Periprocedural Doppler coronary blood flow predictors of myocardial perfusion abnormalities and cardiac events after successful coronary interventions

Periprocedural Doppler coronary blood flow predictors of myocardial perfusion abnormalities and cardiac events after successful coronary interventions D. Douglas Miller, MD, Jose Esparza-Negrete, MD, Thomas J. Donohue, MD, Carol Mechem, RN, Leslee J. Shaw, PhD, Sheila Byers, RN, and Morton J. Kern, MD St. Louis, Mo.

Thirty-four consecutive patients had coronary flow velocity assessed under basal and hyperemic conditions in the proximal and distal coronary artery, followed by rest-stress technetium 99m sestamibi myocardial tomography within 3 months of successful coronary angioplasty. In spite of significant angiographic improvement, 29% of patients had a persistent reversible myocardial perfusion defect associated with a residual abnormality of the proximal-to-distal coronary average peak velocity ratio (p/d APV = 2.2 ± 1.5 vs 1.1 ± 0.6; p = 0.02). Patients with an abnormal p/d APV ratio (>1.7) had more numerous angioplasty-zone perfusion defects (4.2 ± 3.3 vs 0.8 ± 2.0; p = 0.005). Multivariable analysis of clinical, angiographic, coronary flow, and scintigraphic data demonstrated that the relative risk of cardiac events (n = 11) was greatest in patients with a reversible angioplasty-zone perfusion defect (relative risk, 5.5), poststenotic coronary flow reserve <2.0 (relative risk, 8.3) and p/d APV ratio >1.7 (relative risk, 6.2). Residual basal coronary flow-velocity abnormalities are significant physiologic correlates of stress-induced myocardial perfusion defects and are a prognostic covariable associated with future ischemic cardiac events. (Am Heart J 1996;131:1058-66.)

The diagnostic and prognostic value of thallium-201 myocardial perfusion imaging has been extensively studied in percutaneous transluminal coronary angioplasty (PTCA). 1-3 Persistent 3- to 4-hour postStress thallium-201 defects occur in 23% to 33% of patients without angiographic restenosis who are imaged within 4 weeks of angiographically successful PTCA, 4"9 frequently confounding the clinical significance of postangioplasty myocardial perfusion studies. A continuum of mildly malperfused to severely ischemic myocardium exists in these postanFrom the Department of Internal Medicine, Divisions of Cardiology and Nuclear Medicine, Saint Louis University Health Sciences Center. Received for publication Sept. 22, 1995; accepted Nov: 1,. 1995. Reprint requests: D. Douglas Miller, MD, Director of Nuclear Cardiology, Division of Cardiology, 14th floor, Saint Louis University Health Sciences Center, PO Box 15250, 3635 Vista Avenue at Grand Blvd., St. Louis, Missouri 63110-0250. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1/71364

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gioplasty perfusion beds, where resulting abnormalities of thallium-201 clearance can create poststress perfusion defects that are slow to improve after the reestablishment of blood flow. 6, 10 The planar thallium-201 scintigraphic, coronary angiographic, and translesional pressure correlates of postangioplasty restenosis and cardiac events have been described. 11, 12 In spite of its proven clinical value in other popurations with coronary disease, 13-16stress technetium 99m sestamibi myocardial perfusion imaging has not been extensively evaluated after coronary angioplasty.17, is Although it may appear reasonable to extrapolate post-angioplasty thallium-201 imaging results to the use of 99mTc sestamibi, the biokinetic and imaging properties of 99mTcsestamibi are tmique, and no study has evaluated the prognostic value of stress 99mTc sestamibi tomography after coronary angioplasty. It was hypothesized that residual abnormalities of basal coronary blood flow or flow reserve may contribute to the occurrence of angioplasty myocardialperfusion defects and cardiac events. Experimental studies have demonstrated that postbarotrauma disturbances of vasomotor tone can contribute to abnormal coronary flow reserve (CFR) in angioplasty vascular beds. 19 Although basal proximal and distal coronary-flow velocities improve rapidly after successful angioplasty, 2° CFR is initially depressed after balloon dilatation, normalizing in most patients without restenosis who are studied serially. 21 Recently excellent correlations have been observed between directly measured poststenotic coronary flow and noninvasive stress-induced tomographic myocardial defects in poststenotic perfusion beds of medically treated patients with stable angina. 22, 23 The main objectives of this study were to delineate the angiographic and coronary blood-flow correlates and to define the prognostic significance of stress 9 9 m T c sestamibi myocardial perfusion defects ob-

Volume 131, Number 6 American Heart Journal

served w i t h i n 3 m o n t h s of a n g i o g r a p h i c a l l y successful c o r o n a r y a n g i o p l a s t y interventions.

