assessment of the human coronary circulation using a doppler catheter

Assessment of the Human Coronary Circulation Using a Doppler Catheter

Robert F. Wilson, MD

Arteriographic estimates of stenesis severity can fail to reflect the impact of an individual stenosis on delivery of blood to the myocardium. Whether a coronary stenosis is truly flow.limiting can be determined by measuring hyperemic blood flow or coronary flow reserve; however, until recently, the tools needed to measure coronary flow reserve in human= namely, a method of quanti- tating coronary blood flow in individual arterlas and another method for producing maximal microvascular vasodilation--were nat available. Over the last 8 years, our laboratory group has developed a catheter for measuring coronary Mood flow velocity in humans, using the Doppler principle, and studied the effects of microvascular vasodilators. These studies have enabled us to measure coronary flow reserve in humans and to characterize some of the effects of focal and diffuse atherosclerosis on the coronary circulation. In addition, we have used flow reserve measurements in the diagnosis of microvascular dysfunction in patients with chest pain and normal coronary arteries and as a means of assessing nonlnvasive methods for detecting focal coronary artery disease.

(Am J Cardio11991;67:44D-56D)

From the Department of Medicine and the Minnesota Heart and Lung Institute, University of Minnesota, Minneapolis, Minnesota.

Address for reprints: Robert F. Wilson, MD, University of Minnesota, Box 508 UMHC, 425 East River Road, Minneapolis, Minnesota 55455.

B lood flow to the myocardium is regulated primarily by coronary arteries less than 400 Izm in diameter. 1-3 Even at peak flow condi-

tions, the large epicardial vessels (those visible on the angiogram) contribute less than 10% of the total coronary resistance to blood flow. 1 As a stenosis develops in a coronary artery, the resistance produced by the epicardial vessel rises, primarily because turbulent energy losses develop as blood exits the stenosis. 4'5 To maintain normal resting blood flow, the coronary microcirculation dilates, normalizing total coronary resistance and blood flow (Figure 1). As the stenosis becomes more severe, the microvasculature fully dilates. Further increases in stenosis severity result in a fall in resting blood flow. 6

Seminal studies by Gould et al 6 demonstrated in normal canine vessels that a focal stenosis could obstruct up to 90% of the vascular cross-sectional area without altering resting coronary blood flow (Figure 2). Peak hyperemic blood flow, however, began to decline when 75% of the vascular cross- sectional area (50% of the diameter) was compro- mised. Hence the caliber of the epicardial coronary arteries is much larger than that required to conduct blood flow to the myocardium, even during periods of maximum oxygen consumption. Fo- cal coronary stenoses in dogs that produce more than 50% diameter stenosis (75% area stenosis), however, can reduce peak hyperemic flow and are termed "physiologically significant."

How can these studies in dogs be applied to humans with atherosclerotic coronary obstructions? After its introduction in the 1960s, coronary arteriography became the gold standard for assessing the presence and severity of obstructive coronary artery disease. Based on the prior work in animals, a 50% diameter (75% area) stenosis found at arteriography was deemed to be physiologically significant. As a result, patient care decisions were made and the accuracy of noninvasive tests was determined using > 50% diameter stenosis as the criterion for "significant" coronary artery disease.

4 4 D THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67 MAY 21, 1991

FIGURE 1. The effects of an eplcardlal stenosis on coronary flow reserve. Top panel: Dilation of a normal mlcrovascu. lature with papaverlne causes blood flowto increase 4-fold. Middle panel: An eplcardlal stenosis causes partial mlcrovascular dilation; papaverlne has little additional effect. Flow reserve Is reduced. Bottom panel: Mlcrovascular disease prevents normal arterlolar dilation, reducing flow reserve.

Anatomy

Normal

Epicardial Artery

Epicardial Stenosis

Microvascular

Physiology

x I Time Arteriolar Vasodilation (Papaverine)

/ / ,x] ~ Flow x l ~ T i m e

Arteriolar Vasodilatlon (Papaverine)

Arteriolar Vasodilation (Papaverine)

The obvious problem in using 50% diameter stenosis to infer potential flow limitation by a coronary lesion is that humans with atherosclerosis are different from dogs with normal coronary arteries. When clinicians read arteriograms, the diameter of a stenosis is compared to the diameter of an adjacent "normal" vessel. The interpretation of stenosis severity depends on the "normality" of the adjacent arterial segment, and the adjacent segment is usually not normal. Histologic studies of atherosclerotic coronary arteries demonstrate that atherosclerosis causes diffuse infiltration of the coronary wall in addition to the focal severe stenoses seen by arteriography. 7'8 To complicate matters even further, atherosclerotic arteries frequently and somewhat unpredictably dilate in overall size as atherosclerosis progresses. 8'9 Diffuse narrowing and "ablunaenal" dilation in the coronary arterial tree cannot be detected by arteriography because the arteriogram shows only the dimensions of the lumen of the vessel; with rare exceptions, the truly normal dimensions of the artery (for example, at

age 18) are not available. Consequently, it is not surprising that arteriographic estimates of stenosis severity can fail to reflect the actual impact of an individual stenosis on delivery of blood to the myocardium. ]°

If the anatomy, as defined on the angiogram, does not necessarily reflect the physiology, then what standard can we rely on to tell us if a coronary stenosis is truly flow-limiting? Physiologic significance of coronary lesions could be detected by measuring hyperemic blood flow or coronary flow reserve-- the ratio of hyperemic blood flow to resting blood flow--as was done in the canine experiments by Gould et al 6 (Figure 1). In the past, however, the two tools needed to measure coronary flow reserve in humans, a method of measuring coronary blood flow in individual arteries and another method for producing maximal microvascular vasodilation, were not available. Over the last 8 years, our laboratory group has developed a catheter for measuring coronary blood flow velocity in humans and has studied the effects of microvascu-

FIGURE 2. Left panel: In dogs, the relation between coronary flow reserve and percent diameter eplcardlal corona~ stenosis (reproduced wlth permhmlon from Am J Cardlo~). Right panel: In humans with atherosclerosis, the relation between coronary flow reserve and percent diameter eplcardlal stenosis (re- pl~duced wlth permlsslon from N Engl J M~P).

