Myocardial Contrast Echocardiography Can Be Used to Quantify Intramyocardial Blood Volume
New Insights Into Structural Mechanisms of Coronary Autoregulation
Background Changes in intramyocardial blood volume (IBV) mediate autoregulatory adaptations to coronary stenosis. This study investigated whether (1) myocardial contrast echocardiography (MCE) can quantify changes in IBV during coronary stenosis and (2) the relation between coronary resistance– and MCE-derived IBV could yield insight into structural mechanisms of IBV change.
Methods and Results A circulating in vitro model with constant flow and varying volume was used to determine whether indicator dilution theory could be applied to MCE. Contrast echo was performed with albumin microbubbles, and time-intensity data were fit to a gamma-variate function. With six different volumes, bubble transit time was linearly related to volume (r=.91). To determine whether changes in IBV could be quantified in vivo, the left anterior descending coronary artery in 12 dogs was instrumented with a flow probe, occluder, and intracoronary pressure catheter, and non–flow-limiting stenoses were created. IBV was derived by use of coronary resistance measurements applied to models that assumed autoregulation to occur via vasodilatation or microvascular recruitment. MCE-IBV was calculated from microbubble transit rates. At constant flow, MCE and resistance IBV increased with stenosis. Although MCE and resistance IBV were linearly related, MCE overestimated IBV derived from the vasodilatation model and underestimated IBV calculated from the recruitment model.
Conclusions MCE can quantify autoregulatory increases in IBV that maintain resting myocardial perfusion. These data suggest that both microvessel vasodilatation and recruitment are dual mechanisms of IBV change. MCE thus may be a clinically useful technique for the detection and quantification of coronary artery disease at rest.
The myocardial microvasculature undergoes structural and functional modifications in response to different pathophysiological states. For example, microvascular rarefaction and remodeling occur in hypertension and diabetes.1 2 Conversely, the heart may adapt to coronary artery disease and chronic ischemia through angiogenesis.3 Coronary autoregulation, which maintains stable myocardial perfusion despite variations in perfusion pressure, is thought to be mediated by microvascular dilatation and/or recruitment.4 5 6 7 8 9 10 11 Such microvascular responses to altered physiological conditions result in changes in blood volume within the intramyocardial vasculature. Because such changes ultimately manifest as alterations in nutritive flow, quantifying IBV is of both basic physiological and clinical importance.
Current methods for quantifying IBV in vivo are limited. Digital angiographic impulse response analysis is limited in its spatial resolution.12 13 Dye or radioactive labeling techniques cannot be used in humans or performed repeatedly to assess dynamic changes.6 7 9 10 11 Furthermore, such methods do not yield insight into the mechanism of autoregulation, ie, vasodilatation versus vessel recruitment.
In the present study, we proposed that an intravascular tracer can characterize changes in IBV. MCE uses encapsulated gas microbubbles injected into the coronary circulation, which produce myocardial contrast enhancement during two-dimensional echocardiography.14 Because the bubbles remain entirely within the intravascular space, principles of indicator dilution theory applied to MCE give this technique the potential to quantify myocardial perfusion.15 Recent studies in dogs suggest that MCE can quantify increases in IBV during pharmacological hyperemia.15 Whether autoregulatory changes in IBV occurring with non–flow-limiting coronary stenoses can be quantified by MCE at rest, however, is unknown. Furthermore, no study to date has validated MCE against an independent measure of IBV.
On the basis of classic indicator dilution theory, in which the transit of a tracer through a compartment is proportional to the ratio of flow to volume of the compartment,16 we theorized that microbubble transit rates could be used to calculate IBV at constant flow. Accordingly, this study tested the hypotheses that (1) MCE can quantify resting changes in IBV resulting from progressive non–flow-limiting epicardial coronary stenosis and (2) the relationship of resistance- and MCE-derived measures of blood volume can yield insight into structural mechanisms of autoregulation, ie, vasodilatation of existing versus recruitment of new microvessels. A twofold approach was used: First, an in vitro model was constructed to examine the applicability of indicator dilution theory to and the sensitivity of MCE for the detection of volume change. Second, a canine model was used to determine whether MCE could quantify resting changes in IBV in vivo during graded coronary stenosis. To validate the MCE data, an independent index of IBV was derived from simultaneous coronary resistance measurements.