METHODS Patient recruitment. Patients were recruited from a consecutive population referred to the cardiac catheterization laboratory of Saint Louis University Health Sciences Center for coronary angioplasty between February 1991 and June 1994. All patients provided informed consent for the performance of coronary blood-flow determinations during angioplasty and for clinical follow-up according to a protocol approved by the Institutional Review Board. In this study, PTCA was classified as angiographically successful if a <50% residual stenosis and a percentage improvement of >40% diameter stenosis were achieved in the absence of significant procedural complications (i.e., acute reocclusion, flow-limiting arterial dissection). Only those patients with an angiographically successful PTCA were considered for further diagnostic studies and clinical follow-up. Referring physicians were made aware of the angiographic results of the angioplasty procedure but were blinded as to the results of postangioplasty coronary-flow studies. In spite of the angiographic success of the PTCA procedure, these physicians were asked to consider the performance of post-angioplasty stress myocardial-perfusion-imaging studies within 3 months. A total of 34 patients provided informed consent to participate, completed the required diagnostic studies, and was available for follow-up. Coronary velocity measurements. A l l coronary f l o w velocity measurements were performed with a 12 MHz Doppler-tipped 0.018-inch angioplasty guide wire (FloWire, Cardiometrics, Inc., Mountain View, Calif.), as previously described. 2°, 23 Coronary-flow velocities can be recorded up to 4 m/sec without aliasing. This forward-directed ultrasound beam with a 27-degree divergent angle samples the major portion of the coronary-flow profile. Velocity data are processed by online fast Fourier transformation with a real-time scrolling spectral grayscale display. Before coronary angioplasty, each patient received 10,000 units ofheparin intravenously. The Doppler guide wire was then advanced through an 8F balloon-guiding catheter into the coronary artery. Flow velocities were obtained - I cm proximal and then 2 cm distal to the stenosis at rest, and again during maximal coronary hyperemia induced by intracoronary adenosine (6 to 12 ~g in the right coronary artery, 12 to 18 pg in the left coronary attery).20, ~3 The guide wire was carefully positioned to avoid sampling velocities from the peristenotic zone of flow acceleration. Systemic pressure was continuously monitored at the ostium of the coronary catheter to avoid catheter occlusion of the proximal vessel, which could affect pressure and flow responses. The same technique was employed for coronary-flow measurements after angioplasty. All stenoses were located in the proximal or middle portion of a major epicardial vessel. In this study, hyperemic flow reserves were not routinely measured in adjacent normal or less diseased vessels.

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Table I. Clinical characteristics n(%) Gender (male, %) Age (mean ± SD yr) Indication for PTCA Stable angina UnStable angina After MI* Coronary risk factors Hypertension Diabetes mellitus Smoking High cholesterol Previous conditions CABG PTCA Congestive heart failure MI

19 (56) 57 ± 14 8 (23) 20 (59) 6 (18) 20 (59) 8 (26) 16 (47) 12 (35) 4 (12) 3 (9) 3 (9) 10 (29)

*Includes four PTCA procedures performed within 24 hours of myocardial infarction (MI). CABG, Coronary artery bypass grafting of the index coronary artery; PTCA, percutaneous transluminal coronary angioplasty of the index coronary artery.

Doppler signal analysis. The coronary-flow velocity Doppler spectral envelope was automatically identified by custom-developed software interfaced with the signal analyzer. Digitized spectral peak-velocity waveforms from two cardiac cycles were averaged to compute the average peak velocity (centimeters per second). The peak velocity was integrated as the area under the curve defined by the combined systolic and diastolic coronary velocity spectra. The ratio of basal proximal-to-distal average peak velocities (p/d APV) was computed. Coronary flow reserve was computed as the peak hyperemic/resting APV ratio measured at the respective guide wire position: Post-PTCA CFR was measured 10 minutes after angioplasty. From previous studies in our laboratory, a normal distal coronary-flow velocity reserve was defined as >2.0, 23 and a normal p/d APV ratio was defined as -<1.7.24 Quantitative coronary angiography. After intracoronary administration of nitroglycerin, multiple orthogonal coronary angiographic views were obtained in all patients. When feasible, two orthogonal angiographic views, separated by - 90 degrees, were acquired. End-diastolic cineangiographic frames were selected for quantitative analysis to minimize cardiac motion artifact and to maximize contrast filling of the coronary vessel. A commercially available quantitative cardiovascular angiographic software program (Philips D.C.I., Automated Coronary Analysis, The Netherlands) was used. Angiographic analysis was performed by experienced operators who were blinded to the coronary-flow and scintigraphic data. Proximal and distal coronary artery dimensions at the sites of flow measurements, percentage diameter and cross-sectional area stenosis, and obstruction diameter (in millimeters) were measured. Data from the angiographic view demonstrating the most severe stenosis were used for comparison with the coronary-flow and myocardial-imaging results.