C o r o n a r y F l o w Reserve

6 -

5 -

4 -

3 -

2 -

Normal Dog Coronary Arteries Gou ld et al.

20 40 60 80 100

D i a m e t e r S t e n o s l s ( % )

Atherosclerotlc Human Coronary Arteries

White et al.

i • i • / ' i • i 20 40 60 80 100

D i a m e t e r S t e n o s l s (%)

A SYMPOSIUM= ADVANCES IN CARDIOVASCULAR IMAGING 46D

lar vasodilators. "'t2 These studies have enabled us to measure coronary flow reserve definitively in humans and to characterize some of the effects of atherosclerosis on the coronary circulation.

DEVELOPMENt' OF A CORONARY DOPPLER CATHETER

The Doppler principle, described in the 19th century by the Austrian physicist Christian Johann Doppler, states that the reflection of a wave (e.g., photon, sound) from a moving object will change the frequency (Af) of the reflected wave such that

v = ( A f ' c ) / ( 2 f o . cos~)

where v = the velocity of the object (e.g., blood cells), c = the speed of the wave in the medium (e.g., blood), fo = the frequency of the wave sent toward the moving object, Af = the difference between the sent and returned frequencies, and ~b = the angle between the sound wave vector and the moving object vector. Extending the prior work of Cole and Hartley 13 and Benchimol et al, ~4 we developed a catheter-mounted ultrasonic transducer to measure blood flow velocity using the Doppler principle. H

The catheter developed in our laboratory is shown in Figure 3. A small piezoelectric crystal is mounted into the side of a 2-lumen polyethylene tube. The larger lumen contains a standard, steerable angioplasty guidewire. The smaller lumen contains the conductors to the transducer crystal. These conductors are connected to a 20 MHz pulsed Doppler velocimeter. Functioning in the artery, the catheter emits a short 0.8 ~sec, 20 MHz ultrasound burst, 62,500 times/second, and then "listens" between bursts. The 20 MHz sound wave reflects off the moving blood (mainly the red blood

ceils). The sound waves reflected to the crystal transducer (during the "listening" phase ) vibrate the crystal, creating an electric current with the same frequency as the reflected sound. The frequency of the returned signal is then analyzed and the mean frequency shift (Af of the emitted signal minus the reflected signal) is calculated. The frequency shift is linearly proportional to the blood velocity. Consequently, if everything works prop- erly, one can measure relative changes in blood flow velocity using a Doppler catheter. Further, if the angle of incidence (~b) between the sound wave and the mean blood velocity vectors are known, absolute blood flow velocity can be determined.

We performed extensive studies to determine the accuracy of relative blood flow velocity measurements using our catheter." In a tube system, the frequency shift measured using the catheter varied linearly with mean tube flow velocities up to 80 cm/sec (well within the physiologic range). It is important to note that we used a Doppler velocimeter with a "zero-crossing detector"; similar studies using a velocimeter with a fast-Fourier transformation algorithm might extend the range of the linear response.~5

In calves (50-80 kg), we compared relative coronary blood flow velocity measurements obtained with the catheter to similar measurements obtained using an extensively validated epicardial Doppler probe, and to changes in coronary sinus blood flow. Measurements obtained by each method were closely correlated when blood flow varied from 0.1 to 5.7 times resting blood flow (Figure 4). Hence, linearity of measurements was demonstrated over the physiologic range of blood flow in an animal model with coronary vessels the size of a small adult human's.

Steerable Coronary Doppler Catheter Tip Design

Copper wires to

Doppler meter

20 MHz piezoelectric

crystal

Degassed epoxy '

Guidewlre

r Gold band /

Crystal

Transducer l u m e n ~

J

0.016" guidewlre

FIGURE 3. A schematic diagram of a steerable coronary Doppler catheter with a side.mounted piezoelectric transducer. The large central lumen Is for a steerable O.014-1nch guldewire.

4,liD THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67 MAY 21, 1991

FIGURE 4.1he relation In Instrumented dogs between changes In coronary blood flow velocity (CBFV, measured with a coronary Doppler catheter) and timed-volume collections of coronary sinus blood flow (reproduced with per. mission from CirculatlonU),

ZX Coronary Flow ( x resting flow)

Coronary Sinus

4 • o :

t 2 •

0 0 1 2 3 4 5

A Coronary Flow Velocity ( x resting velocity) Doppler Catheter

We also examined the possibility that the catheter could obstruct hyperemic blood flow. These studies showed that maximal coronary blood flow velocity was the same when the 1.0-mm diameter (3 French, 0.75 mm 2 cross-sectional area) catheter was in the artery as when the catheter was re- moved. It has been our experience, however, that catheters more than 1.3 mm in diameter (4 French, 1.33 mm 2 cross-sectional area) reduce hyperemic blood flow in some animals. In our opinion, coronary flow measurement catheters should be < 1.3 mm in size (the smaller, the better).

We have repeated these validation studies in animals whenever major design changes were initi- ated. ]6 In the subsequent developmental studies, we have been unable to validate measurements using a piezoelectric crystal mounted on the end of a catheter. It is unclear whether the problem was in transducer configuration or Doppler velocimeter design. In vivo studies by Sibley et a117 using an end-mounted catheter transducer showed that changes in velocity measured with the catheter tended linearly to overestimate small changes in blood flow while underestimating large increases. Other studies using the same catheter system showed that a linear response could be restored by using a fast-Fourier transformation algorithm velocimeter. 15 In our opinion, end-mount crystal transducers using a zero-crossing detector velocimeter will need to be validated convincingly before their use can be accepted.

Finally, we performed toxicity studies. These demonstrated that the catheter placed in a coronary artery causes minimal changes in endothelial permeability but no microscopically visible endothelial denudation." After these studies, the catheter

was taken to the clinical catheterization laboratory, where coronary blood flow velocity was measured in individual coronary arteries of patients undergoing coronary angiography (Figure 5).

