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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3597_Библиотеки_им_академика_М_И_Перельмана
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Research Techniques
The Doppler guidewire has a forward-directed ultrasound beam
that diverges in a 27-degree arc from the long axis (measured in the
−6-dB round-trip points of the ultrasound beam pattern). A pulse repetition frequency of >
40 Hz, pulse duration of +0.83 seconds, and
sampling delay of 6.5 seconds are standard for clinical use. The system
is coupled to a real-time spectrum analyzer, videocassette recorder,
and video page printer. The spectrum analyzer uses online fast Fourier
transformation to process the Doppler audio signals. Simultaneous
electrocardiographic and arterial pressure data are also displayed
(Fig. 9-6). In vivo testing has demonstrated excellent correlation of the
Doppler guidewire–measured velocity with electromagnetic measurements of flow velocity and volumetric flow.
Proper engagement of the coronary ostium with a guiding catheter is key to assure the administration of the entire specified amount
of any drug to be given. Before the Doppler guidewire is placed into
an artery, the patient should be given intravenous (IV) heparin (40 to
60 U/kg with target activated coagulation time >200 seconds). After
diagnostic angiography or during angioplasty, the Doppler guidewire
is passed through a standard angioplasty Y connector attached to a
guiding catheter. The guidewire is advanced into the artery and
beyond the target location (e.g., stenosis) by a distance equal or
greater than 5 to 10 times the arterial diameter (~2 cm). Avoid placement in any side branches. Obtain distal flow velocity data at rest and
during hyperemia (Figs. 9-7 and 9-8).
It is important to note that Doppler coronar y velocity measures
only relative changes in velocity. Volumetric coronary flow is calculated as velocity (cm/sec) multiplied by vessel area (cm
2
). For measurement of absolute blood flow, the following assumptions must be
made:
1. The cross-sectional area of the vessel being studied remains fixed
during hyperemia.
2. The vessel lumen is cylindrical with a velocity profile that is not
distorted by arterial disease.
Figure 9-6
signals (top) and base and hyperemic signal storage areas (below). Electrocardiogram and aortic pressure are at the top of each signal area. Scale is
0 to 120 cm/sec (far right). Upper left corner, Numbers in dark boxes are
heart rate and systolic and diastolic blood pressure. ACC, Acceleration; APV,
average peak velocity; BAPV, base of average peak velocity; CFR, coronary
flow reserve; D, diastolic marker; DSVR, diastolic -to- systolic velocity ratio;
MPV, maximal peak velocity; PAVP, peak of average peak velocity; S, systolic
marker.
Doppler flow velocity screen is split into continuous phasic
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Figure 9-7 Doppler flow velocity continuous trend plot of average peak
velocity panel. Baseline value (B) is obtained. Intracoronar y (IC) adenosine
is injected (note ar tifact before S [search]). Hyperemia is stimulated, and
peak (P) hyperemia is captured and stored.
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Research Techniques 393
A
C
Figure 9-8 Distal coronary flow velocity before (A) and after (C) successful
percutaneous transluminal coronary balloon angioplasty of the distal right
coronary artery (90% stenosis). B, Distal prepercutaneous transluminal
coronary balloon angioplasty flow velocity is 12 cm/sec with reduced phasic
pattern. D, After percutaneous transluminal coronary balloon angioplasty,
the mean flow velocity is 35 cm/sec with a normal phasic pattern. Black
arrows, Percutaneous transluminal coronary balloon angioplasty sites; white
arrows, Doppler guidewire sample volume location.
B
D
3. The angle between the crystal and sample volume remains con-
stant and <30 degrees from the horizontal flow stream.
Coronary Flow Reserve
Hyperemic measurements are obtained by IC injections of adenosine
(30 to 50 µg in the right coronary artery and 50 to 100 µg in the left
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LAD with collaterals
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Research Techniques
coronary artery). It is important to give doses high enough to induce
complete vasodilation. Some protocols use ultra-high doses of adenosine (>
200 µg); however, the incremental benefit of these larger doses
is unproven. Guide catheter position (i.e., avoid suboptimal selective
engagement into the coronary artery and disengagement with very
forceful manual injection) is critical to accuracy.
