European Heart Journal (1999) 20, 1076–1083
Article No. euhj.1999.1676, available online at http://www.idealibrary.com on
The Denolin Lecture 1998
Towards measurement of coronary blood flow in patients
and its alteration by interventions
W. Rutishauser
University of Geneva, Switzerland AimSeveral methods of measuring coronary blood flow inintact conscious man are reviewed, on the basis of personal contributions or the experiences of our teams.
Methods and Results It is important to distinguish
between global, regional and transmural blood flow measurements. The advantages and limitations of the fol-lowing methods are discussed: diffusible inert and radio-active tracers, dye dilution, roentgendensitometry, magnetic resonance imaging and contrast echocardiography. In inter-ventional cardiology it is most important to be able to measure flow through single coronary vessels. Information on coronary artery Doppler velocity during vasodilation and at rest is less useful than the concept of fractional flow reserve. This is based on pressure measurements under maximal vasodilation to ascertain the presence of
border-line flow-limiting lesions. This information is necessary in order to decide whether to proceed with angioplasty or not.
Conclusions The historical design of percutaneous coronary angioplasty and beta-irradiation of coronary re-stenosis, established under the author’s guidance, are put into perspective. The author pays tribute to many excellent colleagues who worked with him at the Zurich and Geneva University Hospitals.
(Eur Heart J 1999; 20: 1076–1083)
Key Words:Coronary blood flow measurement, coronary
angioplasty, intravascular beta-irradiation, indicator dilu-tion methods, coronary artery Doppler, fracdilu-tional flow reserve.
Introduction
The complex interrelationship between coronary blood flow, myocardial perfusion and metabolism — allowing contraction and relaxation of the heart in health and disease — has enormous implications in modern medi-cine, in view of the high incidence of coronary artery disease. Coronary blood flow is an essential parameter and its critical reduction should be avoided or promptly treated. While a large percentage of coronary artery diseases can be prevented, or at least delayed, by a healthy lifestyle, once significant disease is present, revascularization to restore normal blood flow is the best method of equalizing coronary oxygen support and the needs of the myocardial metabolism. In the 1970s in Zurich this concept was applied to the macrocirculation,
as the basis of our earliest attempts in using balloons to open stenosed coronary arteries ([1] see Fig. 1). This
culminated in Gru¨ntzig’s first PTCA in man[2].
Methods of assessing coronary blood
flow
Coronary blood flow is difficult to measure since the coronary circulation has two inflows with a variable distribution and multiple outflows through the sinus coronarius, the venae cordia anteriores and the venae thebesii. The inflows and outflows are all pulsatile due to varying myocardial elastance. Local blood flow assess-ment is essentially a four-dimensional problem, and different methods must be used to measure global, regional or transmural coronary blood flow.
In interventional cardiology, flow through single cor-onary arteries is the most important. While blood flow through single vessels can be measured in absolute
Manuscript submitted 3 May 1999, and accepted 5 May 1999.
Correspondence: Wilhelm Rutishauser, MD, FESC, FACC,
terms, e.g. ml . min1under different conditions, global
and regional coronary blood flows are mostly expressed as a relative flow in ml . min1 and 100 g of tissue
(Table 1).
Di
ffusible indicators
For global flow measurements — exploiting the Fick or Kety-Schmidt principle[3]— inert gases such as H, N
2O,
He or Ar have been used, the latter three requiring sampling of arterial and coronary sinus blood[4]. A
scintillation camera is used when radioactive gases, such as 133Xe, are injected into the coronary arteries to
demonstrate regional flow differences in patients with cor-onary artery disease[5]. However, the high solubility of
Xe[6] in fat tissue leads to considerable underestimation
of high flows per 100 g of tissue, e.g. during exercise.
201Tl and 99mTc-Sestamibi intravenously injected are
the most widely used radioactive tracers for perfusion imaging[7,8]. Used with a gamma camera, these tracers
do not lend themselves to quantitation of blood flow, but allow by imaging, comparative assessment of per-fusion under stress and distinguish ischaemic from fibrotic areas by repeated scanning. Due to the lower energy of201Tl compared to99mTc image artefacts may
occur, especially with 201Tl in obese patients and in
women.