In Vitro Model
Six Plexiglas flow cells of identical lengths and varying radii (0.65, 0.95, 1.25, 1.6, 1.9, and 2.2 cm) were used to simulate different composite intravascular blood volumes. The proximal end of each cell was connected to an input reservoir and the distal end to an outlet drain, and the system was primed with 0.9% NaCl. Flow was controlled by a varistaltic pump (Mano-stat) and measured with a transit-time flow probe (Transonic Systems Inc). A port proximal to the flow cell was used for contrast injection, and an in-line mixer ensured homogeneous suspension of contrast.
Echocardiographic imaging of the flow cell was performed with a 5-MHz phased-array system (GE Medical Systems). Gain settings were optimized at the beginning of the experiment, and images were obtained in the short-axis plane. Sonicated 5% human albumin microbubbles (Albunex, Molecular Biosystems Inc) were used as the contrast agent (mean diameter, 4.3 μm).
The experimental protocol was as follows: With saline flowing at rate of 130 mL/min, a power injector (Medrad) was used to inject a bolus of 0.1 to 0.2 mL of Albunex into the system. MCE images were recorded continuously beginning immediately before the appearance and extending through washout of contrast. Volume was varied by fitting the system with different flow cells.
The in vivo protocol was approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh and conformed to the American Heart Association Guidelines for Use of Animals in Research. Twelve adult dogs were anesthetized with sodium pentobarbital (30 mg/kg), intubated, and ventilated (Harvard Apparatus). 7F catheters were placed in both femoral arteries for recording of arterial pressure (Gould Electronics) and withdrawal of radiolabeled microsphere reference samples. The pressure signal was conditioned and displayed on a physiological recorder (EVR-130, PPG Biomedical Systems). Another catheter was placed in a femoral vein for administration of fluids and drugs.
A left lateral thoracotomy was performed, and the heart was suspended in a pericardial cradle. A catheter was placed in the left atrium for radiolabeled microsphere injection. The midportion of the LAD and the proximal LCx were encircled by flow probes (Transonic Systems Inc). The proximal LAD was cannulated retrogradely with a 21-gauge catheter for microbubble injection, with the tip positioned in the aorta and the hub connected to a power injector. A variable occluder was placed around the proximal LAD, and the distal LAD was cannulated with a 25-gauge catheter for distal coronary pressure measurement. Hemodynamic data were digitally acquired and stored in a minicomputer.
Myocardial Blood Flow Measurements
Myocardial blood flow was measured by the radioactive microsphere technique.17 Approximately 2×106 to 3×106 11-μm microspheres (New England Nuclear) were injected into the left atrium during simultaneous 90-second arterial blood withdrawal. The short-axis slice of the left ventricle corresponding to the MCE was cut into 16 transmural pieces, specimens were placed in a Gamma counter (Packard Instruments), and corrections were made for spillover of activity between neighboring windows. Flow (mL·min−1·g−1) to the risk bed (defined by use of india ink during premortem LAD occlusion) was calculated for the centrally located segments,17 excluding lateral borders.
Estimation of Intramyocardial Blood Volume by Coronary Resistance Measurements
Because autoregulation is felt to largely involve the adjustment of coronary arteriolar vessels to alter vascular resistance4 5 by vasodilatation and/or recruitment of microvessels, two models were developed for estimating IBV by coronary resistance measurements.
Our approach to measuring IBV premises that resistance of microvessels (R) such as arterioles or capillaries can be approximated on the basis of Poiseuille’s law.18 Assuming that coronary blood flow during acute stenosis is maintained by vasodilatation alone, IBV at a stenosis (IBVs) with respect to baseline (IBVb) can be calculated as (see “Appendix A”): where Rb and Rs represent coronary vascular resistance at baseline and during a stenosis, respectively.