One of the disadvantages of the Doppler method is that velocity is measured rather than volumetric flow (velocity × arterial cross-sectional area). We have circumvented this problem by giving nitroglycerin to maximally dilate and "freeze" the size of the epicardial vessel containing the catheter, main- taining linearity between velocity and flow. Others have used quantitative arteriography to measure the size of the artery at the point of flow velocity measurement. TM Still others have attempted to measure volumetric flow by assuming an angle of incidence between the ultrasound and blood flow (~b) and calculating absolute blood flow by multiply- ing the calculated absolute velocity by the arterial cross-sectional area. Given the major problem of not knowing the angle of incidence with any accuracy (coronary arteries are tortuous) and the spectral nature of the returned signal (the returned frequencies are not identical), these measurements should be viewed with skepticism.

CORONARY VASODILATORS To measure coronary flow reserve in humans, a

maximal coronary vasodilator must be used. The characteristics of an ideal vasodilator are (a) induc- tion of maximal coronary vasodilation, (b) a brief duration of action so that repeated measurements can be obtained in a single study, (c) minimal effects on systemic hemodynamics, and (d) no significant toxicity.

Iodinated contrast material: The development of the Doppler catheter enabled us to study

A SYMPOSIUM= ADVANCES IN CARDIOVASCULAR IMAGING 470

Selective Intracoronary Blood Flow Velocity

Phasic Coronary Velocity

KHz

Left Anterior Descending

0

EKG [ ~ -If" ~ J~ - . , I r I I

1 sec Right Coronary

Phasic Coronary Velocity

KHz

EKG

'1 s e c '

FIGURE 5. Phasic coronary blood flow velocity measured with a coronary Dop. p ie r ca the te r . No te t h a t t h e ra t i o o f sys- toUc to diastolic blood flow velocity is higher In the right coronary artery than In the left anterior descending, reflect. Ing systolic right ventricular and atrial perhJslon (from Wilson et a l , " rep ro - duced with permission from the Amer l . can Heart Association, Clrculation~L).

in humans the effects of vasodilators on the coronary circulation. Iodinated contrast material (e.g., diatrizoate meglumine, iohexol) produced a brief, predictable hyperemia, but was not useful because its vasodilatory effects were submaximal. ~7J9'2° "Ionic" contrast agents caused blood flow velocity in normal human coronary arteries to increase by 3.1 +__ 0.2 x resting velocity (mean _ SEM). Nonionic contrast caused a lesser rise (2.5 ___ 0.4 x resting velocity for iohexol). Additionally, contrast material increases coronary blood flow significantly only when given by the intracoronary route.

Papaverine: In comparison to contrast material, papaverine was an excellent coronary vasodilator. Intracoronary administration caused coronary blood flow in normal humans to increase by an average of 4.8 ___ 0.4 x resting coronary blood flow (Figure 6). "'2° In our experience, 12 mg of papaverine injected into the left coronary artery always produced maximal hyperemia. Additionally, the

time from intracoronary injection to the onset of maximal hyperemia was very brief (17 _ i seconds) and the duration of hyperemia was also short: In most patients, peak hyperemia (90% of the absolute peak value) continued for only 29 ___ 3 seconds and coronary blood flow velocity returned to within 10% of basal levels in 129 +- 16 seconds. The duration of hyperemia and the time required to return to basal levels increased with the dose administered.

Papaverine has 3 major drawbacks. First, it is only effective as a maximal coronary vasodilator when administered by the intracoronary route. Intravenous doses sufficient to cause maximal coronary vasodilation also produce maximal systemic vasodilation and result in severe arterial hypoten- sion. Second, metabolism and excretion of papaverine are slow and the systemic half-life of the drug is in the range of 3.5 hours. 2' Consequently, although useful for measurement of coronary flow reserve in

ACBFV ( x rest ing) 3.

2 -

1j

0 ' I 0 20

m e a n ± s e m

i I I I I ' I I

40 60 80 100 120 140

Time (sec)

FIGURE 6. Effects of Intracoronary adenosine and papavedne on coronary blood flow velocity. Each drug causes a maximal Increase In blood flow velocity, but the effects of adenosine are shorter.

~11) THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67 MAY 21, 1991

the catheterization laboratory, papaverine is not useful as an adjunct for noninvasive studies of the coronary circulation.

A third important disadvantage of papaverine is that it significantly lengthens the QT interval of the electrocardiogram. 22 We have observed torsades de pointes in approximately 1% of patients receiving the drug. The arrhythmia is facilitated by coexistent hypokalemia, hypomagnesemia, and alkalosis. Although we have observed the arrhythmia primarily in patients with a predisposing factor, and there have been no important sequelae, torsades de pointes remains a troublesome potential side effect. Since QT prolongation is dose-dependent, we still perform a stair-step dose-response curve in each patient so that we use the minimum dose required to cause maximal hyperemia (frequently less than 12 mg in the left coronary). Despite these potential problems, papaverine is an excellent agent for producing brief, maximal coronary hyperemia.

Dipyridamole: Intravenous administration of dipyridamole causes an increase in interstitial adenosine concentration, in part by blocking adenosine reuptake. 23 In humans, dipyridamole (total dose of 0.56 mg/kg given intravenously over 4 minutes) caused a 4.8 - 0.6-fold increase in resting coronary blood flow (equal to that produced by intracoronary papaverine), lt't2 Maximal coronary dilation occurred 2--4 minutes after the drug was administered and coronary blood flow velocity remained elevated above basal levels for more than 30 minutes.

Dipyridamole is an excellent agent for noninvasive studies of the coronary circulation because it can be given intravenously, and it causes maximal coronary hyperemia in most patients. Its use in the catheterization laboratory to measure coronary flow reserve, however, is limited because the long duration of action precludes multiple studies during a single catheterization.

Another disadvantage of dipyridamole is that approximately 10% of patients fail to achieve maximal coronary vasodilation with a dose of 0.56 mg/kg. H't2'24 In some patients, maximum dilation can be achieved by increasing the dose to 0.7 mg/kg. In a small group of patients, the drug seems incapable of causing hyperemia equivalent to that obtained with intracoronary papaverine. The rea- son for the submaximal response is unclear.

