(Circulation. 2000;101:1344.)
© 2000 American Heart Association, Inc.
From Bench to Bedside |
From the Department of Internal Medicine, Division of Cardiology, Saint Louis University Health Sciences Center, St. Louis, Mo.
Correspondence to Morton J. Kern, MD, Director, J.G. Mudd Cardiac Catheterization Laboratory, Saint Louis University Health Sciences Center, 3635 Vista Avenue at Grand Blvd, St. Louis, MO 63110. E-mail kernm{at}slu.edu
Abstract
AbstractVarious coronary physiological measurements can be made in the cardiac catheterization laboratory using sensor-tipped guidewires; they include the measurement of poststenotic absolute coronary flow reserve, the relative coronary flow reserve, and the pressure-derived fractional flow reserve of the myocardium. Ambiguity regarding abnormal microcirculation has been reduced or eliminated with measurements of relative coronary flow reserve and fractional flow reserve. The role of microvascular flow impairment can be separately determined with coronary flow velocity reserve measurements. In addition to lesion assessment before and after intervention, emerging applications of coronary physiology include the determination of physiological responses to new pharmacological agents, such as glycoprotein IIb/IIIa blockers, in patients with acute myocardial infarction. Measurements of coronary physiology in the catheterization laboratory provide objective data that complement angiography for clinical decision-making.
Key Words: physiology catheterization heart coronary blood flow
An appreciation of coronary physiology is an integral part of clinical decision-making for cardiologists treating patients with coronary artery disease. The pioneering research efforts of Dr Lance Gould, who explored the relationship between the anatomic severity of a stenosis and its flow resistance,1 2 have been transferred to clinical practice.3 4 Within the last few years, technology has advanced such that, in patients undergoing coronary angiography, the influence of a coronary stenosis on the distal arterial pressure-flow relationship can now be easily and safely determined with sensor-tipped angioplasty guidewires that measure the poststenotic absolute coronary flow velocity reserve (CVR), the relative CVR (rCVR), and the pressure-derived fractional flow reserve of the myocardium (FFR). However, theoretical concerns regarding the translation of basic physiology from experimental animal models has given some clinicians pause in applying the available techniques for patient care.5 6 This review will discuss the current concepts, methods, and clinical outcomes of these techniques and provide practical insights for patient management.
Before applying these physiological measurements, a brief review of several fundamental principles is in order. Recall that when an epicardial stenosis produces an increased resistance to flow, the distant microvascular resistance vessels dilate to maintain regional basal flow at a level appropriate for concurrent myocardial oxygen demand. The increased dilation reduces the potential maximal flow reserve available. Because the distal microcirculation has compensated for the potential reduction in regional flow, the resting poststenotic epicardial conduit blood flow, depending on the severity of the stenosis, may be somewhat diminished; however, this epicardial flow usually satisfactorily maintains myocardial function and metabolism. Under these conditions, any increase in myocardial oxygen demand or other hyperemic stimuli now results in a smaller increment in poststenotic flow relative to the coronary flow increase that would be elicited in the same (or another) myocardial region without a stenosis (ie, diminished CVR and rCVR).