CFR is computed as the ratio of hyperemic and basal mean flow
velocities. A normal CFR is >2.0. Comparisons of CFR and FFR for
detection of ischemia based on noninvasive testing as a gold standard
are shown in Table 9-3.
Measurement of Collateral Circulation
Coronary collateral flow can be measured with the use of the Dopplertipped flow wire (Fig. 9-9) and pressure wire. Before placing the wire
in the patient, a 0.014-inch pressure wire is set at 0 (atmosphere), calibrated, and advanced through a balloon catheter and positioned
Table 9 -3
Physiologic Criteria Associated with Clinical Applications
Indication CFR rCFR HSRv* FFR
Ischemia detection
Deferred angioplasty
Endpoint of angioplasty
Endpoint of stenting — — —
From Kern MJ, Lerman A, Bech JW, et al: Physiological assessment of coronar y
artery disease in the cardiac catheterizatio n laborator y: a scientific statement from
the American Heart Association Commit tee on Diagnostic and Inter ventional Cardiac
Catheterization, Council on Clinical Cardiolo gy. Cir culation 114:1321–1341, 2006.
CFR, Coronary vasodilatory reser ve; FFR, fractional flow reser ve; H SRv, hyperemic
stenosis resistance index; rCFR, relative coronar y vasodilatory reser ve.
*Measured in mm Hg/cm/sec.
†
With <35% diameter stenosis.
<2.0 <0.8 >0.8 <0.75
>2.0
>2.0 to 2.5
†
— —
— —
>0.80
>0.90
>0.90
Figure 9-9 Time sequence of flow velocity during coronary balloon occlu-
sion in a patient with a lef t anterior descending (LAD) coronary arter y filled
with collaterals originating from the right coronary artery. Note the retro grade collateral flow velocity below the baseline in a phasic pattern, appearing after 15 seconds of coronary occlusion. On release of balloon occlusion,
immediate anterograde hyperemia can be observed in the distal bed with a
loss of the retrograde flow pattern, corresponding with successful angioplasty. APV, Average peak velocit y (mean); DSVR, diastolic-to-systolic velocity
ratio. (From Kern MJ, Donohue TJ, Bach RG, et al: Quantitating coronar y
collateral flow velocity in patients during coronary angioplast y using a
Doppler guidewire. Am J Cardiol 71:34D– 40D, 1993.)
Balloon occlusion Hyperemia
Collateral
flow
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Research Techniques 395
in the vessel of interest. Collateral flow is measured by simultaneous measurement of mean aortic pressure (PAo; mm Hg), coronar y
occlusion pressure (Poccl; mm Hg), and central venous pressure
(CVP; mm Hg). Collateral flow is calculated as (Poccl–CVP)/
(PAo–CVP).
Translesional Hemodynamics
Although the hemodynamics of coronary flow can be assessed by
Doppler flow velocity as described earlier, there are instances in
which it is also important to examine translesional pressure at rest and
at hyperemia.
Fractional Flow Reserve
In clinical practice, the ischemic potential of a questionable or intermediate (40% to 70%) stenosis can be determined by FFR. FFR is
computed as the ratio of aortic pressure (from the guide catheter) to
poststenotic pressure measured from a pressure guidewire placed
beyond the stenosis at rest followed by hyperemia (adenosine IV infusion or IC bolus). The technique of FFR for clinical practice is described
in detail in Chapter 10.
For research into coronary hemodynamics, note that FFR can be
subdivided into three components describing the flow contributions
by the coronary artery, myocardium, and collateral supply. FFR of the
coronary artery (FFR
flow in the presence of a stenosis divided by the theoretic normal
maximum flow of the same artery (i.e., the maximum flow in that
artery if no stenosis were present). Similarly, FFR of the myocardium
(FFR
) is defined as maximum myocardial (artery and bed) flow
myo
distal to an epicardial stenosis divided by its value if no epicardial
stenosis were present. Stated another way, FFR represents that fraction
of normal maximum flow that remains despite the presence of an
epicardial lesion. Note that at maximal hyperemia, FFR
equal to FFR
myo
difference between FFR
The following equations are used to calculate the FFR of a coronary artery and its dependent myocardium:
where Pa, Pd, Pv, and Pw are pressures of the aorta, distal artery, venous
(or right atrial), and coronary wedge (during balloon occlusion) pressures, respectively. Because FFR
during coronary angioplasty. In most clinical circumstances, P
negligible relative to aortic pressure and is omitted from calculations.
