When Collateral Supply is Accounted For Epicardial
Stenosis Does Not Increase Microvascular Resistance
Jamie Layland, MBChB, MRCP (UK), FRACP; Andrew I. MacIsaac, MBBS, MD, FRACP;
Andrew T. Burns, MBBS, MD, FRACP; Jithendra B. Somaratne, MBChB, FRACP;
George Leitl, MBBS, FRACP; Robert J. Whitbourn, MBBS, BSc(Hons), FRACP;
Andrew M. Wilson, MBBS, PhD, FRACP
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Background—The relationship between epicardial stenosis and microvascular resistance remains controversial. Exploring
the relationship is critical, as many tools used in interventional cardiology imply minimal and constant resistance.
However, variable collateralization may impact well on these measures. We hypothesized that when collateral supply
was accounted for, microvascular resistance would be independent of epicardial stenosis.
Methods and Results—Forty patients with stable angina were studied before and following percutaneous intervention. A
temperature and pressure sensing guide wire was used to derive microvascular resistance using the index of
microcirculatory resistance (IMR), defined as the hyperemic distal pressure multiplied by the hyperemic mean transit
time. Lesion severity was assessed using fractional flow reserve. For comparison, evaluation of an angiographically
normal reference vessel from the same subject also was undertaken. Both simple IMR (sIMR) and IMR corrected for
collateral flow (cIMR) were calculated. When collateral supply was not accounted for, there was a significant difference
in IMR values between the culprit, the post PCI, and nonculprit values (culprit sIMR 26.68⫾2.06, nonculprit sIMR
18.37⫾1.89, P⫽0.002; post percutaneous intervention sIMR 18.5⫾1.94 versus culprit sIMR 26.68⫾2.06, P⬍0.0001).
However, when collateral supply was accounted for there was no difference observed (cIMR 16.96⫾1.78 versus nonculprit
sIMR 18.37⫾1.89, P⫽0.52; post percutaneous intervention sIMR 18.5⫾1.94 versus cIMR 16.96⫾1.78, P⫽0.42).
Conclusions—When collateral supply is accounted for, epicardial stenosis does not increase microvascular resistance in
patients with stable angina. (Circ Cardiovasc Interv. 2012;5:97-102.)
Key Words: microcirculation 䡲 epicardial stenosis 䡲 FFR 䡲 PCI
T
here is increasing interest in the importance of microcirculation in patients with ischemic heart disease. Novel
invasive techniques allow assessment of microcirculation at
the time of coronary angiography.1 Recently, the index of
microvascular resistance (IMR) has been described and validated as a tool to assess the coronary microcirculation.2 It
involves the use of a temperature and pressure sensing guide
wire (TPSG) that now is used routinely for the assessment of
fractional flow reserve (FFR), and can be used for the
assessment of microvascular resistance in patients with coronary artery disease using a validated algorithm.3
Whether an epicardial stenosis has an impact on microvascular resistance remains controversial. Recent studies examining the relationship using different methodologies and
techniques to assess microvascular resistance have produced
conflicting results.4,5 Severe coronary stenosis may lead to a
reduction in perfusion pressure, resulting in conformational
changes within the resistance arteriolar vessels to maintain
myocardial blood flow.6 The pressure dependence of the
distal arterioles is such that at very low perfusion pressures
they possess a capacity to collapse, a fact that may explain the
curvilinear pattern of the diastolic pressure flow relationship
at lower perfusion pressures.7 Evidence for this originates
from animal models, whereby a severe stenosis led to a
reduction in diameter of arterioles greater than 100 ␮m.8 This
may account for the observed increase in microvascular
resistance produced by an epicardial stenosis.
However, other investigators have shown that even in the
presence of epicardial vessel occlusion, microvessels remain
open with continued antegrade flow, possibly a result of
collateral flow.9 It also has been demonstrated that collateral
flow results in a shift of the pressure intercept of the pressure
flow relationship above venous pressure, but only at lower
perfusion pressures (⬍40 mm Hg).10 This would have the
effect of maintaining antegrade flow at lower perfusion
pressures. Thus collateral flow could minimize the impact of
an epicardial stenosis on microvascular resistance by maintaining the patency of the resistance vessels.
Received March 23, 2011; accepted November 15, 2011.
