocardial ischemia.1-4 Patients who undergo successful PTCA provide an excellent model for assessing important alterations of coronary blood flow and coronary flow reserve. The value of coronary flow reserve in assessing the physiologic significance of coronary stenoses is well established.5-10 Digital subtraction imaging performed during coronary angiography before and after intracoronary papavarine administration enables determination of an index that reflects regional coronary flow reserve.11-15 We used digital angiography to investigate coronary flow reserve alterations in 20 paFrom the Division of Cardiology, Rhode Island Hospital and Brown University Program in Medicine, Providence, Rhode Island. Manuscript received January l&1987; revised manuscript received and accepted February 19,1987. Address for reprints: David 0. Williams, MD, Division of Cardiology, Rhode Island Hospital, Providence, Rhode Island 02902.
(range 1.7 to 5.2, n = 20) (p
tients who had clearcut evidence of significant stenoses before PTCA and in whom the procedure was successful, that is, resulted in a final translesional gradient of 16 mm Hg or less, an angiographic stenosis less than 50% in diameter, and absence of stress-induced ischemia.
Methods Patient selection: All patients with l-vessel coronary artery disease [CAD] undergoing PTCA between January and May 1985 were eligible (n”= 45). Coronary flow reserve measurements were routinely attempted in all patients undergoing PTCA unless the patient’s condition was unstable or when logistic constraints existed. In some patients, technical factors (such as atria1 fibrillation, excessive motion and inadequate catheter support) precluded adequate studies. Patients who also met the following criteria were selected for this study: successful PTCA with residual stenosis less than 50% diameter narrowing; electrocardiographic or thallium-201 scintigraphic exercise evaluation before PTCA that was positive for ischemia; exercise evalu-
62
CORONARY
RESERVE
BEFORE
AND AFTER
ANGIOPLASTY
ation after PTCA that was negative for &hernia; and absence of associated valve disease or evidence of left ventricular hypertrophy by electrocardiogram or echocardiogram. Ten patients who met the following criteria were studied as controls: 11) normal epicardial coronary arteries by angiography; (2) normal exercise electrocardiographic response; (3) absence of left ventricular hypertrophy by electrocardiogram or echocardiogram; (4) absence of congenital or acquired structural cardiac abnormalities; (5) normal contrast ventriculographic or radionuclide angiographic findings. All control patients were undergoing clinically indicated diagnostic catheterization for evaluation of chest pain. Coronary flow reserve determinations: Coronary flow reserve was determined using digital angiography as previously described.12*13 Heart rate was controlled by atria1 pacing. Digital images were obtained during precisely timed electrocardiographically gated power injections of meglumine and sodium diatrizoate (Renografin 76@). Image acquisition was programmed to begin precisely at the time of injection and once during each subsequent cardiac cycle for 15 cycles. Radiographic variables were held constant throughout image acquisition. Composite images were constructed that display the progression of radiographic contrast through the coronary circulation using color modulation, and the volume of contrast distribution using intensity modulation. Composite images were produced during baseline flow and during induced hyperemia 30 to 45 seconds after intracoronary injection of papavarine hydrochloride (10 mg for the left coronary, 5 mg for the right coronary). For analysis, regions of interest were operator selected over the distal myocardial perfusion bed of the artery under study. A flow index was calculated for each defined region using both intensity and transit time information. Regional coronary flow reserve was calculated as the ratio of hyperemic to baseline flow indexes. Reproducibility of this technique was assessed by repeated baseline flow determinations in patients with both stenotic and nonstenotic vessels (n = 27). Determinations 1 and 2 differed by an average of 6 f 9% (mean f standard deviation; 95% confidence limits f27%).
