effects of coronary bypass surgery and angioplasty on coronary blood flow and flow reserve

Effects of Coronary Bypass Surgery and Angioplasty On Coronary Blood Flow and Flow Reserve

Robert F. Wilson, Melvin L. Marcus. and Carl W. White

M YOCARDIAL revascularization with an aortocoronary bypass graft or angio-

plasty is an effective means of reducing the symptoms of myocardial ischemia and normaliz- ing previously positive tests of provokable myocardial ischemia. The effect of these procedures on coronary hemodynamics and their efficacy in restoring normal myocardial perfusion is less clear. Unlike studies performed in normal animals, the effects of the coronary revascularization in patients must be studied in the setting of coronary atherosclerosis, a pathologic process that is complex and variable in severity and distribution. Additionally, techniques for studying the effects of revascularization in humans (quantitation of coronary arterial geometry, measurement of coronary blood flow, and determination of the flow reserve capacity of revascularized arteries) suffer serious deficien- cies. As a result, studies of the effects of revascularization procedures on coronary blood flow and coronary reserve should be interpreted cautious- ly, taking into account their many methodologic limitations.

The purpose of this article is to define the limitations of current techniques for measuring coronary blood flow and flow reserve following revascularization, to review prior studies of the effects of coronary bypass surgery or angioplasty on coronary blood flow and flow reserve, and to elucidate what these studies tell us about the coronary circulation of humans.

LIMITATIONS IN THE MEASUREMENT OF CORONARY BLOOD FLOW AND FLOW RESERVE

FOLLOWING REVASCULARIZATION

Methodologic Considerations

Techniques for measuring myocardial blood flow in humans have been discussed by White et al in this symposium.’ Importantly, all methodologies for measuring coronary blood flow in humans have major shortcomings (Table 1).

Three methodologic requirements for measuring coronary blood flow or flow reserve following revascularization should be emphasized. First, since angioplasty or bypass surgery are per-

formed on individual coronary vessels, the technique for measuring coronary blood flow must be capable of selectively assessing blood flow in the revascularized vessel. Inert gas indicator dilution techniques (eg, argon or helium clearance) and coronary sinus thermodilution blood flow measurements cannot relate blood flow to an individual coronary vessel and consequently should not be used to assess the effects of revascularization on blood flow.”

Second, the technique for measuring blood flow must be accurate over the range of flow that can occur in normal coronary vessels (niaximal hyperemic blood flow four to eight fold resting flow; 400 to 600 mL/min/lOO g tissue). Three techniques for measuring blood flow in individual vessels of humans meet this requirement, but each has other limitations. Electromagnetic flow meters have been widely used intraoperatively to measure blood flow in internal mammary or vein bypass grafts. Although these flow meters have been extensively validated in chronic animal studies (in which their position is secure because of scarring into the vessel wall), the accuracy of measurements obtained using these devices acutely in the operating room is open to ques- tion.5 When used acutely, alterations in contact with the vessel and lack of adequate calibration may significantly alter the accuracy of blood flow measurements. Additionally, these flow meters are not commonly used to measure blood flow in native coronary vessels because this use

From the Z?eZmrtments of Internal Medicine, University of Zowa and Veterans Administration Hospital, Iowa City, and the University of Minnesota, MinneaZmlis.

Supported by grants from the National Heart, Lung. and Blood Institute (HL 27633.14388. and 29976). the Zschemic Specialized Center of Research (SCOR) (HL 32295-01). and the Veterans Administration (MRZS I ZoO.2). This work was done during the tenure of the Clinician&?entist Award from the American Heart Assaciation with funds contrib- uted in port by the Iowa and Minnesota Afiliates.

Address reprint requests to Robert F. Wilson, MD. Divi- sion of Cardiovascuiar Diseaes, Department of Medicine, University of Minnesota Hospital and Clinic, Minneapolis, MN 55455.

@ 1988 by Grune & Stratton, Inc. 0033-0620/88/3Z02~2$5.00/0

Pr0ges-s in C8r&vascUlar Diseases, Vol XXXI. No 2 6eptember/Octobed, 1988: pp 85-l 14 95

96 WILSON, MARCUS, AND WHITE

Table 1. Techniques for Measuring Coronary Blood Flow and Flow Reserve After Revascularization

Technique

B&ctii Accurate at Ahmhlta Phasic Coronary Flow HypaMliC Bbod Flow Blood Flow On-line Measuremsnts Flow Rate-a hlesswemsm Measuremam Raadout Comments

Coronan/ sinus thermodilu-

tion catheter

Inert gas indicator dilution

(He, Ag, N,O)

Xenon 133 indicator dilution

Digital subtraction + angio

graphic contrast transit

time

Coronary Doppler catheter

Electromagnetic flow meter

Positron emission tomogra-

phy

- 7 + - + Catheter position subject to move-

ment

+ + - - Requires steady flow for 5-20 min

during measurement of flow

+ - + - -

+ - - - - Accuracy at high flow rates may im-

prove with development of new

algorithms

+ + - + + Measures flow velocity; sensitive to

changes in arterial caliber

f + + + + Only for intraoperative use. Poor

vessel contact and calibration

problems limit reliability of mea-

surements - + - - - Regional blood flow measurements

possible

would require circumferential dissection of the coronary vessel.

A small 3-French (Fr) coronary Doppler catheter has recently become available and permits accurate on-line measurement of phasic coronary blood flow velocity in individual vessels.6 This catheter has been extensively validated in animals and has also been shown not to obstruct hyperemic coronary blood flow in proximal coronary vessels of calves. Although the catheter may be highly useful in measuring coronary blood flow velocity in patients undergoing catheterization, it also has major drawbacks. Since it measures blood velocity rather than blood flow, changes in the vascular cross-sectional area at the site of the catheter could significantly alter the relationship between changes in blood flow velocity and changes in blood flow. Fortunately, most vasodilators do not alter coronary diameter in vessels previously treated with nitroglycerin.7 An additional limitation of Doppler catheters is that they measure only relative (rather than absolute) blood flow velocity. Consequently, only a ratio between maximal hyperemic blood flow velocity and resting blood flow velocity can be obtained. Since all measurements must be recorded in relation to resting blood flow, a change in resting blood flow (which may be unrecognized) could result in a proportional change in the measured effects of an interven- tion.

More recently, a hydrogen based indicator dilution cathether that is capable of measuring

absolute coronary blood flow over a wide range of flows in individual coronary vessels has been introduced.8 Although this catheter may hold great promise for assessing blood flow in individual coronary vessels following revascularization, its validation is at present incomplete.

Two other techniques commonly used to measure flow reserve in conscious humans tend to underestimate maximal coronary hyperemia. Myocardial blood flow >200 mL/min/lOO g is known to be underestimated using xenon 133 scintigraphy.g*‘O Similarly, currently reported coronary flow reserve measurements in normal vessels using digital subtraction angiographic techniques suggest that intracoronary injection of radiographic contrast media produces only a 1.9 to 2.6 fold increase in resting blood flow.“*” This value is well below that measured following contrast medium injection in animals using an electromagnetic flow meter (3.9 rtr 0.9 peak/ resting flow ratio, mean + SD) and in normal humans using a coronary Doppler catheter (3.1 k 0.2, mean k SEM).7V’3 Over time, however, the subtraction angiographic techniques for measurements of coronary blood flow measurement may improve and allow for more accurate determinations of flow reserve.