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1060 Miller et al.

Table II. Coronary angiography, Doppler flow, a n d angio-

Table IV. Postangioplasty coronary angiographic a n d flow

plasty d a t a

correlates of 99mTc sestamibi perfusion abnormalities

PTCA vessel Left anterior descending artery First diagonal branch Left circumflex artery Right coronary artery Bypass graft Pre-PTCA Mean %DS Mean MLD (mm) Change in DS (%) Distal coronary-flow reserve p/d APV ratio Post-PTCA Mean %DS Mean MLD (ram) Change in DS (%) Distal coronary-flow reserve p/d APV ratio

13 (38%) 2 (6%) 6 (18%) 10 (29%) 3 (9%) 78.3 ± 15.1 0.7 ± 0.4 1.6 ± 0.7 2.4 ± 2.3 23.8 ± 2.1 ± 55 ± 1.7 ±

11.0" 0.54 9 0.6

1.4 ± 1.0

%DS, Percentage diameter stenosis; MLD, minimal luminal diameter. *p < 0.01 vs before PTCA. tP < 0.05 vs before PTCA.

Table III. Postangioplasty stress a n d myocardial perfusion imaging data Stress testing ST depression ->1 mm Angina Time from PTCA to stress test (wk) 99raTa sestamibi myocardial imaging* Abnormal scan ->1 reversible perfusion defect No. total defects No. fLxed defects No. reversible defects No. combined defects Increased lung activity Increased left ventricular sizet

8 (24%) 2 (6%) 4.7 _+ 3.7 13 (38%) 10 (29%) 1.6 +- 2.5 0.9 _+ 1.7 0.8 ± 1.5 0.4 ± 1.0 0 (0) 6 (13%)

*Myocardial defect data restricted to PTCA vessel-perfusion bed. tResting LV dilation in 4 patients, transient in 2 patients.

Myocardial perfusion imaging. A previously described 1316 99mTc s e s t a m i b i single-photon emission comp u t e d t o m o g r a p h y (SPECT) protocol was used with either exercise or pharmacologic stress. A large field-of-view single-crystal tomographic i m a g i n g system was equipped w i t h a high-resolution collimator to acquire i m a g i n g d a t a into a 64 × 64 computer m a t r i x with a 2.0 zoom. A noncontinuous rotational acquisition was performed with 30 stops of 40 seconds each in t h e prone position over a 180-degree angle of rotation beginning a t +150 degrees. S a m e day rest-stress i m a g i n g was performed at 45 to 60 m i n u t e s after the r e s t injection of 7 to 10 mCi of99mTc sestamibi. Stress images were acquired within 60 m i n u t e s aft e r the injection of 20 to 25 mCi of 99mTc sestamibi. Stan-

PTCA-scan interval (wk) %DS Change in DS (%) Min. luminal diameter (mm) Distal CFR Distal APV (cm/sec) Proximal APV (cm/sec) p/d APV ratio

No reversible defect (n = 24)

Reversible defect (n = 10)

p Value

4.9 _+ 3.3

4.2 _+4.6

NS

24 -+ 11 -51.5 -+ 18.6

23 -+ 13 -61.7 _+ 20.3

NS NS

2.1 +- 0.5

2.3 ± 0.6

NS

1.8 _+ 0.6 28.6 -+ 14.7

1.6 _+0.8 22.5 + 12.7

NS NS

28.4 ± 15.6

31.1 -+ 10.6

NS

1.1 -+ 0.6

2.2 _+ 1.5

0.02

%DS, Percentage diameter stenosis.