From the Department of Cardiology, St Vincent’s Hospital, Fitzroy, Victoria, Melbourne, Australia (J.L., A.I.M., A.T.B., J.B.S., G.L., R.J.W.,
A.M.W.); University of Melbourne, Department of Medicine, St Vincent’s Hospital, Melbourne, Australia (J.L., A.I.M., A.T.B., R.J.W., A.M.W.).
Correspondence to Dr Jamie Layland, Department of Cardiology, St Vincent’s Hospital, Fitzroy, Victoria, Melbourne, Australia. E-mail
[email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org
97
DOI: 10.1161/CIRCINTERVENTIONS.111.964718
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Circ Cardiovasc Interv
February 2012
Knowing the effect of a stenosis on microvascular resistance is critical, as many techniques used in interventional
cardiology assume minimal and constant resistance.7,11 Also
of interest is whether microvascular resistance is homogenously distributed across coronary beds within the same
patient.12 We hypothesized that microvascular resistance
would be independent of epicardial stenosis, and that collateral supply would reduce the downstream impact an epicardial stenosis has on the microvasculature.
WHAT IS KNOWN
●
The relationship between epicardial stenosis and
microvascular resistance remains uncertain.
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WHAT THE STUDY ADDS
●
●
When compared with an angiographically normal
control vessel, epicardial stenosis does not increase
microvascular resistance.
Collateral supply reduces the impact of an epicardial
stenosis on microvascular resistance.
IMR Calculation
IMR was calculated in 2 ways, with and without the incorporation of
coronary wedge pressure. Simplified IMR (sIMR) was defined as:2
sIMR⫽PdHyp⫻TmnHyp
where Pd is the hyperemic distal pressure and Tmn is the hyperemic
mean transit time. In order to account for the effect of microvascular
collateral supply on microvascular resistance, a modified equation
was used, herewith referred to as the corrected IMR (cIMR):4
cIMR⫽Pa⫻Hyperemic Tmn (Pd⫺Pw)/(Pa⫺Pw)
where Pa was the mean hyperemic aortic pressure and Pw the
coronary wedge pressure, defined as the distal coronary pressure
obtained during a 30 second balloon occlusion of the culprit vessel
and representing recruitable collateral vessels.15 Both simplified and
corrected IMR were measured in the target vessel before and
following PCI. Only sIMR was calculated in the nonculprit artery.
Coronary flow reserve (CFR) was defined as the mean resting
transit time divided by the mean hyperemic transit time. FFR was
defined as the mean distal coronary pressure divided by the mean
aortic pressure during hyperemia. Care was taken to ensure that the
distal sensor was in the same position between measurements to
avoid errors in transit time acquisition.
As a reference, the procedure was repeated in a major epicardial
nonculprit vessel free of epicardial stenosis. Only simplified IMR,
CFR, and FFR were calculated in the nonculprit vessel.
Study Protocol
Methods
Patient Selection
The study population consisted of patients undergoing elective
percutaneous coronary intervention for stable angina, with single
vessel disease angiographically and a positive noninvasive functional test. Patients were excluded if they had a recent myocardial
infarction (within 7 days) or any history of myocardial infarction in
the culprit/nonculprit territory, severe renal impairment (estimated
glomerular filtration rate ⬍30 mls/min), left ventricular hypertrophy
on ECG, acute inflammatory illness, significant peri-procedural
myocardial injury, defined as a troponin I level ⬎12⫻99th percentile
(Troponin I 0.8 ␮g/L)13 or creatine phosphokinase myocardial band
3 times the 99th percentile, chronic atrial fibrillation, left ventricular
dysfunction (ejection fraction ⱕ35%), previous coronary artery
bypass surgery, significant valvular heart disease, or if the lesion
involved a major side branch (⬎2.0 mm). The Human Research
Ethics Committee at St Vincent’s Hospital Melbourne approved the
study protocol.
For the procedure, all patients received an initial bolus of 5000 U
of intravenous heparin, with additional bolus dosing to maintain an
activated clotting time of 250 seconds, and were receiving aspirin
and clopidogrel. A 6F coronary guiding catheter was used to engage
the selected coronary artery. A 5F sheath was placed within the right
femoral vein for measurement of right atrial pressure and drug
delivery. All patients received 200 micrograms of intracoronary
nitroglycerin in each study artery. A 0.014 coronary TPSG was
calibrated, and then equalized to the guiding catheter pressure, with
the distal sensor placed at the ostium of the coronary artery. The wire
then was passed beyond the stenosis into the distal third of the vessel.