The third methodologic requirement for measuring coronary flow reserve following revascularization is the availability of a technique for producing maximal coronary arteriolar vasodilation. Without total arteriolar vasodilation, maximal flow reserve cannot be measured, an.d conse-

CORONARY RESERM AFI-ER REVASCLJLARIZATION 97

quently the difference between normal and abnormal responses cannot adequately be distin- guished. To date only three methods have been shown to produce maximal increases in coronary blood flow in humans: transient coronary occlusion of 220 seconds’ duration, intravenous (IV) infusion of dipyridamol (>0.56 mg/kg), and intracoronary administration of a maximally vasodilating dose of papaverine.7*‘4*‘5 Ventricular pacing, IV isoproterenol or dobutamine infusion, and intracoronary iodinated contrast material (eg, Renografin 76) or submaximal doses of papaverine have been used in many studies to measure coronary flow reserve.7”6-18 These techniques, however, produce submaximal arteriolar vasodilation, clouding the interpretation of studies in which they are used.

It is obvious from even this brief review that currently available techniques for measuring blood flow before and after revascularization are all fraught with major hazards. Hence, each study must be viewed in light of the strengths and weaknesses of the measurement technique.

PHYSIOLOGIC CONSIDERATIONS

Many physiologic factors affecting coronary blood flow and flow reserve must also be considered to interpret appropriately the effects of revascularization on the coronary circulation. First, in a normal coronary circulation, blood flow is regulated by the arteriolar bed; the epicardial coronary vessels provide little resistance to flow.” To determine accurately if revascularization has accomplished its goal of removing a physiologically significant obstruction to blood flow in the large arteries, one must know that the microvasculature can function normally. Many abnormalities of the microcirculation may diminish vasodilator capacity independent of the ability of the epicardial coronary artery to conduct blood flow. These abnormalities include ventricular hypertrophy, dilated cadiomyopathy, prior myocardial infarction, collagen vascular diseases, prolonged hypertension, recent cardiopulmonary bypass, and idiopathic limitation of arteriolar vasodilator capacity (syndrome X).2o26 To interpret flow reserve measurements obtained after revascularization, these conditions that alter arteriolar vasomotor capacity must be excluded.

Second, if a ratio of maximal hyperemic to resting coronary blood flow is measured (eg,

using digital subtraction angiographic measurements or Doppler methodologies), resting coronary blood flow must be normal. In addition to well-known factors that result in a physiologically appropriate increase in resting coronary blood flow (severe anemia, increased heart rate or systolic arterial pressure, increased inotropic state), revascularization itself may also increase resting coronary blood flow. Hiratzka et al have shown in animals that the use of cardiopulmonary bypass results in a 25% increase in resting blood flow without a concomitant change in myocardial oxygen demand.25 If the revascularization procedure were to effect an increase in resting blood flow, then measurement of the peak to resting flow ratio immediately following the procedure might not accurately reflect the physiologic improvement in minimal coronary vascular resistance.

Finally, several other factors related to the underlying pathologic process occurring in the epicardial coronary vessel may increase resistance to hyperemic flow. Diffuse coronary atherosclerosis might increase epicardial coronary resistance, thus reducing maximal coronary hyperemia in the absence of a significant focal residual coronary stenosis.27 Coronary lesions causing unstable angina frequently contain intralumenal thrombi.28 Embolization of thrombi might increase resting blood flow or diminish maximal coronary hyperemia.29 Conversely, humoral agents elaborated from embolized thrombi could cause distal arterial vasoconstriction and a resulting fall in resting blood flo~.~’ When interpreting studies performed shortly after revascularization, these factors should be taken into account.

EFFECT OF AORTOCORONARY ARTERY VEIN BYPASS SURGERY ON CORONARY BLOOD

FLOW AND FLOW RESERVE

Many noninvasive studies (exercise electro- cardiography, 31 20’T1 scintigraphy,32 exercise ven- triculography)” have demonstrated that bypass surgery effects a remarkable improvement in cardiac function, symptoms, and exercise tolerance. It would not be surprising, then, to find that after this method of revascularization the blood supply to the myocardium would be improved during periods of increased metabolic demand.

Many other questions, however, remain unan- swered. Are measurements of resting coronary

98

blood flow or flow reserve in bypass grafts predictive of subsequent graft occlusion? Does vein bypass surgery restore normal maximal hyper- emit blood flow or does residual diffuse atherosclerotic narrowing of coronary vasculature per- manently impair the ability of the epicardial vessels to conduct blood flow? At what level of obstruction does the vein graft itself limit maximal hyperemic blood flow?

INTRAOPERATIVE STUDIES OF VEIN BYPASS BLOOD FLOW

Coronary blood flow and tIow reserve in bypassed coronary perfusion fields have been studied in two settings: in the operating room soon after the vein graft anastamosis and in the catheterization laboratory weeks to years following surgery.

Measurements of bypass graft blood flow obtained in the operating room soon after discon- tinuance of cardiopulmonary bypass when normal arterial pressure and heart rate have been reestablished were first performed by Johnson et al in 1970.34 Since then, a plethora of studies performed in a similar manner have been reported. 35-56 In most of these studies, blood flow in the newly anastomosed vein bypass graft was measured using an electromagnetic flow meter placed circumferentially about the graft. Vein bypass blood flow has averaged 40 to 80 mL/ min, but ranged widely from t20 mL/min to >200 mL/min. Blood flow through the graft is

WILSON, MARCUS, AND WHITE

directly proportional to the gradient between aortic pressure and the pressure in the distal native coronary artery (Fig 1).35 Blood flow through the bypass graft is also influenced by other factors including the size of the bypassed perfusion field and the extent of stenosis in the proximal coronary vessel.35-38 Larger perfusion fields offer less absolute resistance to blood flow and consequently result in higher coronary blood Aow. Additionally, if the proximal coronary vessel supplies some distal blood flow, the distal coronary pressure would be increased and less blood would enter via the bypass graft. Unfortu- nately, it is difficult to measure proximal coronary blood flow and the mass of myocardium subserved by individual coronary vessels. Hence, it is difficult to predict graft blood flow in individual patients.

The majority of investigators have reported that graft patency is inversely proportional to early intraoperative measurements of graft blood flow (Fig 2).36*3W3 It is postulated that bypass grafts with higher flow rates (and hence less stasis) are less likely to develop thrombosis. Similarly, this explanation could account for a greater patency rate in grafts perfusing multiple rather than single vessels.43@ Other investigators, however, have not found a clear relationship between intraoperative measurements of graft blood flow and subsequent graft closure.36*45*46 Many factors may account for the disparity in results. First, and most importantly, these studies

Fig 1. (A) Flow measurements with an ekctromagnotic flow mater in vein bypass grafts. Mean values for each group are indicated by a tina. LAD. left ante&or mng; RCA. right coronary artery; (AL number of observations. (B) Relation betw-n preoxisttng comnary arterial pressure gradient and flow in the vein bypass graft. (Rsprintad with permicuion from Kreulen et al, Am J Car&o/ 34~129.1974~~)

CORONARY RESERVE AFTER REVASCULARIZATION 99

are performed in the operating room under unstable conditions. Heart rate, BP, hemoglobin, arterial oxygen saturation, and drug therapy vary widely between patients. Second, if graft blood flow velocity is the primary determinant of graft closure (rather than absolute blood flow), then direct absolute measurements of velocity within an individual vein graft (mean, maximal, or at the graft wall) might provide better predic- tions of ultimate graft patency.49 Third, resting blood flow through the graft may vary late after surgery, depending upon the continued patency of the proximal native coronary vessel. After surgery, the native artery may totally occlude, resulting in a decrease in distal coronary pressure and an increase in graft blood flow.‘* Fourth, although cardiopulmonary bypass, as discussed above, transiently increases resting coronary blood flow, its effects on blood flow are heterogenous among patients and consequently may obscure the importance of individual intraoperative measurements in patients. Fifth, graft blood flow measurements in almost all studies were obtained using an inherently unreliable acutely placed electromagnetic flow meter.