A significant stenosis also produces distal artery pressure
loss (ie, a translesional pressure gradient) because of a loss of
kinetic (flow) energy to viscous friction, turbulence, and flow
separation. The reduction of the distal distending arterial
pressure results in a pressure differential or gradient between the
driving aortic pressure and the poststenotic coronary
pressure. The degree of pressure loss is directly related to the flow
rate as described by the curvilinear pressure-flow relationship of the
particular lesion resistance (Figure 1
).1 2
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Beyond Coronary Pressure Gradients
For clinical coronary artery lesion assessment, resting pressure gradients measured during the early experience with coronary angioplasty were unsatisfactory because of (1) in-adequate devices (ie, balloon catheters), (2) data being used in an incompletely understood manner (ie, only at rest and not during maximal blood flow),7 8 and (3) a weak correlation to ischemic testing and clinical outcomes.7 9 10 Pijls et al11 12 13 demonstrated that the hyperemic absolute distal coronary pressure, but not the resting pressure gradient, is related to the ischemic potential of a stenosis. Moreover, they derived a new concept of a pressure-derived estimate of coronary blood flow, the FFR. The FFR is the fraction of maximal coronary blood flow that goes through the stenotic vessel, expressed as a percentage of blood flow through the same artery in the theoretical absence of the stenosis. The FFR, calculated as the ratio of the absolute distal coronary and aortic pressures measured during maximal hyperemia (ie, when minimal resistance is present across both the epicardial and microvascular beds), reflects myocardial perfusion (both antegrade and collateral) rather than merely trans-stenotic pressure loss. Unlike CVR, FFR is independent of driving pressure, heart rate, systemic blood pressure, and the status of the microcirculation,14 and it reflects both antegrade and collateral blood flow. The normal value for FFR is 1 for each patient, coronary artery, myocardial distribution, and microcirculatory status.
Lesion-Specific Physiological Measurements
A normal absolute CVR, the ratio of hyperemic to basal mean flow (velocity), indicates a normal 2-component system, with a patent epicardial conduit supplying a normal myocardial bed. In the absence of epicardial conduit obstruction, the CVR may be abnormal when the microvascular circulation is compromised by left ventricular hypertrophy, chronic or acute ischemia, diabetes mellitus, or other diseased rheological conditions.15 16 An abnormal CVR cannot differentiate which of the 2 components is responsible for flow impairment. In this setting, an additional measurement of CVR in an adjacent, normal vessel as a reference value (CVRreference) can confirm the significance of the coronary lesion and compute the rCVR (rCVR=CVRtarget/CVRreference).17 Assuming that systemic hemodynamic and microcirculatory abnormalities affect the different regions of the myocardium to the same degree, the rCVR should nullify the influence of the variables and provide an enhanced discrimination of flow impairment due to a stenosis.17 The CVR in angiographically normal vessels from adult patients with coronary artery disease risk factors is 2.7±0.618 and, in most studies, it seems to have little regional variation (<15%) in both cardiac transplant patients and patients with chest pain syndromes. The normal value of the rCVR is >0.8.18 19
Unlike absolute CVR, both rCVR and the FFR are considered more lesion-specific physiological measurements. Baumgart et al19 compared FFR to both absolute CVR and rCVR in 24 vessels that had stenoses ranging from 40% to 95% (average, 74±15%). Target and reference vessel CVR were 2.1±0.5 and 2.6±0.7, respectively; the rCVR was 0.82±0.13 (range, 0.53 to 1.0), and the FFR was 0.81±0.15 (range, 0.49 to 0.99). FFR and rCVR, but not CVR, showed a strong curvilinear relationship to percent area stenosis (r=0.89 and r=0.79; P<0.0001), with a close linear relationship between FFR and rCVR (r=0.95; P<0.0001) that supported the lesion-specific nature of these 2 measurements.
Limitations of Coronary Flow Reserve
Microcirculatory impairment is the major limitation in assessing a stenosis using absolute CVR; this issue is addressed by rCVR or FFR. In patients in whom the target vessel supplies an area of myocardial infarction, neither CVR nor rCVR can confidently identify flow impairment due solely to a stenosis because the assumption that the microvascular circulation is uniform no longer applies. In patients with 3-vessel coronary disease, no suitable reference vessel may exist, which compromises the use of rCVR. A lesion in these situations may be best assessed by FFR.