P
may be included when right atrial pressure is >10 mm Hg and
v
may influence FFR ± 0.02 units in patients with elevated right atrial
pressure.
) is defined as the maximum coronary artery
cor
is about
cor
because myocardial bed resistance is minimal. The
and FFR
myo
FFR P P P P
= − −( )/( )
cor d w a w
FFR P P P P
= − −( )/( )
myo d v a v
FFR FFR FFR
collateral myo cor
is FFR of the collateral flow.
cor
= −
uses Pw, it can be calculated only
cor
v
is
Microcirculatory Resistance
The index of microvascular resistance (IMR) is defined as the ratio of
distal coronary pressure to the inverse of mean transit time during
maximal hyperemia. It is a quantitative index that is unique to the
microcirculation and independent of epicardial coronary artery
disease. IMR uses distal pressure and thermodilution flow obtained
from a single pressure wire (St. Jude Medical, St. Paul, MN), as assessed
by the inverse of the arrival (transit) time of a room-temperature saline
bolus to the distal coronary artery segment (Fig. 9-10). By measuring
the mean transit time at rest and comparing it with the mean transit
time at peak hyperemia, a thermodilution CFR can be calculated.
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Rest Hyperemia
Figure 9 -10 Simultaneous measurement of pressure and flow (by thermo-
dilution). Top, Proximal (Pa) and distal (Pd) pressures at rest (left) and during
hyperemia (right). Bottom, Thermodilution curves at rest and during hyperemia, with associated average transit times at baseline and hyperemia
circled. These values are used to calculate coronary flow reserve (CFR) and
the index of microcirculatory resistance (IMR) (right). FFR, Fractional flow
reserve. (From Martin KC, Yeung AC, Fearon WF: Invasive assessment of
the coronar y microcirculation. Circulation 113:2054–2061, 2006.)
Baseline
Pa
Pd
FFR
CFR
IMR
Although CFR has been studied in microvascular dysfunction, IMR
is superior to CFR, because it is not affected by resting hemodynamics, making it more reproducible, even after hemodynamic perturbations. When measured immediately after primary PCI for ST-segment
eleva tion myocardial infarction (STEMI), IMR predicts the amount of
myocardial damage and left ventricular (LV) recovery better than
other indices, such as CFR, ST-segment resolution, or Thrombolysis in
Myocardial Infarction (TIMI) Study Group myocardial perfusion grade,
and is an independent predictor of long-term clinical outcomes including death and rehospitalization for heart failure.
Another calculation of coronary hemodynamics, hyperemic
microvascular resistance (HMR), is defined as the ratio of mean distal
coronary pressure to flow velocity at hyperemia. When compared with
actual microvascular resistance, HMR is overestimated in the presence
of coronary stenosis, due to the absence of coronary collateral flow
input. HMR is reflective of an increase in actual myocardial resistance, identifying a pertinent pathophysiologic alteration in microvasculature. The status of coronary microcirculation plays a role in
determining susceptibility toward periprocedural myocardial infarction (MI) during elective PCI and may guide adjunctive preventive
therapies.