d a r d filtered back-projection techniques were used to generate t r a n s a x i a l tomograms with a B u t t e r w o r t h filter with a cut-offfrequency of 0.66 cycle/cm a n d power of 2.5 (stress) or 0.50 cycle/cm and power of 5.0 (rest). Oblique-angle tom o g r a m s h a d a thickness of one pixel (0.625 cm). I m a g e i n t e n s i t y was m a x i m i z e d for rest a n d stress studies to the hottest pixel in each image set. A Y-directional filter was used for interslice averaging. Review of r a w d a t a sets by rotation projection revealed no evidence of significant soft-tissue a t t e n u a t i o n and motion artifact. Oblique-image reconstruction was performed in the vertical long-axis, horizontal short-axis, and horizontal-long axis views. 25 A 20-segment per s t u d y division of myocardial activity was used. 26 Myocardial territories subtended by each of the three m a i n coronary arteries (left anterior descending, left circumflex, a n d right coronary arteries) were assigned from previous reports of SPECT perfusion territories. 27 I m a g e s were reviewed by two i n d e p e n d e n t expert observers blinded to the catheterization results with both radiographic film a n d computerized (Delta M a n a g e r System, Medimage Co., A n n Arbor, Mich.) displays of corresponding r e s t and stress oblique tomograms. A perfusion a b n o r m a l i t y was defined as at l e a s t one s e g m e n t in the perfusion territory of the target vessel t h a t d e m o n s t r a t e d decreased activity in poststress images, with p a r t i a l or complete reversibility on the corresponding rest images. Apical segments were counted as defects only when contiguous with adjacent a b n o r m a l myocardial segments. Discordance between the two observers was resolved by a t h i r d blinded reviewer. Hyperemic pharmacologic stress testing. The drug infusion protocols for i m a g i n g studies used s t a n d a r d intravenous doses of adenosine a n d dipyridamole, which have been v a l i d a t e d and a r e routinely used in our laboratory.16, 23 Testing was performed in the morning, w i t h the p a t i e n t in a fasting state, by experienced personnel who r a n d o m l y selected the pharmacologic stress agent to be

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Table V. Postangioplasty angiographic flow and scinti-

Table VI. Postangioplasty clinical, angiographic, coronary

graphic correlates of a n abnormal* proximal-to-distal APV ratio

flow a n d 99mTc sestamibi scintigraphic characteristics of patients with recent M I versus no MI

PTCA-scan interval (wk) %DS Change in DS (%) Min. luminal diameter (mm) Distal CFR Distal APV (cm/sec) Proximal APV (cm/sec) No. total defects No. fixed defects No. reversible defects

Abnormal p / d A P V ratio

Normal p / d A P V ratio

p Value

2.7 _+ 3.4

3.9 -+ 2.9

NS

18 -+ 11 -68 -+ 21

26 _+ 11 -55 -+ 17

NS NS

2.0 ± 0.6

2.2 -+ 0.5

NS

2.2 -+ 0.9 15 ± 5

1.5 ± 0.4 29 -+ 15

NS 0.03

36 ± 10

28 _+ 15

NS

4.2 -+ 3.3

0.8 -+ 2.0

0.005

2.4 -+ 2.9

0.3 z 1.1

0.01

1.8 -+ 2.2

0.5 -+ 1.2

0.07

%DS, Percentage diameter stenosis. *Proximal-to-distal APV ratio >1.7.

used. H e a r t rate, 12-lead electrocardiogram, and blood p r e s s u r e m e a s u r e m e n t s were obtained with the p a t i e n t in a supine position before initiation of the infusion, a n d at 1-minute intervals thereafter. Adenosine was administ e r e d by a controlled infusion system at a r a t e of 0.14 mg/ kg/min for 6 m i n u t e s in three patients. Isometric handgrip exercise was performed in the supine position for 3 m i n u t e s after the completion of adenosine infusion. I n eight patients, dipyridamole was infused at a r a t e of 0.14 mg/kg/min for 4 minutes, after which the p a t i e n t a s s u m e d a sitting position a n d b e g a n active leg swinging for 4 minutes. 99mTc S e s t a m i b i was infused 4 m i n u t e s after the initiation of adenosine infusion a n d 4 to 5 m i n u t e s after the completion of dipyridamole infusion. No changes or interruptions were m a d e in cardiac medication regimens before vasodilator drug infusion, although methylxanthine-cont a i n i n g medications were withheld for 48 hours before these studies. Exercise stress testing. A symptom-limited treadmill stress protocol 2s was used in 23 patients. The h e a r t r a t e a n d blood p r e s s u r e were m e a s u r e d , a n d a 12-lead electrocardiogram (ECG) was obtained before exercise, at the end of each exercise stage, and every 3 m i n u t e s for ->6 m i n u t e s after exercise. I n p a t i e n t s without ST abnormalities on the p r e t e s t 12-lead ECG, horizontal or downs]oping ST depression ->1 m m was considered to be diagnostic of myocardial ischemia. ST-segment responses were not analyzed in p a t i e n t s receiving digoxin a n d those with left ventricul a r hypertrophy, left bundle b r a n c h block, or nonspecific ST repolarization a b n o r m a l i t i e s on the p r e t e s t ECG. 99mTc

Age

(mean _+ SD yrs) % Diam. stenosis change Distal APV (cm/sec) p/d APV ratio Distal CFR No. total defects No. fixed defects No. reversible defects