Microvascular resistance was measured using the IMR, as previously described2 in both the culprit vessel and the nonculprit vessel.
Three milliliters of room temperature saline were injected intracoronary to produce 3 reproducible and consistent thermodilution curves.
The average of the 3 values was taken as the mean baseline transit
time (TmnBase), which has been shown to be inversely proportional
to coronary blood flow.14 Intravenous adenosine then was administered via the right femoral vein (140 ␮g/kg/min) to achieve maximal
hyperemia. Once more, 3 mL of room temperature saline was
injected into the study artery to achieve 3 consistent thermodilution
curves and to derive the hyperemic transit time (TmnHyp).
IMR, CFR, and FFR were measured in an angiographically normal
reference vessel and then in the culprit artery at baseline. Stenting of
the culprit vessel then was performed and physiological measures
were repeated. The decision to intervene was at the operators’
discretion.
Statistical Analysis
Statistical analysis was performed using a SPSS (SPSS Inc.) statistical software package. Normality of data were assessed with the
Kolmogorov-Smironov statistic. Continuous variables are summarized as mean⫾SEM. Physiological values obtained in the nonculprit
vessel were compared with the culprit vessel pre PCI and post PCI
using paired T tests. P⬍0.05 was considered statistically significant.
Strength of relationships was assessed using the Pearson correlation
coefficient.
Based on previous human data that demonstrated an absolute
difference of 14 U of IMR in patients with significant epicardial
stenosis if collateral flow was not accounted for,4 we hypothesized a
mean difference of 14 U of IMR in vessels with and without
correction for collateral flow. With an alpha error of 0.05 and a
power of 90%, and a standard deviation of 14, we estimated that a
minimal sample size of 23 subjects would be required to demonstrate
the true effect of epicardial stenosis on microvascular resistance.
With 40 patients in the study population we anticipated that a type II
error would be less likely.
Results
One hundred forty-nine patients were potentially eligible for
inclusion in the study. However, a significant number of
patients were excluded following either coronary angiography or PCI. Figure 1 provides information on the reasons for
patient exclusion. The total study population consisted of 40
patients with stable angina. Patient demographic and procedural data are shown in Tables 1 and 2. Physiological data are
shown in Table 3, and the distribution of IMR across
territories with and without correction for collateral supply is
shown in Figure 2. FFR and CFR were lower in the culprit
artery compared with the nonculprit values (FFR culprit
0.65⫾0.03 versus FFR nonculprit 0.93⫾0.05, P⬍0.0001,
Layland et al
Epicardial Stenosis and Microvascular Resistance
99
Table 1. Baseline Patient Characteristics
Patient Characteristic
Gender
Age (y)
Symptom duration (days)
Culprit vessel
Variable
Male/female 27/13
61.2⫾1.8
38 (Q1, Q3/6, 367)
LAD 17 (42.5),
LCx 14 (35),
RCA 9 (22.5)
Nonculprit vessel
LAD 17 (42.5),
LCx 16 (40),
RCA 7 (17.5)
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HMG co-enzyme A inhibitor
33 (82.5)
ACE inhibitor
17 (43.6)
Beta blocker
28 (71.8)
Smoker
21 (51.2)
Diabetes
14 (34.1)
Hypertension
30 (73.2)
Hypercholesterolemia
28 (68.3)
LV ejection fraction (%)
Figure 1. Study sample and reasons for patient exclusion if
eligible.
CFR culprit 1.97⫾0.18 versus CFR nonculprit 2.81⫾0.18,
P⫽0.01). There was a significant difference in sIMR values
between the culprit territory and nonculprit vessels (culprit
sIMR 26.68⫾2.06, nonculprit sIMR 18.37⫾1.89, P⫽0.002).
However, when collateral supply was accounted for by
correcting for coronary wedge pressure, there was no difference between the nonculprit microvascular resistance and
culprit microvascular resistance (cIMR 16.96⫾1.78 versus
nonculprit sIMR 18.37⫾1.89, P⫽0.52).
Mean TmnHyp was increased (coronary blood flow was
reduced) in the culprit territory compared with the nonculprit
vessel (TmnHyp culprit 0.57⫾0.06 versus TmnHyp nonculprit
0.24⫾0.02, P⬍0.001), and also when compared with mean
post PCI values (TmnHyp post PCI 0.25⫾0.02, P⬍0.001).