Nonhyperemic Indices
Use of an adenosine-free or adenosine-independent pressure-derived
index of coronary stenosis severity is a desirable feature among those
working in the cardiac catheterization lab. The assessment of stenosis
severity by FFR requires that coronary resistance is stable and minimal,
usually achieved by the administration of adenosine. Sen et al used
wave-intensity analysis to identify a period in the cardiac cycle during
which equilibration or balance between pressure waves moving
forward and reflecting back from the aorta and distal microcirculatory
ceased in a portion of diastole called the wave-free period. This wavefree period begins at 75% of diastole and ends immediately before
systole. The microvascular resistance in this period is fixed and potentially has the ability to differentiate mild from severe lesions hemodynamically. Like FFR, the ratio of proximal to distal coronary pressures
during the wave-free period, called the instantaneous wave-free ratio
(iFR), provides a measure of lesion significance (Fig. 9-11). In several
Systole Diastole
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Wave intensity
–2s–2
(W m
Separated
pressures
Resistance
(mm Hg/m
)
(mm Hg)
–2
Pressure
(mm Hg)
5
x10
4
A
2
0
–2
–4
–6
40
B
20
0
200
C
600
)
300
200
D
150
100
0 100 200 300 400 500 600 700
Time (ms)
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Research Techniques 397
1.0
Wave-
free
period
0.8
0.6
iFR
0.4
0.2
0
0 0.2 0.4 0.6 0.8 1.0
FFR
Figure 9-11 Wave-intensity analysis (A) demonstrates proximal and micro -
circulatory (distal) originating waves generated during the cardiac cycle. A
wave-free period can be seen in diastole when no new waves are generated
(left panel, shaded, most right). This corresponds to a time period in which
there is minimal microcirculator y (distal)- originating pressure (B), minimal
and constant resistance (C), and a nearly constant rate of change in flow
velocity (D). (Separated pressure above diastole is the residual pulsatile
separated pressure component after subtraction of diastolic pressure.) FFR,
Fractional flow reserve; iFR, instantaneous wave-free ratio. (Right panel,
comparison of FFR vs iFR) (Data from Davies JE, et al: Circulation 113:1767–
1778, 2006; Sen S, Escaned J, Malik IS, et al: Development and validation
of a new adenosine-independent index of stenosis severity from coronar y
wave- intensit y analysis: results of the ADVISE (ADenosine Vasodilator Inde pendent Stenosis Evaluation) study. J Am Coll Cardiol 59:1392–1402, 2012.)
studies (ADVISE, REVISE, and RESOLVE), the iFR and resting
distal coronary pressure (Pd)/aortic pressure (Pa) ratio have been
shown to correlate closely with FFR (r = 0.90) and thus may obviate
the need for hyperemic stimulus in selected patients. In the RESOLVE
study, which examined 1974 lesions, the optimal iFR to predict an FFR
<0.8 was 0.92, with accuracy of 80%. For the resting Pd/Pa ratio, the
cutpoint was 0.92, with an overall accuracy of 92% and no significant
differences between iFR and Pd/Pa. Both measures have 90% accuracy in predicting positive or negative FFR in 65% and 48% of lesions,
respectively (Fig. 9-12). These data suggest that resting indices of
lesion severity demonstrated an overall accuracy, with an FFR
of approximately 80%, which can be improved to 90% in a subset of
lesions. Clinical outcome studies, currently in progress, are required
to determine whether use of iFR or Pd/Pa might obviate the need for
hyperemia in selected patients.
Endothelial Function Assessment
The endothelium is the innermost lining of all blood vessels, composed of a single layer of endothelial cells that fulfill a number of
important functions for vascular biology. Normal endothelial function
is responsible for control of coronary blood flow through appropriate
signaling to the arterial vascular smooth muscle to dilate or constrict
and has a second function of regulating vascular thrombosis through
release of antithrombin and antiplatelet factors to deter inappropriate clot formation on the vessel walls. Dysfunction of the endothelium resulting in pathologic vasomotion and thrombus formation is
due to multiple etiologies, many of which also are implicated in the
pathogenesis of atherosclerosis. The presence of endothelial dysfunction has been associated with increased risk for cardiac events,
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1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
A
1.0
0.9
0.8
0.7
0.6
0.5
Pd/Pa iFR
0.4
0.3
0.2
0.1
0.0
B
Figure 9-12 Scatter plots show the relationship between instanta-
neous wave-free ratio (iFR) and fractional flow reserve (FFR) and distal
coronary pressure (Pd)/aortic pressure (Pa) ratio and FFR. Dashed lines,
Lines of best fit. A, Horizontal dashed line, Optimal iFR cutoff of 0.90 on the
basis of receiver-operating characteristic (ROC) analysis. B, Horizontal
dashed line, Optimal Pd/Pa cutof f of 0.92. R2 regression value. The wave -
free period was calculated using a fully automated algorithm. The iFR, calculated by dividing the mean Pd by Pa during the wave-free period under
basal conditions, was found to closely agree with the FFR (r = 0.9, p =
0.001). A and B, Right, dotted lines, Threshold cutoff values for the iFR and
FFR. R2, Ratio squared. (From Jeramias A, Maehara A, Genereux P, et al:
Multicenter core laboratory comparison of the Instantaneous wave-free ratio
and resting Pd/Pa with fractional flow reserve: the RESOLVE study. J Am
Coll Cardiol 63[13]:1253–1261, 2014.)