If IBV changes due to vessel recruitment, then IBV at a stenosis relative to baseline can be calculated (see “Appendix ”): Coronary vascular resistance (R) was computed by the following equation: where Pa is LAD pressure distal to the stenosis, Qc is microsphere flow, and Pla is left atrial pressure.19
Myocardial Contrast Echocardiography: In Vivo Studies
With the echocardiographic system described above, MCE imaging with Albunex was performed at the mid–papillary muscle short-axis level. In vivo, Albunex has an intravascular rheology similar to that of red blood cells14 and causes no changes in systemic and coronary hemodynamics at the intracoronary doses required to achieve myocardial opacification.20
Off-line Analysis of MCE Images
MCE images were analyzed off-line by use of previously described methods.21 22 23 Briefly, images were digitized in real time (Mipron, Kontron Electronics), and consecutive end-diastolic frames were aligned by use of computer cross-correlation techniques.23 Regions of interest were drawn manually. For the in vitro experiment, the entire internal cross-sectional area of the flow cell was selected. For the animal studies, a region of interest corresponding to the LAD bed (determined during the experiment by MCE performed during transient LAD occlusion) was drawn, excluding the lateral 25% of borders of the bed to avoid areas of overlap between LAD and LCx territories. Average pixel video intensity within the region of interest was measured for each frame, time-intensity data were transferred to another computer (VAXstation 4000/90, Digital Equipment Corp), and background-subtracted time-intensity plots were fit to a gamma-variate function (y=At e−αt), where A is a scaling factor, t is time, and α is a parameter of tracer transit rate14 equal to the ratio of flow (Q) to the volume of distribution of a tracer (Vd)16 : In this case, Vd is the IBV. By use of this relationship, the change in IBV during a stenosis (IBVs) relative to baseline blood volume (IBVb) was derived: where Qb and Qs are radiolabeled microsphere–derived flows at baseline and stenosis, respectively.
Experimental Protocol: In Vivo Study
The increment in stenosis gradient required for each of three to five progressive stenoses was initially determined so that a range of non–flow-limiting gradients could be evaluated. The occluder was tightened until a maximal non–flow-limiting stenosis occurred, and the gradient across this stenosis divided by the number of stenoses was set as the target increase in gradient for each successive stenosis.
MCE was performed by power-injecting 0.5 to 1.5 mL of Albunex into the aorta. The injection volume yielding the best visual result was used for subsequent stages. Baseline arterial and distal LAD pressure and epicardial flow were recorded, followed by MCE and radiolabeled microsphere measurements. The occluder was tightened to create the first stenosis based on the target gradient as defined above, followed by a brief waiting period to permit hemodynamic stabilization, and hemodynamic, MCE, and microsphere measures were repeated. A total of 5 stenoses were created in 5 dogs and 3 stenoses in 7 dogs. To adjust for possible bias resulting from creating stenoses in incremental fashion, the order in which stenoses were created was randomly varied in 4 dogs.
At the completion of data collection, the proximal LAD was ligated, MCE was performed, and 20 mL of india ink was injected into the left atrium to define LAD bed borders. The dog was immediately killed by KCl and pentobarbital overdose, the heart was excised, and the cross section corresponding to the MCE image was processed to determine radiolabeled microsphere blood flow.
Data are expressed as mean±SEM. Data were compared by repeated-measures ANOVA (SAS Institute). Paired t testing (two-tailed) with Bonferroni criteria for significance was used when a significant difference was found by ANOVA. The relation between MCE- and resistance-derived IBV was assessed by linear regression. Statistical significance was defined as P<.05.
In Vitro Studies
Flow cell volumes were expressed as a function of cross-sectional area. At constant flow, there was a linear correlation between mean microbubble transit time (1/α) and flow cell cross-sectional area (r=.91, P<.01) (Fig 1⇓). These data indicate that at constant flow, microbubble transit rates vary with volume and confirm the applicability of indicator dilution theory to the measurement of volume using MCE.
In Vivo Studies
Hemodynamic measurements. The Table⇓ depicts the mean hemodynamic and blood flow measurements at baseline and during the experimental stages in the 7 dogs with 3 stenoses and during stenoses 1, 3, and 5 in the 5 dogs with 5 stenoses. Heart rate and aortic and left atrial pressures remained constant. Similarly, microsphere-derived LAD flow was unchanged despite stenosis gradients ranging from 11±1 mm Hg at the mildest to 39±3 mm Hg at the most severe stenosis. Although microsphere-derived LCx flow changed by ANOVA, the difference between baseline and the final stenosis was insignificant by Bonferroni criteria. Total coronary flow (sum of LCx and LAD flow-probe measurements) remained stable.