Finally, a small fraction of patients with severe coronary artery disease develop profound myocardial ischemia after dipyridamole infusionY The mechanism of the ischemia might be dipyridamole-

induced subendocardial "steal. ''26 The deleterious effects of adenosine (and thus, dipyridamole) can be antagonized partially by administration of meth- ylxanthines, such as aminophylline. In our experience, however, aminophylline (250 mg, intravenously) causes a reduction in dipyridamole-induced vasodilation but does not diminish blood flow to normal levels.

Adenemine: More recently, we investigated the effects of adenosine on coronary and systemic hemodynamics in humans. 27 Adenosine is a natu- rally occurring nucleoside that has been known for over 50 years to cause microvascular coronary dilation. Although used extensively in animal studies; the use of adenosine in humans has been tempered by its propensity to cause profound depression of the sinoatrial and atrioventricular (AV) nodes. In animals, doses of adenosine required to produce maximal coronary vasodilation frequently cause transient heart block, sinus brady- cardia, and systemic vasodilation resulting in hy- potension. It is curious, however, that dipyridamole is relatively well tolerated, because it acts indirectly by increasing interstitial adenosine concentration.

Our studies showed that injection of > 16 p~g boluses of adenosine into the left coronary (12 ~g into the right coronary) caused maximal coronary hyperemia in 91% of patients, without significantly changing heart rate, AV conduction, or arterial pressure (Figure 6). 27 Similarly, intracoronary infu- sions of > 80 ~g/min into the left coronary caused maximal hyperemia without altering systemic hemodynamics or conduction. The duration of hyperemia after intracoronary adenosine (maximal hyperemia lasted 12 __- 5 seconds and blood flow velocity returned to within 10% of baseline in 37 --- 7 seconds) was significantly shorter than papaverine hyperemia. Additionally, after stopping a continu- ous left coronary infusion of 240 ~g/kg/min (3 times the maximal vasodilatory dose), blood flow velocity returned to normal in 143 --- 75 seconds.

Intravenous administration of 140 i~g/kg/min caused maximal hyperemia in 83% of patients, and also caused a small fall in mean arterial pressure ( - 5 - 1 mm Hg) and a moderate reflex-mediated rise in heart rate (19 _ 4 beats/min). It is important to emphasize that at submaximal intravenous doses, coronary blood flow velocity fluctuated widely, with a periodicity of about 30 seconds (Figure 7). Additional intracoronary adenosine caused a prompt rise in flow velocity, suggesting that cyclic variations in adenosine concentration are the cause of the cyclic variations in flow. The time required

A SYMPOSIUM: ADVANCES IN CARDIOVASCULAR IMAGING 49D

Effect Of Intravenous Adenosine On

Coronary Blood Flow Velocity ( C B F V )

(Left Coronary Artery)

Phasic 5- CSFV

(kHz shif t) 0-

Mean peak CBFV 1.0 ~ / ,~ A j ~ ~u ~ e . ~ . ~ 3 6 3a

+ - - L,0+ 0m,o 1OF - - ( k H z s h l f t ) o- I 35.gtkOlm,° " ~70.gtkSml.

(mmHg) . . . . . . . . - - - r . . . . . . . . . . . . o°

20o- Coronary ~ Pressure I

(mmHg) o-

ECG

- . % - . - - - . - _ Y _ - - . ' . . . . . . . . . .

1 sec 30 s.c

. . . . . . . . . . . . d . . . . . . . . . .

FIGURE 7. A record obtained In the catheterization laboratory fxom a normal patient receiving an Intravenous adenosine Infusion. The top two traces show phasic and mean coronary blood flow velocity (ACBFV), the middle two traces display the aortic and Intracoronary pressures, and the bottom trace shows the electrocardiogram. An Infusion at 70 i~g/kg/mln caused blood flow velocity to fluctuate widely. When Mood flow velocity fell, it was Increased rapidly by additional Intra- coronary adenosine, suggesting that the aortic adenosine concentration may have fluctuated at the 70 pg/kg/mln infusion rate. Increasing the infusion to 100 and 140 I,g/kg/mln caused sustained maximal hyperemla.

for blood flow velocity to return to basal levels after stopping a 140 i~g/kg/min infusion was 145 _ 67 seconds.

Adenosine is generally well tolerated when given by the intracoronary route. Intravenous administration causes flushing, palpitations, and, in one instance in our experience, brief 2:1 AV block in a patient taking a 13-adrenoreceptor antagonist and a calcium channel antagonist.

From these studies, it is clear that intracoronary papaverine or adenosine are the two vasodilators best suited for measurement of coronary flow reserve in the catheterization laboratory (Figure 6). Both are maximal dilators with a short duration of action and a low incidence of side effects; neither importantly alters systemic hemodynamics. For noninvasive studies outside the laboratory, either adenosine or dipyridamole offers maximal coronary vasodilation in the vast majority of patients. Adenosine has the added advantage of a very brief duration of action but the disadvantage of cyclic variation in flow at submaximal doses and infrequent episodes of AV block.

CORONARY FLOW RESERVE MEASUREMENTS IN HUMANS

To measure flow reserve, a Doppler catheter is placed selectively into the coronary artery under study by the same method used to place angioplasty ca the t e r s (guide ca the te r , s t ee rab le guidewire). Heparin should be given in a dose sufficient to prolong the activated clotting time to > 300 seconds. The Doppler catheter is positioned in a location where an acceptable signal of coro-

nary blood flow velocity can be obtained. An acceptable signal shows the typical phasic pattern of coronary blood flow velocity (diastolic domi- nant), a resting frequency shift of at least 1 kHz, and the absence of low frequency sounds typical of vessel wall artifact (Figure 5). Under normal conditions, flow velocity should " touchdown" to zero (or reverse flow velocity) at the onset of systole; this might not happen if the artery has significant resting tone (e.g., prior to nitrate-induced dilation) or resting flow is fast (e.g., during rapid atrial pacing). We usually predilate the artery with intracoronary nitroglycerin (100 to 200 ~g bolus) so that changes in velocity are linear with changes in flow, obviating the problem of hyperemia or vasodilator- mediated arterial dilation.