INTRAOPERATIVE MEASUREMENTS OF VEIN BYPASS GRAFT FLOW RESERVE

Many investigators have also studied the presence and significance of coronary flow reserve in acutely placed vein bypass grafts. These studies have provided very conflicting results. They can be divided into studies of ischemically mediated reactive hyperemia and pharmacologically induced hyperemia.

Greenefield et al measured the reactive hyper- emit response in 32 bypassed coronary vessels by occluding the graft for 10 seconds.5o Seventeen of 32 bypass grafts demonstrated some reactive hyperemia (mean peak flow 1.6 x control flow). The duration of the hyperemic response (8 to 15 seconds) was much shorter than that measured in normal animals and did not correlate with the duration of occlusion, the patency of the proximal native artery, ventricular function of the segment perfused by the vein graft, the presence or absence of collaterals to the grafted vessel, or the type of perfusion field studied (left v right). Similar results have been reported by Bittar et a1.5’

Conversely, Stinson et al measured reactive hyperemia following transient vein graft and

l Blood flow in all grafts (103)-+8 cc/min

oxblood flow in occluded grafts (161-27 cc/min

T

Fig 2. The relationship between aortocoronary vein bypass graft blood flow measured intreoperatively (using an electromagnetic flow meter) and subaeguent bypass

graft occlusion. Mean flows, standard deviation, and proba- bility values are indited at right. 0. Grafts that were open at the time of reevaluation: 0. grafts oocluded at reevalue- tion. (Reprinted by permission of the American Heart

Assoc. Inc., from Grondin et al, Circulation 44:816, 1971 .‘I

proximal coronary arterial occlusion.39 Seventy percent of vein grafts showed some hyperemia (ie, hyperemic blood flow > 1 .l fold resting flow), and a minimal level reactive hyperemia was seen in 92% of grafts placed distal to total coronary occlusions. The peak hyperemic flow in grafts placed into occluded arteries (1.5 x resting flow) was significantly higher than that measured in vein bypass grafts placed into stenotic but patent vessels (1.2 x resting flow). Similar findings have been reported by others.36*37

Flow reserve measured intraoperatively in normal coronary vessels prior to bypass surgery ranges from 3.5 to 10 peak/resting blood flow velocity.14 Why are the reactive hyperemic responses measured after coronary bypass anastamosis so heterogenous and so meager? First and most importantly, elevated resting flow from cardiopulmonary bypass or acute anemia may have reduced the ratio of hyperemic to resting flow?’ Second, persistence of antegrade flow in a patent native coronary artery or collateral blood supply from an adjacent coronary vessel may have prevented ischemia from developing during occlusion of bybass grafts36p5456 (Fig 3). Thus, the true reactive hyperemic capacity of the bypassed level may not have been tested in many studies because an adequate stimulus for distal ateriolar

100

MLeAa Coronary

“~lYy Shift


PRE-CARDIOPULMONARY POST-CARDIOPULMONARY BY-PASS BY-PASS

ol&& t t TCO

gggg ::

UC?>> 0 z’

-- 8 gg

0 aa > > > =-a

= 4 (L =

+ t 200

t

a a u Arterial

P~gswi$ 100 w-m-

0

Fig 3. Recording of coronary blood flow velocity in the left anterior descending coronary artery (LAD) before (precardiopulmonary bypass) and after (postcardiopulmonary bypass) placement of a saphenous vein bypass graft into the left

anterior descending coronary artery beyond the point of severe proximal obstruction. (A) The reacthre hyperemic response following a ZfI-second occlusion of the left anterior descending coronary artery was markedly attenuated before vein bypass graftlng. (B) Occlusion of the graft (G. Dee.) alone did not alter downstream coronary blood flow velocity. Thus. both the graft and the left anterior descending coronary artery could deliver adeguate flow to maintain resting blood Rwv. (C) Simultaneous occlusion of the graft end the proximal left anterior descending coronary artery reduced blood flow velocity to zero. Following release of a 2Gsecond occlusion of both the graft and the proximel left anterior descending coronary artery, there was a

substantial reactive hyperemic response. (D) Simuttaneous occlusion of the graft and the proximal left anterior descending coronary artery decreased coronery blood flow velocii to zero. Following a 2Gsecond occlusion, release of only the proximal

left anterior descending coronery artery resulted in a markedly blunted reactive hyperemic response. subsequent release of the graft cccluslon a few seconds later permitted e slgniiicant vasodiletor response of the downstream vascubr bed to become manifest. (In. Marcus ML: The Coronary Circubtion in Hea/tfr and Disease. New York, McGraw-Hill, 1983. Reprinted with permission.?

vasodilation (ischemia) was never present. Third, in many patients, the coronary vessel perfused infarcted or hypertrophied muscle that had limited ability to vasodilate at the arteriolar level. Fourth, the extent of diffuse atherosclerotic narrowing of the epicardial coronary vessels may have been quite variable. Consequently, the con- tribution of diffuse disease in reducing coronary flow reserve may have varied between patients and study populations.

Intraoperative measurements of vein bypass graft flow reserve have also been obtained following administration of a potent arteriolar vasodilator (intragraft injection of papaverine, or sodium nitroprusside or IV administration of dipyridamole). W~42~s2~53~55 The advantage of pharmacologic vasodilation over ischemic reactive hyperemia is that it is not necessary to insure that all sources of perfusion have been interrupted (eg, collateral or proximal vessel blood flow) to obtain maximal arteriolar vasodilation. Grondin et al demonstrated a significant increase in blood flow in nearly all of 103 vein bypass grafts following intragraft injection of papaverine.40 Other investigators have also shown a very high incidence of pharmacologically induced hyper-

emia in bypassed vessels (ranging to >4 peak/ resting velocity ratio).42*52.53

Measurements of ischemic or pharmacologically induced hyperemia have correlated with late graft occlusion in some laboratories369”S42 but not in others.39v4’ Measurements of pharmacologically induced flow reserve suffer from many of the same factors that confound interpretation of reactive hyperemia measured immediately after bypass surgery-alteration in resting blood flow, coexistent abnormalities in the arteriolar microcirculation, and possibly residual diffuse atherosclerosis. Additionally, it cannot be assured that complete arteriolar vasodilation was achieved in these studies, because a dose-response relationship to the vasodilators administered was never obtained.

These intraoperative studies suggest that measurements of graft blood tlow can be predictive of subsequent graft occlusion, and that flow reserve is depressed immediately after surgery. Unfortu- nately, inability to control abnormalities in the microcirculation, faulty measurement techniques, and undefined residual diffuse narrowing of the epicardial coronary vessels cloud the interpretation of these studies. Thus, although studies

CORONARY RESERVE AFTER REVASCULARZATION 101

of coronary flow reserve immediately following bypass surgery are numerous, they provide only limited information.

MEASUREMENT OF CORONARY FLOW RESERVE LATE AFTER BYPASS SURGERY

Development of blood flow measurement techniques in awake humans has enabled studies of coronary blood flow and flow reserve in patients undergoing coronary angiography months to years after surgery. The advantage of measuring coronary flow reserve in the catheterization laboratory is that alterations in coronary hemodynamics produced by the operative procedure (eg, cardiopulmonary bypass, arterial trauma, acute anemia) are no longer present. Hence, these studies may more accurately reflect the long- term impact of bypass surgery on coronary blood flow.