Relationship between stenosis severity and IBV. Fig 2A⇓ summarizes the resistance-derived volume measurements in all dogs. At constant flow, IBV calculated from the vasodilatation model significantly increased as stenosis severity progressed, with a 20±3% increase between baseline and the maximum non–flow-limiting stenosis (P≤.0001). Likewise, when the recruitment model of autoregulation was used, there was an increase in IBV with progressive stenosis amounting to a 64±7% increase with the maximum stenosis (P≤.0001). Because right atrial pressure has also been used to approximate distal coronary pressure,19 resistance-derived IBV was also calculated with an assumed right atrial pressure of 5 mm Hg. IBV derived by this approach was not significantly different from the values derived by use of left atrial pressures.
Fig 2B⇑ illustrates mean MCE-derived IBV at each stenosis. Like the resistance-based calculations, MCE measures of IBV increased significantly with progressive stenosis (P≤.0002).
Relationship between resistance- and MCE-derived measures of IBV. MCE-determined IBV measurements were compared with those derived from coronary resistance data and are shown in Fig 3⇓, which also includes the data from all stages in the 5 dogs undergoing 5 stenoses. There was a significant linear relationship between the vasodilatation model and MCE estimates of IBV (y=1.84x−0.40, r=.66, P<.0001) (Fig 3A⇓). MCE measurements, however, overestimated the coronary resistance–derived IBV, predicting an 84% greater change in IBV at any given stenosis.
As shown in Fig 3B⇑, there was a linear relationship between MCE- and recruitment model–derived measurements of blood volume (y=0.81x+0.13, r=.70, P<.0001). Unlike the relationship when the vasodilatation model was used, MCE underestimated IBV when recruitment was assumed to be the mechanism of autoregulation, with a 19% smaller change in blood volume at a given degree of stenosis than that predicted by coronary resistance measures.
This study used measures of coronary resistance to evaluate the accuracy of MCE for IBV assessment. The three major findings were as follows: (1) At constant resting flow, IBV increases with progressive coronary stenosis; (2) MCE is capable of quantifying changes in IBV in response to non–flow-limiting stenosis; and (3) both microvascular vasodilatation and recruitment concurrently participate in coronary autoregulatory increases in IBV.
Basis for Using MCE to Quantify IBV
The theoretical underpinnings for measuring volume by use of MCE are shown in Fig 4⇓. This figure illustrates three scenarios in which constant resting flow despite progressive stenosis is maintained by microvascular vasodilatation of existing vessels or recruitment of new vessels, resulting in an increase in the composite IBV (boxes). On the basis of a two-compartment model and indicator dilution theory, the transit rate (α) of a tracer will decrease as volume enlarges, providing that the input function and flow are constant.16
Before this approach was applied in vivo, an in vitro model was used to determine whether microbubble transit rates would detect changes in volume. The in vitro experiment demonstrated that at constant flow, there was a linear relationship between volume and mean transit time (1/α), thus confirming predictions of indicator dilution theory and validating the theoretical basis for using MCE to assess changes in microbubble distribution volumes.
We then sought to determine whether MCE could detect IBV changes in response to non–flow-limiting stenoses. We quantified IBV change using two models derived from coronary resistance measurements to validate the MCE findings. The in vivo study demonstrated that over a broad range of stenoses and at constant flow, IBV measured by use of MCE and the resistance models increased as stenosis severity progressed. Furthermore, MCE and resistance measures of relative volume were linearly related, confirming the applicability of MCE for quantifying volume change in the beating heart.