Advantages and Limitations of FFR
Although FFR seems to be independent of microvascular responses or changing hemodynamics,14 which is a significant advantage over CVR, the magnitude of the flow increase during maximal vasodilatation still influences FFR.11 12 A limited increase in flow across a stenosis could minimize the true FFR value. However, because the FFR reflects the extent to which the epicardial resistance reduces myocardial perfusion, it can be argued that in the setting of microvascular disease, a normal FFR indicates that the conduit resistance (ie, the stenosis in question) is not a major contributing factor to perfusion impairment and that the enlargement of such a conduit obstruction would not restore normal perfusion. In such diagnostic dilemmas, FFR and Doppler velocimetry are complementary; they describe the physiology of both the epicardial stenosis and the microvascular disease (if present) as potential contributors to inducible myocardial ischemia.
It should be recognized that the normal threshold of FFR (<0.75) for
ischemia was derived from a selected, stable patient population
with single-vessel coronary disease and normal left
ventricular function. The data are limited for patients
with microvascular disease, acute or remote myocardial infarction, and
unstable angina. Caution should be applied in extending the current
physiological criteria to such patients. The
advantages and limitations of the 3 physiological
measurements for patients with coronary artery disease are
summarized in Table 1
.
|
Concerns Regarding the Practical Application of Physiological Measurements in Patients
Although the discussed techniques are particularly well suited for both diagnostic and interventional therapy, several investigators have expressed concerns over the potential technical and biological limitations of in-laboratory physiological measurements.5 6 20 Technical or operator-related artifacts, such as variability in Doppler velocity envelopes, pressure signal drift, or malalignment, should be avoided as previously described.11 18 Similarly, the cross-sectional area of a sensor guidewire (0.16 mm2) is negligible relative to all but the most critical stenoses.21
Although a potentially false-negative physiological evaluation could occur in the setting of transient vasoconstriction of a stenotic lesion or the microcirculation, episodic or dynamic ischemia that is not detectable by measurements at the time of investigation can be attenuated or eliminated by concomitant antianginal therapies. Dynamic stenotic resistance with inducible variations may occur both at rest and during maximal hyperemia22 in response to a variety of intrinsic and extrinsic stimuli.22 23 24 A false-negative CVR could also be obtained if the ischemic myocardium was confined to only a small region, such as the subendocardium or papillary muscle. Like any diagnostic modality, the results must be considered in the dynamic course of the clinical presentation.
The pharmacological hyperemic agents used to identify impaired
flow are thought to be equivalent to exercise stress hyperemia.
These agents may be unsatisfactory in rare individuals with increased
susceptibility to myocardial ischemia that is not reflected
solely in the flow-limiting nature of the stenosis. Figure 2
illustrates the
physiological assessment of difficult intermediate
coronary stenoses.
|
Clinical Validation
Although some of the theoretical concerns regarding the limitations of direct physiological measurements cannot be completely satisfied, the clinical validation and outcomes strongly support the practical value of in-laboratory measurements. Many of the above-noted concerns and potential complexities of using coronary physiological measurements for clinical decisions arise from the failure of suitable experimental animal and clinical studies to define unambiguous criteria of myocardial ischemia. In patients, the validation of coronary physiological criteria has been established by population correlations with clinically accepted norms of several types of ischemic stress provocation.13 25 26 27 28 29 30 31 32 33
For poststenotic coronary flow velocity reserve,
several single-center studies26 27 28 and one multicenter
trial29 have reported strong correlations with myocardial
stress perfusion; one study using 2D echocardiographic
stress imaging32 reported correlations with an abnormal
distal CVR<2.0, which corresponded to reversible myocardial perfusion
imaging defects (and stress-induced wall motion). These studies had
high sensitivity (86% to 92%), specificity (89% to 100%),
predictive accuracy (89% to 96%), and positive and negative
predictive values (94% to 100% and 77% to 95%, respectively; Table 2
).
|
Similarly, for FFR, Pijls et al13 and De Bruyne et al25 also report high correlations for identifying reversible ischemia with an FFR<0.75. In the study by Pijls et al,13 sensitivity was 88%, specificity was 100%, and positive and negative predictive values were 100% and 88%, respectively; the study had a predictive accuracy of 93%.
