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Part II
Stenting
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3
Pressure and flow
measurements in the
catheterization laboratory
NARBEH MELIKIAN, PHILIP A MacCARTHY

Introduction
The shortcomings of coronary angiography in providing a comprehensive simul-
taneous anatomical and physiological assessment of patients with coronary artery
disease (CAD) is well documented 1. Angiography is often complemented by more
sophisticated anatomical imaging of the coronary artery cross-section [for example,
with intravascular ultrasound (IVUS)], or information from non-invasive functional
tests (for example, nuclear scans) in order to help accurate clinical decision-making.
Extra investigations to complement angiography commonly result in either pro-
longed procedures or the need for a second visit to the cardiac catheterization labora-
tory and in the ‘real world’, patients often arrive in the catheter laboratory without
decisive non-invasive evidence of myocardial ischaemia. The deficiencies of coronary
angiography are particularly evident in the context of patients with chest discomfort
and coronary lesions of intermediate severity.
To overcome the aforementioned problems a number of invasive indices (using
both pressure and flow velocity measurements) have been developed, which allow
assessment of the physiological status of the coronary vascular bed at the time of
cardiac catheterization. Coronary flow reserve (CFR) and fractional flow reserve
(FFR) are the two indices that are used most often clinically 2.
The principles used to derive CFR and FFR and a number of their clinical applica-
tions have already been reviewed in the Year In Interventional Cardiology 2003. Over
the past year there have been a number of further studies increasing our understand-
ing of the clinical applications of FFR and CFR. A selection of the important changes
are discussed in this chapter.
CFR is the ratio between coronary blood flow at rest and maximal hyperaemia
(achieved pharmacologically) 2,3. Both the epicardial and microvascular com-
ponents of the coronary vascular bed influence the CFR. Therefore, the role of an
abnormal CFR in the context of angiographically intermediate/severe coronary
lesions is limited by its inability to distinguish between the epicardial and micro-

© Atlas Medical Publishing Ltd

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38 II . S T E N T I N G

vascular compartments. In the absence of epicardial disease a CFR of <2.5 is broadly

accepted as being an indicator of coronary microvascular dysfunction 2. However,
CFR is influenced by systemic haemodynamics, including blood pressure, heart rate,
myocardial contractility, as well as previous myocardial infarction (MI), valve disease
and left ventricular (LV) hypertrophy 2.
FFR is defined as the ratio between maximum blood flow in the presence of a
stenosis as compared with the maximum flow possible in that vessel if it were not
stenosed 4,5. It can be derived from calculating the ratio of the mean distal coronary
pressure (beyond the stenosis) to aortic pressure during maximal coronary hyper-
aemia (for derivation, see Pijls and De Bruyne 4). It is a lesion-specific index with a
uniform value of 1 6. In contrast to CFR, FFR is not influenced by systemic haemo-
dynamics and takes into account collateral function 2,4. An important advantage
of FFR is its narrow threshold for inducible myocardial ischaemia. The current
threshold of 0.75 has been extensively evaluated 2,5–7. FFR can be used to assess
physiological significance of lesions in patients with multivessel CAD, as well as to
interrogate serial lesions within one vessel 2,4.
With its multiple advantages as a clinically applicable index, the role of FFR in the
catheterization laboratory is well established. Routine indications for FFR calculation
include functional assessment of epicardial lesions of intermediate severity prior to
intervention 2,4, assessment of ‘culprit lesions’ in multivessel disease and evaluation
of stent deployment postintervention 8. Furthermore, in patients with multiple,
serial coronary stenoses and diffuse atheroma it can be used to identify the culprit
lesion, which may be difficult with alternative functional strategies. The pressure wire
‘pull-back’ under conditions of maximal hyperaemia provides excellent spatial reso-
lution, allowing the operator to pinpoint accurately areas of obstruction to flow
along the course of the vessel.
Coronary physiological measurements have emerging clinical applications,
which extend beyond the immediate decision-making process regarding treatment in
the catheterization laboratory. Such techniques can be accurate tools in risk strati-
fication of coronary patients. For example, the level of microvascular dysfunction
in the context of acute MI 9, or as a result of percutaneous intervention 10,11
can determine short- and long-term outcome. Similarly, microvascular dysfunction
has been shown to correlate with cardiac transplant vasculopathy and/or rejection
12,13.
Clinical evaluation of the microvasculature remains difficult and an overall assess-
ment of the cause of myocardial ischaemia requires the combination of FFR and
CFR (to assess both epicardial and microvascular compartments). To date this has
been technically demanding, requiring two different guide wires (an intracoronary
Doppler and pressure wire). Repeated coronary instrumentation increases potential
risks of the procedure and adds significantly to the time and cost. The use of a
thermodilution technique with the dual temperature/pressure sensor-tipped guide
wire allows simultaneous measurement of both CFR and FFR with a single wire
14,15. Single wires that can measure both blood flow velocity and intracoronary
pressure are under development.
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PRESSURE AND FLOW MEASUREMENTS 39

We have selected nine recent papers to highlight the development in this field over
the past year. These include further validation studies for the thermodilution
CFR technique (CFRthermo), studies confirming the reproducibility of previous trial
data in heterogeneous groups of patients, the prognostic values of CFR, and the cost-
effectiveness of using FFR as a functional test during treatment of angiographically
intermediate lesions.