Furthermore, baseline and hyperemic transit time were inversely correlated with FFR (r⫽⫺0.44, P⫽0.004, r⫽⫺0.73,
P⬍0.0001, respectively; Figures 3 and 4, respectively). However, lesion severity as assessed by quantitative coronary
angiography did not correlate with baseline transit time, yet
there was a significant relationship between stenosis severity
and hyperemic transit time (r⫽0.56, P⫽0.01). There also was
a significant negative correlation between FFR in the culprit
territory and coronary wedge pressure (r⫽⫺0.44, P⫽0.005;
Figure 5), and a positive correlation between TmnHyp in the
culprit vessel and the coronary wedge pressure (r⫽0.46,
P⫽0.003).
Changes in Coronary Physiology Following PCI
FFR and CFR were higher following PCI when compared
with pre PCI values (FFR pre PCI 0.65⫾0.03 versus FFR
63⫾2.1
Continuous variables expressed as mean⫾SEM. Discrete variables expressed as number and percentage in brackets. Non-normally distributed
variables expressed as median plus QI, Q3.
Drug treatment mentioned refers to percentage of patients on specific
medication at the time of the procedure.
LAD indicates left anterior descending artery; LCx, left circumflex artery;
RCA, right coronary artery; HMG, HMG : 3-hydroxy-3-methylglutaryl-coenzyme
A; ACE, angiotensin converting enzyme; LV, left ventricle.
post PCI 0.92⫾0.01, P⬍0.0001; pre PCI CFR 1.97⫾0.18
versus post PCI CFR 2.41⫾0.17, P⫽0.007).
Microvascular resistance decreased following PCI (culprit
sIMR 26.68⫾2.06 versus post PCI sIMR 18.51⫾1.94,
P⬍0.0001). However, when collateral supply was accounted
for using the corrected IMR equation, no effect of PCI on
microvascular resistance was observed (culprit cIMR
16.96⫾1.78 versus post PCI sIMR 18.51⫾1.94, P⫽0.424).
There was a similar relationship observed with post PCI
cIMR (culprit cIMR 16.96⫾1.78 versus post PCI cIMR
17.06⫾1.88, P⫽0.91).
There also was no difference between post PCI IMR and
the nonculprit IMR (nonculprit sIMR 18.37⫾1.89 versus
Table 2. Angiographic Data
Procedural Data
AHA lesion class
DES/BMS
QCA pre PCI (%)
QCA post PCI (%)
Value
A (25), B (75), C (0)
35/5 (87.5/12.5)
72.13⫾2.7
6.4⫾1.3
Stent size (diameter mm)
3.01⫾0.07
Maximum pressure (atm)
18.2⫾0.58
No. of inflations
4.5⫾0.35
Continuous variables expressed as mean⫾SEM. Discrete variables expressed as No. and percentage in brackets.
AHA indicates American Heart Association; DES, drug eluting stent; BMS
bare metal stent; QCA, quantitative coronary angiography; atm, atmospheres.
American Heart Association lesion class A (low risk, ⬎85% success rate), B
(moderate risk, 60% to 85% success rate).
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Circ Cardiovasc Interv
February 2012
Table 3. Coronary Physiology Pre- and Post-PCI
Culprit
Pre PCI
Nonculprit
Culprit
Post PCI
FFR
0.93⫾0.05
0.65⫾0.03*
0.92⫾0.01†
CFR
2.81⫾0.18
1.97⫾0.18*
2.41⫾0.17†
sIMR
18.37⫾1.89
26.68⫾2.06*
18.51⫾1.94†
‡
16.96⫾1.78
17.06⫾1.88
cIMR
TmnBase
0.64⫾0.07
0.92⫾0.09*
0.57⫾0.06†
TmnHyp
0.24⫾0.02
0.57⫾0.36*
0.25⫾0.03†
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Values displayed as mean⫾SEM.
FFR indicates fractional flow reserve; CFR, coronary flow reserve; sIMR,
simplified index of microcirculatory resistance; cIMR, corrected index of
microcirculatory resistance, TmnBase, mean baseline transit time; TmnHyp,
hyperemic mean transit time.
*Significant (P⬍0.05) difference between pre PCI and nonculprit values.