The clinical outcomes of deferring coronary intervention for
intermediate stenoses with normal physiology that are now
reported in
5 studies13 34 35 36 37 38 are remarkably
consistent, with clinical event rates of <10% over a 2-year
follow-up period. In these studies, because of clinical requirements,
it was not feasible to defer treatment in symptomatic
patients with abnormal translesional physiology. It is highly likely
that these individuals would, at the least, continue to be
symptomatic or have higher event rates. It should also be
noted that although the safety of deferring angioplasty on the basis of
a normal CVR can be demonstrated, some patients with deferred
procedures had a lower rate of angina-free follow-up compared with
patients who underwent angioplasty.35 Nonetheless, when
physiologically normal, the functional and
clinical impact of medically-treated, angiographically
intermediately-severe stenoses is associated with an excellent
clinical outcome. Physiological criteria support
decisions to defer intervention in such situations while
continuing medical therapy for endothelial
dysfunction, hypertension, hyperlipidemia, and episodic
coronary vasoconstriction.
Comparison With Intravascular Ultrasound Imaging
Despite sophisticated quantitative modeling, neither intravascular ultrasound imaging (IVUS) nor coronary angiography can predict the resistance to flow through intermediately-narrowed epicardial coronary conduits. This is due to factors such as stenosis length, entrance and exit angles, coefficients of viscous friction and separation, and the status of the distal microvascular bed.
Moses et al39 studied 42 patients with coronary
stenoses ranging from 18% to 95%; they reported that in those
patients with a CVR<1.8, the IVUS reference segment area, IVUS lumen
area, and angiographic percent diameter stenosis were higher
(17.7±0.3 versus 12.9±4.4 mm2,
P<0.05; 6.2±3.76 versus 4.34±2.0
mm2, P<0.05; and 60±14 versus
46±17%, P<0.01, respectively) compared with patients with
a CVR
1.8. However, the IVUS minimal luminal diameter and
angiographic percent stenosis were only weakly correlated with
poststenotic CVR (r=0.312, P=0.047; and
r=0.305, P=0.052, respectively). In contrast,
Abizaid et al40 found that before intervention, the
CVR and IVUS minimal luminal cross-sectional areas were correlated
(r=0.83, P<0.0001); after the procedure,
this relationship was attenuated (r=0.514,
P=0.006; and, after stent placement, r=0.62,
P=0.031). An IVUS minimal lumen cross-sectional area
4 mm2 had a diagnostic
accuracy of 89% for a CVR
2.0. Recently, Takagi et
al41 demonstrated that an IVUS minimal lumen area
<3.0 mm2 and an area stenosis
<60% had 100% predictive accuracy for a FFR<0.75. Despite a precise
dimensional measurement, a single tomographic IVUS image (except in the
extremes) correlated weakly with measured coronary
physiological responses.
Conversely, FFR may be equivalent to IVUS in the assessment of optimal stent deployment. Hanekamp et al42 found IVUS and FFR>0.94 had 91% concordance in the identification of optimal stent apposition and deployment.
Physiological End Points for Coronary Interventions
It is now known that the failure of coronary blood flow
reserve to improve after balloon angioplasty in
50% of
patients43 44 is principally due to 2 mechanisms:
impairment of microcirculatory responses (either preexisting or induced
after vessel trauma) and/or inadequate epicardial lumen expansion not
readily appreciated by angiography. Microvascular circulatory
impairment, which was initially thought to be the predominant
mechanism, is likely the less common condition because stenting,
compared with angioplasty alone, achieves a larger and more uniformly
cylindrical lumen by IVUS and normalizes CVR in most (
80%)
patients.45 In the 20% of patients with a poststent
CVR<2.0, rCVR or FFR may be useful in identifying persistent conduit
abnormalities. A typical example of pressure and flow measurements
after coronary angioplasty and stenting is illustrated in
Figure 3
.
|
A physiological end point associated with improved
late outcomes after coronary angioplasty was identified in the
Doppler End point Balloon Angioplasty Trial, Europe (DEBATE I),
trial.46 A CVR>2.5 coupled with an acceptable
quantitative coronary angiographic result (<35% diameter
stenosis) identified a subset of patients after single-vessel
balloon angioplasty in whom there was a 16% angiographic
restenosis rate and a 16% target lesion
revascularization rate at the 6-month follow-up.