Cost-effectiveness of fractional flow reserve

measurements
In this section we present a paper outlining the cost-effectiveness of utilizing invasive
coronary measurements with a one-stop catheterization laboratory visit in patients
with intermediate coronary lesions and chest pain. The values are compared with a
two-stop catheterization laboratory visit and nuclear scanning or direct intervention
in all patients.

✍
Cost-effectiveness of measuring fractional flow reserve
to guide coronary interventions
Fearon WF, Yeung AC, Lee DP, et al. Am Heart J 2003a; 145: 882–7

B A C K G R O U N D . The majority of patients with chest discomfort and intermediate

coronary lesions, present for angiography without prior functional investigations.
The authors have developed a model to compare the long-term costs and benefits of
treating such patients with three different strategies: (i) deferring decision for
percutaneous intervention (PCI) in order to obtain a nuclear stress image (NUC
group); (ii) measuring FFR to guide the need for PCI (FFR group); and (iii) stenting all
intermediate lesions without a functional assessment of the lesion (STENT group).
In order to calculate costs, a number of assumptions have been made based on
accepted values from the current literature. It is estimated that 40% of the
intermediate lesions are physiologically significant and that 70% of PCI patients and
30% of the medically treated patients will be free of angina at 4 years. Quality-of-life
adjustment for living with angina is taken to be 0.9 (1.0 = perfect health). The cost
for each procedure is taken from the hospital cost-accounting data. It is estimated
that the FFR strategy saved $1795 per patient compared with the NUC strategy, and
$3830 in comparison with the STENT strategy. Quality-adjusted life expectancy is
similar among the three groups. Both screening strategies were superior to (less cost
and better outcome) the STENT strategy.

I N T E R P R E T A T I O N . The study demonstrates that using FFR at the time of initial

angiography to evaluate the functional significance of an intermediate lesion (in the absence
of prior functional data) can lead to significant cost savings as compared with performing
nuclear stress imaging or with stenting all lesions without a functional test.
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40 II . S T E N T I N G

Comment
FFR is an accepted method of determining the functional significance of inter-
mediate coronary lesions in patients with CAD. FFR values have been validated in
both select as well as heterogeneous groups of patients (with and without chest pain)
against other recognized functional modalities 5–7. Pijls and colleagues compared
FFR values with three other different functional modalities. The overall sensitivity
and specificity of FFR from this study in comparison with stress testing was 88% and
100% respectively 6.
As indicated above, Fearon and colleagues have demonstrated that measuring FFR
to guide intervention in patients with intermediate coronary lesions is more cost-
effective than a nuclear or indiscriminate stenting strategy for at least the same
outcome. Despite altering the cost of various procedures within a reasonable range
(including FFR, nuclear scanning, or the cost of splitting the angiogram and PCI),
FFR remained the most cost-effective method of managing intermediate lesions in
this model. Further manipulation of the costs shows that FFR continues to be the
more cost-effective method (by $331 per case) even if the cost of a second angiogram
is eliminated completely. It is important to note that the current model does not
include start-up costs for any one of the strategies. If initial set-up costs were included
the nuclear strategy would clearly be the least cost effective in view of the large capital
investment required.
Adopting FFR as the method of choice for the management of intermediate
lesions has several advantages. It provides a safe, rapid and accurate estimation of the
physiological significance of an intermediate coronary lesion, which has been well
validated 2,4. It is cost-effective in comparison with other strategies. Furthermore,
using newer pressure-temperature sensor-tipped guide wires other physiological
parameters, such as thermodilution CFR 14,15, can also be measured allowing a
comprehensive evaluation of myocardial perfusion in one sitting.

Thermodilution coronary flow reserve

The introduction of pressure-temperature sensor-tipped guide wires has facilitated
the ability to measure both FFR and CFR with a single device, which in turn can be
used for coronary intervention. The original studies outlining the technique 14 and
validation in humans 15 have been discussed previously in Year in Interventional
Cardiology 2003. The papers in this section outline clinical applications of this tech-
nique in ‘real world’ practice and further confirm the validity of thermodilution-
derived CFR values by comparison with absolute flow in an open chest model.
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PRESSURE AND FLOW MEASUREMENTS 41

✍
Comparison of coronary thermodilution and Doppler
velocity for assessing coronary flow reserve
Fearon WF, Farouque HM, Balsam LB, et al. Circulation 2003b; 108(18):
2198–200

B A C K G R O U N D . CFRthermo is a novel method of assessing CFR using an

intracoronary pressure wire. This article investigates the correlation between
CFRthermo with absolute flow-derived CFR (CFRflow) and conventional intracoronary
Doppler wire-derived CFR (CFRDoppler). Measurements are made in the left anterior
descending (LAD) artery in an open chest pig model. An external flow probe is used to
measure absolute flow. Sixty-one paired measurements were made in nine pigs. CFR
is measured simultaneously by all three means in the normal LAD, after creation of
an epicardial LAD stenosis and after disruption of coronary microcirculation (using
embolized microspheres). As demonstrated in Figure 3.1, CFRthermo has a stronger
correlation with the reference standard CFRflow than CFRDoppler. Corresponding
Bland–Altman analysis shows a closer agreement between CFRthermo and CFRflow.