Catheterization protocol: Patients who underwent PTCA received nitrates, calcium channel blocking drugs, aspirin and dipyridamole for at least 12 hours before PTCA, and were premeditated with diazepam, 10 mg orally and 5 mg intravenously, diphenhydramine, 50 mg orally, and nifedipine, 10 mg orally, at the beginning of the procedure. In control patients all medications were withheld for at least 8 hours before catheterization. Control patients then received premedication of diphenydramine, 50 mg orally, and diazepam, 10 mg orally. Control patients did not receive nifedipine. Cardiac catheterization and coronary angiography were performed using the Judkins technique. Selective angiograms of the coronary arteries were recorded, after which coronary flow reserve was measured as described above using a standard angiograph-
ic catheter. PTCA was then performed. Final translesional gradient was defined as the mean pressure differential across the dilated segment measured at least 10 minutes after the final balloon inflation, At least 20 minutes after the final balloon inflation, postPTCA coronary flow reserve was determined at the same heart rate and using the same radiographic and injection parameters as the pre-PTCA flow reserve determination. When possible (14 of 20 cases], coronary flow reserve was also determined for an adjacent nondilated, nonstenotic coronary artery. No patients received intracoronary vasodilating drugs within 20 minutes of flow reserve determination. Maximal stenoses before and after PTCA were determined by averaging hand-held-caliper-measured percent diameter reduction obtained from at least 2 angiographic projections that clearly displayed the lesion. Minimal luminal diameter in the lesion was compared with that in the normal adjacent proximal segment. Exercise stress evaluation: Sixteen patients underwent pre-PTCA upright treadmill exercise evaluation using either the Bruce or modified Naughton protocols. Exercise electrocardiograms were interpreted by 2 experienced cardiologists and were graded positive or negative for ischemia using the criteria of Ellestad.16 Eight of these patients underwent associated thallium201 scintigraphy immediately after exercise and 3 to 4 hours later. These were interpreted by a blinded, experienced nuclear cardiologist and graded positive for ischemia if they showed a qualitative or quantitative immediate postexercise perfusion defect with partial or complete redistribution on the delayed images. All patients evaluated with exercise testing had either an ischemic electrocardiographic result, an ischemic thallium result or both. Four other patients presented with unstable angina and had reversible electrocardiographic repolarization abnormalities during chest pain. They were considered to have objective evidence of ischemia. All patients underwent post-PTCA upright treadmill exercise evaluation and 4 underwent associated thallium-201 scintigraphy. These examinations were graded as described above and none showed evidence of stress induced ischemia. Thus, all PTCA patients had objective evidence of ischemia before PTCA that was no longer present after the procedure. Control patients all had upright treadmill exercise evaluations. In all cases a pressure-rate product of more than 250,000 was achieved without electrocardiographic evidence of ischemia or angina1 chest pain. Statistical analysis: Paired t tests were used to compare variables before and after PTCA. Unpaired t tests were used to compare PTCA patients and control patients. A p value <&@?I was considered significant. All values are given as mean f standard error of the mean unless otherwise noted.
Results Clinical characteristics: Twenty patients who underwent PTCA were identified who met criteria for
duly 1, 1987
TABLE
I
Catheterization
Results
Before
and
After
THE AMERICAN
JOURNAL
Translesional Gradient (mm Hg)
% Stenosis Pt
1 LAD 2 LAD 3 LAD 4 LAD 5 LAD 6 LAD 7 LAD 8 LAD 9 LAD IO LAD 11 LAD 12 LAD 13 LAD 14 LAD 15 LAD 16 OM 17 OM 18 Right 19 Right 20 Right Mean i SEM
Prior AMI
-
+ + -
+ + -
Dilated
Pre
Post
Pre
Post
76 85 57 78 73 95 75 78 80 95 50 77 67 a4 57 68 83 81 94 58 76 i 3
33 41
67 65 81 63 55 58 68 52 59 71 56 64 37 67 61 40 51 65 60 60 60 rt 2
13 4 14 13 4
1.4 1.2 1.8 1.3 3.9 0.9 1.0 1.7 1.2 1.4 1.5 1.9 2.3 1.2 1.2 2.1 2.6 0.9 0.9 1.8 1.6 f 0.2
3.4 2.4 3.7 2.2 3.3 1.7 3.9 3.3 5.2 3.0 1.8 2.8 1.7 2.2 3.6 2.8 3.0 1.7 3.4 3.4 3.1 f 0.2
AMI = prior non-Q-wave infarction; CA = coronary marginal artery; SEM = standard error of the mean.
