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(Circulation. 2000;102:2411.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Minimally Invasive Evaluation of Coronary Microvascular Function by Electron Beam Computed Tomography
i
, MD, PhDFrom the Departments of Physiology and Biophysics (S.M., E.L.R.), and Internal Medicine, Divisions of Hypertension (L.O.L.) and Cardiovascular Diseases (A.L., T.R.B.), Anesthesiology (Z.S.K.), and Diagnostic Radiology (P.F.S.), Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Erik L. Ritman, MD, PhD, Department of Physiology and Biophysics, Alfred 2-409, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905. E-mail elran{at}mayo.edu
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Abstract |
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Background—We previously demonstrated that in vivo electron-beam computed tomography (EBCT)–based indicator-dilution methods provide an estimate of intramyocardial blood volume (BV) and perfusion (F), which relate as BV=aF+b
F, where a characterizes the recruitable (exchange) and b the
nonrecruitable (conduit) component of the myocardial microcirculation.
In the present study, we compared BV and F with
intracoronary Doppler ultrasound–based coronary
blood flow (CBF) as a method for detecting and quantifying differential
responses of these microvascular components to vasoactive drugs in
normal (control) and hypercholesterolemic (HC)
pigs. Methods and Results—BV and F values were obtained from contrast-enhanced EBCT studies in 14 HC and 14 control pigs. BV, F, and CBF values were obtained at baseline (intracoronary infusion of saline) and after 5 minutes each of intracoronary infusion of adenosine (100 µg · kg-1 · min-1) and nitroglycerin (40 µg/min). BV and CBF reserves in response to adenosine were attenuated in HC pigs compared with controls (90±36% versus 127±42%, P<0.03, and 485±182% versus 688±160%, P<0.01, respectively). The relationship between BV and F showed consistently lower recruitable BV in HC versus control pigs. Nonrecruitable BV reserve in response to adenosine was attenuated in HC compared with controls (77±20% versus 135±28%, P<0.001). Our findings are consistent with HC-induced impairment of intramyocardial resistance vessel function.
Conclusions—EBCT technology allows minimally invasive evaluation of intramyocardial microcirculatory function and permits assessment of microvascular BV distribution in different functional components. This method may be of value in evaluating the coronary microcirculation in pathophysiological states such as hypercholesterolemia.
Key Words: myocardium • microcirculation • blood volume • ultrasonics • hypercholesterolemia
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The intramyocardial microvasculature plays a major role in regulating myocardial perfusion and flow reserve. Differential responses of different-size microvessels may be of significance in this regulatory process.1 Advances in the ability to assess the coronary microcirculation in the past decade have led to a better understanding of the involvement of intramyocardial microvascular dysfunction in early stages of coronary artery disease.1 2 3 However, whether particular pathophysiological situations involve selective impairment of specific microvascular components remains to be established.
Quantification of vasodilator reserve with intracoronary Doppler ultrasound is a clinically accepted method to evaluate coronary microvascular function.4 However, measuring coronary blood flow (CBF) in a fairly proximal segment of the coronary artery provides only an index for the integrated physiological response of all vessels downstream of that segment, with limited ability to distinguish functionally distinct microvascular components.
Electron-beam computed tomography (EBCT)–based indicator dilution techniques have been shown to provide minimally invasive quantitative indices of the functional status of the coronary microcirculation.5 6 However, the ability of EBCT methods to discern functional alterations in intramyocardial microcirculatory functional components, ie, exchange vessels and larger intramyocardial conduit vessels, during a chronic pathophysiological condition that targets the coronary microvasculature, has not been evaluated.