I N T E R P R E T A T I O N . This study demonstrates that CFRthermo correlates well with the

reference standard of CFRflow. Therefore, a single pressure-temperature sensor-tipped guide
wire can be used to interrogate accurately both the epicardial and microcirculatory
components of coronary arteries.

Comment
Invasive interrogation of epicardial and microvascular coronary physiology is
becoming increasingly important in coronary intervention. FFR measured by an
intracoronary pressure wire is an accurate and specific index of severity of an epi-
cardial stenosis. The FFR is the ratio of flow in a coronary artery in the presence of a
stenosis to the flow that would be expected down the same artery if that stenosis were
not present 2,4. CFR measured by an intracoronary Doppler wire investigates both
epicardial and microvascular function, but does not allow discrimination between
the two entities 2,3. Simultaneous measurement of both FFR and CFR provides
complementary information, allowing a better insight into the respective contribu-
tion of epicardial stenosis and microvascular function towards overall myocardial
perfusion.
To date such simultaneous measurements have been hampered by the require-
ment for two coronary wires: a pressure wire and a Doppler wire. The introduction
of the pressure-temperature sensor-tipped guide wire and the CFRthermo technique
has eliminated the need for two wires 14,15.
Initial studies in humans have demonstrated a close relationship between
CFRthermo and CFRDoppler 15. Pijls and colleagues showed an absolute difference of
17  14% between the two values 15. The current study, which uses an invasive
(non-clinically applicable) method of determining coronary flow (CFRflow) has
demonstrated that CFRthermo is a better representation of true coronary blood flow
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42 II . S T E N T I N G

than CFRDoppler (the current standard clinical method). Other studies have demon-
strated that CFRDoppler (especially at higher levels of CFR) tends to be less accurate
16.
The inaccuracies of CFRDoppler are multifactorial and complex. The Doppler wire
assumes that coronary flow is parabolic (same flow profile) at all flow rates. This may
be true in a smooth lumen. However, in a heavily atheromatous coronary artery the
pattern of luminal irregularities determine flow profile, which in turn will be con-
stantly changing both along the length of the vessel as well as at different levels of flow.
The Doppler wire cannot account for these changes hence often underestimating

Fig. 3.1 Linear regression and corresponding Bland–Altman plots comparing CFRflow with
the reference standard of CFRthermo and CFRDoppler. Source: Fearon et al. (2003b).
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PRESSURE AND FLOW MEASUREMENTS 43

true flow 16. Furthermore, vessel tortuosity may prevent optimal positioning of the
Doppler sensor in the middle of the coronary lumen and hence further interfere with
the results.
CFRthermo not only overcomes some of the aforementioned inaccuracies but also
allows simultaneous FFR and CFR calculation with a single wire. Simultaneous
assessment of FFR and CFR should facilitate the delivery of physiologically guided
coronary intervention as discussed in other articles in this chapter.

✍
Validation of coronary flow reserve measurements by
thermodilution in clinical practice
Barbato E, Aarnoudse W, Aengevaeren WR, et al. Eur Heart J 2004;
25(3): 219–23

B A C K G R O U N D . Recent developments in invasive coronary physiology have made

simultaneous FFR and CFR measurements possible. A dual pressure-temperature
sensor-tipped guide wire can be used to measure CFRthermo. This multicentre study
investigates the feasibility of obtaining CFRthermo (using a standardized algorithm
and injection technique) and its correlation to CFRDoppler in a non-trial setting.
Eighty-six patients with CAD were recruited over a period of 1 week in eight centres.
FFR, CFRthermo and CFRDoppler were measured in all patients. FFR was obtained in
100% of patients, CFRDoppler in 69% and CFRthermo in 97% of patients. A significant
correlation was found between CFRDoppler and CFRthermo (r = 0.79; P <0.0001) as
seen in Figure 3.2 (only results of patients in whom an optimal Doppler tracing was
obtained were used for correlation).

I N T E R P R E T A T I O N . This study confirms that in a setting close to ‘real world’ practice

CFRthermo measurements are feasible and reliable. The ability to assess CFR and FFR with a
single guide wire should enhance our ability to assess coronary physiological parameters
during day-to-day interventional procedures.

Comment
To date all publications on CFRthermo have been conducted in centres with extensive
experience and specific interest in invasive coronary physiology. This study was
the only multicentre study of CFRthermo outside specialist centres, thus assessing the
feasibility of measurements in a ‘real world’ setting.
The study demonstrates that in an unselected cohort of elective/stable patients
CFRthermo is significantly easier to obtain than CFRDoppler (measurements obtained
in 97% versus 67% of cases respectively). The higher success rates with CFRthermo are
multifactorial and have been discussed briefly in the previous paper. In particular,
unlike a Doppler wire the exact position of the pressure/temperature sensor in the
lumen is less influential on thermodilution (Tmn) values. Furthermore, neither
the volume nor the temperature of the saline injected influence CFRthermo. Accurate
measurements can be made as long as a good thermodilution curve is obtained.
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44 II . S T E N T I N G