Research Techniques
2
R
FFR
FFR
R
= 0.66
2
= 0.69
iFR = 0.21 + 0.85 FFR
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Pd/Pa = 0.45 + 0.60 FFR
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
even in the presence of angiographically normal-appearing coronar y
arteries.
The assessment of status of endothelial function requires an infusion catheter containing the Doppler wire. This system is placed in
the artery using standard techniques (usually the proximal left anterior descending [LAD] artery). Following baseline measurements of
flow (i.e., velocity via the Doppler wire multiplied by area via the
quantitative measurement of the coronary diameter), graduated infusions of acetylcholine (10
the coronar y artery.
−6
M to 10−4 M) are administered directly into
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Baseline Postinfusion
Figure 9-13 Assessment of endothelial function with acetylcholine infu -
sion. Lef t, Baseline angiography of the left coronary arter y. Right, Severe
vasoconstriction of the lef t anterior descending (LAD) artery following infusion of 6 to 10 M acetylcholine.
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In patients with normal endothelial function, acetylcholine infusion causes endothelial-dependent production of nitric oxide and
results in vasodilatation (i.e., epicardial vasodilatation and/or increase
in Doppler flow velocity; Fig. 9-13). Conversely, in patients with
dysfunctional endothelia, coronary flow either fails to increase or
decreases because of vasoconstriction, which manifests either as
blunting of the rise or an actual fall in Doppler flow velocity. Changes
in the Doppler flow pattern can also be caused by vasoconstriction of
the epicardial vessel, which would be an equally abnormal (paradoxical) response. QCA is used to differentiate between epicardial and
microvascular endothelial dysfunction. Nitroglycerin is given at the
end of the procedure to reverse any constriction of the larger vessels.
It may not, however, reverse profound vasoconstriction of the distal
vasculature, which may require nitroprusside. Administering calcium
channel blockers (usually verapamil) can also be an alternative for
refractory vasoconstriction.
The most commonly used agent to determine endotheliumindependent vasorelaxation is adenosine, which is given before
administration of acetylcholine (alternatives include dipyridamole
and papaverine). In the past, additional agents to test endotheliumdependent vasorelaxation included bradykinin, substance P, and
calcium inophore.
Other techniques to study vasoreactivity involve complex neurovascular mechanisms, such as cold pressure and mental stress testing.
Atrial pacing and exercise can also be used to study the endotheliumdependent, flow-related response to increase in myocardial oxygen
demand. All of these studies can be combined with other tests (such
as blood sampling for metabolic parameters, multilead electrocardiograms, or [speckle tracking] echocardiograms) to assess, for instance,
the association among vasoreactivity, myocardial ischemia, and
symptoms.
As indicted earlier, with specific catheters, IMR can be calculated
as the distal coronary pressure divided by the inverse of the hyperemic
mean transit time measured simultaneously. This index was validated
in experimental models but limitations need to be entertained if this
technique is applied. For instance, any collateral blood flow has to be
incorporated into the calculations (by multiplying IMR by the ratio of
coronary FFR and myocardial FFR), because IMR will otherwise progressively increase with increasing degrees of epicardial coronary
artery stenoses (as seen with studies using Doppler-derived FFR).