Therefore, the 2 aims of this study were to (1) use the discriminatory power of intracoronary Doppler ultrasound studies as the basis for evaluating the feasibility of EBCT to describe normal and altered microcirculatory function and (2) evaluate the degree to which EBCT technology can detect, discriminate, and quantify blood volume (BV) in different components of the porcine coronary microcirculation in normal and hypercholesterolemic (HC) pigs.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Preparation
The study was reviewed and approved by the Mayo Foundation’s Institutional Animal Care and Use Committee in accordance with the National Institutes of Health guidelines. All animals were male domestic crossbred pigs. The 14 control group pigs (59±4 kg) were fed a standard pig chow, and the 14 HC group animals (56±5 kg) were fed a standardized high-cholesterol diet (2% cholesterol, 15% lard, Harlan Teklad), both over a period of 10 to 12 weeks before the study. Anesthesia was initiated with ketamine 12.5 mg/kg IM and xylazine 2 mg/kg IM and maintained by a titrated infusion of 100 mg ketamine IV in 500 mL normal saline. All animals were intubated, ventilated, and placed supine in a cast for the duration of both EBCT and Doppler studies. A bipolar pacing catheter and a pigtail catheter were inserted via the jugular veins into the coronary sinus and the superior vena cava, respectively, to permit injection of contrast agent and atrial pacing if needed. After injection of 10 000 U heparin IV (followed by infusion of 1000 U heparin/h IV), a left coronary guide catheter was placed in the left main coronary artery through the external carotid artery for coronary angiography and monitoring proximal coronary artery pressure. A 2.2F dual-lumen infusion catheter was placed in the proximal left anterior descending coronary artery (LAD) to selectively infuse drugs and for Doppler ultrasound studies.
Electron Beam Computed Tomography
All animals were positioned in the scanner with the heart
centered in the imaging field. The field of view was 26 or 30 cm (pixel
size 0.52 to 0.69 mm2, voxel size 3.64 to
4.83 mm3, 7-mm slice thickness, acquisition
time 50 ms). Short-axis images were obtained at a mid left
ventricular level at 80% of the RR interval. Initially,
contrast agent was injected selectively into the LAD (5 mL over 1.3
seconds) to highlight the cross-sectional LAD perfusion territories
(Figure 1
), which were of similar sizes
in HC and control pigs (435±65 versus 417±118
mm2, respectively, P>0.1). The volume
of myocardium encompassed by these regions of interest
averaged 
3000 mm3. The initial scan
sequence was followed by a series of flow studies, each performed with
a rapid bolus injection of the contrast agent iopamidol (0.33 mL/kg
over 2 seconds) into the superior vena cava. The same region of
interest as in the initial scan sequence was used for all these
consecutive scanning sequences, which were each followed by 20-minute
recovery and washout periods with intracoronary injection of
saline (infusion rate 1 mL/min). Each sequence included 40 scans
obtained every 1 to 2 heartbeats. Hemodynamic data were
recorded just before each EBCT study. The first image in each
sequence was obtained before injection of contrast agent to obtain
background image intensity. The first scanning sequence was a baseline
study (selective intracoronary infusion of normal saline at 1
mL/min), followed by scanning sequences after 5 minutes of
intracoronary infusion of adenosine (100 µg ·
kg-1 ·
min-1) and then after 5
minutes of intracoronary infusion of
nitroglycerin (NTG, 40 µg/min). Image data were
evaluated with the Analyze software package (Biomedical Imaging
Resource) to obtain indices of intramyocardial perfusion (F [mL
· g-1 ·
min-1]) and
intramyocardial BV (mL/g) as previously
described.6
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Calculation of Intramyocardial Microvascular BV in Functional
Components
We modeled the intramyocardial microcirculation as 2 sets of
vessels arranged in series as previously described.5 6 In
brief, 1 set consists of functionally nonrecruitable conducting
vessels, which are assumed to be always patent but can change their
diameter in response to various stimuli. Vascular resistance in these
vessels is assumed to follow Poiseuille’s law, which relates flow to
the fourth power of the vessel radius, ie, the square of the cross
sectional area (CSA), and thus F
CSA.2 Because the
length of these vessels does not change much relative to the change in
CSA, the intraluminal BV of these nonrecruitable vessels
(BVnr) should be proportional to CSA. Hence, it
should follow that FBVnr2, or
BVnrF. The other microvascular component
consists of functionally recruitable vessels (presumably mostly
capillaries, small arterioles, and venules), which are assumed not to
change appreciably in diameter but in the number of vessels perfused.
Because the BV within recruitable vessels (BVr)
should be proportional to the number of recruited vessels, it should
follow that FBVr. Because the 2 sets of
vessels are arranged in series, the relationship
BV=BVr+BVnr=aF+bF should
hold, where a and b are coefficients to be established
experimentally.
Intracoronary Doppler Ultrasound and Coronary
Angiography
Average peak velocities (cm/s) and selective coronary
artery diameters were measured to calculate CBF (mL/min) as previously
described.7 8 As in the EBCT study, 100 µg ·
kg-1 ·
min-1 of adenosine
and 40 µg/min of NTG were infused into the LAD continuously over 5
minutes before Doppler and hemodynamic measurements
were recorded.