Schmidt et al increased myocardial oxygen consumption by an isoproterenol infusion in patients with prior left anterior descending aor- tocornary vein bypass surgery to determine if coronary bypass restored normal myocardial perfusion in response to increased metabolic demands.” In these patients, the peak heart rate to systolic arterial pressure product increased from a mean of 11,297 to 16,359. The increase in myocardial blood flow in bypassed coronary vessels was significantly greater than that measured in severely stenosed arteries but not significantly different than that measured in normal coronary vessels.

Studies from two other laboratories suggest that both resting blood flow and coronary flow reserve can normalize following bypass surgery. Goldman et al measured blood flow in normal and bypassed left anterior descending vessels using ‘33Xe scintigraphy. They found that resting blood flow in the bypassed arteries (63 r 5 mL/ min/lOO g) was similar to that measured in normal coronary vessels (61 + 4 mL/min/ 100 g).58 Coronary hyperemia following intragraft injection of 5 mg papaverine was also similar in bypassed arteries 144 f 7 mL/min/ 100 g) to that measured in normal coronary vessels (145 + 8 mL/min/lOO g). Although the study demonstrates that resting blood flow is normalized following bypass surgery, the low dose of papaverine used to produce arteriolar vasodilation precludes any conclusion regarding

the ability of bypass surgery to restore maximal flow reserve. A similar study by Hodgson et al found that flow reserve measured in vein bypass grafts (2.1 f 3 peak/resting velocity ratio) was not significantly different than that measured in normal coronary vessels (2.0 * 1 .0).59 The use of a submaximal coronary vasodilator (Renografin 76) and digital subtraction angiographic measurements of hyperemic blood flow, however, similarly prohibit conclusions to be drawn from these studies about the ability of bypass surgery to restore normal flow reserve.

In contrast to the above studies, Bates et al have suggested that flow reserve measured in bypassed coronary arteries is diminished when compared to normal coronary vessels (Fig 4).@’ In their studies, flow reserve in bypassed vessels (2.0 + 0.2 peak/resting blood flow) was significantly less than that measured in normal coronary vessels (2.6 f 0.1) but not significantly different from arteries revascularized by coronary angioplasty (2.0 f 0.1). Their results suggest that diffuse coronary atherosclerosis, present in most patients with widespread coronary artery disease, results in a residual impairment of

GFIWP I CAD nzt2

GROUP II CABG

ll:16

GROUP III PTCA

n-.14

GROUP IV NORMAL

Il.29

Fig 4. Coronary flow reserve measured in vessels with obstructive coronary artery disease (CAD), late after coronary bypass surgery (CABGL late after percutaneous trans- luminel coronary angioplasty (PTCA), and in normal coronary vessels. Coronary flow reserve late after bypass surgery and coronary angiopiasty was significantly less than that measured in normal coronary vessels. (Reprinted by permission of the American Heart Assoc. Inc., from Bates et al. Circulation 72:833. 188L”)


7- . x Inladbn

B- i- 06temda . n HII#r(rophY

5- i : f Flow Reserve 4 - (m,rml,“g I” - - - i*- - - - - - - - - - r:- - -

v&lclty) 3 -

2- ; gi

l- o

0 I I I Namalcaawy Namd Abmmml

Gdta Yycwdhl

Fig 6. Coronary flow reserve measured in normal

native arteries perfusing normal myocardium. late following bypass surgery in normal vein bypass grafts perfusing normal myocardium. and late following bypass surgery in

vein bypass graftr with more than W% area stenosis at the coronary insertion or perfusing abnormal myocardium kg, hypertrophy or infarction). These measurements of coro-

nary flow reserve, obtained udng a coronary Doppler catheter and a maximally vasodilating dose of intracoronsry papsverine, demonstrate that coronary flow reserve is normalized later following surgery in normal myocardium

perfused via a nonatenotic vein bypass graft. Okprinted from Wilson et al, Circulation 7g583.1987 wlth permission from the American Heart Association.“)

maximal hyperemia. If true, these findings would mean that angiographic estimates of the impact of individual coronary lesions would have to take into account the additional resistance provided by diffuse arterial narrowing. Their study, however, had methodologic flaws similar to those discussed above. Digital subtraction angiography underestimates maximal hyperemic flow, and the method used to produce maximal arteriolar vasodilation (Renografin 76) is not a potent dilator stimulus. Moreover, patients with

12- Mid LAD

10 - : l

l

8- l

Cross Sectional Area (mm21

6- i

l

abnormalities in the myocardium that could have decreased coronary flow were not clearly excluded (eg, patients with systolic contraction abnormalities or subclinical hypertrophy may have been included in their study).

Because of the limitations of prior studies, we recently studied the effects on coronary flow reserve of diffuse atherosclerosis and focal stenosis at the vein bypass graft-coronary insertion.61 Sixteen patients with 26 vein bypass grafts underwent coronary angiography 4 months to 10 years following successful surgery. Coronary flow reserve was measured as the peak to resting velocity ratio using a 3-Fr coronary Doppler catheter positioned in the mid portion of the graft. Arteriolar vasodilation was produced by selective graft injection of a maximally vasodilating dose of papaverine. We were careful to exclude patients with abnormalities that might alter the vasodilator capacity of the distal arteriolar bed (hypertrophy, infarction, cardiomyopathy, etc). The flow reserve in 13 bypass grafts perfusing nonstenotic coronary vessels and normal myocardium was normal (5.0 + 0.4 mean f SEM) and not significantly different from flow reserve measured in 13 patients with normal coronary arteries (5.1 + 0.6) (Fig 5). This was so even though the cross-sectional area of the bypassed native coronary vessel was 53% smaller than the cross-sectional area of matched normal coronary vessels (Fig 6). We also found that, as predicted, bypass grafts perfusing hypertrophied or infarcted myocardium had signifi-

Distal RCA

0

0 0

0 0 :

P 0 0

P 0

0

0.

a 0

0 P

0 0

‘ps.05 Normal Coronary

Fig 6. The average cross- sectional area of the mid left anterior descending (LAD) coronary ertery or distal right coronary artery IRCAI In patients with normal coronary atterles and in bypassed coronary ves-

ads. The averege crou-aec- tional area of bypassed vessels

wee 63% lass than that measured in normal coronary vessels. Wprintod with permission from Wilson et al.” 1

CORONARY RESERVE AFTER REVA!XlJLARlZATlON 103

cantly reduced flow reserve compared to normal vessels (2.4 + 0.3, P < .Ol). This was true even when the infarcted wall had only minimal residual hypokinesis. Quantitative angiographic measurements of the vein bypass graft-coronary insertion demonstrated that seven of nine of the focal lesions producing more than 50% area stenosis (compared to the cross-sectional area of the native coronary artery) resulted in diminished flow reserve (Fig 7). All bypass grafts having graft-coronary insertion stenoses producing ~50% cross-sectional area stenosis or more than 2.0 mm’ minimum cross-sectional area had normal coronary flow reserve.

These results demonstrate that myocardial revascularization with an aortocoronary vein bypass graft restores a normal maximal flow reserve capacity to the perfusion field of the graft, providing that the graft perfuses a nonstenotic coronary vessel and normal myocardium. Consequently, it is unlikely that moderate, diffuse coronary atherosclerosis significantly im- pairs maximal flow reserve. Flow reserve in bypassed coronary vessels with severe diffuse atherosclerosis, however, might be significantly impaired. Further investigation will be required to determine the extent of diffuse lumenal narrowing required to significantly reduce the ability of the epicardial coronary vessel to conduct maximal hyperemic flow. To be interpretable,

Area Stenosis ($1 Minimum Cross-Sectional Area

(mm?