Recent M I (n = 6)

No M I (n = 28)

p Value

48_+11

60_+13

NS

-64 _+22

-53 ± 19

NS

20 _+ 3

28 _+ 15

NS

1.6 _+0.8 1.1 _+ 0.1 2.7 = 2.8

1.5 _+ 1.6 1.9 _+0.6 1.3 _+2.4

NS <0.05 NS

1.3 + 2.0

0.7 ± 1.7

NS

1.4 + 1.9

0.6 _+ 1.3

NS

MI, Myocardial infarction.

sestamibi was a d m i n i s t e r e d I to 2 m i n u t e s before the end of exercise stress. Statistics. Two-way analysis of variance with Scheff~'s test was used to compare multiple subgroups of continuous variables. Continuous angiographic a n d clinical variables are reported as the m e a n value - 1 s t a n d a r d deviation. Intergroup differences were considered significant at a probability (p) value <0.05. Relative risks and 95% confidence limits (Cox proportional h a z a r d s model) also were calculated for variables t h a t were significant by u n i v a r i a t e analysis.29, 30 Model overfitting procedures were followed with no more t h a n t h r e e variables included in a n y multivariable model. Variables with a u n i v a r i a t e p < 0.20 were used in the m u l t i v a r i a b l e models. A final mu]tivariable model was defined by forward stepwise procedure and included only two variables. Multicolinearity (r > 0.80) was not p r e s e n t among a n y of the i n d e p e n d e n t variables.

RESULTS Patient population. T h e c l i n i c a l c h a r a c t e r i s t i c s o f t h e s t u d y p o p u l a t i o n a r e s u m m a r i z e d i n T a b l e I. T h e m a j o r i t y o f p a t i e n t s h a d e i t h e r s t a b l e (23%) o r u n s t a b l e (59%) a n g i n a p e c t o r i s t h a t w a s u n r e s p o n s i v e to m e d i c a t i o n a s t h e i n d i c a t i o n for a n g i o p l a s t y . S i x (18%) p a t i e n t s u n d e r w e n t a n g i o p l a s t y w i t h i n 1 w e e k a f t e r a m y o c a r d i a l i n f a r c t i o n . F i v e (15%) p a t i e n t s had previously undergone coronary revascularizat i o n s u r g e r y , i n c l u d i n g 4 (12%) p a t i e n t s w i t h s t e n o t i c o r o c c l u d e d g r a f t s to t h e i n d e x a r t e r y . S i x (18%) p a t i e n t s h a d p r i o r P T C A p r o c e d u r e s , i n c l u d i n g 3 (9%) p a t i e n t s w i t h a n a n g i o p l a s t y 4 -+ 3 m o n t h s b e f o r e to the index coronary artery. Coronary angiography and angioplasty. T h e q u a n t i tative coronary angiographic findings obtained before and after angioplasty are summarized in Table

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1062 Miller et al.

Table VII, Comparison of stress myocardial imaging, coronary flow, and angiographic data in patients with and without cardiac events

ECG stress Angina (%) ST depression (%) PTCA-scan interval (wk) Myocardial imaging Abnormal scan (%) No. total defects No. f~xed defects No. rev. or combined defects Angiography Before PTCA %DS* Before PTCA MLD* After PTCA %DS After PTCA MLD Coronary flow after PTCA~ Distal CFR p/d APV ratio

N o cardiac event (n = 23)

Cardiac event (n = 11)

p Value

9% 22% 5.1 +_ 3.8

4% 27% 3.8 _+ 3.4

NS NS NS

27% 1.6 _+ 2.5 1.1 _+ 2.0 0.2 +_ 0.6

43% 1.3 _+ 2.4 0.3 _+ 0.8 0.8 +- 1.7

NS NS NS NS

77.1 0.8 24.6 1.5

-- 14.9 -+ 0.4 +_ 12.5 _+ 1.1

80.7 0.6 22.2 2.0

!.7 -+ 0.6 1.5 -+ 1.1

_ 15.9 __ 0.4 -+ 7.5 -+ 0.5

NS NS NS NS

1.9 -- 0.9 1.3 +- 0.8

NS NS

%DS, percentage diameter stenosis; MLD, minimal luminal diameter (ram). *Includes 4 patients after MI with subtotal coronary occlusion before PTCA. tMeasured 5-10 minutes after PTCA.