Statistical Analysis
The values for each group are reported as mean±SD. Paired and
unpaired Student’s t tests were used to evaluate the
significance of differences between the reported variables. An
ANCOVA model was used to evaluate differences in BV between HC and
control pigs after adjustment for changes in
perfusion.9 Initially, we assessed whether the slopes
of the lines summarizing the group-specific relationship between BV and
perfusion were significantly different between the groups. When this
was not the case, we fit a model under the assumption of equal slopes
and tested for differences between groups. Differences were considered
significant at a value of P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cholesterol Levels and Hemodynamic Parameters
Serum cholesterol levels were 326±99 mg/dL in HC pigs versus 82±15 mg/dL in control pigs (P<0.0001). In the Doppler ultrasound study, heart rates of control pigs increased in response to adenosine (from 59±17 to 63±17 bpm, P<0.05) and NTG (to 66±15 bpm, P<0.05). Mean blood pressure decreased in response to adenosine (from 108±15 to 103±17 mm Hg, P<0.05) and NTG (to 104±12 mm Hg, P=NS). Mean blood pressure during NTG administration in the Doppler study was significantly lower in HC versus control pigs, with no difference between groups in changes from baseline values (-5.9±13% versus -2.6±4%, P=NS, for HC and control pigs, respectively). All other parameters were indistinguishable between HC and control pigs and between EBCT and Doppler studies.
Doppler CBF
Baseline CBF was similar in HC and control pigs (23.2±8.1 versus
27.1±13.0 mL/min, P=NS). CBF increased significantly in
both groups in response to adenosine, but the increase was
attenuated in HC animals (Figure 2A). CBF
also increased significantly in both groups (P<0.05) in
response to NTG, by 33±38% versus 38±28%, respectively, with no
differences between groups.
|
P<0.05 vs BL).
EBCT-Based Intramyocardial Perfusion
F was similar in HC and control animals at baseline (0.91±0.2 and
0.79±0.1 mL ·
g-1 ·
min-1, P=NS). F
increased significantly in both groups in response to
adenosine, by 200±70% in HC pigs (P<0.001) and by
262±99% in control pigs (P<0.001). The increase in F in
response to adenosine tended to be lower in HC than in control
pigs (P=0.086). F increased in both groups in response to
NTG, by 10±29% and 16±17%, respectively (P=NS for the
difference between groups), which reached statistical significance only
in the control group (P<0.05).
CBF Versus Myocardial Perfusion
We compared Doppler-based CBF with EBCT measurements of F for
all animals at baseline and after administration of drugs and found a
good linear correlation between these 2 variables (Figure 3).
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EBCT-Based Intramyocardial BV
Total intramyocardial BV was similar between control and HC pigs
at baseline (0.13±0.02 versus 0.14±0.02 mL/g, P=NS). BV
increased significantly in both groups in response to
adenosine, but the increase was blunted in HC pigs (Figure 2B
). Total BV increased in response to NTG by 0.002±0.02 mL/g
in HC pigs (P=NS) and by 0.01±0.03 mL/g in the control
group (P=NS), with no difference between the groups.
Myocardial BV in Relation to Myocardial Perfusion
Figure 4 shows the BV-to-F
relationship for baseline and adenosine values in control and
HC pigs. In both groups, experimental data were fitted with the
function BV=aF+bF. The figure demonstrates an attenuated increase in
BV per increase in F in HC pigs during adenosine
administration. ANCOVA confirmed that during adenosine
infusion, HC pigs reached a significantly lower BV (by 0.02 mL/g) than
control pigs after control for perfusion (P<0.05). In
response to NTG, there was no difference between groups in changes in
BV per change in perfusion.
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BV in the Recruitable Component of the Microvasculature
In the recruitable component (Figure 5), BVr at baseline
was lower in HC than in control pigs (0.018±0.004 versus 0.039±0.005
mL/g, P<0.0001). In response to adenosine, these
values increased in both groups (P<0.001, Figure 5)
by a similar amount (0.030±0.018 mL/g in HC and 0.031±0.011 mL/g in
control pigs, P=NS for differences between groups). Relative
to baseline, these changes were higher in HC than in control pigs
(179±67% versus 80±50%, P<0.001). After NTG,
BVr increased in HC pigs by 9±28%
(P=NS) and in control pigs by 16±17% (P<0.02),
with no differences between groups.