A number of modifications have been used in this study to minimize confounding

factors in Tmn calculation.
Similar to thermodilation cardiac output studies, the authors take the mean value
of three consecutive Tmn values for calculation of the final CFRthermo. They also use a
modified algorithm to calculate Tmn. In previous validation studies Tmn is taken as
the time elapsed between half the volume of saline injected (t0) and half the time
taken for that volume of saline to pass over the sensor. A proportion of the volume of
saline will therefore be the volume contained in the catheter. This volume appears to
have minimal impact on the temperature sensor. In the modified algorithm this

Fig. 3.2 (a) The correlation between CFRDoppler and CFRthermo, and (b) the Bland–Altman
plot of the relationship between CFRDoppler and CFRthermo. Source: Barbato et al. (2004).
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PRESSURE AND FLOW MEASUREMENTS 45

discrepancy has been accounted for by taking t0 as the nadir of the temperature curve
obtained. Calculation of CFR is based on the ratio of hyperaemic to resting flow. To
minimize discrepancies in baseline thermodilution curves it is suggested that the
guide catheter should be flushed with saline for at least 30 s. This will prevent poten-
tial discrepancies secondary to contrast-induced hyperaemia. Furthermore, in order
to prevent flow disturbances the bolus of saline injected should not exceed 4 ml.
Despite significant advantages of CFRthermo in comparison with CFRDoppler, the
former method is not entirely independent of the pattern of coronary disease. In
the final analysis coronary anatomy must be accounted for. For example, a major side
branch between the guiding catheter and a stenosis may lead to a false elevation of the
CFR value (a ‘steal’ phenomenon). There is also little data on the effects of vessel
interdependence on CFR, or the influence of multivessel disease on CFR calculation
(underestimation of readings).
Validation of CFRthermo has paved the way for simultaneous assessment of FFR
and CFR values. The complementary information derived should allow a more
accurate and robust routine clinical assessment of coronary physiology.

✍
Simultaneous assessment of fractional and coronary
flow reserve in cardiac transplant recipients: Physiologic
Investigation for Transplant Arteriopathy (PITA Study)
Fearon WF, Nakamura M, Lee DP, et al. Circulation 2003c; 108(13):
1065–70

B A C K G R O U N D . This study evaluates cardiac transplant arteriopathy by

simultaneous measurement of FFR and CFRthermo using a single intracoronary
pressure wire. Fifty-three asymptomatic cardiac transplant patients without
angiographically significant CAD were studied. FFR, CFRthermo and volumetric IVUS
evaluation of the LAD is performed in each patient. The mean FFR is 0.88 ± 0.07 (in
75% FFR <0.94 [normal threshold], in 15% FFR ≤0.80 [borderline ischaemia] and in
6% ≤0.75 [ischaemic]) and mean CFRthermo is 2.5 ± 1.2 (in 47% ≤2.0). There is a
significant inverse correlation between FFR and IVUS-derived parameters (Table 3.1),
with the strongest correlation being with plaque burden (r = 0.55; P <0.0001).
Further analysis of the results demonstrates that 14% of patients with a normal FFR
(>0.94) have an abnormal CFR (<2.0), suggesting a predominant microvascular
problem.

I N T E R P R E T A T I O N . This study demonstrates that FFR correlates with IVUS-derived plaque

burden and both indices are significantly abnormal in a large proportion of asymptomatic
cardiac transplant patients with angiographically normal coronary arteries. The ability to
measure CFRthermo and FFR simultaneously allows assessment of microvascular and
epicardial artery status. As demonstrated CFRthermo values are important in a small group of
patients where a normal FFR value alone would not detect a significant microvascular
abnormality.
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46 II . S T E N T I N G

Comment
Cardiac transplant-related coronary arteriopathy and microvascular dysfunction
remain two major causes of morbidity and mortality in transplant recipients. To
date, invasive assessment of coronary physiology in cardiac transplant patients has
been confined to Doppler wire-derived CFR (CFRDoppler) 12,13,17,18. CFRDoppler
values in isolation can be misleading, as it is not possible to distinguish between
epicardial and microcirculatory dysfunction.
This study is the first simultaneous analysis of FFR and CFR in cardiac transplant
recipients. Information derived from evaluation of both epicardial and micro-
vascular systems will be invaluable in (i) monitoring and determining medium- to
long-term outcome, and (ii) helping direct the most relevant treatment strategy.
Coronary arteries in the transplanted heart develop diffuse atheromatous changes.
As demonstrated in this study, angiography without additional physiological (e.g.
FFR) or alternative anatomical assessment (e.g. IVUS) is a weak tool in detecting the
significance of diffuse coronary changes. The results demonstrate that despite angio-
graphically normal vessels a significant proportion of cases have some level of func-
tional abnormality and in about 6% there is silent ischaemia secondary to epicardial
disease. The functional results correlate with more sophisticated imaging analysis of
disease burden using IVUS.
Results from this study are concordant with previous findings that pressure drop
across a coronary artery can correlate with either tight angiographic lesions or diffuse
disease affecting the entire length of the artery 19,20.
The importance of simultaneous FFR and CFR evaluation is evident in the 14% of
cases demonstrated to have microvascular dysfunction. As already mentioned micro-
vascular dysfunction has important prognostic implications and should prompt

Table 3.1 Correlation between FFR and various 2D and 3D IVUS-derived parameters

IVUS variable r value P value

2D analysis
Mean lumen diameter 0.40 0.003
Mean lumen area 0.43 0.002
Maximum lumen diameter 0.26 0.06
Minimum lumen diameter 0.33 0.02
Maximum lumen area 0.44 0.001
Minimum lumen area 0.37 0.007
Mean plaque area 0.43 0.001
Maximum % plaque area 0.48 0.0002
Minimum % plaque area 0.52 <0.0001
3D analysis
Lumen volume 0.23 0.10
Plaque volume 0.47 0.0004
% plaque volume 0.55 <0.0001

Source: Fearon et al. (2003c).