Discrepancies Between MCE- and Resistance-Derived IBV
Although MCE volume calculations were linearly related to resistance-derived measurements when autoregulation was assumed to occur via vasodilatation, they systematically overestimated resistance-derived volumes by ≈84%. There are several possible reasons for this discrepancy. One explanation may be related to the fact that the two techniques interrogate slightly different vascular compartments. Coronary resistance measurements reflect changes predominantly in coronary microvessels (arterioles <170 μm and venules <150 μm in diameter), in which 70% of resistance resides,24 and are less sensitive to changes in veins. Microbubbles, on the other hand, traverse not only the arterioles, capillaries, and small venules but also larger intramyocardial vessels that contribute less to coronary resistance. Hence, the microbubble transit could theoretically become prolonged by an increase in venous capacitance, which would not be “detected” by our resistance measurements. It is unlikely, however, that isolated increases in venous volume occurred that would have been singularly detected by MCE; others have shown that even in the presence of maximal dipyridamole-induced hyperemia, coronary venous resistance is not significantly changed.24
The second reason for the discrepancy could be phasic changes in IBV. Liu et al25 showed that IBV varies throughout the cardiac cycle. Because our time-intensity data were derived from end-diastolic frames, the MCE volume probably represents IBV at end diastole, which is at its maximum. On the other hand, the resistance-based IBV was computed from mean coronary resistance and most likely represents mean IBV for the entire cardiac cycle. Conceivably, the larger IBV detected by MCE compared with the vasodilatation model may be due to differences in the specific phase of the cardiac cycle that was sampled. On the basis of Liu’s data, however, the difference between the mean and the peak IBV was between 10% and 20%, which accounts for only one fifth to one third of the additional volume detected by MCE. Cyclic changes in blood volume are therefore unlikely to fully account for our observations.
A third possible explanation for the discrepancy in MCE and resistance measurements of volume with the vasodilatation model may be that vasodilatation is not the sole structural correlate to coronary autoregulation. Considerable evidence suggests that vasodilatation is a major mechanism for regulating coronary perfusion. Using intravital microscopy, Kanatsuka et al5 observed that arterioles <100 μm in diameter dilated in response to a mild coronary stenosis. Similarly, Chilian and Layne4 showed that coronary arterioles <150 μm in diameter vasodilated when perfusion pressure was reduced to 40 mm Hg. Such data support the prevailing notion that a primary mechanism of autoregulation is vasodilatation of already patent resistance arterioles and lend credence to the vasodilatation model on which our resistance-derived IBV calculations were based.
Vasodilatation, however, may not fully account for the entire IBV increase. Recruitable vessels may exist in the coronary microvasculature.7 8 9 10 11 Measuring the intercapillary distance in rat hearts, Henquell and Honig8 concluded that ≈21% to 37% of capillaries were not perfused under normoxic conditions. Crystal et al7 demonstrated in dogs a twofold increase in small-vessel blood volume (index of open capillaries) during asphyxia. Weiss and Conway9 reported that 36% to 45% of capillaries and 46% to 49% of arterioles in rabbits were not perfused or were underperfused at rest. Furthermore, these arterioles appear to be functional and recruitable by vasopressin or chemical sympathectomy.10 11
Measurement of microbubble transit rates would not necessarily have discriminated between vasodilatation and recruitment as mechanisms of volume change. Resistance measures of volume, however, would be affected by microvessel recruitment. A resistance model was developed that assumed the primary mechanism of autoregulation to be recruitment (“Appendix B”). Fig 5⇓ illustrates the regression lines (from Fig 3⇑) for MCE estimates of IBV versus resistance-derived measures when the mechanism of autoregulation is assumed to be vasodilatation only or recruitment only. The bold solid line represents the line of identity, which would theoretically represent the data had either model completely accounted for the observations. Although MCE overestimated IBV derived with the vasodilatation model, it underestimated volumes when recruitment was assumed to be the primary mechanism of autoregulation. Fig 5⇓ thus suggests that both vasodilatation and recruitment of microvessels contributed to the observed increases in IBV.