Table VIII. Multivariable Cox regression modeling of cardiac event risk after PTCA Event rate (%) ECG ST depression >-1 m m Post-PTCA %DS >30% Reversible defect >-1 Distal coronary flow reserve -<2.0 p/d APV ratio >1.7 >-1 Reversible defect + p/d APV ratio >1.7

38 15 50 60 53 60

Relative risk (95% C.I.) 2.1 0.3 5.5 8.3 6.2 2.3

(0.5-8.9) (0.1-1.7) (1.0-10.0) (2.5-17.1) (1.2-10.4) (1.5-3.6)

Chi-square

p Value

1.12 1.94 2.93 2.56 3.94 4.22

0.30 0.16 0.08 0.07 0.04 0.03

%DS, Percentage diameter stenosis; 95% C.I., 95% confidence intervals.

II. A total of 24 (71%) patients had multiple vessel coronary artery disease. After angioplasty, the percentage diameter stenosis and minimal luminal diameter both improved significantly (bothp < 0.001). The average change in pre-PTCA to post-PTCA percentage diameter stenosis was 55% - 19%. Three patients required endoluminal stent placement to optimize vessel patency after PTCA. Coronary blood flow. Proximal and distal intracoronary parameters of coronary-flow velocity are summarized in Table II. When distal (i.e., poststenotic) Doppler APV was measured and corrected for proximal coronary inflow velocity, the ratio of p/d APV values improved from 2.4 +_ 2.3 before PTCA to 1.4 _+ 1.0 after PTCA (p < 0.10). The distal coronary flow-velocity reserve did not change after angioplasty (from 1.6 _+ 0.7 to 1.7 +_ 0.6; p = NS) (Fig. 1). Stress testing. The results of symptom-limited stress testing are presented in Table III. An average

interval of 4.7 -+ 3.7 weeks (range, 1 to 12 weeks) elapsed between the index angioplasty procedure and stress testing with perfusion imaging. The majority (82%) of stress-imaging studies were ordered as part of the routine follow-up of patients enrolled in this protocol. In 3 (9%) patients, stress imaging was performed to evaluate recurrent chest pain. No serious adverse effects were observed during either exercise-stress or drug-stress testing. 99mTCsestamibi myocardial tomography. The results of postangioplasty rest-stress 99mWc sestamibi myocardial perfusion studies are presented in Table III. Myocardial perfusion defects were present in the angioplasty vessel perfusion bed of 13 (38%) patients, with 10 (29%) patients demonstrating predominantly reversible defects. The number of perfusion angioplasty-zone defects averaged 1.6 __ 2.5, with a mean of 0.9 _+ 1.7 fLxed and 0.8 +_ 1.5 reversible perfusion defects per study.

Volume 131, Number 6 American Heart Journal

Millel" et al.

2.F

__._t,

lO

,

,

1063

n=N.q

IZ:

1.1.1.1

O "O 0.I PrePTCA

PostPTCA

(-) (+) Rev. MIBI Defect*

Fig. 1. Distal Doppler coronary-flow reserve (dCFR;normal >2.0) from 34 patients with angioplasty. No significant change in preangioplasty to postangioplasty distal CFR was observed. Distal CFR values did not differ in patients with (+) and without (-) a reversible 99mTcsestamibi myocardial perfusion defect in the postangioplasty vessel-perfusion bed (*).

O

{----p=NS

im

i

I

.....p=.02

,m-, 4

>

13.

3

"¢2 "O

PrePTCA

PostPTCA

Rev. (" ) MIBI Defe (+ct)

Fig. 2. Basal p/d APV ratios (normal <1.7) in 34 patients with angioplasty. A Nonsignificant (p = 0.10) trend toward decreased basal p/d APV ratio was observed after angioplasty. The mean p/d APV ratio in patients without a reversible 99mTcsestamibi perfusion defect was normal (-<1.7) and was significantlyless than that observed in patients with a reversible sestamibi perfusion defect after angioplasty. Correlates of angioplasty-zone 99mTCsestamibi defects. The clinical, angiographic, and flow characteristics of 10 patients with and 24 patients without reversible stress 99raTa sestamibi perfusion defects are given in Table IV. The interval between PTCA and stress imaging did not differ. The mean post-PTCA percentage diameter stenosis and minimal luminal diameter were also comparable (p = NS). Although hyperemic postangioplasty Doppler distal CFR values were similar (1.6 _+ 0.8 vs 1.8 _+ 0.6;p = NS; Fig. 1), the post-PTCA ratio of p/d APV indicated lower relative basal coronary flow in patients with reversible perfusion defects (2.2 _+ 1.5 vs 1.1 _+ 0.6;p = 0.02; Fig. 2).