After resting coronary blood flow velocity is measured, the guide catheter system is flushed with the vasodilator solution (typically 3 ml). In our laboratory, we use papaverine (2 mg/ml normal saline) or adenosine (4 I~g/ml normal saline). Resting blood flow velocity should be measured for several minutes, because the iodinated contrast used for catheter placement and the loading of the guide catheter with a vasodilator can cause small, transient increases in resting blood flow. After the mean blood flow velocity is determined, a moderate dose of vasodilator (e.g., 8 to 10 mg papaverine, 12 to 16 I~g adenosine) is injected at 1 ml/sec (to avoid spillage out of the artery) and the resultant increase in blood flow velocity is recorded. If the hyperemia is prolonged, then a smaller dose can be given to prove that the first dose was maximal. If the response is not prolonged, a stepwise increase

500 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67 MAY 21, 1991

in bolus dose should be given until a maximal response is achieved.

Absolute coronary flow reserve is calculated as the ratio of the peak mean hyperemic blood flow velocity to the mean resting flow velocity; peak phasic flow velocity is subject to too much artifact to be used for decision making. Minimal coronary resistance can also be determined as the quotient of (mean aortic pressure at peak flow velocity [mm Hg]/peak flow velocity [kHz shift]) and (mean pressure at resting flow velocity/resting flow velocity). Minimum coronary resistance or maximal coronary conductance (1/resistance) should be used when the vasodilator causes a significant change in coronary driving pressure.

We have recently shown that coronary flow reserve measurements are highly reproducible over time, but that they are dependent on the heart rate and left ventricular filling pressure at which they are obtained (Figure 8). 2~ Consequently, we usually measure coronary flow reserve at a heart rate of 100 beats/min (atrial paced).

Four technical factors deserve mention. First, subselectively infused vasodilators (e.g., into the left anterior descending artery) sometimes do not mix adequately with the arterial blood flow. As a result, proximal branches may not receive a maximally dilating dose and coronary reserve will not be maximal. Second, the guide catheter can obstruct maximal hyperemic blood flow, especially in the right coronary artery. In this setting, pressure damping is not seen with regularity. If the coronary reserve is low, the guide catheter should be with- drawn at peak hyperemia to exclude guide catheter obstruction. Third, in an artery with a stenosis, coronary reserve must be measured proximal to the stenosis but distal to any major side branches; this may not be possible in all patients. Fourth, if the

artery under study gives collateral blood flow to an adjacent vascular bed, resting blood flow will be elevated and the coronary flow reserve ratio will be reduced. Although the reduced reserve reflects the "stenosis" in the collateral bed, it does not indicate that the epicardial vessel containing the catheter significantly obstructs blood flow.

CUNICAL IMPUCATIONS OF FLOW RESERVE MEASUREMENTS IN HUMANS

Effects of focal atherosclerosis on coronary Mood flow:, How well does the angiogram predict which lesions obstruct coronary blood flow under physiologic conditions? In the first test, White et al 1° measured coronary flow reserve at the time of open heart (primarily coronary bypass) surgery in patients with multivessel coronary artery disease (Figure 2). They found that angiographic measurements of percent stenosis correlated poorly with physiologic measurements of coronary flow reserve. However, when the stenosis was in the proximal left anterior descending artery, the minimum cross-sectional area of the stenosis (the numerator of percent stenosis) predicted the flow reserve in the artery (Figure 9). 29 These findings suggest that diffuse coronary narrowing altered the perception of percent stenosis, while the cross- sectional area of the residual lumen area was a constant parameter unaffected by diffuse disease in the adjacent "normal" arterial segment.

We and others extended those studies to patients undergoing coronary angiography for a chest pain syndromeP °'3~ In patients with normal coronary arteries and a normal exercise electrocardiogram, coronary flow reserve averaged 5.0 --+ 0.6 peak/resting blood flow velocity. In contrast to the studies by White et al, 1° we found in patients with limited coronary artery disease (single vessel/single

FIGURE 8. The change In coronary flow reserve associated with an increase In heart rate. Coronary flow reserve fell progressively as heart rate was In- creased by atrial pacing (reproduced with permission from the American Heart Association, Circulation=S).

A Corona ry F low Reserve

(peak/resting ratio)

-0 .5

- 1.0

- 1.5

-2 .0

A Hear t Rate ( b e a t s / m i n )

< 20 20 - 39 I> 40

A SYMPOSIUM: ADVANCES IN CARDIOVASCULAR IMAGING 5 1 0

6

Coronary Flow Reserve 4

(peak/resting velocity)

2

0

Studies In The Operating Room Studies In The Catheterization Laboratory Proximal LAD Lesions Only All Lesions (Proximal and Mild Vessel)

Harrison et al. Wilson el al.

4 • e e

d i e

• , , , , , 0 !

2 4 6 8 10 12 0 2 4 6

Minimum Cross-Sectional Area (mm2)

fiGURE 9. Left panel: The relation between the minimum cross-sectional area of left anterior descending lesions and coronary flow reserve (~CBFV) In patients with atherosclerosis studied in the operating room (reproduced with permission fTom CirculationS). Right panel: The same relationship In pa. tlents with limited atherosclerosis stud- led in the catheterization laboratory. The relationships are similar in both patient populations. (Reproduced with permission fTom the American Heart Association, Circulatlon~°.)

lesion or double vessel/double lesion) that the angiogram was a good predictor of the physiology. Percent area stenosis was moderately well correlated with coronary flow reserve (r = 0.85), and all lesions that caused < 70% area stenosis also failed to impede significantly maximal blood flow (Figure 10). As with the studies of Harrison e t a l , 29 minimum lesion cross-sectional area also predicted the impact of the lesion on coronary reserve (r = 0.79; Figure 9).