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BV in the Nonrecruitable Component of the Microvasculature
In the nonrecruitable component (Figure 6), BVnr at
baseline was higher in HC than in control pigs (0.119±0.013 versus
0.090±0.006 mL/g, P<0.05). In response to
adenosine, these values increased in both groups
(P<0.001, Figure 6). The increase in absolute
BVnr was attenuated in HC versus control pigs
(0.09±0.02 versus 0.12±0.02 mL/g, P<0.01), as was the
change relative to baseline (77±20% versus 135±28%,
P<0.001). After NTG, BVnr increased
by 3.6±13% (P=NS) in HC pigs and by 7.1±9%
(P<0.01) in controls, with no difference between
groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we evaluated intramyocardial microvascular function in normal and HC pigs by virtue of intramyocardial microvascular BV and perfusion quantification with EBCT. We found that (1) intramyocardial microvascular BV and perfusion quantification identified alterations in microvascular function in HC pigs consistent with findings in intracoronary Doppler ultrasound studies, (2) the EBCT-based indices also provided BV quantities in the intramyocardial microvascular functional components, and (3) changes in recruitable and nonrecruitable microvessels showed appreciable differences in HC versus control pigs consistent with HC-induced impairment of resistance vessel function.
These findings suggest that minimally invasive EBCT-based indicator dilution methods may be of value for the detection and quantification of altered coronary microvascular function as the basis for the evaluation of normal and pathological states such as hypercholesterolemia.
Intramyocardial BV Quantification at Baseline
Total intramyocardial vascular BV in control pigs at baseline was
similar to values previously reported by Lerman et al,6
who used similar methodology. Moreover, Kassab et al10
quantified BVs in porcine coronary arteries, capillaries, and
veins in isolated hearts using a capillary silicone cast and reported
BV of magnitudes comparable to our findings in the recruitable and
nonrecruitable components at resting conditions in control pigs. The
similarity of their data to ours supports the ability of our model to
estimate BV distribution in functional components of the porcine
microvasculature.
BV in the recruitable component was significantly and consistently lower in HC than in control pigs, whereas BV in the nonrecruitable component was higher in HC than in control pigs. Lerman et al6 recently demonstrated that intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide (NO) synthase, led to a significant decrease in BVr, whereas BVnr increased. Because experimental hypercholesterolemia is associated with a decrease in endogenous NO bioavailability,11 12 it probably induces physiological effects similar to those with L-NMMA. The NO pathway is involved in modulating basal vasomotion,13 14 and it may be speculated that our observation at baseline is related to "derecruitment," ie, a functional shift of BV from recruitable to nonrecruitable microvessels.6 Impaired resistance vessel function may be responsible for this decrease in capillary recruitment distal to the resistance component, whereas proximal vessels dilate with an associated increase in nonrecruitable BV. Another possible mechanism is an HC-induced decrease in the number of recruitable vessels with an increased number of less responsive nonrecruitable vessels or a combination of both. However, the previous observation that a similar trend was elicited in normal pigs in response to L-NMMA infusion6 favors the hypothesis of derecruitment being a functional phenomenon.
Effect of Drugs on Intramyocardial BV and BV Distribution
In control and also in HC pigs, adenosine increased BV in
both the recruitable (BVr) and nonrecruitable
(BVnr) components. It has previously been shown
that the microcirculatory effects of adenosine are mediated
through both capillary recruitment6 15 and vasodilation of
resistance and conducting microvessels.1 16 In the HC
group, however, the increase in BVnr was
significantly attenuated, conceivably as a result of a combination of a
higher BVnr at baseline and an impaired
responsiveness of these conducting and resistance vessels. This is
consistent with findings by Stepp et al,17 who
recently suggested that flow-related vasodilation (as induced by
adenosine), particularly in arteries with diameters >160
µm, is regulated partly by endothelial NO release,
which is impaired in experimental
hypercholesterolemia.11 12
Interestingly, we observed that BVr increased by
similar absolute amounts in HC and control pigs, suggesting a similar
number of recruited exchange vessels. Given effectively similar levels
of BVnr after adenosine, it is
conceivable that recruitment of capillaries and the functional status
of the governing conducting and resistance vessels are interrelated.
However, the underlying mechanism(s) and their interactions in this
regulatory process still remain to be defined.