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PRESSURE AND FLOW MEASUREMENTS 47

re-evaluation of the overall management strategy of patients. The apparent normal

FFR value (>0.94) in this group of patients may be misleading. Significant micro-
vascular abnormalities may impair coronary flow with resultant artefactually high
FFR values.
As abnormalities of both the epicardial arteries and microvascular dysfunction
have long-term prognostic implications, cardiac transplant patients could have full
physiological assessment of the coronary vascular bed whenever necessary. This could
be performed in conjunction with their predetermined endomyocardial biopsy.
FFR/CFR abnormalities may allow earlier detection of complications, as well as help
in the identification of novel modifiable risk factors.

Clinical applications of fractional flow reserve and

coronary flow reserve
We present four papers discussing the validity of coronary physiological measure-
ments with a particular reference to potential confounding factors in day-to-day
catheterization laboratory practice.

✍
Effects of microvascular dysfunction on myocardial
fractional flow reserve after percutaneous coronary
intervention in patients with acute myocardial infarction
Tamita K, Akasaka T, Takagi T, et al. Catheter Cardiovasc Interv 2002; 57(4):
452–9

B A C K G R O U N D . FFR is an accepted index of epicardial coronary stenosis. It is used

to determine the physiological significance of epicardial lesions prior to a procedure
and/or assess optimal results postintervention. However, the accuracy of this index
in the context of significant myocardial microvascular dysfunction (as seen in an
acute MI) is unclear. This study explored the effects of microvascular dysfunction on
FFR postintervention. Thirty-three patients with acute MI undergoing coronary
stenting within 12 h of onset of pain were compared with 15 stable angina patients
undergoing elective stenting. The study vessels were interrogated after intervention
by calculating FFR and IVUS imaging. The results demonstrated a higher FFR in
patients with acute MI in comparison with the stable angina group of patients
(0.95 ± 0.04 vs 0.90 ± 0.04; P = 0.002). There was no difference in IVUS
parameters between the two groups. The study further subdivided the acute MI
patients on the basis of their postprocedure Thrombolysis in MI (TIMI) flow grade.
Twenty-three patients had TIMI 3 flow and 10 patients had TIMI 2 flow. The FFR values
in the TIMI 2 group were higher than the TIMI 3 group (0.98 ± 0.02 vs 0.93 ± 0.05;
P = 0.017) despite no difference in the IVUS parameters.

I N T E R P R E T A T I O N . Postcoronary intervention FFR is higher in patients with acute MI than

in patients with stable angina for the same level of anatomical stenosis as demonstrated by
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48 II . S T E N T I N G

IVUS. In patients with poor coronary flow (TIMI 2) all FFR values are high (all over >0.94).
This indicates that FFR may not be a reliable indicator of lesion severity in acute MI patients,
in particular in the context of poor coronary flow (TIMI 2).

Comment
Both FFR and IVUS can be used to assess lesion severity prior to intervention and the
effectiveness of stent deployment postprocedure. FFR values postintervention have
been shown to determine medium- to long-term outcome from interventional pro-
cedures 8,9,11.
FFR values are dependent on the ratio of pressure changes across a given coronary
lesion at baseline and maximal hyperaemic blood flow. Therefore, factors interfering
with overall coronary flow (such as microvascular dysfunction) will effect pressure
changes and in turn influence the FFR value obtained.
Integrity of the coronary microvascular bed in acute MI patients has a significant
influence on coronary blood flow postreperfusion (thrombolysis as well as primary
angioplasty). Ischaemia-induced microvascular damage (by a combination of plate-
let and leucocyte plugging, abnormal endothelial function and perivascular oedema)
often interferes with coronary flow postreperfusion. Coronary microvascular dys-
function postreperfusion therapy has been characterized with an intracoronary
Doppler wire 21,22. Doppler-derived systolic flow reversal and rapid deceleration of
diastolic flow are two hallmarks of significant coronary microvascular dysfunction
23,24. These changes have been shown to correlate with poor postreperfusion
angiographic markers of coronary blood flow (TIMI 1–2) 21,22. Doppler studies
have further demonstrated that in acute infarction, even patients with TIMI 3 flow
have some level of microvascular dysfunction 24.
Therefore, FFR values calculated in the context of poor coronary flow/significant
microvascular dysfunction will be artefactually higher than in patients with normal
flow. Thus FFR cannot be recommended as a reliable index of successful stenting in
patients who have a poor postreperfusion blood flow (TIMI 1–2).
However, there are a number of limitations of this study. Patient numbers are
small and there is no information on how acute physiological parameters translate
into medium- to long-clinical outcome and/or ventricular contractile recovery.
Furthermore, there is no information on the evolution of physiological coronary
parameters in the context of acute MI. In an ideal setting, results from serial mea-
surements subsequent to the last balloon inflation should be recorded and analysed
in the context of clinical outcome and LV recovery.
This study once again highlights the interdependence of epicardial and micro-
vascular components of the coronary circulation and the value of simultaneous
interrogation of both systems to aid optimal clinical decision-making.
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PRESSURE AND FLOW MEASUREMENTS 49