<3.5 >3.5 <3.5 >3.5 Flow Reserve

(peak/resting velocity)

Fig 7. The minimum arterial cross-sectional area and percent area stenosis produced by stenoaes at the vein graft-coronary insertion in grafts with normal (23.5 peak/ resting velocity ratio) and abnormal (~3.6) flow reserve. Flow reserve measured in bypass grafts with a coronary insertion stenosis of >2.0 mm’ minimum cross-sectional area or 40% erea stenosis (compared to the native artery) was normal. (Reprinted from Wilson et al, Circulation 76563. 1987 with permission from the American Heart Association.“)

however, these studies should employ techniques capable of measuring maximal flow reserve and quantitative measurements of the extent of diffuse atherosclerosis present in the bypassed vessel.

Although studies of flow reserve late following bypass surgery are subject to many methodologic limitations, they suggest that coronary blood flow in bypassed coronary vessels is similar to that found in normal coronary vessels and that myocardial blood flow can increase normally in response to moderate increases in myocardial oxygen demand or submaximal arteriolar vasodilation. Studies from our laboratory show that even maximal coronary flow reserve is normalized following bypass surgery, despite the presence of moderate diffuse atherosclerosis in the bypassed vessels. Together, these findings demonstrate that coronary bypass surgery produces a sustained improvement in coronary hemodynam- its and that moderate diffuse coronary atherosclerosis has negligible residual effects on coronary resistance. The effects of severe diffuse atherosclerosis and the adequacy of revascularization in patients with increased blood flow requirements (eg, hypertrophy) remain to be demonstrated.

CORONARY FLOW RESERVE FOLLOWING BYPASS SURGERY USING THE INTERNAL

MAMMARY ARTERY

Intraoperative Studies

Recent studies have shown that coronary bypass surgery utilizing the internal mammary artery may reduce the incidence of subsequent bypass graft occlusion.62*63 The internal mammary artery, however, is of smaller caliber and greater length than most vein bypass grafts. Consequently, it might provide greater resistance to coronary blood flow, making it a physiologically inferior method of revascularization.

Several intraoperative studies of internal mammary artery bypass graft flow and flow reserve have been reported.6e69 These studies are also clouded by the methodologic limitations present in studies of vein bypass grafts. The majority of investigators have reported that resting blood flow in newly placed internal mammary artery-coronary artery bypass grafts is significantly lower than that measured simultaneously in vein grafts. Additionally, both

104

ischemic reactive hyperemic responses and pharmacologically induced coronary hyperemia have been reported to be less in vessels grafted with the internal mammary artery compared to vessels grafted with vein bypass segments.@-67 Other investigators, however, have shown resting blood flow and maximal hyperemia in internal mammary artery bypass grafts to be similar to that obtained in vein bypass grafts.‘j’

Alterations in the ability of internal mammary artery grafts to conduct hyperemic blood flow might be modulated not only by the smaller caliber of the internal mammary artery, but also from perioperative vasospasm in the artery. Internal mammary arteries are thought to have increased vascular tone and to be prone to vasospasm in the immediate postoperative period.‘j7 Perioperative differences in arterial tone in addition to problems in intraoperative measurement of flow reserve might account for the diversity of intraoperative findings.

The etiology of the apparent decrease in resting blood flow, however, is not clear. Resting flow might be diminished by the higher resistance of the internal mammary artery. In fact, Grondin found that resting blood flow through internal mammary artery bypass grafts was similar to that measured in vein grafts when the internal mammary artery was larger than the recipient native coronary vessel. When the internal mammary artery was of equal or smaller size, however, flow was diminished compared to vein grafts.64 Since the vast majority of internal mammary artery grafted vessels demonstrated some reactive or pharmacologic hyperemia, however, the diminution in resting flow cannot be attrib- uted solely to the resistance of the arterial graft.64*65

It is also possible that internal mammary artery grafts were routinely placed into vascular beds of smaller size or into arteries with more severe proximal stenoses than those served by vein grafts. A study by Flemma et al, however, demonstrates that differences in the native coronary artery perfusion bed cannot explain a reduction in resting flow.6’ By anastamosing an internal mammary artery graft into a distal saphenous vein graft in 14 patients, they demonstrated that blood flow with the coronary arteries perfused by only the internal mammary artery graft (40 mL/min) was significantly less than that provided at rest by the saphenous vein


IMA VEIN GRAFT

Range IO - 65 40 - 175

Mean: 43ml 117

200.

L

AA 150,

.

I

f 50 ; :::p . i A hfeon . 0 Meon

IMA V Graft

Fig 8. Comparison of internal mammary artery (IMA) and vein bypass IV Graft) blood flow when each graft was

simultaneously anastamosad to the same left anterior descending coronary artery. Vein bypass graft blood flow ranged from 2.6 to 4.6 times higher than correapondlng blood flow via the internal mammary artery bypass graft (Reprinted with permission from Flemma et al, Ann TItoruc

surg20:619.1976.-~

bypass graft alone (117 mL/min) (Fig 8). It is possible that vasoconstrictor substances elaborated from the arterial graft may have reduced resting flow by inducing vasoconstriction in the distal coronary vessel or that differences in the function of acutely placed electromagnetic flow meters around bypass grafts of substantially different sizes may have artifactually given rise to these findings. Additionally, the increased resistance (if any) of blood flow from the internal mammary artery passing into the vein graft and then through the vein graft-coronary anastomo- sis might also increase resistance to blood flow. Any diminution in measured resting blood flow, however, appears to be short-lived. Barner et al found that resting blood flow measured six to eight hours following the initial surgery in three patients had increased 40% over the immediate postoperative measurement6’ Additionally, studies by Grondin demonstrate only a weak relationship between intraoperative measurements of internal mammary artery graft flow and long-term patency.64

Late Postoperative Studies

Two groups of investigators have measured blood Bow and the flow reserve capacity of internal mammary artery bypass grafts late following surgery. Schmidt et al found that resting

CORONARY RESERVE AFTER REVASCUIARIZATION 105

blood flow in internal mammary artery bypass grafts to the left anterior descending artery (79 mL/min/lOO g) was not significantly different from that measured in normal left anterior descending vessels (83 mL/min/lOO g).” Addi- tionally, the increase in coronary blood flow observed following isoproterenol infusion sufficient to increase the heart rate to 120 beats/min, following intragraft injection of Renografin 76, after IV infusion of dipyridamole was not significantly different in vessels perfused by internal mammary artery grafts than in normal vessels (Fig 9).70-72 The techniques used to measure coronary blood flow (xenon 133 scintigraphy and digital subtraction angiographic techniques) unfortunately underestimate hyperemic flow, and consequently one cannot determine whether bypass grafting with internal mammary arteries restores normal maximal flow reserve.

EFFECTS OF CORONARY ANGIOPLASTY ON CORONARY BLOOD FLOW AND FLOW RESERVE

Coronary angioplasty is an effective means of increasing coronary lumen caliber, reducing the translesional pressure gradient across atherosclerotic stenoses, and reducing the symptoms of myocardial ischemia.73-76 Consequently, it would be expected that coronary flow reserve would improve following the procedure.

These studies performed late following bypass surgery with an internal mammary artery suggest that alterations in resting blood flow, present immediately after surgery, are transient. Al- though methodologic problems have not permitted accurate measurement of maximal coronary flow reserve in these vessels, the studies available at this time show that submaximal induced coronary hyperemia in internal mammary artery grafts is similar to that measured in vein bypass grafts and is sufficient to respond to moderate increases in myocardial oxygen demand.