Using FFR after angioplasty without stenting, Bech et al47
found that when a FFR>0.9 was achieved, repeat interventions at 6, 12,
and 24 months were 12%, 12%, and 15%, respectively, compared with
patients who had a FFR
0.9 after angioplasty, with
restenosis rates of 24%, 28%, and 30% at 2 years.
A physiologically-guided angioplasty approach is being prospectively evaluated in 3 multicenter trials: DESTINI-CFR (Doppler Endpoint Stent International Investigation of Coronary Flow Reserve), DEBATE II, and FROST (French Optimal Stent Trial. These studies will confirm whether a provisional, physiologically-guided approach will produce clinical outcomes equivalent to a mandatory or primary stent approach without the adverse effects of stenting.
Preliminary data from studies in >1000 patients indicate that although
crossover to stenting was required in
40% to 50% of patients, the
major adverse in-hospital and 6-month clinical cardiac event rates were
similar in both provisional and primary stent strategies. The
physiologically-guided approach to balloon
angioplasty, although clinically supported and economically attractive,
seems limited by operator preferences and advances in stent technology
that have reduced stent-related complications and
restenosis.
Emerging Developments in Catheterization Laboratory-Based Coronary Physiology
The coronary physiology after acute myocardial infarction and reperfusion strongly influences clinical outcomes.48 In patients with acute infarction, the microcirculatory responses to pharmacological and mechanical interventions that release or remove thrombus or particulate matter can be quantitated in physiological terms and, using FFR, discriminated from epicardial flow impairment.
For example, Claeys et al49 reported that for similar angiographic stenoses, the CVR measured 13±7 days after acute myocardial infarction in 36 patients was lower both before and after angioplasty compared with the 38 patients without myocardial infarctions (1.22±0.26 versus 1.50±0.45 and 1.72±0.43 versus 2.21±0.74, respectively). Although CVR increased after angioplasty in both patient groups, a persistently impaired CVR was present in 80% of patients with acute myocardial infarctions and in only 44% of patients without myocardial infarctions, which suggests that CVR was related more to conduit narrowing than myocardial viability and that increasing the residual lumen by stenting may improve myocardial recovery.
Similarly, Neumann et al50 examined acute and 14-day coronary flow and left ventricular wall motion in 102 patients with acute myocardial infarction who received abciximab and in 98 patients who received standard care with heparin. With similar degrees of residual stenosis, the change in peak (but not resting) flow velocity was greater (P<0.024) and wall motion index improved more (P<0.007) in the patients receiving abciximab. Coronary physiological responses correlated with left ventricular functional recovery, which suggests that mechanisms involving microvascular perfusion may identify new therapeutic avenues in these patients.
Summary
Recent advances in our understanding of human coronary
circulation and clinically-validated physiological
relationships to ischemic stress testing in patients have
enhanced the conceptual applications of and overcome most technical
limitations surrounding the usefulness of in-laboratory
coronary physiological measurements to
facilitate clinical decisions to treat or defer intervention. Although
current clinical practice favors primary stenting, when considering
strategies for optimal balloon angioplasty compared with obligatory
stenting, multicenter preliminary reports indicate that a
physiologically-guided approach can
identify
50% of patients who will have equivalent clinical outcomes
without the additional cost of stents and the potential for in-stent
restenosis.
The practical application of physiological concepts in patients strongly complements coronary lumenology51 and has important clinical and economic implications for the care of patients with coronary artery disease.
Acknowledgments
The author thanks the J.G. Mudd Cardiac Catheterization Laboratory team and Donna Sander for help with manuscript preparation.
References
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