artery;
inclusion in this study. The dilated artery was the left anterior descending in 15 cases, a major obtuse marginal in 2 and the right coronary in 3. In 4 patients the dilated artery supplied a myocardial region with previous non-Q-wave infarction; these 4 patients had normal motion or mild hypokinesia of the infarct region on contrast ventriculography. Catheterization results: Catheterization results are summarized in Table I. The nondilated arteries were free of discrete stenoses. Many, however, had intimal irregularities. Mean coronary flow reserve for the dilated artery increased from 1.6 f 0.2 to 3.1 f 0.2 (p
53
Vessel
Post
a
60
Flow Reserve
Pre
40 18 26 38 18 10 10 40 40 22 25 8 0 0 15 38 0 22 f 3
Volume
Successful Coronary
CA Dilated
OF CARDIOLOGY
’ 1. 10
a a 15 12 11 9 11 8 4 16 15 5 10 1oi
1
LAD = left anterior
descending
artery;
Nondilated Vessel 2.1 3.3 1.8 2.3 4.5 2.6
2.8 2.8 1.4 3.1 3.4 3.9 2.7
1.6
2.6 f
0.2
QM = obtuse
i
Pre
i
Post
Diluted Vessel FIGURE 1. Coronary flow reserve values for the dilated artery before and after successful percutaneous transluminal coronary angioplasty. Before and after values for individual patients are connected. The mean value after was significantly greater than that before (p
64
CORONARY
RESERVE
BEFORE
AND AFTER
ANGIOPLASTY
lished for this technique in the 10 control patients, Their average age was 45 years (range 31 to 58). Average flow reserve for arteries in these patients was 4.8 f 0.6 (n = 22; range 2.3 to 12.6). This value is similar to that found in humans by other investigators using Doppler velocity probesI or xenon washout techniques.18 Our patients who underwent PTCA had significantly lower flow reserve values in both successfully dilated (3.1 f 0.2; n = 20, range: 1.7 to 5.2, p
Discussion The most important finding of this study is that digital angiographic determination of coronary flow reserve provides information indicative of the physiologic significance of individual coronary stenoses. This study was designed to evaluate the ability of this technique to detect important changes in coronary flow reserve. Accordingly, we measured flow reserve in patients with l-vessel CAD who showed a physiologically significant coronary stenosis before PTCA and no significant stenosis after PTCA. Specifically, each patient had conversion from a positive exercise stress evaluation [or unstable angina] to a negative evaluation, a final stenosis of less than 50% and a final translesional gradient of 16 mm Hg or less. These anatomic and functional factors taken together provided convincing evidence that PTCA was successful in abolishing the physiologic abnormalities associated with the dilated stenoses. The changes in coronary flow reserve determined by digital angiographic techniques in this “best case” situation indicate a nearly uniform increase in the flow reserve after PTCA, with two-thirds of the patients increasing it 85% or more. The considerable overlap evident between patients indicates that the greatest value of individual coronary flow reserve determinations is for within subject rather than between subject comparisons. Compared with flow reserve values determined for adjacent nonstenotic arteries, values in the dilated artery increased in all but 1 patient. Several factors may influence the immediate postPTCA measurement of coronary flow reserve. The first may be responsible for the modest changes in flow reserve observed in patients 13 and 5 in this study. Coronary flow reserve is a relative measurement. Changes in basal blood flow values may markedly influence the reserve ratio. For example, the basal blood flow index (see Methods) in patient 13 doubled, from 0.08 before PTCA to 0.16 after PTCA. Hyperemic flow index, however, also increased after PTCA from 0.19 to 0.27. Thus, although hyperemic flow actually increased, the flow reserve value after PTCA (1.7) was less than that before PTCA (2.3) due to the associated increase in basal blood flow. If the basal flow index before PTCA is used to calculate flow reserve after PTCA, a value of 3.4 is obtained and is compatible with a successful procedure. No consistent, significant change in basal flow index was observed in our 20 patients. The basal flow index after PTCA was unchanged in 10 patients, higher in 6 and lower in 4
compared with the index before PTCA. In comparison, the hyperemic flow index after PTCA was higher than that before PTCA in 18 patients and was unchanged in 2. If all post-PTCA flow reserve values are recalculated using the pre-PTCA basal flow index, the average value is 3.9 f 0.4 (n = 20, range 1.4 to 7.7). Thus, due to changes in basal flow there is a tendency to underestimate flow reserve after PTCA. Although flow reserve was measured at least 20 minutes after final balloon inflation, it is possible that basal flow remained elevated in response to the dilatation process. Pathologic processes other than epicardial coronary stenoses may also influence coronary flow reserve. Myocardial hypertrophy secondary to valvular disease or hypertension,lgJO recurrent ischemia 21 and transmural myocardial infarctior+ may result’in reduced coronary flow reserve. These factors must be taken into account when interpreting flow reserve values. The coronary flow reserve in the nonstenotic neighboring arteries and in the successfully treated post-PTCA arteries was less than in normal patients. This has also been noted after successful coronary bypass surgery.23J4 Identification of factors responsible for this difference was not the objective of this investigation. However, microvascular disease, alterations of vascular regulatory mechanisms or diffuse atherosclerosis of large epicardial arteries without discrete stenoses could be present in patients with CAD. Acknowledgment: We thank Sylvia Berry and Shirley McCray for the preparation of the manuscript and the Cardiac Catheterization Laboratory staff for assistance in obtaining the data.
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