Figure 1 The first experimental set-up for balloon dilatation of coronary stenoses in the dog. The guide catheter introduced from the left femoral artery lies in the ostium of the left coronary artery. The double lumen dilatation catheter is introduced into the circumflex branch. One lumen allows dilatation pressure to be applied in the low compliance balloon which widens up to 1·6 mm diameter. The main lumen is hocked to a three-way stopcock through which either the distal coronary pressure is measured or arterial blood is perfused by a roller pump from the contralateral femoral artery. For demonstration of the perfusion of the distal coronary segment, contrast medium was injected showing the circumflex branch. The ECG, distal coronary pressure (CoP), aortic pressure (AoP), left ventricular pressure (LVP) and pressure in the perfusion system were recorded simultaneously (reproduced from[1]).
The most powerful non-invasive method, that allows measurement of regional myocardial blood flow com-bined with metabolic information in as little as 10–15 g of myocardium, is positron emission tomography (PET). Labelled water (H215O) and nitrogen-13 labelled
ammo-nium (13NH
3)[9]are used as an intravenous bolus. For 13NH
3 measurements, a three-compartment model is
normally used. A correction for metabolic extraction of ammonium has to be realized at higher flows. Labelled water is independent of flow but has a weaker signal.
Indicator dilution methods
Although Doriot et al. have recently written a critique of indicator dilution methods[10], all indicator dilution
methods are based on the principle of conservation of mass, or in the case of thermodilution, on the conser-vation of energy. The thermodilution method in the coronary sinus was introduced byGanz et al. in 1971[11].
The problem of incomplete mixing between injection and sampling may lead to considerable errors[12].
Together with Sigwart[13,14] we used selective injection
of cardiogreen — a dye which remains in the cirulation — into the left coronary artery and sampled the coronary veins using a fibreoptic catheter (Fig. 2). Besides absolute blood flow through the left coronary artery, this method shows the transfer function of the coronary bed under different conditions and allows, by the mean transit time, intravascular blood volume between coronary ostium and coronary vein to be calculated.
Roentgendensitometry
Roentgen contrast media have been widely used to characterize the coronary circulation. In the late 1960s we used roentgendensitometric curves to study regional myocardial perfusion and blood flow measurements[15].
Digital subtraction angiography was subsequently intro-duced to colour code the temporal sequence of myocar-dial perfusion[16]before and after maximal vasodilation.
De Bruyne et al.[17] showed a significant decrease of
several time parameters during hyperaemia in the nor-mally perfused but not in the stenotic areas. Coronary
flow ratios under the two conditions were only valid if the mean transit time was used. However, this time is difficult to calculate because of the superposition of the different structures of a three-dimensional organ into a two-dimensional display, leading to a shift in the base-line. The mean transit time after maximal vasodilation, corrected for changes in mean arterial pressure, allows the physiological result of coronary artery angioplasty, as shown byPijls et al.[18], to be satisfactorily evaluated.
For the first time in 1970, after extensive experimental studies in models and dogs[19,20], we were able to
measure blood flow by roentgendensitometry through the right coronary artery during routine coronary angi-ography in conscious man[21]. The method is based on
the passage of a small contrast bolus through a proximal and a distal window placed over the artery, and the measurement of the mean transit time and the volume between both windows (Fig. 3). Together with Simon we measured the flow through bypass grafts, which early after operation, correspond to unbranched tubes and are easy to measure for exact flow using this principle.Smith et al.[22] at the Mayo Clinic were using a video system
with the same goal. Guggenheim et al. and Dorsaz et al. from our group later studied the progression of con-trast medium during a single heart beat in triggering biplane X-ray sources by the QRS-complex. A three-dimensional reconstruction of the coronary tree using a projection matrix was developed[23–25], and automated
densitometric evaluation of the progression of the bolus allowed measurement of flow in the different branches of the left and right coronary artery tree[26].