Comparison With Other Studies
Assessment of IBV during autoregulation has been attempted by others using different techniques in animal models. Measuring digital angiographic impulse response, Schuhlen et al13 reported a 74% increase in IBV with subcritical stenosis, which is higher than the maximum MCE-derived IBV. Wu et al26 used high-speed computed tomographic scanning and estimated an 11% increase in IBV at a stenosis gradient of 9 mm Hg, which increased to 25% at a gradient of 40 mm Hg, which is lower than our MCE-derived IBV. Because both these studies applied indicator dilution theory, we might have expected MCE approximations of IBV to be comparable to that reported by these investigators. Although the increase in MCE-IBV is within an order of magnitude roughly comparable to that found by these authors, there are important differences between these two studies and ours. The first relates to possible differences in stenosis severity in each study, which are difficult to precisely compare on the basis of the information provided. Second, these studies used iodinated angiographic agents, which are coronary dilators.26 Schuhlen et al injected ionic dye, which could have accounted for the larger IBV increase in that study. Third, angiographic dyes are not pure intravascular tracers, and 15% extravasation occurs during the first pass.27 Extravasation of dye would result in an overestimation of IBV by time-intensity curves, whereas subtraction of this effect by mathematical correction techniques as done by Wu et al26 could potentially underestimate IBV. In this regard, MCE offers a distinct advantage over angiographic techniques, because the microbubbles are purely intravascular and physiologically inert.
Using atrial injection, Skyba et al15 performed MCE during hyperemia in dogs with stenosis and showed that the peak myocardial video intensity can detect presumed changes in IBV. However, Skyba et al did not confirm an actual increase in IBV or validate MCE against other independent indices of volume change. The use of coronary resistance as an independent measure of IBV is thus an important differentiation of our present study. Also, our study used microbubble transit rate, a parameter less influenced by variations in bubble concentration and dose, instead of peak intensity, to measure IBV. Furthermore, unlike Skyba et al, we assessed IBV in the absence of pharmacological stress.
Critique of Our Methods
The determination of α is subject to the limitations inherent to MCE. Analysis of time-intensity curves presumes a linear relationship between microbubble concentration and video intensity, and comparisons among curves are optimized by reproducible microbubble doses. The use of a commercially prepared agent should have minimized microbubble injection variability. Other limitations include image attenuation,15 28 and conversely, thresholding for detecting backscatter.28 The dose of contrast agent was chosen to achieve optimal opacification while avoiding attenuation. Furthermore, a linear signal-to-video postprocessing algorithm was used.
Serial comparison of α is valid only if the input function is constant; variability in the input function would affect tracer transit time independent of changes in flow or volume.16 A power injector was used to standardize the injection method. Additionally, since total coronary flow stayed constant, the contribution of left main artery flow to the input function should have remained unchanged.
The method for deriving coronary resistance is in itself controversial because multiple parameters affect small-vessel resistance, and the true backpressure to coronary inflow is difficult to quantify. We used a generally accepted measure of coronary resistance, in which coronary driving pressure was calculated as the difference between distal LAD pressure and left ventricular end-diastolic pressure.19
An independent measure of IBV based on Poiseuille’s equation was derived, and it is important to understand the limitations related to its application in vivo. Poiseuille’s equation was derived from steady-state fluid flow through small rigid tubing,18 whereas larger arteries are elastic and flow through them is pulsatile. Nonetheless, Baez et al29 and others30 have found that the diameter of capillaries and small arterioles varied little despite large changes in internal pressure. Thus, the relationship most likely still pertains to the resistance measurements in small arterioles and capillaries. In larger arterioles, where flow is still pulsatile, it has been suggested31 that resistance is proportional to the third instead of the fourth power of the radius. However, even if most coronary resistance resided in these larger arterioles, however, which dilate by ≈5% to 20% during moderate to severe stenosis,4 5 the error in volume estimation would be only between 2.5% and 10%.
Another assumption made in deriving the coronary resistance–IBV relationship was that the response from the coronary microvessels is homogeneous, ie, that the degree of vasodilatation is uniform among vessels. There is, however, both spatial and temporal heterogeneity to myocardial perfusion,32 and microvessels also respond heterogeneously to hypoperfusion.4 5 Like all models, ours simplify the complexities of the physiological situation under study. Nonetheless, these models do provide a first-order approximation of the minimum (vasodilatation) and maximum (recruitment) IBV increments that correspond to changes in measured coronary vascular resistance. However simplified, the models appear to provide a useful conceptual structure for understanding the dual mechanisms of coronary autoregulation.