†Significant (P⬍0.05) difference between pre and post PCI values.
‡Value not calculated (see text for explanation).
18.51⫾1.94, P⫽0.95). Coronary blood flow indices improved following PCI (pre PCI Culprit TmnBase 0.92⫾0.09
versus post PCI TmnBase 0.57⫾0.06, P⬍0.0001; pre PCI
Tmn Hyp culprit 0.57⫾0.06 versus post PCI Tmn Hyp
0.25⫾0.03, P⬍0.0001), but there was no difference between
indices of coronary blood flow between post PCI values in
the culprit vessel and the nonculprit territory (nonculprit
TmnBase 0.64⫾0.07 versus post PCI TmnBase 0.57⫾0.06,
P⫽0.32; nonculprit TmnHyp 0.24⫾0.02 versus post PCI
TmnHyp 0.25⫾0.03, P⫽0.7).
Discussion
Our results suggest that, when the effect of microvascular
collaterals is accounted for, epicardial stenosis does not affect
microvascular resistance.
The effect of collateral circulation pre PCI is accounted
for by using the corrected IMR equation that incorporates
coronary wedge pressure. In accordance with prior studies,
Figure 2. Index of microcirculatory resistance across the culprit
and nonculprit territories and values following PCI. Correction
for collateral supply pre and following PCI. *P⫽0.005,
**P⬍0.001. IMR indicates index of microcirculatory resistance;
PCI, percutaneous intervention.
Figure 3. Baseline (non hyperemic) blood flow reduced as fractional flow reserve reduced. FFR indicates fractional flow
reserve; TmnBase, mean baseline transit time.
improvements in antegrade flow following PCI meant that
the contribution of microvascular collaterals was assumed
to be negligible, and thus correction for collaterals was not
performed.16 However, for completeness of data we have
provided the corrected IMR as well as the simplified IMR
post PCI.
Secondly, as stenosis severity increased, both resting and
hyperemic blood flow was reduced. However, there was an
increasing contribution of collaterals, evident from an increase in coronary wedge pressure, suggesting a possible
compensatory mechanism to maintain myocardial blood flow
and maintain patency of the microvessels.
The concept of increasing stenosis severity leading to
increased microvascular resistance is controversial.4,5 Some
have shown that as the severity of epicardial stenosis increases, microvascular resistance increases.17,18 Using combined Doppler and pressure derived measures, Chamuleau et
al18 demonstrated that minimal microvascular resistance increased distal to a significant epicardial stenosis when compared with a normal vessel without stenosis in the same
Figure 4. Hyperemic blood flow reduced as fractional flow
reserve reduced. FFR indicates fractional flow reserve; TmnHyp,
hyperemic mean transit time.
Layland et al
Figure 5. Increasing coronary wedge pressure with increasing
severity of stenosis. FFR indicates fractional flow reserve.
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patient. Verhoeff5 and colleagues drew similar conclusions,
showing that microvascular resistance increased secondary to
a coronary stenosis in 23 patients with stable angina. Furthermore, following PCI, resistance fell below the level of an
angiographically normal reference vessel also studied. However, despite the measurement of collateral flow, this was not
incorporated into the calculation of microvascular resistance,
and therefore this may have been overestimated in patients
with significant epicardial stenoses. Thus, by using a TPSG
for IMR analysis and incorporating the effect of collaterals
into the calculation of microvascular resistance, we have
expanded significantly on these findings.
Prior animal models using IMR as a technique to investigate the impact of a stenosis on minimal achievable resistance
demonstrated that there was no increase in microvascular
resistance secondary to an epicardial stenosis.19 However,
previous IMR studies in humans have measured microcirculatory resistance using balloon inflation within a stent to
mimic a stenosis post PCI rather than actual de novo
stenoses.4 Furthermore, the impact of peri-procedural infarction on IMR has not been documented well, and the incidence
of cardiac biomarker elevation was not reported in previous
IMR studies. Significant myonecrosis is likely to confound
evaluation of microvascular resistance by increasing distal
pressure and limiting capillary recruitment. Although not
statistically significant, Cuisset et al16 demonstrated a higher
IMR following PCI, which was associated with higher
troponin levels. In our population, significant myonecrosis
was incorporated into our exclusion criteria to minimize its
confounding effect. Thus, we were able to use the post PCI
IMR value reliably as a point of reference. Our findings may,
therefore, be more representative of coronary physiology than
artificially induced stenoses post PCI. We also have extended
this concept to incorporate assessment of a nonculprit, angiographically normal vessel as a further point of reference.