Magnetic resonance imaging (MRI)
MRI is a tomographic method which exploits the spatial variation of nuclear magnetic resonance signal intensity.
Hess[27] and others have shown that MRI has great
potential if the action of the heart and lungs remains absolutely repetitive.
Gadolinium-DTPA injection enables proximal cor-onary arteries and bypass grafts to be visualized by first pass imaging. The phase rather than the amplitude of the magnetic resonance signal is used to produce so-called velocity maps. It is possible to visualize
Table 1 Terminology, calculation and units for blood flow measurement
Flow through a vessel or organ Q~ [ml/min] Flow based on indicator dilution Q~ =I/c dt
I injected amount
c concentration after mixing
Flow based on mean velocity and cross-section A Q~ =v . A
Flow based on blood volume between detectors V and mean transit time t Q~ =V/t t¯=c.t dt/cdt
Global or regional relative flow Q~ /mass [ml/min . 100 g]
Flow reserve Q~ Hyperemia/Q~ Rest —
Transmural flow Q~ endo/Q~ epi —
Velocity in a vessel v (t) [cm/s]
Velocity reserve v Hyperaemia/v Rest —
myocardial perfusion[28] and in principle transmural
myocardial blood flow[29].
Microspheres and myocardial contrast
echography
Methods using labelled deposit microspheres, not appli-cable in intact man, have shown a transmural hetero-geneity, with greater inner as compared to outer wall perfusion at rest, and a close coupling between systolic wall thickening or regional shortening and regional myocardial blood flow[30]. Spatial heterogeneity of
per-fusion and metabolism may extend down to the level of the individual microcirculatory unit.
Because of its large clinical availability, the greatest potential for transmural flow assessment in man, how-ever, probably lies in the measurement of myocardial contrast by echocardiography. Large bubbles, injected into the left atrium act as deposit tracers to assess myocardial perfusion in the spatial domain. Small 4 ìm stable gas bubbles, of similar rheologic properties as erythrocytes passing the lung, can be infused intra-venously and used as flow tracers. If these bubbles are exposed to their resonant frequency they oscillate and
emit harmonics of that frequency. Harmonic imaging improves the signal-to-noise ratio. Since ultrasound also destroys microbubbles, intermittent imaging enables the study of reappearance of new bubbles in a given cross-sectional area. Provided there is linearity between microbubble concentration and the videosignal, if â is the rate constant of rise reflecting bubble velocity and A is the plateau intensity of the videosignal reflecting the microvascular cross-sectional area the product â.A is a measure of capillary flow[31]. Since subendocardial
flow is always the first to be reduced in a situation of decreasing coronary perfusion, methods to assess trans-mural distribution of capillary flow are very important.
Coronary artery Doppler
The ultrasonic Doppler principle offers a high temporal resolution for online velocity measurements in larger coronary arteries[32]. Use of the 0·014 inch guide wire
has gained this method considerable interest in interven-tional cardiology[33]. However, optimal placement in the
vessel axis of the low profile Doppler guide is crucial for representative velocity measurements. Jenni et al. have recently devised a method based on the normalized first
Figure 2 Measurement of left coronary artery flow by coronary sinus fibre optic and femoral artery
dye dilution in a 54-year-old patient with coronary artery disease and minor right coronary artery. Upper panel: 0·75 mg Cardiogreen were injected into the left main trunk. A small amount of the Cardiogreen spilt in the aorta and was recorded at the femoral artery. Calibrations were indicated on both sides of the panels. Lower panel: 1·5 mg Cardiogreen were injected into the left atrium to measure cardiac output (3·85 l . min1). The amount of Cardiogreen spilt over can now be
calculated as the product of cardiac output and the area under the upper panel femoral artery curve, and was subtracted from the 0·75 mg to calculate left coronary flow (145 ml . min1). The aortic
moment of the Doppler frequency shift, which allows optimal placement control[34]. Under maximal
hyperae-mia, by adenosine or dipyridamole, the velocity ratio between hyperaemia and rest in non-stenosed coronary vessels — without using Jenni’s method — has been re-ported to be largely variable, from as low as 1·8 to 3·0. It is known, however, that the normal heart can increase its coronary flow during maximal exercise four to five times the resting value. It is unfortunate that the terms velocity and flow reserve are often mixed up. The difference in the flow ratios and the velocity ratios may be due to the fact that exercise increases perfusion pressure, while these drugs have the tendency to decrease it, and also that the cross-section of the vessel increases during vasodilation. This is why the coronary resistance ratio rather than coronary flow should be the optimal measure for the coronary reserve ratio.