Correlates of abnormal basal postangioplasty p/d APV ratio. Patients with an abnormal postangioplasty p/d APV ratio (>1.7) are compared with those with a

normal basal p/d APV flow ratio in Table V. 99mTc sestamibi defects were more numerous in the angioplasty-vessel perfusion bed in patients with a lower distal APV (4.2 _+ 3.3 vs 0.8 _+ 2,0; p = 0.005; Fig. 3). No other significant angiographic or flow differences were detected.

Post-myocardial infarction studies. A detailed comparison of the 6 patients with recent acute myocardial infarction with the 28 without a recent infarction (Table VI) failed to demonstrate significant differences in age, percentage change in angiographic diameter stenosis after PTCA, the number of abnormal postangioplasty myocardial perfusion defects, basal APV, or the p/d APV ratio. The average postangioplasty distal CFR was lower in the patients studied after myocardial infarction (1.1 _+ 0.1 vs 1.9 _ 0.6; p = 0.04). This finding is consistent with those of

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1064 Miller et al.

American Heart Journal

p=NS

6

il •

m Total Fixed

[] Reversible

® =21I T

~1.

T

Normal

Abnormal

p/d APV ratio

No

Yes

Recent MI

Fig. 3, 99mTcsestamibi myocardial defects observed in postangioplasty bed of 34 patients classified by their p/d APV ratio demonstrated significantly greater and total fixed defects in patients with abnormal basal p/d APV ratio. A trend toward increased reversible defects also was observed (p = 0.07). No difference in mean number of defects was observed between patients with or without recent myocardial infarction ( M I ; p = NS). *p < 0.01 vs normal p/d APV.

previous studies 31-33 but was not associated with a difference in the total number (2.7 _+ 2.8 vs 1.3 _+ 2.4) or type or 99mTc sestamibi perfusion defects. Cardiac events and prognostic variables, Eleven patients had cardiac events during the 13 -+ 10 months after angioplasty. These events were cardiac death (n = 1), myocardial infarction (n = 2), and coronary artery bypass surgery (n = 2) or repeated PTCA (n = 6) for severe recurrent myocardial ischemia (i.e., chest pain with ST-segment changes). Univariate comparison of patients with and without cardiac events (Table VII) demonstrated no difference in the postangioplasty interval to stress, the presence of stress-induced ECG ST-segment depression or angina, the number of 99mTc sestamibi perfusion defects, the preangioplasty and postangioplasty percentage diameter stenosis or minimal luminal diameter, the distal CFR, and the p/d APV ratio between patients with and without cardiac events (all p = NS). Cox multivariable regression modeling (Table VIII) determined that an abnormal basal p/d APV ratio and the combination of this Doppler-flow variable and a reversible angioplasty-zone perfusion defect were independent predictors of adverse cardiac events. Cardiac event rates of ->50% were observed in patients with PTCA-zone reversible 99mTcsestamibi defects (relative risk [RR], 5.5), Doppler distal CFR -<2.0 (RR, 8.3) and a p/d APV ratio >1.7 (RR, 6.2). In five patients, the combination of ->1 reversible 99mTc sestamibi defects and a Doppler APV ratio >1.7 was associated with a 60% risk of a cardiac event (p = 0.03). DISCUSSION

Successful percutaneous coronary arterial balloon dilatation improves the symptoms and physiologic

manifestations of myocardial ischemia. However, coronary angioplasty may not immediately improve coronary blood flow reserve because of several factors, including residual barotraumatic vasomotor "stunning" and delayed lesional remodeling of epicardial conduit vessels, 19"21as well as postinfarction coronary microvascular dysfunction. 31-32 These factors, in combination with the attenuation of radiotracer clearance as a result of residual myocardial ischemia, may contribute to the slow recovery of poststress thallium-201 perfusion abnormalities after a successful angioplasty procedure. 6, 7, 10 The prognostic value of early (i.e., <4 weeks) post-angioplasty 2°1T1 scintigraphy may be limited by these phenomena. 3 In this study, the previous correlations between poststenotic CFR and myocardial perfusion in medically treated stable angina patients 22, 23 were not reproduced after interventional procedures in a typical angioplasty referral population with a high frequency of recent acute ischemic events. In these patients, myocardial perfusion defects, a relative reduction in basal poststenotic APV and p/d coronary flow-velocity ratio occurred in the absence of angiographically significant residual stenoses. These physiologic perturbations suggest that postprocedural abnormalities of the epicardial conduit vessel persisted and were undetected by CFR assessment or angiography. Residual physiologic flow-perfusion abnormalities were also predictive of subsequent cardiac events in this population. Although residual angiographic coronary stenosis and associated limitations of blood flow have been previously implicated in the pathogenesis of 2°1T1 abnormalities in coronary artery disease populations,ll, 22, 23 our study is the first to examine these