Interpretation of coronary flow reserve measurements obtained following angioplasty, however, is confounded not only by problems in blood flow measurement, but also by a variety of other factors. The extent of residual arterial stenosis is difficult to quantitate using available angiograp- hit techniques. Dilation and splitting of the atherosclerotic plaque often produces a residual lesion that, angiographically, has indistinct bor- ders that complicate angiopgraphic definition of the residual lumen. Serruys et al found that quantitative angiographic measurements of stenosis severity correlated poorly with videodensi- tometric measurement of lumenal compromise (a nongeometric determination of stenosis dimensions not requiring exact border defini-

1.6

1.4

5.0

r-

: B 4.0 -

iz

g 3.0- ii :

6 .

I - 2.0

. . - 4 :

8

l.O- *

f L-l SE0 IMA SE0 IMA SNGLE

PROX OlSTAL IMA

S’,“,,“,“” SE0 SVG SINGLE DISTAL SVG

.

.

t-

i

1 . .

.

Fig 9. Coronary flow reserve measured using digital subtrection sngiographii tachniquas in sequential (SEQ)

and single internal mammary artery (IMA) bypass grafts, and saphenous vain byPass grafts (SVGJ. Coronary flow reserve was similar in vassals parfusad by each typa of graft and in vassals msad from the proximal (PROXY and distal anastomosas of sequential grafts. (Reprinted with permitsion from Hodgson at al, J Am Coil Cardid 732. 19SS.Y

1.f

0.’ 8-

f 0

. PAE PTCA

0 POST PTCA

20 40 80 GRADIENT / MAP [%]

80

Fig 10. Coronary flow reserve maasurad bafora and after parcutanaous translumiml coronary angioplasty (PTCA) using diiital subtraction angiographic maasura- mants of coronary blood flow and itiracoronary adminiatra-

tion of Ranografin 78. The quotiants of tba tranlaeional prassure gradient and maan arterial prassura ware signifi-

cantly corralated with maaauramanta of coronary flow reserve both bafora and after angioplasty. (Raprintad with permission from G’Neill et al, J Am Cdl Cardiol 6:13S2. 1 SS4.Y


tion).77 Residual thombus within the lesion might additionally compound errors in angiographic evaluation of the residual lesion.28 The inability to assess the severity of the residual lesion has hampered interpretation of coronary flow reserve values obtained immediately after angioplasty.

Another problem in interpreting the immediate effects of angioplasty on the ability of the dilated vessel to conduct blood flow is that the procedure itself causes vascular trauma. The denudation of the endothelium results in platelet deposition and may additionally result in elabo- ration of humoral substances that alter the function of the distal arteriolar bed.‘* A variety of drugs that might alter resting flow or the vasodilator capacity of the distal arteriolar bed (eg, calcium channel blockers and nitroglycerin) are also administered during the procedure.79-8’

Finally, just as in patients undergoing coronary bypass surgery, the presence of diffuse and often unrecognized arterial narrowing might reduce maximal hyperemic blood flow independent of the residual dilated coronary lesion. Our finding of normal coronary flow reserve (despite moderate diffuse atherosclerosis) in bypassed coronary vessels and the usually discrete nature of atherosclerosis in vessels undergoing angioplasty, however, argues against any significant role for diffuse atherosclerosis in the majority of patients. However, in interpreting the effect of angioplasty on coronary flow reserve, all these factors must be taken into account.

CORONARY BLOOD FLOW AND FLOW RESERVE MEASURED IMMEDIATELY

FOLLOWING ANGIOPLASTY

The first studies of the effects of resting and hyperemic blood flow were reported by Hartzler et al in 1981.82 Since then, many other groups have studied the effects of coronary angioplasty on the restoration of coronary hemodynamics.@‘*83-88 In many studies, blood flow in the left anterior descending artery was estimated by thermodilution measurements of great cardiac vein flo~.~‘*‘~ These measurements revealed an increase in resting and hyperemic blood flow after coronary dilation. Studies employing xenon 133 scintigraphic measurements of resting blood flows have also shown that resting blood flow, in some patients, increases immediately following coronary dilation. ” Since very severe coronary lesions (ie. >90% area stenosis) may reduce

resting coronary blood flow, it is not surprising that resting flow would rise in some patients following successful dilation of the stenosis.89 It is not clear whether an inappropriate increase in resting flow (over that required by metabolic demand) occurs with restoration of normal perfusion pressure.

Two groups of investigators have measured coronary flow reserve in patients immediately following coronary dilation (peak to resting Bow ratio obtained using digital subtraction angiographic techniques). Hodgson and Williams found that papaverine-induced hyperemia before angioplasty (1.6 + 0.8 peak/resting flow ratio) increased to 2.8 f 0.8 following angioplasty.86 Importantly, they found a linear relationship between the percent residual stenosis (assessed using calipers) and coronary flow reserve (r = - .66). Conversely, O’Neill et al found that angioplasty increased the hyperemic response to Renografin 76 from 1.03 + 0.15 before dilation to 1.29 + 0.13 following dilation.84 Although there existed a correlation between the change in coronary flow reserve and the change in resting translesional pressure gradient (r = .77) (Fig lo), there was a poor correlation between angiographically assessed diameter stenosis and both the translesional pressure gradient and coronary flow reserve. Unfortunately, lack of an adequate

- - -

z

Fig 11. Coronary flow reserve measured before, imme- diatety after, and late after coronary angioplaaty using a coronary Doppler catheter and a maximally vasodibting dore of intracoronary papaverine. Compared to normal coronary vessels, coronary flow reserve before angiopbty was depressed in all patients. lmmediiteiy following angioplasty. coronary gow reserve was improved in all patients and normalized in 14 of 30. Df all vessels studied late following angioplasty, tour developed restenosls with a subseguent decline in coronary flow reserve. In the remain- ing vessels, coronary flow reserve increased from that measured immediately following angioplasty. (Reprinted from Wilson et al, Circulation 78:873.191)8 with permission from the American Heart Association.?

CORONARY RESERVE AFTER REVASCULARIZATION 107

Fig 12. The relationship batween coronary flow reserve and percent area stenosis in (A) stammad hut undibted coronary arteries, 16) coronary arteries studied immediately after angiopbsty, and (C) in corMary~erlesstudlodk0afterwronary

angiopbrty. Coronary flow resarve was highly correfated with peraant area stano8b both in undihtad oaronary vassal8 and late folfowing angioplasty. lmmadiataiy aftar angiopiaaty. howevar. thare existad no rakbwhip batwaan percent area

stenosis and coronary flow reserve. (Reprinted from Wilson at al. Cirwlation 78S73. lgee with parmission from the American Heart Association.“)

vasodilator stimulus, underestimation of hyper- emit blood flow, or inability to quantitate the residual arterial stenosis has hampered interpretation of these studies.

We recently measured coronary flow reserve in 30 patients undergoing angioplasty using a coronary Doppler catheter and intracoronary injection of a maximally vasodilating dose of papaverine.% Coronary lumenal dimensions before and immediately following angioplasty were defined using the Brown-Dodge method of quantitative coronary angiography. Following angioplasty, the percent area stenosis decreased from 90% f 1% to 61% + 2% (mean + SEM), and the minimum cross-sectional area of the dilated vessel increased from 0.7 f 0.1 mm* to 2.5 * 0.1 mm*. Similarly, the translesional pressure gradient measured using the dilating catheter (cross-sectional area 1.5 mm’) decreased from 56 + 2 mm Hg to 12 f 1 mm Hg, suggesting that the coronary lesions were adequately dilated according to standard criteria.g1 Coronary flow

reserve (measured as the peak to resting velocity ratio) increased from a mean of 2.0 + 0.1 before angioplasty to 3.6 f 0.3 after angioplasty (Fig 11).