How can the findings in the catheterization laboratory that percent area stenosis (determined by quantitative arteriography) predicts coronary reserve be reconciled with the opposite results found in the operating room? In our opinion, differences in the amount of diffuse (and unpredict- able) atherosclerosis probably account for most of the disparity. 32 Patients studied in the catheterization laboratory had far more limited coronary artery disease, and the cross-sectional area of the "normal" segment adjacent to the stenosis was significantly larger (Figure 1 1). 30 One would anticipate more variability in the dimensions of the normal segment in patients with widespread athero-

sclerosis and a poorer relation between percent lumen stenosis and actual flow impairment.

One additional explanation for the divergent findings is that some of the patients studied in the operating room may have had coexistent disease in the microvasculature (e.g., from hypertension). 33-36 As a result, reduced coronary flow reserve in some patients may have reflected obstruction in both the epicardial stenosis and the microvasculature.

Assessment of diffuse atherosclerosis: Does diffuse atherosclerosis itself impair hyperemic blood flow or does it just "hide" focal lesions? From hemodynamic principles one would anticipate that diffuse atherosclerosis, unless very severe, would have minimal effects on coronary blood flow. Hy- draulic equations state that most of the energy (hence pressure) loss across a coronary stenosis is due to turbulence at the stenosis exit; entrance losses and intra-stenosis frictional losses (Poussel- lian losses) account for only a small fraction of pressure drop? As flow increases, the turbulent losses increase with the square of flow, but frictional losses increase linearly• Diffuse arterial nar-

ACBFV ( x resting)

8

7

6,

5-

4-

3-

2 -

I-

0

0

r = 0.85 y = 6.0-0.005 x -0.00044 x =

~ e

I I I I i 20 40 60 80 100

A rea S t e n o s i s ( % )

FIGURE 10. The relation between quan- titatively measured percent area stenosis and coronary flow reserve (~CBFV) in patients with limited coronary artery disease. The relation is much different than that found by White et al, = but similar to that found in normal dogs* (see Figure 2).

52D THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67 MAY 21, 1991

FIGURE 11. The cross-sectional area of the "normal" arterial segment next to a focal stenosis In patients studied In the operating room before bypass surgery (Harrison) and patients with single or double lesion coronary artery disease studied in the catheterization labora. tory (Wilson). The patients studied In the operating room had more severe diffuse narrowing.

Percent of

Tota l

5O

25

• Harrison et al. studies in OR (n = 23) [ ] Wilson et al. studies in Cath Lab (n = 50)

3-4 5-6 7-8 9-10 >tl l

C ross -Sec t iona l Area (mm 2)

rowing increases frictional losses but usually should not result in turbulent blood flow.

To study in humans the effects of diffuse atherosclerosis on coronary flow reserve, we measured flow reserve in normal vein bypass grafts leading to coronary arteries that perfused normal myocardium. 37 In these patients, the bypass graft was the sole source of blood flow to the distal myocardium because the bypassed coronary artery was occluded proximal to the graft insertion. We estimated the extent of diffuse disease present in the bypassed artery by comparing the cross-sectional area of the artery (immediately distal to bypass graft insertion) to that of normal coronary arteries (matched for coronary dominance and position). Bypassed arteries were 40% smaller in cross-sectional area than their normal counterparts--a significant amount of diffuse narrowing. Despite the diffuse narrowing, coronary flow reserve in the bypassed arteries was normal (Figure 12). These observations confirm that diffuse atherosclerosis itself, unless very severe (i.e., minimum cross-sectional area <2.5-3.5 mm 2 in a major vessel), does not importantly impair delivery of blood to the myocardium.

Flow reserve was reduced, however, when the microvasculature was abnormal (e.g., from hyper-

trophy or infarction). Additionally, when patients with a stenosis in the bypassed native artery were studied, it was apparent that >50% (rather than 70%) cross-sectional area stenosis resulted in a fall in coronary reserve. Furthermore, the results are consistent with the concept that diffuse arterial narrowing hides focal lesions and makes them appear less significant. Measurements of minimum luminal area, taken in the context of the perfusion field size, might be a better method of evaluating the physiologic importance of focal lesions in the setting of advanced atherosclerosis.

Diagnosis of microvascular disease: Since the microvasculature is normally the place where coronary blood flow is regulated, one might anticipate that diseases affecting these small vessels might also interfere with regulation of myocardial blood flow and cause transient myocardial ischemia. Several diseases are known to alter micro- circulatory function: structural abnormalities such as hypertrophy, infarction, vasculitic syndromes, and functional abnormalities such as those charac- terized by Cannon and co-workers . 33-36'38 In one center, 50% of patients with chest pain and normal coronary arteries had microvascular disease that resulted in a significant reduction in hyperemic

FIGURE 12. Coronary flow reserve (~CBFV) after bypass surgery. Coronary reserve was normal In diffusely dis. eased arteries perl~slng normal myo- cardlum. A focal stmmsls or mlcrovascular disease, however, reduced coronary reserve.

Flow Reserve (peak/resting

velocity)

7 u

6- -

5 - -

4 - -

3 - -

2 - -

1 8

0

Infarction • ! | • o Stenosis

• Hypertrophy

i ] t i ' I n 8

1 1 - 0 - - ~

11 O"

0

I I I Normal Coronary Normal Abnormal

and Graft and Graft or Myocardium Myocardium Myocardium

A SYMPOSIUM: ADVANCES IN CARDIOVASCULAR IMAGING U P

Immediately After Angioplasty 5 Months After Angioplasty

Phasic CBFV

(kHz shift)

Mean CBFV

(kHz shift)

Arterial Pressure (mmHg)

Heart Rate

(bpm)

O--

0 - -

200 I

0t.-

200 I

0 L-

peak velocity resting velocity 2.1 injection , , - P - ~ 5.6

ECG

t I 1 sec 6 mg papaverine 30 sec 6 mg papaverine

69% Area Stenosis 3.1 mm 2 Minimum cross- 63% Area Stenosis 3.7 mm ~ Minimum cross- sectional area sectional area

FIGURE 13. A record obtained h ~ m a pat ien t Immediate ly and 5 months after angloplasty. The top two traces show pha. sic and mean coronary blood f low ve loc i ty (~CBFV), the middle trace displays the aortic pressure, and the bottom two traces show the heart rate and electrocardiogram. Coronary flow reserve (ACBFV) was subnormal Immediately after an- glioplasty, but Improved markedly later, despite minimal changes In the residual stenosis.

blood flow (and presumably caused chest pain). 39 Our experience is similar, suggesting that clinically important microvascular disease is not rare. One of the important uses of flow reserve measurements is the diagnosis of microvascular dysfunction in patients with chest pain and normal coronary arteries.