For the functional assessment of epicardial stenoses and on-site clinical decision making Baumgart et al.[35]
have recently proposed a concept called the ‘relative flow velocity reserve’ in order to account for structural and functional changes in the microvasculature in individual patients. They defined ‘relative flow velocity reserve’ by adenosine as the ratio of the distal velocity ratio in the target vessel to a distal velocity ratio in a non-stenosed reference vessel. The resulting value obviously lies below 1·0. Even this approach leads to the expected curvilinear relationship between the ‘relative flow velocity reserve’
and the percent area stenosis, there is still considerable scatter, no clear cut-off value, and the concept cannot be applied to three-vessel disease or if the reference vessel is diffusely diseased.
Fractional flow reserve
The best documented parameter for on-site clinical decision making in the catheter laboratory, to find out whether a stenosis might lead to ischaemia, is, however the ‘fractional flow reserve’ as defined by Pijls and de Bruyne[36]. This measures the ratio of hyperaemic flow in
the stenotic region to hyperaemic flow in the same region if no stenosis is present. It is independent of the driving pressure and other loading conditions, appli-cable in three-vessel disease, lends itself even to assess-ment of collaterals if the balloon is inflated, is easy to measure and highly reproducible. Pressure measurement with a hollow wire (fluid filled system) in the coronary tree downstream from a stenosis does not depend on the position of a wire tip. However, when using a catheter tip-manometer, its vertical height has obviously to be taken into consideration.
These coronary flow and coronary reserve parameters under various conditions[37]indicate significant
obstruc-tions to blood flow and justify on-site clinical decision
Figure 3 Blood flow measurement by roentgen-cinedensitometry. A small amount of contrast medium is injected upstream
and the passage of the dye is recorded over two cross-sections A and B of the vessel. Each of the two resulting density-time curves has a mean transit time tAand tB. The blood flow is calculated as a quotient of the vascular volume between A and
B and the difference in both transit times Ä t. The calibration is achieved with contrast filled cuvettes drawn over the area of interest; it shows linearity (reproduced from[19]).
making during cardiac catheterization in interventional cardiology and even predict outcome[38].
Interventional cardiology
This lecture could have been named the ‘Gru¨ntzig Lecture’. I introduced Andreas Gru¨ntzig to cardiology, realizing that what worked in the femoral and iliac arteries had to work in the coronary arteries. And it was a great pleasure to teach him coronary angiography, transseptal catheterization and many other things about our fascinating specialty; in particular that we have to be critical and carefully control each step towards the unknown. There has been enormous evolution since Gru¨ntzig’s first successful dilatation. In Geneva we were very much at the pulse of this evolution since Bernhard Meier, who had trained with Gru¨ntzig in Atlanta, joined our team from 1983–1992[39].
Restenosis
In the last part of my lecture, let me turn to a disease which was actually created by Gru¨ntzig and which impedes coronary flow, I mean restenosis. The 30–40% restenosis rate is the main reason why three-vessel disease cannot be treated by PTCA without the patient probably coming back in the next few months. And that is truly not in the interest of the patient. Only if the restenosis problem can be solved can angioplasty really be widely justified in two- and three-vessel diseases. Stents have not fundamentally changed this; even though they act against recoil and remodelling, they augment proliferation and lead frequently, especially in
small vessels, to in-stent restenosis, which is much worse than restenosis without a stent.