Although flow reserve increased in all patients, the range of flow reserve following angioplasty was quite diverse (2.5 to 7.5 peak/ resting velocity ratio). In a previous study, we demonstrated a close relationship between coronary lesion geometry (percent area stenosis, minimum cross-sectional area) and coronary flow reserve in undilated coronary vessels (Figs 12 and 13).‘* In that study, lesions with >2.5 mm*- cross-sectional area or ~70% area stenosis uni- formly had normal coronary flow reserve (ie, >3.5 peak/resting velocity ratio, Figs 14 and 15). Importantly, immediately after angioplasty, we found no correlation between the percent area stenosis nor the minimum arterial cross-sectional area and coronary flow reserve measurements. Moreover, of the 27 patients studied immediately following angioplasty and found to have a resid-

r = -70 y = 1.8 + 1.54x - .lW

.

-. - .

.

/

.: . . . .

: . *- . :. . C

I I I I I 1 I I 1 I 1 I 1 1 I I I I 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5

Minimum Crosssedi Area (mmz)

Fig 13. Coronary flow reserve measured in arteries with ~70% araa stanosis. Before and later aftor angicpla8ty. all vaasale with ~70% area stenosis had normal coronary flow rasarve b-3.6 paak/rasting vafaaity ratio maasurad using an

intraaoronary Doppler catheter foilowing a maximally vasodgating dosa of imry -1. knadiatafy after angioplasty, howaver, 11 of 24 vauels with ~70% area nenosis had diminishad coronaryfiow remrve. (Raprinted from Wilson at al. Circulation 76S73.1988 with permission from the American Haart Asso&a&n.?


6 7 F - : . . 6 * . . . 5 .

ACBFV ;. I’

(x resllng) 4 1 :

3 --Lf ------- -‘----_-.

P

Fig 14. The relationship between minimum cross- sectional area and coronary flow reserve (ACBFVI in vessels with an undiited stenosis and vessels studied immedi-

ately and later after coronary angioplasty. The bar in the upper right corner of each panel diiplays the mean and range of coronary flow reserve measured in normal coro-

nary vessels. (A) Coronary flow reserve was hiihiy dependent on minimum arterial cross-sectional area in undilated vessels. (6) Immediitefy after angioplasty, coronary flow reserve was unrelated to minimum cross-sectional

area. (C) Late after angiopbsty there was a signifkant curvilinear relationship between flow reserve and minimum arterial cro8s-sectional area. Importantly. coronary flow

reserve was normal in all vessels with undilated lesions and in those studied late after angioplasty if the lesion had more than 2.6 mm* minimum cross-sectional area (the area

defined by the box in the lower right-hand corner of each

panel).

ual lesion with >2.5-mm2 minimum cross- sectional area or ~70% area stenosis (ie, adequate lumenal caliber to normally conduct hyperemic blood flow), 14 had depressed coronary flow reserve (Figs 14 and 15).

Since quantitative angiographic measurements may not reflect the true lumen caliber of recently dilated arteries, we also analyzed each dilated lesion using videodensitometry. These studies also demonstrated a lack of correlation between flow reserve measurements and the integrated optical density of the dilated stenosis immediately after angioplasty (Fig 16). Thus, two techniques for assessing the severity of the residual lesion, one not dependent on definition of arterial border, failed to correlate with measurements of flow reserve obtained immediately after angioplasty.

Importantly, a similar lack of correlation was found between measurements of flow reserve obtained immediately after angioplasty and the translesional pressure gradient at rest or at maximal hyperemia. Moreover, mean translesional pressure gradient and distal coronary pressure at hyperemia were similar in vessels with normal and abnormally low flow reserve immediately after dilation (Fig 17).

---- ----

‘PC.05 vs. hmedhwy afw n9w-w

lmmodhtdy after mwm AZ

m CSA (mm’) 3.1: 0.1 3.4 -* 0.2

Fii 15. The maximal change in coronary blood flow velocity (ACBFC) following a maximalfy vasodiitlng dose of intracoronary papaverine into coronary vessels with more than 2.6 mm* miminum arterial cross-seotional area. Thir-

teen vessals with more than 2.5 mm’ minimum cross- sectional area immediat ely after angioplasty (mean minimum cross-sectional area 3.1 f .Ol mm’) had an average of flow reserve of 3.6 f 0.4. bnportantly. 8even of 13 vessels

with more than 2.6 mm’ minbnal cross-sectional area had diminished flow reserve. Late after angioplasty, each of 12 vessels with more than 2.5 mm’ minimum cross-sectional

area had normal coronary flow reserve (mean minimum cross-rectional area 3.4 f 0.2 mm’). Mteprinted from Wil- son et al, Circulation 7M73.1 gee with permission from the

American Heart Aseociation.wl

These studies demonstrate that coronary reserve improves immediately following angioplasty, but in many patients does not normalize. Additionally, flow reserve measured immediately following dilation was not related to quantitative angiographic or hemodynamic measurements of the anatomic success achieved by the dilation.

This dissociation between flow reserve and the measurements of lesion geometry could result from three sources. First, angiographic methods of any type (edge detection or videodensitometry) may not predict the resistance of the residual lesion.” Second, angioplasty might directly alter the function of the coronary microcirculation. As previously discussed, humoral agents liberated at the site of vascular dilation, denudation of the endothelium, changes in neural control of the coronary microcirculation, or administration of drugs that might cause inappropriate changes in arteriolar tone might limit arteriolar vasodilator capacity. Third, resting blood flow might be elevated immediately following angioplasty. This could result from drugs, embolization, or transient abnormalities in coronary autoregulation of blood flow from long-standing arteriolar vasodilation prior to angioplasty. A recent study dem-


ACBFV (x r=wl)

B

0 2 4 6 6 10 12 14

Integrated Optiid Denstty (units)

Fig 16. The relationship between stenosis integrated optical density and coronary flow reserve (ACBFV) in vessels with undiited stenoaes and vessek studied immediately and later after angioplasty. The bar in the upper left-hand corner of each

panel displays the mean and range of coronary flow measured in normal coronary arteries. (A) Immediately after angioplasty,

coronary flow reserve was unrelated in stenosis integrated optical density. (B) Coronary flow reserve was sfgnificantly correlated with the lesion den&y of undibted stenoses. Late after angioplasty there was a l ignffcant curviliiar rekXionship between flow reserve and stenosis integrated optical density. Immediately after angioplasty, six of 13 vessels with an

integrated density of more than 7 U had reduced flow reserve whereas seven of eight vessels with more than 7 U integrated density late after difation had normal reserve. (Reprinted from Wilson et al, Circuiation 7gzB73.1988 with permission from the American Heart Association.“)

onstrated that coronary embolization with small (15 to loo-pm) microspheres results in increased resting blood flow and a diminution of hyperemic blood flo~.‘~ At present, however, the mechanism of this inappropriate decrease in peak to velocity ratio measured immediately after angioplasty is unclear.

LATE EFFECTS OF ANGIOPLASTY ON CORONARY FLOW RESERVE

Measurements of coronary flow reserve weeks or months after coronary angioplasty might more accurately reflect the true flow reserve capacity of the vessel because many of the factors con- founding angiographic estimates of the residual lesion and other factors that might alter coronary hemodynamics about the time of the dilation are

no longer present. The arterial plaque fracture (and in some patients thrombus) has healed by the time of follow-up angiography, and videoden- sitometric and quantitative angiographic measurements of arterial stenosis again correlate closely.“~” Moreover, the direct effects of vascular trauma, platelet adhesion, and the presence of drugs acting on the coronary circulation are no longer present.