Microvascular disease often accompanies epicardial coronary atherosclerosis because many factors associated with atherosclerosis independently injure the microcirculation (e.g., hypertension, hypertrophy, and possibly diabetes mellitus). Addi- tionally, transient ischemia sufficient to cause myocardial "s tunning" or micro-infarction causes transient microvascular dysfunction and a fall in coronary flow reserve. 4° Moreover, about one-half of patients undergoing coronary angioplasty have transient microvascular dysfunction lasting for days to weeks after the procedure (Figure 13). 4t In these patients, measurements of coronary flow reserve reflect the resistance provided by the entire coronary circulation (epicardial and microscopic); a low flow reserve does not necessarily connote that the epicardial lesion is flow-limiting. Therefore, the translesional pressure gradient (corrected for the size of the pressure measurement catheter)

might more accurately reflect the physiologic impact of individual stenoses. Using a 1.4 mm catheter (4.5F), a pressure gradient of >20 mm Hg corresponds to a reduced coronary reserve in patients with a normal microcirculation? °

Assessment of noninvasive methods for detecting focal coronary artery disease: Knowing the problems inherent in arteriographic assessment of coronary lesions, is it appropriate to use the angiogram as the gold standard against which noninvasive studies are compared? Probably not. If the angiogram shows a minimally ( < 30% diameter) or severely ( > 80% diameter) narrowed artery, then the angiogram may be an accurate predictor in the majority of instances. Intermediate lesions, however, cannot be judged with accuracy. Conse- quently, a truly accurate noninvasive study should not always agree with the arteriographic findings because the arteriogram itself is impossible to interpret accurately.

We compared the accuracy of the exercise electrocardiogram to quantitative measurements of stenosis severity and coronary flow reserve. 42 In the patients studied, the resting electrocardiogram was normal; only one coronary lesion was present;

S4,D THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67 MAY 21, 1991

and there was no prior infarction, hypertrophy, or other condition that alters microvascular function. We found in this highly selected group that the exercise electrocardiogram was linked more closely to coronary flow reserve than to angiographic measurements of percent diameter stenosis. These findings suggest that the exercise electrocardiogram is a better predictor of physiology than anatomy. Moreover, the accuracy of the exercise electrocardiogram may be better than that shown in prior studies using diameter stenosis as the gold standard for physiologic significance.

Long-term clinical significance: Are any of these physiologic parameters important in taking care of patients? In a preliminary study, we examined the long-term follow-up of 26 patients re- ferred for coronary angioplasty of a lesion that, on closer inspection, was not flow-limiting. 43 The lesions appeared severe by arteriographic standards (average percent area stenosis 78 --- 9%), but none was thrombotic. In each patient, coronary flow reserve was normal (in the artery with the stenosis) or a mean translesional pressure gradient was less than 20 mm Hg (corresponding to normal coronary reserve). As a result of the physiologic measurements, angioplasty was deferred. At late follow-up (22 --- 11 months), 96% of patients became asymp- tomatic or Canadian Heart Association Functional Class II, and no patients had a cardiac event related to the original lesion under study (one patient had angioplasty of another, new lesion). These preliminary data suggest that closer attention to physiologic factors might prevent unneces- sary revascularization. Clearly, further attention should be given to these studies before a definitive conclusion is drawn.

CONCLUSION The catheterization laboratory has always been

a place where physiology has blended with anatomy. Myocardial ischemia is a physiologic event that usually results from an anatomic problem. Coronary angiography defines only one part of the coronary circulation. Physiologic measurements, available now to all clinical laboratories, enable us to understand another part and to place the coronary arteriogram in the context of the entire coronary circulation. The days when "normal coronary arteries" connoted the absence of heart disease are over. It is time to use these new methods in clinical practice.

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2. Chillian WM, Layne SM, Klausner EC, Eastham CL, Marcus ML. Redistribu- tion of coronary microvascular resistance produced by dipyridamole.ArnJPhysiol 1989;256:H383-H390. 3. Chillian WM, Eastham CL, Marcus ML. Microvascular distribution of corn- nat 3, vascular resistance in the beating left ventride.AmJPhysio11986;251:H779- H788.

Young DF, Tsai FY. Flow characteristics in models of arterial stenoses I1. Unsteady flow.JBiomech 1973;6:547-559. 5. Gould KL, Kelly KO, Bolson EL. Experimental validation of quantitative coronary arteriography for determining pressure-flow characteristics of coronary stenosis. Circulation 1980;66:930-941. 6. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis: instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve.Am J Cardio11974;33: 87-94. 7. Arnett EN, Isner JM, Redwood DR, Kent KM, Baker WP, Ackerstein H, Roberts WC. Coronary artery narrowing in coronary heart disease: comparison of cine-angiographic and necropsy findings.Ann Intern Med 1979;91:350-356. 8. McPherson DD, Hiratzka LF, Lamberth WC, Brandt B, Hunt M, Kieso RA, Marcus ML, Kerber RE. Delineation of the extent of coronary atheroselerosis by high frequency epicardial echocardiography. NEnglJMed 1987;316:304-308. 9. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compen- satory enlargement of haman atherosclerotic coronary arteries. N Engl J Med 1987;316:1371-1375. 10. White CW, Wright CB, Doty D, Eastham C, Harrison DG, Marcus ME Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? NEnglJMed 1984;310:819--823. 11. Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holida MD, Hartley CJ, Armstrong ML, Marcus ML, White CW. Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man. Circulation 1985;72:82-92. 1.2. Wilson RF, White CW. lntracoronary papaverine: an ideal vasodilator for studies of the coronary circulation in conscious humans. Circulation 1986;73:444- 452. 13. Cole JS, Hartley CJ. The pulsed Doppler coronary artery catheter, preliminary report of a new technique for measuring rapid changes in coronary artery blood flow velocity in man. Circulation 1977;56:18-25.