In response to NTG, we found an increase in total microvascular BV in the control group due to an increase in BV in both the nonrecruitable and the recruitable components. Lerman et al6 also found a significant increase in total microvascular BV in response to NTG administration in normal pigs, which, however, was attributable to an increased nonrecruitable BV only. NTG elicits its effect primarily in the nonrecruitable component of the coronary microvasculature, ie, microvessels with diameters >200 µm,18 19 which most likely explains the increase in BVnr. Whereas Lerman et al obtained their data after a bolus injection of NTG, our measurements were obtained at steady state after 5 minutes of continuous NTG infusion. Capillary recruitment, ie, the increase in BVr in control pigs, may have occurred secondary to prolonged changes in upstream vasomotion. In our HC pigs, however, this increase in BVnr was not observed, suggesting an impaired vasodilatory response in resistance and upstream conducting vessels, similar to our findings after adenosine infusion. BVr also remained unchanged in HC pigs, which, again, is consistent with a modulating effect of upstream resistance vessel function on capillary recruitment.
Methodological Considerations
In this study, EBCT-based indices of microvascular function were
directly compared with intracoronary Doppler–based CBF.
Although these 2 methods provide different measures of myocardial blood
supply, regional myocardial perfusion measurements correlated well with
Doppler measurements of CBF. CBF measurements showed an impaired
microvascular response to adenosine compared with control pigs.
Whereas the trend toward an attenuated increase in intramyocardial
perfusion in response to adenosine in HC pigs reached no
statistical significance, changes in total intramyocardial BV and also
the relationship between intramyocardial BV and perfusion allowed us to
distinguish HC from control pigs. This is consistent with
previous studies that recognized that intramyocardial BV quantification
may be a highly sensitive indicator of microvascular function and
appears to provide an independent evaluation of microvascular sequelae
of diseases such as epicardial coronary artery
stenosis20 21 or, as in this study, chronic
hypercholesterolemia. The
physiological significance of a reduced maximal BV
in chronic hypercholesterolemia, however,
remains to be defined.
In addition to showing that quantification of intramyocardial BV alone allowed us to distinguish HC from normal pigs, we demonstrated how the relation of intramyocardial BV to perfusion can be used to distinguish recruitable and nonrecruitable microvessels. These microvessels, however, are not visually resolvable by EBCT technology. Other investigators have used more invasive techniques to directly visualize microvessels on myocardial surfaces in vivo,22 23 which could potentially be used as an independent reference technique to quantify intramyocardial BV distribution in chronic hypercholesterolemia in response to vasoactive drugs. To the best of our knowledge, however, such studies have not yet been performed. Nonetheless, EBCT-based quantification of BV distribution in the 2 components corresponded to measurements obtained with other methods,10 and the functional behavioral trend of these components, as inferred from the relationship between myocardial BV and perfusion, is consistent with previously described hypercholesterolemia-induced impaired resistance vessel function.24
It has been shown that myocardial perfusion is spatially heterogeneous.25 Consequently, our evaluation, which focused on 1 midventricular cross-sectional level, could conceivably not be representative of the entire LAD perfusion territory. However, heterogeneity of myocardial BV and perfusion can be quantified by evaluating relative dispersion, ie, the SD of measurements in all subregions divided by their mean value, of these estimates.26 Relative dispersion decreases with increasing areas of regions of interest by integrating the spatially heterogeneous functional phenomenon. BV and perfusion values obtained in an area of the region of interest >1000 mm3 is adequately representative for the entire perfusion territory.27 In addition, even though both intramyocardial perfusion and BV are spatially heterogeneous, the BV-to-flow relationship is spatially homogeneous27 and hence is representative of the entire myocardium.
Conclusions
This study demonstrates that EBCT imaging provides
information similar to that of intracoronary Doppler
ultrasound by virtue of quantifying intramyocardial BV and perfusion.
Moreover, the relationship of intramyocardial BV to perfusion also
allowed characterization of differential functional behavior of
microvascular components. This approach might be applicable to any
technique providing simultaneous quantitative measurements
of intramyocardial BV and perfusion21 28 and may provide
useful insight into microvascular function in normal and
pathophysiological states, especially
presymptomatic stages of cardiac diseases such as
cardiomyopathies and of major systemic diseases
such as atherosclerosis,
hypercholesterolemia, arterial
hypertension, and diabetes mellitus.