Bates and colleagues measured coronary flow reserve 4 to 9 months after angioplasty in 14 vessels using digital subtraction angiographic measurements of contrast density to contrast appearance time following intracoronary administration of Renografin 76 (Fig 4).60 They found that flow reserve late after angioplasty (1.97 rt 0.12) was similar to that measured in 16

y -- 47-067x + .xo5tx~

C IX ‘=m) ACBFV ,‘-1. :‘iT fq. , , r=,20, rp;,. . .,

0 xl 40 w 60 0 20 40 60 60 0 20 40 60 60 Pressure Gradient (mmi-lg)

Fig 17. The relationship of the transleskmal pressure gradient to coronary flow reserve (ACBFV) in vessels with an undilated stenosis and arteries studied immediately and later after angioplasty. (A) Coronary ffow reserve was correfated with the translesional preesure gradient in undibted vessels. All vessels with a gradient of 40 mm Hg had normal flow reserve (23.5~1 peak/resting veknzity ratio). (Bl Immediitefy after angfoplasty. coronary ffow reserve was not correiated with the tranalesionel pressure gradiint. Thirteen of 27 vessels with a gradient of ~20 mm Hg had diminished flow reserve (the area deffned by the box in the lower left-hand corner). (Cl Late after angiopfasty. coronary flow reserve was correkrted with the tranrlesional pressure gradient. All vessels with a gradient of t20 mm Hg had normal reserve. (Reprinted from Wilson et al, Circulation 7gB73.1988 with permission from the American Heart Association.‘D)


vessels revascularized with a vein bypass graft (2.02 rt 0.17) but significantly lower than that measured in 29 normal coronary vessels (2.59 + 0.11). In this study, the residual stenosis was not evaluated, although all patients had a residual translesional pressure gradient of ~20 mm Hg at the time of angioplasty and no visual evidence of restenosis was present. Since flow reserve capacity was measured using a submaximal coronary vasodilator, it is unclear whether maximal coronary reserve was normalized and, if not, if the decrease in flow reserve was propor- tionate to the residual coronary stenosis.

We recently measured flow reserve in 30 patients who had previously undergone coronary angioplasty (mean follow-up 7.5 f 1.2 months).gO Flow reserve, measured with a 3-Fr coronary Doppler catheter following intracoronary administration of papaverine, was uni- formly >3.5 peak/resting velocity ratio (our lower limit of normal) in vessels with ~70% area residual stenosis. Moreover, when all vessels were considered, there was a close relationship between flow reserve and percent area stenosis (Figs 12, 14, and 16). This relationship was not significantly different from that observed in patients with l- or 2-vessel coronary artery dis-

01 oi 0 1 2 3 4 5 0 20406060100 Minllmuncmn-sectiulsl Area StmPsi~

Are* (mm2, (%I

,zzg, &J jg--j 0 2 4 6 6 10 12 0 20 40 60 60

Fii 18. The relationship of coronary flow reserve (ACBFV after a maximally vaxodileting dose of papavarine)

and each pxrameter of arterial stmnoxis. In undilated. xta- nuwd wronuy veael8 and l8ter 8fter 8ngl@wty. ooro- wry flow reserve w8a wrrel8ted with the are8 atenods. minimum arterial crssetionx I uw. integr8ted optical den&y, and tm nsl&onalprosxuregradinntoftheste nosed veaael~’ Immmktoly aftar coronary 8ngioplasty. 8owrea8rvewa8notoorr~with8nypr8meterof obxtruction.

ease studied prior to coronary angioplasty (Figs 12 through 14, 18). In three patients, coronary flow reserve measured immediately following angioplasty was ~3.5 peak/resting velocity ratio despite a residual lesion with >2.5 mm* cross- sectional area and ~70% area stenosis. At follow- up angiography, all three patients had a significant increase in coronary flow reserve (average flow reserve at follow-up 4.6 f 0.5, mean increase 86%) (Fig 19). These sequential studies in individual patients clearly demonstrate that the dissociation between coronary flow reserve and angiographically defined stenosis geometry observed immediately following angioplasty is transient and that flow reserve is normalized to the degree of residual stenosis months following angioplasty (Fig 20).

An important consequence of the transient alterations in coronary hemodynamics after angioplasty is that noninvasive studies of provoc- able ischemia may not immediately normalize. One preliminary study suggests that ZO’Tl scintigraphic studies may be abnormal several days after successful coronary dilation.93

IMPLICATIONS

The first implication from these studies is that a thorough understanding of the methodologies for measuring coronary blood flow and provoking coronary hyperemia are essential in interpreting the effects of revascularization on coronary hemodynamics. No single measurement technique can provide all of the answers needed to properly assess alterations in resting blood flow or coronary flow reserve following revascularization. Furthermore, most methods have serious shortcomings.

Despite these limitations in measurement techniques, prior studies suggest that there are transient alterations in coronary hemodynamics following both coronary angioplasty and bypass surgery. After both procedures, the peak hyper- emit to resting blood flow ratio is significantly reduced, compared to normal vessels. After bypass surgery, the resting and hyperemic blood flow is affected by the cardiopulmonary bypass pump, the distal coronary pressure, the size and type of bypass graft, and a host of other factors. Similarly, multiple factors may alter resting and hyperemic blood flow after angioplasty, including the resistance of the residual dilated stenosis.


Immediately After

Angioplasty

5 Months After

Angioplasty

Phaslc CBFV

(ktiz shift)

Mean CBFV

(ktiz shift)

Arterial Pressure (mmHg)

0

200

Heart Rate

@Pm)

ECG

Ill---

69% Area Stenosis 3 1 mm’ Minimum cross- 63% Area Stenosis 3.7 mm2 Mmimum cross- sectional area sectional area

Fig 19. A record obtained from a patient undergoing right coronary sngioplasty demonstrating the late return of normal flow reserve. (A) Record obtained immediately after angioplasty. The top tracing diiys phasic coronary blood flow velocity

(CBFV). The next tracing shows mean coronary blood flow velocity, and the three bottom panels show the arterial pressure, heart rate. and ECG readings. Immediately after angioplasty, intrawronary administration of 6 mg papaverine produced only a 2.1 fold increase in blood flow velocity, despite the presence of 3.1 mm’ minimum arteM cross-sectionel area and 89% area stenosis. (B) Record obtained from the same petient studied 6 months after angioplesty. This time, intracoronsry

adminstration of 6 mg papeverine increase blood flow velocity to 6.6 fold resting velocity, demonstrating normal coronary flow reserve. (Reprinted from Wilson et al, Circulation 7BzB73.1988 with permission from the American Heart Association.a)

Before Angioplasty

n=ll

Immediately after AwWasty

Late after Anolaplaty

sequentially studii vessels. Late nfter angio-

plasty. coronery #ow reserve increased in vessels without restsnosh. (Reprinted from Wilson et al, Circuletion 78:873. 1988 with permission from the American Heclrt Asso- ciation.9

No Restmosis

n=6


Whether the increases in resting blood flow eventually result in a functionally important following each procedure are inappropriate for improvement in coronary flow reserve. Addition- metabolic requirements is not clear. Further ally, studies from our laboratory show that maxi- studies will be required to determine the impor- ma1 flow reserve is appropriate for the degree of tance of flow reserve measurements obtained residual focal stenosis, suggesting that mild to immediately after revascularization. moderate diffuse atherosclerosis has negligible

Third, although coronary hemodynamics are effects on coronary hemodynamics in the pres- altered immediately following revascularization, ence of a normal bypass graft or effective angio- both angioplasty and coronary bypass surgery plasty.

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effects of coronary bypass surgery and angioplasty on coronary blood flow and flow reserve

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