✍
Short- and long-term recovery of left ventricular function
predicted at the time of primary percutaneous coronary
intervention in anterior myocardial infarction
Bax M, de Winter RJ, Schotborgh CE, et al. J Am Coll Cardiol 2004;
43(4): 534–41

B A C K G R O U N D . Multiple factors have been proposed to predict recovery of LV

systolic function in the context of acute MI. In this study the predictive value of TIMI
flow grade, corrected TIMI frame count (cTfc), myocardial blush grade, CFR and
resolution of ST segment elevation are compared directly with LV recovery.
Seventy-three patients undergoing primary PCI for acute anterior ST elevation MI
were recruited. Recovery of LV systolic function was assessed using an
echocardiographic 16-segment wall motion index (WMI) before and at intervals up to
6 months post-PCI. There is a significant improvement in both mean and global WMI
over a 6-month period (Fig. 3.3). In a multivariate analysis the CFR value directly
post-PCI is the only independent predictor of global (0.17; confidence interval [CI]
0.06–0.27; P = 0.002) and regional (0.28; CI 0.14–0.41; P <0.0001) LV systolic
recovery at 6 months. As demonstrated in Figure 3.4, all patients with a CFR ≥2.0
immediately after primary PCI show an improvement in LV function. No relation exists
between other angiographic parameters and recovery of LV function.

I N T E R P R E T A T I O N . In a homogeneous group of patients with a first acute ST elevation

anterior MI, CFR measured directly after primary PCI is the only marker of long-term
(6 months) recovery of LV systolic function.

Fig. 3.3 Improvement in mean and global WMI over a 6-month period.
Source: Bax et al. (2004).
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50 II . S T E N T I N G

Comment
This study demonstrates that CFR is superior to certain other conventional param-
eters used to predict LV recovery in acute MI. In the absence of significant epicardial
disease, CFR is an accurate marker of microvascular function, providing an estimate
of overall myocardial perfusion and extent of permanent myocardial damage. Other
markers of poor myocardial perfusion such as flow velocity reversal (see previous
section) correlate well with in-hospital and 1-month recovery of LV function, but the
results do not predict long-term outcome. Similarly TIMI and myocardial blush
grade postintervention correlate weakly with 1-day outcome but their ability to pre-
dict recovery of LV contractile function is controversial.
Coronary microvascular dysfunction has important emerging clinical applica-
tions in diagnosis, risk stratification and prognosis of patients with CAD. Patients

Figure 3.4 Relation between 6-month change in global wall motion index (WMI) and
coronary flow velocity reserve after percutaneous coronary intervention (a) and change in
WMI as a function of corrected Thrombolysis In MI (TIMI) frame count, (b) myocardial blush
grade (c), and TIMI flow grade (d). The regression lines and 95% CIs are shown. Change in
WMI >0 reflects improvement of LV function after 6 months. Source: Bax et al. (2004).
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PRESSURE AND FLOW MEASUREMENTS 51

(such as diabetics and cardiac transplant patients) with abnormal microvascular

function have been shown to have a higher incidence of cardiovascular com-
plications 25,26. Acute MI and percutaneous coronary intervention (both balloon
angioplasty as well as stent deployment) can also both lead to various levels of micro-
vascular dysfunction, which in turn determines short- and long-term outcome 9,10.
Furthermore, factors that improve microvascular function (such as  blockers and
glycoprotein IIb–IIIa antagonists) have the potential to reduce cardiovascular com-
plications 27. For example, glycoprotein IIb–IIIa antagonists are now used routinely
in high-risk coronary intervention to alter outcome.
To date there are no studies that have been large enough to investigate the rela-
tionship between microvascular function and long-term mortality post-MI. An ideal
trial design would include data on the effectiveness of intervention in the epicardial
vessel (see Tamita et al. 2002), microvascular dysfunction (as in this study), long-
term recovery of LV function and would have sufficient power to predict long-term
survival. Clinically, coronary microvascular function has always been difficult to
measure and quantify accurately. Improvements in our ability to measure FFR and
CFR simultaneously using a single pressure-temperature sensor-tipped guide wire
should facilitate the design of such a study in the future.