Brachytherapy
Restenosis has resisted most pharmacological agents and all types of exotic razors, drills and lasers. In fact the more the artery is injured the stronger the reaction of the vascular wall. Local drug delivery is difficult to achieve because the drug is quickly distributed through the side branches and vasa vasorum into the body and only minute amounts stay locally. Many basic scientists believe that inhibition of a growth factor or a gene will limit hypertrophic scar formation which we call resteno-sis. But wound healing, in particular intravascular wound healing and formation of a strong scar, are essential goals after an injury. Nature had millions of years to develop adequate mechanisms, probably in the form of a network of growth factors/enzymes depending on multiple genes, which are responsible for this important goal.
Brachytherapy attacks genetic material non-selectively. Ionizing radiation damages DNA, but some damages are repairable, namely, if only one strand of DNA or both but at distant sites are damaged. Brachy-therapy is ‘in simplified terms’ a massive gene Brachy-therapy. Verin et al. started animal work in our laboratories with beta irradiation in 1992[40] and with Urban we
per-formed intracoronary radiation with a centred source in patients in 1995[41] (Fig. 4). When Teirstein et al.
in 1996[42] presented evidence that brachytherapy with
non-centered iridium, which is highly penetrating gamma radiation, limits restenosis in stented patients, many groups reasoned that only gamma radiation would be adequate. Since the biological effect of scar Figure 4 Panel A: 0·014-inch yttrium coil (arrows) for beta-irradiation coated with titanium at the end of the thrust wire. Tungsten markers at both ends of the yttrium coil permit precise localization of the coil. Panel B: Centering balloon of 30 mm length with four interconnected segments on a double lumen plastic shaft. The 20 mm distal tip permits introduction of the balloon into the desired coronary artery in a monorail fashion over a conventional 0·014-inch guidewire. Three tungsten markers (arrows) are located at the waists of the balloon. The radioactive yttrium coil is inserted into the main blind lumen of the centering balloon inflated by carbondioxide (reproduced from[41]).
reduction can be obtained with gamma or beta radiation (but the latter is much easier to handle and is truly a local delivery) the right dose for centered beta radiation has to be found in relation to artery size. Such a multicentre trial is presently under way between Geneva, Aalst, Essen, Kiel and London[43]and randomized trials
will show proof of efficacy.
A personal word
I have contributed to coronary blood flow measure-ments and personally influenced the gradual evolution of interventional cardiology, from the first animal experi-ences with the double lumen balloon until the time the remedy overcame its Achille’s heel, restenosis. I am today as fascinated about cardiology as when I started my training in 1958 with Robert Hegglin in Zurich and in 1963 with Earl Wood at the Mayo Clinic.
In this lecture I have presented and referenced mainly the industrious work of many colleagues and post-doctoral fellows with whom I had the good fortune to work over a period of 30 years. I had the great advantage of having excellent collaborators as chief of Cardiology in the Zurich University Hospital from 1968 to 1976: (Hanspeter Krayenbu¨hl≥, Andreas Gru¨ntzig≥, Ulrich Sigwart (now London), Otto Hess (now Berne), Felix Mahler (now Berne), Ru¨diger Simon (now Kiel), Andre´ Kle´ber (now Berne), Ivo Amende (now Hanover), Heinz Hirzel, Rolf Jenni, and many others); and later as director of the Cardiology Center in Geneva: Bernhard Meier (now Berne), Bernard de Bruyne (now Aalst), Osman Ratib (now Los Angeles), Daniel Scheidegger (now Basel), Michel de Lorgeril (Lyon and Saint Etienne), Rene´ Lerch, Philip Urban, Vitali Verin, Alberto Righetti, Pierre-Andre´ Doriot, Pierre-Andre´ Dorsaz and many others. I am very proud of them and would like to thank them all whole-heartedly.
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