For any of these functional studies, cessation of drugs and stimu-
cially for the validity of research protocols. Anxiety and sedation can
also have an effect, which needs to be taken into consideration.
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Invasive Coronary Imaging
for Research
Intravascular Ultrasound
High-frequency, two-dimensional (2D) IVUS imaging uses catheters
of ≤
2.9 F with either mechanically or electronically rotating 20- to
40-MHz echo crystals that produce cross-sectional images of the artery
(Fig. 9-14). (See Chapter 10 for additional information about IVUS.)
A
Base
3.9/24 cm/sec
B
Adenosine, 12 µg
3.9/64 cm/sec
NTG, 200 mg
4.1/56 cm/sec
C
Figure 9-14 Simultaneously obtained Doppler guidewire flow velocity
signals (A) and IVUS coronary lumen dimensions (B). B, Cross-sectional
artery images show a normal lumen with a diameter of 3.9 mm and minimal
changes to adenosine or nitroglycerin (NTG). C, Intravascular ultrasound
(IVUS) display screen in catheterization laboratory. APV, Average peak velocity; DPVi, diastolic peak velocity integral; LAD, left anterior descending
artery; MPV, maximal peak velocity; Ratio, coronary reserve ratio; VEL, velocity scale.
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Ultrasound catheters are introduced over guidewires in a monorail
fashion, followed by image acquisition during manual or automated
(0.5 to 1.0 mm/sec) pull back. In mildly diseased or normal arteries, a
characteristic three-layered image is usually observed. These images
are more accurate than those using angiography for characterizing the
amount of atherosclerosis as well as identifying other characteristics,
such as lipid pool and calcium. IVUS can also reveal remodeling patterns, in which there is either an increase or a decrease in vessel size
with atherosclerotic plaque growth. Indeed, the technique has revealed
important differences among patient groups, such as diabetics and
nondiabetics. For patients who have undergone or are planning to
undergo placement of IC stents, IVUS can be used to assess reference
vessel diameter and stent expansion. Nowadays, research studies
using this tool are investigating the in vivo characterization of atherosclerotic plaque, progression and regression of atherosclerosis,
responses to new pharmacologic agents, and results of percutaneous
interventional techniques.
Gray-scale IVUS can characterize the extent and distribution of
atherosclerotic plaques. However, the low echo frequency of tissue
representing the composition of lipid-containing and mixed plaque is
not well defined by gray-scale IVUS.
Using spectral analysis and Fourier transforms of the radiofrequency (RF), ultrasound backscatter signals produce images known
as virtual histology (VH), which permit tissue level assessment of
plaque composition. VH IVUS technology (Volcano Corporation,
Rancho Cordova, CA) has been shown to have an 80% to 92% in vitro
accuracy to identify the four different types of atherosclerotic plaques
(e.g., fibrous, fibrofatty, dense calcium, and necrotic core). Validation
of atherosclerotic coronary plaques by VH is based on mathematical
autoregressive spectral analysis of IVUS backscattered data. The presence of fibrous, fibrofatty, necrotic core, and dense calcium areas are
assessed within the histologic region of target plaque using RF data
collection scans. Fibrous areas are designated as green, fibrofatty as
yellow, dense calcium as white, and necrotic core as red. The predicted plaque composition is displayed as a color-coded tissue map.
IVUS signals, processed by discrete Fourier transforms, result in high
resolution of spectral estimates. Figure 9-15 shows VH images and the
corresponding histology of coronary atherosclerosis.
Optical Coherence Tomography
Optical coherence tomography (OCT) is a catheter-based imaging
system that uses near-infrared (NIR) light (wavelengths of 1250 to
Figure 9-15
(IVUS) for five atherosclerotic pathologies.
Images of virtual histology ( VH) by intravascular ultrasound
1. Fibrotic
2. Fibrocalcific
3. Pathological intimal thickening
4. Thick cap fibroatheroma
5. VH–thin cap fibroatheroma
(presumed to be high risk)
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