✍
Correlation between thallium-201 myocardial perfusion
defects and functional severity of coronary artery
stensosis as assessed by pressure-derived myocardial
fractional flow reserve
Yanagisawa H, Chikamori T, Tanaka N, et al. Circulation J 2002; 66(12): 1105–9

B A C K G R O U N D . The relationship between coronary FFR and radionucleotide imaging

has previously been reported. However, the data came from a highly selective group
of patients. This study investigated whether the relation between FFR and
radionucleotide imaging (stress thallium myocardial scintigraphy [201Tl]) holds true in
a clinical setting with a heterogeneous group of patients: 165 patients (194 coronary
lesions) were recruited; 70 patients had stable angina and 95 patients previous MI.
Positive FFR (<0.75) correlated significantly with radionucleotide evidence of
myocardial ischaemia (P <0.0001), with a sensitivity of 79% and specificity of 73%.
In arteries subtending infarcted areas (70 vessels) the sensitivity and specificity
were 79% and 75%, respectively, and in the remaining arteries (124 vessels) the
values were 80% and 72%, respectively. FFR also showed an inverse correlation with
201Tl reversibility score (a marker of myocardial ischaemia) (r = –0.62; P <0.0001).

I N T E R P R E T A T I O N . The FFR cut-off value of 0.75–0.80 correlated with 201Tl evidence of

myocardial ischaemia in ‘true-life’ clinical settings with a heterogeneous group of patients.

Comment
The FFR cut-off value of <0.75 as a threshold for myocardial ischaemia has been
established from a number of studies using select groups of patients with CAD. The
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52 II . S T E N T I N G

original data were based on patients with single-vessel disease without previous MI.
The results demonstrated a sensitivity of 88% and specificity of 100% for scinti-
graphic evidence of myocardial ischaemia 5. There are also comparable data on
select patient groups with multivessel disease (sensitivity 69% and specificity 79%) 7
and previous MI (sensitivity 82% and specificity 87%) 28.
This is the first study that has addressed the current ischaemic cut-off value of FFR
(<0.75) in a heterogeneous group of patients resembling the ‘real world’ practice. As
outlined, the sensitivity and specificity from this study is similar to previous studies
for both stable patients as well as patients with previous MI. The investigators also
plotted a regression curve of FFR against 201Tl uptake, demonstrating a negative
correlation between FFR <0.75 and a 201Tl-derived marker of ischaemia (the revers-
ibility score). Therefore, the higher the value of scintigraphic evidence of myocardial
ischaemia, the lower the FFR value obtained. The cut-off FFR value showing a signifi-
cant correlation with 201Tl-derived ischaemia (reversibility score 0–1) is between
0.733 and 0.778. The current clinically accepted FFR value of 0.75 clearly falls within
this range.
Calculation of FFR is indirectly dependent on the integrity of the microvascular
bed subtended by the study artery. A reduction in absolute flow (at maximal hyper-
aemia) secondary to microvascular dysfunction (as seen in MI) can result in signifi-
cant underestimation of FFR and in turn the true extent of the epicardial stenosis
under investigation. However, unlike the previous study in this section by Tamita
and colleagues, the diagnostic value of FFR is similar in both infarcted and stable
patients. This observation is suggestive of an overall improvement in microvascular
function (and hence coronary flow) in infarct-related arteries with time.
The temporal changes in microvascular function postacute MI highlight the need
for further studies with serial simultaneous measurements of FFR and CFR from
presentation into recovery. A better understanding of the dynamic changes in
coronary physiology will help identify optimal diagnostic tools and development of
novel therapeutic measures directed specifically at the various stages of myocardial
recovery.

✍
Microvascular resistance is not influenced by epicardial
coronary artery stenosis severity: experimental
validation
Fearon WF, Aaroundse W, Pijls NHJ, et al. Circulation 2004; 109(19): 2269–72

B A C K G R O U N D . The effect of epicardial artery stenosis and the resultant

recruitment of collateral flow on myocardial microvascular resistance are unclear. An
open-chest pig model was used to investigate this relationship. Apparent and actual
microvascular resistance (R) and index of microvascular resistance (IMR) were
measured in the absence of coronary stenosis and after creation of moderate/severe
epicardial stenosis. Apparent microvascular resistance was calculated during peak
hyperaemia (papaverine induced) as pressure divided by flow. Measurements are
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PRESSURE AND FLOW MEASUREMENTS 53

made with either a flow probe around the coronary artery (Rmicro app) or with a
thermodilution technique (IMRapp). These apparent resistances are compared with
actual Rmicro and IMR by incorporating coronary wedge pressure and collateral flow
into the calculation. A total of 189 measurements (54 measurements with no
epicardial stenosis, 80 with moderate stenosis, 55 with severe stenosis) were made
in six pigs. Rmicro app increases significantly with an increase in epicardial stenosis
(0.43 ± 0.12 to 0.46 ± 0.10 to 0.51 ± 0.11 mmHg/ml per min; P <0.001) as does
IMRapp (14 ± 4 to 17 ± 7 to 20 ± 10 U; P <0.001) (Fig. 3.5). However, on
incorporating the effects of collateral flow neither Rmicro (0.43 ± 0.12 to 0.42 ± 0.08
to 0.40 ± 0.13 mmHg/ml per min; P = 0.25), nor IMR (14 ± 4 to 16 ± 7 to 16 ± 9 U;
P = 0.30) (Fig. 3.5) change significantly with an increase in epicardial stenosis.