In our population, there was no significant difference
between microvascular resistance pre PCI compared with
post PCI values. There also was no difference between the
nonculprit and the post PCI microvascular resistance values
when we accounted for the effect of collaterals. This suggests
that microvascular resistance is not related to epicardial
stenosis severity because there is no difference between the
culprit and the nonculprit, or the culprit and post PCI values.
Epicardial Stenosis and Microvascular Resistance
101
Prior animal studies have demonstrated that resting coronary blood flow only begins to reduce once a coronary
stenosis reaches 85%.20 In contrast, hyperemic blood flow
reduced when an epicardial stenosis was greater than 50%. In
a group of 35 humans with single vessel coronary artery
disease using positron emission tomography, Uren and colleagues21 suggested that epicardial stenosis had no influence
on resting coronary blood flow, but hyperemic blood flow
began to reduce once a stenosis reached 40%. The conflicting
results can be explained by the inherent differences between
animals and humans, but also by the fact that the stenoses
included in the human study were less severe. A further point
is that collateral flow was not accounted for in the animal
study, so that true myocardial flow may have been underestimated. Our results are in accordance with previous human
studies suggesting that basal flow is not significantly influenced by epicardial stenosis severity as assessed angiographically, but hyperemic blood flow progressively reduces as the
stenosis severity increases. However, we did find a significant negative correlation between FFR and basal coronary
blood flow suggesting that, contrary to our angiographic
estimation of severity, FFR estimation was a better predictor
for the hemodynamic consequence of a stenosis compared
with angiographic assessment. Stenosis is only 1 determinant
of the hemodynamic significance of a lesion,22 and the poor
correlation between angiographic severity and FFR has been
confirmed with recent clinical trials.3,23
When using the nonculprit vessel as a control, we assume
homogeneity of microvascular resistance within the myocardium, an assumption that has underpinned other studies.5,12,18
Our results suggest that microvascular resistance is homogenously distributed between different vascular territories
within the same patient. However, as we are measuring
thermodilution derived blood flow rather than absolute myocardial blood flow in the calculation of microvascular resistance, we cannot be certain of this relationship. Furthermore,
not all epicardial vessels were assessed in each patient.
Limitations
The complexity of our study was such that only a small
number of patients were studied. However, it is one of the
largest cohorts of patients studied in this field, with sufficient
power to explore the underlying hypotheses. A small proportion of our patients had a postprocedural troponin elevation,
and this may have had an effect on the distal pressure and
thus, IMR. Troponin elevation following PCI is common,
with studies showing an incidence of up to 30% in elective
PCI.24 However, we excluded any patient with a troponin rise
greater than 12 times the upper limit of normal, as elevations
above this level have been shown to correlate with areas of
infarction on cardiac magnetic resonance imaging.13 In fact,
no patient had a troponin level greater than 5 times the upper
limit of normal. Lower troponin levels are not associated with
myocardial injury on magnetic resonance imaging, and thus
their effect on IMR is likely to be minimal.
As the decision to perform PCI was at the discretion of the
operators, some patients with an FFR ⬎0.8 underwent intervention. This may have tended to underestimate the impact
that an epicardial stenosis has on microvascular resistance in
102
Circ Cardiovasc Interv
February 2012
the overall cohort. However, by including such patients, a
broader range of actual stenoses was assessed so that more
informed conclusions about the effects of epicardial stenosis
on microvascular resistance could be made.
Adjustment for multiple comparisons was not undertaken,
however, and where statistically significant, the differences in
measurements were substantial, making a Type I error
unlikely.
Conclusion
In conclusion, when collateral flow is accounted for we have
shown that epicardial stenosis does not increase microvascular resistance.
Disclosures
None.
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When Collateral Supply is Accounted For Epicardial Stenosis Does Not Increase
Microvascular Resistance
Jamie Layland, Andrew I. MacIsaac, Andrew T. Burns, Jithendra B. Somaratne, George Leitl,
Robert J. Whitbourn and Andrew M. Wilson
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Circ Cardiovasc Interv. 2012;5:97-102; originally published online February 7, 2012;
doi: 10.1161/CIRCINTERVENTIONS.111.964718
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