Assessment of Blood Flow Distal to Coronary Artery Stenoses
Correlations Between Myocardial Positron Emission Tomography and Poststenotic Intracoronary Doppler Flow Reserve
Background Previous studies have correlated quantitative coronary angiographic stenosis severity with positron emission tomography (PET) myocardial perfusion and proximal measurements of intracoronary flow velocities in normal and diseased coronary arteries. The aim of this study was to correlate regional myocardial blood flow (RMBF) derived from [15O]H2O PET with directly measured poststenotic intracoronary Doppler flow velocity data acquired under basal conditions and dipyridamole-induced hyperemia.
Methods and Results Eleven consecutive patients 53±13 years old with ischemic chest pain and isolated proximal left coronary artery stenoses (left anterior descending, 9; left circumflex, 2; mean, 59±23% diameter stenosis) underwent [15O]H2O myocardial PET and intracoronary Doppler flow velocity studies within 1 week. PET RMBF (mL·g−1·min−1) and myocardial perfusion reserve (MPR) were calculated in poststenotic and normal reference vascular beds. Poststenotic Doppler average peak flow velocities (APV; cm/s) and coronary flow velocity reserve (CFR) were compared with corresponding PET data and quantitative angiographic lesional parameters. PET RMBF and Doppler APV were linearly correlated (r=.60; P<.001), as were poststenotic PET MPR and Doppler CFR (r=.76; P<.0002). Relative coronary flow velocity and MPR ratios between poststenotic and angiographically normal vascular beds were comparably reduced (0.83±0.25 versus 0.86±0.21, respectively; P=NS).
Conclusions Intracoronary Doppler flow velocities acquired distal to isolated left coronary artery stenoses correlated with [15O]H2O PET regional myocardial perfusion and are useful for assessment of the physiological significance of coronary stenoses in humans.
Clinical decisions regarding the need for angioplasty or bypass surgery are frequently based on qualitative angiographic evaluations of coronary stenoses. However, it is well known that coronary anatomy, even when defined with quantitative tools, does not correlate precisely with the physiological significance of lesions.1 2 3 4 5 6 Physiological stenosis significance is a complex relationship between coronary pressure, lesion length and shape, the number and size of branching arteries, and their relationship to the coronary lesion.7 8 9 10 Both PET,11 12 13 14 which permits noninvasive quantitative assessment of absolute nutritive myocardial perfusion (ie, mL·g−1·min−1), and intracoronary Doppler techniques, which directly assess coronary flow velocity and relative flow reserve, have been proposed for evaluation of the physiological significance of coronary lesions.
Although basal RMBF (mL·g−1·min−1) derived by use of [15O]H2O PET is unchanged by angiographically mild coronary stenoses, hyperemic RMBF progressively decreases distal to stenoses with >40% diameter reduction15 and is significantly augmented after successful coronary angioplasty of more severe coronary stenoses.16 PET MPR has been correlated with intracoronary flow velocity data acquired with Doppler catheters positioned proximal to stenoses in branching coronary arteries.17 18
However, proximal intracoronary hemodynamic measurements are potentially confounded by competitive flow in branch vessels and collateral flow effects.19 20 This and the technical limitations of 3F (1.0-mm2 cross-sectional area) Doppler catheters prompted the development of 0.018-in.-diameter (0.164-mm2 cross-sectional area) Doppler crystal-tipped angioplasty flow sensor devices that can atraumatically acquire poststenotic coronary flow velocities that are less subject to the problems associated with proximally recorded values.21 22 Studies with this device have shown that although basal Doppler coronary blood flow velocities remain unchanged distal to angiographically mild to moderate coronary stenoses, hyperemic poststenotic CFR is blunted as stenosis severity worsens8 and is improved by successful coronary angioplasty.23
These two methodologically diverse physiological techniques, [15O]H2O PET RMBF and poststenotic Doppler coronary blood flow, have not been directly compared in humans. The clinical application of these studies could improve the accuracy of coronary artery disease assessment, particularly in patients with functionally unpredictable angiographic stenoses of moderate severity. The objective of the present study was to evaluate the relationship between quantitative measurements of angiographic stenosis severity, [15O]H2O PET RMBF, and Doppler coronary flow velocity in the poststenotic vascular bed of patients with stable chest pain with an isolated proximal stenosis in the left anterior descending or circumflex coronary arteries.
It was postulated that correlations between these two physiological parameters (ie, coronary flow and nutritive myocardial perfusion) would exceed correlations of these functional data with quantitative coronary angiographic descriptors of anatomic stenosis severity under basal and hyperemic conditions.
Six male and five female consecutive patients undergoing diagnostic coronary angiography for the evaluation of stable chest pain syndromes between April 1993 and November 1993 were enrolled after providing informed consent. Patients <70 years old (mean age, 53±13 years; range, 30 to 69 years) with an isolated proximal coronary stenosis of the left coronary artery (left anterior descending, 9 patients; left circumflex, 2 patients) and without hypertensive heart disease, microvascular disease (ie, diabetes, collagen-vascular disease, etc), left ventricular dysfunction, prior myocardial infarction, left bundle-branch block, or an allergy or contraindication to dipyridamole were recruited.