Benchimol A, Stegall HF, Gartlan JL. New method to measure phasic coronary blood velocity in man.Am HeanJ 1971;81:93-101. 15. Johnson EL, Yock PG, Hargrave VK, Srebro JP, Manubens SM, Seitz W, Ports TA. Assessment of the severity of coronary stenoses using a Doppler catheter: validation of a method based on the continuity equation. Circulation 1989;80:625-635. :!~. White CW, Wilson RF, Marcus ML. Measurement of coronary blood flow in humans. Prog Cardiovasc D/s 1988;31:79-94. 17. Sibley DH, Millar HD, Hartley CJ, Whitlow PL. Subselective measurement of coronary blood flow velocity using a steerable Doppler catheter. J Am Coil Cardio11986;8:1332-1340. 18. Hodgson JMB, Cohen MD, Szentpetery S, Thames MD. Effects of regional alpha and beta-blockade on resting and hyperemic coronary blood flow in conscious, unstressed humans. Circulation 1989;79:797~09. 19. Wilson RF, White CW. lohexol does not have minimal effects on coronary hemodynamics (abstr). Circulation 1986;74(suppl 1I):405. 20. Bookstein J J, Higgins CB. Comparative etficacy of vasodilatory methods. Invest Radio11977;12:121. 21. Kramer WG, Romagnoli A. Papaverine disposition in cardiac surgery patients and the effect of cardiopulmonary bypass. Eur J Clin Pharmacol 1984;27:127-130. 22. Wilson RF, White CW. Serious ventricular dysrhythmias after intracoronary papaverine.Arn J Cardio11988; 62:1301-1302.

Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmaco11983;93:21-26. 24. Rosen JD, Simonetti I, Marcus ML, Winneford MD. Coronary dilation with standard dose dipyridamole and dipyridamole combined with handgrip. Circula- tion 1989;79:566--572. 25. Homma S, Gilliland Y, Guiney TE, Strauss HW, Boucher CA. Safety of intravenous dipyridamole for stress testing with thallium imaging. Am J Cardiol 1987;59:152-154. 26. Becker LC. Conditions for vasodilator-induced coronary steal in experimental myocardial isehemia. Chrulation 1978; 57:1103-11 I0. 27. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. The effects of adenosine on human coronary circulation. Circulation 1990;82:1595-1606.

McGinn AL, White CW, Wilson RF. Interstudy variability in coronary flow reserve: the importance of heart rate, arterial pressure, and ventricular preload. Circulation 1990;81:1319-1330. 29. Harrison DG, White CW, Hiratzka LF, Doty DB, Barnes DH, Eastham CL,

A SYMPOSIUM= ADVANCES IN CARDIOVASCULAR IMAGING

Marcus ML. The value of lesion cross-sectional area determined by quantitative coronary angiography in assessing the physiologic significance of proximal left anterior descending coronary arterial stenoses. Circulation 1984;69:1111-1119. 30. Wilson RF, Marcus ML, White CW. Prediction of the physiologic significance of coronary arterial lesions by quantitative lesion geometry in patients with limited coronary artery disease. Circulation 1987;75:723-732. 3:1. Zijlstra F, van Ommeren J, Reiber JHC, Serruys PW. Does the quantitative assessment of coronary artery stenosis dimensions predict the physiologic significance of a coronary stenusis? Circulation 1987;75:1154-1161. ~'1. Marcus ML, Harrison DG, White CW, Mcpherson DD, Wilson RF, Kerber RE. Assessing the physiologic significance of coronary obstructions in patients: importance of diffuse undetected atherosclerosis. Prog Cardiovasc Dg 1988;31:39- 56. 33. Brush JE, Cannon RO, Schenke WH, Bonow RO, Leon MB, Maron BJ, Epstein SE. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N EnglJ Med 1988;319:1302-1307. 34. Klein LW, Agarwal JB, Schneider RM, Herman G, Weintraub WS, Helfant RH. Effects of previous myocardial infarction on measurements of reactive hyperemia and coronary vascular reserve.JAm Coil Carth'o11986;8:357-363. 35. Opherk D, Schwartz F, Mall G, Manthey J, Bailer D, Kubler W. Coronary dilatory Capacity in idiopathic dilated cardiomyopathy: analysis of 16 patients.Am J Cardio11983 ;51:165 7-166 2. 36. Marcus ML, Mueller TM, Gascho JA, Kerber KE. Effects of cardiac

hypertrophy secondary to hypertension in the coronary circulation.Am J Cardiol 1979;44:747-753. 37. Wilson RF, White CW. Does coronary bypass surgery restore normal coronary flow reserve? The effect of diffuse atheruscleresis and focal obstructive lesions. Circulation 1987;76:563--571. 38. Sax FL, Cannon RO, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. N EnglJ Med 1987;317:1366-1370. 39. Geltman EM, Henes CG, Senneff MJ, Sobel BE, Bergman SR. Increased myocardial perfusinn at rest and diminished perfusion reserve in patients with angina and angiographically normal coronary arteries.JAm Coil Cardiol 1990;16: 586--595. 40. Bolli R, Triana JF, Jeroudi MO. Prolonged impairment of coronary vasodilation after reversible ischemia: evidence for microvascular stunning. C/rc Res 1990;67:332-343. 4L Wilson RF, Marcus ML, Aylward PE, Talman CL, White CW. The effect of coronary angioplasty on coronary flow reserve. CircMation 1988;77:873--885. 42. Wilson RF, Marcus ML, Christensen BV, Talman CL, White CW. The accuracy of exercise electrocardiography in predicting the physiologic significance of coronary arterial stenoses. Circulation 1991;83:412--421. 40. Lesser JL, Wilson RF, White CW. Can a physiologic assessment of coronary stenoses of intermediate severity facilitate patient selection for coronary angioplasty ? J Coronary Artery Di~ 1990;1:697-705.

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assessment of the human coronary circulation using a doppler catheter

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