The quantification of IBV can be applied to the clinical evaluation of patients with suspected coronary artery disease. There are advantages to measuring myocardial blood volume rather than coronary blood flow, which is the current standard used by stress scintigraphy.33 In the presence of pharmacologically induced maximal vasodilatation, for example, coronary flow can be affected by alterations in aortic pressure independently of the microvascular responses under investigation. The measurement only of changes in flow may thus not fully encompass the microvascular events that more truly reflect the physiological sequelae of a coronary stenosis. Measuring IBV with MCE, therefore, may provide a better approach to measurement of coronary vascular reserve.
Quantification of IBV by use of MCE could obviate the need for performing exercise or pharmacological stress to detect coronary stenoses noninvasively. Because most patients with coronary artery disease have normal perfusion at rest, current noninvasive techniques to diagnose coronary disease require some form of stress to elicit flow heterogeneity between normal and stenosed beds. As shown here, in regions subserved by stenosed arteries, normal flow at rest is maintained by an increase in IBV, and the magnitude of increase is proportional to the severity of stenosis. Assessing blood volume, therefore, yields information about the severity of and microvascular response to stenosis, without having to elicit an increase in flow. As such, measuring IBV heterogeneity with MCE may enable detection of coronary stenosis in the resting state.
Selected Abbreviations and Acronyms
|IBV||=||intramyocardial blood volume|
|LAD||=||left anterior descending coronary artery|
|LCx||=||left circumflex coronary artery|
|MCE||=||myocardial contrast echocardiography|
Calculation of IBV Using Coronary Resistance Measurements: Model of Coronary Autoregulation by Vasodilatation
Our approach to calculating IBV is based on Poiseuille’s law. Coronary vascular resistance and blood volume reside largely in the arterioles and capillaries. Resistance of these microvessels, R, can be estimated by Poiseuille’s equation18 : where μ is the viscosity of the fluid, L is the length, and r is the internal radius. If a cylindrical geometry is assumed, R can be expressed in terms of intravascular volume (V): The coronary microvasculature was modeled as a composite compartment. Although the precise quantitative relationship between total blood volume within a vascular bed and coronary vascular resistance is unknown, if the length of microvessels is assumed to remain constant and Poiseuille’s law is applicable, the following equation can be used to approximate the relationship: where K is a constant. If IBV increases due to vasodilatation of preexisting microvessels, R at baseline (Rb) and at a given stenosis (Rs) can be obtained from Equation 2: where IBVb and IBVs are volumes of the composite compartment and Kb and Ks are constants at baseline and during a stenosis, respectively. If it is assumed that with vasodilatation there is no change in overall length and orientation of the microvessels, Kb and Ks can be presumed to be similar: Kb≈ Ks=K. On the basis of these assumptions, the vasodilatation model (vaso) predicts that IBV at a stenosis relative to baseline IBV can be estimated:
Calculation of IBV From Coronary Resistance Measurements: Model of Coronary Autoregulation by Microvessel Recruitment
If coronary autoregulation occurs solely by recruitment of microvascular units and these recruited vessels are modeled as a composite compartment parallel to the existing microvascular bed, the total coronary resistance at each stenosis is expressed as where Rb is the baseline coronary resistance and Rrecruit is the resistance of the newly recruited microvessels. Assuming that the resistance/volume relationship for the preexisting and the recruited vascular beds is governed by Equation 2, then Rs can be expressed as where IBVrecruit is the composite volume of the recruited microvascular bed and Krecruit is a constant. If the recruited vessels have physical dimensions and structural orientation similar to those of the preexisting vessels, then it can be assumed that Kb≈ Krecruit=K. Coronary resistance at a given stenosis can therefore be expressed as Combining Equations 2, and 4, in this recruitment model, IBV at each stenosis compared with baseline can be derived:
This study was supported by Grants-in-Aid from the National Center of the American Heart Association and the Pennsylvania Affiliate of the American Heart Association (Dr Villanueva) and a FIRST Award from the National Institutes of Health (R29-H247046-01) (Dr Feldman). Dr Mills is the recipient of a fellowship training grant from the Pennsylvania Affiliate of the American Heart Association. Albunex was provided by Molecular Biosystems, Inc.
- Received August 19, 1996.
- Revision received February 3, 1997.
- Accepted February 11, 1997.
- Copyright © 1997 by American Heart Association
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