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Acknowledgments |
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This study was funded in part by research grant HL-43025, National Institutes of Health, Bethesda, Md. We are indebted to Patricia E. Lund and Kelly A. Swiggum for their expert technical assistance with the experiments. The authors gratefully acknowledge the help and assistance from the radiology technical staff operating the EBCT scanner. We also thank Amy L. Weaver and V. Shane Pankratz, PhD, for their contributions to the statistical model; Julie M. Patterson, who made the illustrations; and Delories Darling, for her help with preparing the manuscript.
Received March 27, 2000; revision received May 31, 2000; accepted June 8, 2000.
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A. Indermuhle, R. Vogel, P. Meier, S. Wirth, R. Stoop, M. G. Mohaupt, and C. Seiler The relative myocardial blood volume differentiates between hypertensive heart disease and athlete's heart in humans Eur. Heart J., July 1, 2006; 27(13): 1571 - 1578. [Abstract] [Full Text] [PDF]
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 U. Hoffmann, A. J. Pena, R. C. Cury, S. Abbara, M. Ferencik, F. Moselewski, U. Siebert, T. J. Brady, and J. T. Nagurney Cardiac CT in Emergency Department Patients with Acute Chest Pain. RadioGraphics, July 1, 2006; 26(4): 963 - 978. [Abstract] [Full Text] [PDF]
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 M. Rodriguez-Porcel, X.-Y. Zhu, A. R. Chade, B. Amores-Arriaga, N. M. Caplice, E. L. Ritman, A. Lerman, and L. O. Lerman Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H978 - H984. [Abstract] [Full Text] [PDF]
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M. Gossl, P. E. Beighley, N. M. Malyar, and E. L. Ritman Role of vasa vasorum in transendothelial solute transport in the coronary vessel wall: a study with cryostatic micro-CT Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2346 - H2351. [Abstract] [Full Text] [PDF]
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 N. M. Malyar, L. O. Lerman, M. Gossl, P. E. Beighley, and E. L. Ritman Relation of Nonperfused Myocardial Volume and Surface Area to Left Ventricular Performance in Coronary Microembolization Circulation, October 5, 2004; 110(14): 1946 - 1952. [Abstract] [Full Text] [PDF]
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 U. J. Schoepf, C. R. Becker, B. M. Ohnesorge, and E. K. Yucel CT of Coronary Artery Disease Radiology, July 1, 2004; 232(1): 18 - 37. [Abstract] [Full Text] [PDF]
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M. Rodriguez-Porcel, A. Lerman, J. Herrmann, R. S. Schwartz, T. Sawamura, M. Condorelli, C. Napoli, and L. O. Lerman Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature Cardiovasc Res, April 1, 2003; 58(1): 213 - 221. [Abstract] [Full Text] [PDF]
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S. Mohlenkamp, P. E Beighley, E. A Pfeifer, T. R Behrenbeck, P. F Sheedy II, and E. L Ritman Intramyocardial blood volume, perfusion and transit time in response to embolization of different sized microvessels Cardiovasc Res, March 1, 2003; 57(3): 843 - 852. [Abstract] [Full Text] [PDF]
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 P. O. Bonetti, S. H. Wilson, M. Rodriguez-Porcel, D. R. Holmes Jr, L. O. Lerman, and A. Lerman Simvastatin preserves myocardial perfusion and coronary microvascular permeability in experimental hypercholesterolemia independent of lipid lowering J. Am. Coll. Cardiol., August 7, 2002; 40(3): 546 - 554. [Abstract] [Full Text] [PDF]
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 T. C. Gerber, R. S. Kuzo, N. Karstaedt, G. E. Lane, R. L. Morin, P. F Sheedy II, R. E. Safford, J. L. Blackshear, and J. H. Pietan Current Results and New Developments of Coronary Angiography With Use of Contrast-Enhanced Computed Tomography of the Heart Mayo Clin. Proc., January 1, 2002; 77(1): 55 - 71. [Abstract] [PDF]
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S. Mohlenkamp, T. R. Behrenbeck, A. Lerman, L. O. Lerman, V. S. Pankratz, P. F. Sheedy II, A. L. Weaver, and E. L. Ritman Coronary Microvascular Functional Reserve: Quantification of Long-term Changes with Electron-Beam CT—Preliminary Results in a Porcine Model Radiology, October 1, 2001; 221(1): 229 - 236. [Abstract] [Full Text] [PDF]
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