Volume 131, Number 6 American Heart Journal

physiologic interactions in patients undergoing 99mTc sestamibi imaging after angioplasty. In contrast to previous studies of stable angina patients not undergoing interventional procedures,23 99mTc sestamibi perfusion abnormalities were not correlated with abnormal postangioplasty CFR, possibly as the result ofbarotrauma or postinfarction microvascular damage. Our data suggest another mechanism for postangioplasty myocardial perfusion defect pathogenesis beyond a suboptimal angiographic outcome or microvascular dysfunction. The combined physiologic assessments of poststenotic coronary flow and myocardial perfusion in our patients have extended previous studies that used clinical, angiographic, or scintigraphic risk markers to predict postangioplasty outcomes. Poststress 99mTcsestamibi perfusion and basal coronary flow-velocity abnormalities were significant covariables for defining future cardiac risk. Although the sustained effects of chronic myocardial ischemia on postangioplasty 99mTc sestamibi uptake and clearance could not be directly assessed in this study, the >4-week mean delay between PTCA and stress imaging renders chronic residual myocardial ischemia in the absence of a coexisting rheologic limitation an unlikely mechanism for the observed perfusion defects. Although early restenosis cannot be excluded, a more tenable explanation would be persistence of attenuated coronary flow in the epicardial conduit because of a suboptimal PTCA result or lesional remodeling that was not detected by angiography. The persistence of abnormal post-angioplasty CFR would be uncommon at this point, 21 even in patients with a recent myocardial infarction. 33 Study limitations. As with previous studies examining the relation between intracoronary flow and myocardial perfusion, 11, 22, 23 our investigation enrolled relatively few patients, potentially reducing the power of its findings. Whereas inclusion of coronary artery revascularization is generally discouraged as an adverse outcome in natural history studies of patients with coronary artery disease, the inclusion as a surrogate event of PTCA o r coronary bypass surgery resulting from recurrent myocardial ischemia is widely implemented in postangioplasty studies. 3 A relative basal flow abnormality may have contributed to persistent myocardial perfusion abnormalities after angioplasty. 34 Sampling of coronary flow in a normal non-angioplasty vascular bed (not performed in our study) would be required to confirm this possibility. Angiographic follow-up to detect restenosis was not completed in this study. Angiography has limited value for the prediction of physiologic responses. 23 Further studies are in progress to establish the rela-

Miller et al.

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tion between the observed physiologic parameters and the biologically complex phenomenon ofpostangioplasty restenosis. The precision of quantitative measurements of coronary;stenosis anatomy and flow velocity was not matched by the semiquantitative scoring of 99mTcsestamibi defects. These scintigraphic studies predated the availability of 99n~Tc sestamibi image-quantitation software in our laboratory. However, the method of image interpretation used in our study is clinically relevant and has been widely used in several previous studies of stable anginal5, 16, 2.3 and angioplasty3 populations. Potential clinical implications. Although the CFR is frequently attenuated for several weeks after an otherwise successful interventional procedure, thereby reducing its predictive value for cardiac outcomes, the physiologic assessment of basal distal coronary blood flow and p/d APV ratio proved to be useful. Failure to improve distal APV or to achieve a p/d APV ratio <1.7 suggests a suboptimal angioplasty result within the epicardial lesion, independent of vasomotor CFR. This finding is also an important covariable for predicting future cardiac events, in association with the persistence of myocardial perfusion abnormalities observed at 4 to 5 weeks after angioplasty. Because the routine use of postangioplasty myocardial perfusion imaging is neither clinically indicated nor cost-efficient,3 it is possible that the identification of a periprocedural coronary blood flow abnormality may be useful in the selection of pctients who require more intensive clinical followup and subsequent scintigraphic studies to detect unfavorable remodeling and to predict future ischemic cardiac events. A prospective study evaluating this approach may be warranted, from the results of our study and the lack of a well-defined algorithm for the performance of stress cardiac imaging after angiographically successful angioplasty procedures. Conclusions. Basal coronary flow velocity and poststress reversible 99mTc sestamibi myocardial-perfusion abnormalities are significant physiologic covariables associated with an increased risk ofpostangioplasty ischemic events after an angiographically successful coronary interventional procedure. The observed absolute and relative reductions in basal post-stenotic coronary flow suggest that angiographically occult luminal reduction is the mechanism for postangioplasty myocardial perfusion-defect pathogenesis, independent of residual abnormalities of CFR. The authors t h a n k Lori Gallini for her secretarial assis~ tance.

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June 1996 American Heart Journal

Miller et al.

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