Fig. 3.5 A comparison of Rmicro and Rmicro app (a) and IMR and IMRapp values (b) at
different degrees of epicardial artery stenosis. Source: Fearon et al. (2004).
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54 II . S T E N T I N G

I N T E R P R E T A T I O N . The complex relationship between collateral flow, epicardial stenosis

and microvascular resistance was poorly understood. This study demonstrated that in a pig
model after accounting for collateral flow microvascular resistance is not affected by
increasing epicardial artery stenosis.

Comment
Previous work on microvascular function has demonstrated that in the presence of
epicardial coronary stenosis there is a rise in microvascular resistance 29,30. The
findings in this paper by Fearon and colleagues demonstrate that rises in micro-
vascular resistance in relation to epicardial coronary stenosis appear to be artefactual,
the result of neglecting the contribution of collateral flow to the distal coronary
vascular bed.
Although the porcine coronary collateral flow model is similar to the human
myocardium the current study has a number of limitations. Unlike the natural
history of coronary disease, in the pig model epicardial stenoses are created acutely.
As a result microvascular measurements are performed in a previously normal
microvascular bed. This is in sharp contrast to the complex pathological process in
human atheroma, where chronic disturbances in haemodynamics may have differing
effects on collateral behaviour. However, the exciting prospect of a reliable, clinically
applicable index of microvascular function that is independent of epicardial disease
is coming closer.

✍
Single-wire pressure and flow velocity measurement to
quantify coronary stenosis hemodynamics and effects of
percutaneous interventions
Siebes M, Verhoeff B-J, Meuwissen M, et al. Circulation 2004; 109(6): 756–62

B A C K G R O U N D . Lack of high-fidelity simultaneous measurements of pressure and

flow velocity distal to a coronary artery stenosis has hampered the study of stenosis
pressure drop-velocity ([DELTA]P-v) relationships in patients. A novel 0.014-inch
dual-sensor (pressure and Doppler velocity) guidewire was used in 15 coronary
lesions to obtain per-beat averages of pressure drop and velocity after an
intracoronary bolus of adenosine. [DELTA]P-v relations from resting to maximal
hyperaemic velocity are constructed before and after stepwise executed PCI. Before
PCI, half of the [DELTA]P-v relations revealed the presence of a compliant stenosis,
which was stabilized by angioplasty. FFR, CFR and velocity-based indices of stenosis
resistance (h-SRv) and microvascular resistance (h-MRv) at maximal hyperaemia
were compared. Stepwise PCI significantly lowered h-SRv, with an initial marked
reduction in hyperaemic pressure drop followed by further gains in velocity. A
concomitant significant reduction of h-MRv accounted for half of the gain in velocity
after PCI. The average magnitude of absolute incremental haemodynamic change
was highest for h-SRv (56.8 ± 39.2%) compared with CFVR (35.3 ± 34.5%;
P <0.005) or FFR (19.5 ± 25.2%; P <0.0001).
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PRESSURE AND FLOW MEASUREMENTS 55

I N T E R P R E T A T I O N . [DELTA]P-v relations comprehensively visualize improvements in

coronary haemodynamics after PCI. h-SRv is a powerful and sensitive descriptor of the
functional gain achieved by PCI, combining information about both pressure gradient and
velocity, which are oppositely affected by PCI. Simultaneous assessment of stenosis and
microvascular resistance may provide a valuable tool for guidance of PCI.

Comment
This study illustrates the use of the more complex pressure–velocity relations of
coronary stenoses, which provide interesting research data but are not in widespread
clinical use. More importantly, these data are acquired with a new device, which
measures coronary flow velocity and high fidelity pressure simultaneously. This may
prove a valuable tool in the clinical assessment of coronary flow in forthcoming years.

Conclusions
Coronary physiological measurements have over the past few years become an
important component of the armamentarium of investigations available to the inter-
ventional cardiologist. Continued investigations in coronary physiology have sig-
nificantly improved our understanding of myocardial perfusion and in particular
the complex inter-relationship between its three main components: the coronary
microvasculature, the stenosed epicardial vessel and the collateral circulation. An
appreciation has been gained of the obstruction to blood flow imposed by diffuse
atheroma along the length of a coronary artery.
The original publications in the area concentrated primarily on validation of the
novel techniques in both animal models and humans. However, more recent work
(as outlined in this chapter) concentrates on the application of coronary physiology
to ‘real life’ catheterization laboratory practice. There is now information demon-
strating that physiological indices/measurements can also be applied to a hetero-
geneous population of patients. In turn, data from a larger non-select group of
patients have allowed further refinement of the techniques, highlighting a number of
important confounding factors that can introduce significant errors during day-to-
day coronary interrogation.
Invasive coronary physiology is a rapidly evolving field. Improvements in equip-
ment leading to more reliable sampling techniques, increasing ease of use with
miniaturization/better manoeuvrability, accompanied with our increasing know-
ledge of myocardial perfusion are moving the entire field out of the domain of the
specialist centres with a specific interest in coronary physiology to the general
catheterization laboratory. It is no longer acceptable to treat the anatomy presented
by the coronary angiogram without an appreciation of its physiological conse-
quences, particularly in the drug-eluting stent era. More widespread use of reliable
physiological indices should translate into better patient care and improved long-
term outcome, with one-stop catheterization laboratory visits at lower costs.
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56 II . S T E N T I N G

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