Angiographic, PET, and Doppler studies were performed within 1 week of each other without intercurrent changes in clinical status or medical therapy.
Quantitative Coronary Angiography
Selective coronary arteriography was performed in multiple orthogonal views and angulations to optimally define the coronary artery stenosis and to exclude additional coronary lesions. End-diastolic cineangiographic frames were used for quantitative analysis to minimize cardiac motion artifact and to maximize coronary contrast. Overlapping vessels and backfield bony structures adjacent to the index coronary lesion were avoided.24 Coronary artery stenoses of >10% luminal diameter reduction (ie, %DS) of the left anterior descending or left circumflex coronary arteries were measured with a quantitative cardiovascular angiographic software program in two orthogonal angiographic views separated by 90°. The most severe coronary stenosis measurement derived from this analysis was used for comparison with Doppler flow and PET data. The quantification software program (Automated Coronary Analysis, Philips, D.C.I.25 26 ) was used by experienced operators blinded to the intracoronary Doppler and PET data. The following coronary stenosis parameters were derived: vessel segment diameter (in millimeters) proximal to, distal to, and within the obstructive lesion; %DS; and %AS.
Premedications and intraprocedural vasodilator medications were minimized and carefully recorded. Nitroglycerin was not administered before contrast injections during coronary angiography. The contrast agent used was ioxaglate meglumine (39%) and ioxaglate sodium (20%) (Hexabrix). Contrast left ventriculography was performed after diagnostic angiography and Doppler studies.
Coronary Flow Velocity Measurement
Coronary flow velocity measurements were performed by experienced operators using a Doppler-tipped angioplasty guidewire (Cardiometrics, Inc), as previously described.8 21 22 23 In brief, this 175-cm-long, flexible, steerable angioplasty guidewire 0.018 in. in diameter is equipped with a 12-MHz piezoelectric ultrasound transducer at its tip that permits velocity acquisition with a high pulse repetition frequency (up to 90 kHz) from a sampling depth of 5 mm. Coronary flow velocities up to 4 m/s can be recorded without aliasing. This forward-directed ultrasound beam with a 25° divergent angle samples a large portion of the coronary flow profile. The velocity data are processed by on-line fast Fourier transformation with a real-time scrolling spectral gray-scale display and are recorded onto a ½-in. videotape for subsequent off-line analysis. This technique has been used without complications in more than 800 studies at our institution.
After diagnostic angiography and heparinization (5000 U IV), the Doppler guidewire was advanced through a 6F angiographic catheter into the normal reference coronary artery. Baseline flow velocities were first recorded in the angiographically normal reference vessel, after which the guidewire was repositioned in the proximal portion of the stenotic artery. Flow velocities were acquired at least 1 cm proximal to the stenosis at baseline. The guidewire was then advanced 5 to 10 artery diameters beyond the stenosis to record baseline distal coronary velocities. After intravenous administration of dipyridamole, peak stress coronary flow velocities were recorded beginning 4 to 6 minutes later from the poststenotic and the proximal coronary sites and again after the rapid (1 to 2 minutes) transfer of the guidewire back to the normal reference vessel.
Doppler signal analysis was performed by digitization of the coronary flow velocity spectral envelope off-line using a PC/AT computer with custom-developed software interfaced with a digitizing tablet. The outermost margin of each velocity spectrum was digitized to minimize significant intraobserver and interobserver variability. Digitized spectral peak velocity waveforms from five cardiac cycles were averaged to compute the coronary flow velocity under basal and dipyridamole hyperemic conditions. The APV (in cm/s) was derived under basal and hyperemic conditions. The CFR was computed as the ratio of hyperemic to basal APV. On the basis of previous validation studies in our own and other laboratories,20 21 22 23 the lower limit of normal poststenotic CFR is defined as >2.0, the mean value minus 1 SD in patients with angiographically normal coronary arteries.
The relative CFR ratio (theoretically equaling 1.0) between the stenotic and normal reference coronary arterial beds was also computed and compared with a similar [15O]H2O PET MPR ratio derived from corresponding vascular beds.10 The nondiseased left coronary artery branch was used as the reference vessel for the acquisition of normal coronary flow and myocardial perfusion data in all but one patient, in whom the right coronary vessel was used.
Pharmacological Stress With Dipyridamole
To ensure sustained and comparable hyperemic coronary flow between the Doppler and PET studies, an intravenous infusion of dipyridamole in a dose of 0.56 mg/kg over a period of 4 minutes (140 μg·kg−1·min−1) was initiated with the guidewire positioned in the poststenotic portion of the stenotic artery. Maximal dipyridamole hyperemic intracoronary flow velocity data were recorded beginning 4 to 6 minutes after the end of drug infusion; flows, heart rate, and blood pressure were monitored continuously during the infusion. Maximal dipyridamole-induced coronary hyperemia is sustained at peak levels for ≥20 minutes in humans.27
All studies were performed in the morning with the patients in a fasting state. Cardiac medications were not interrupted before drug stress studies. Methyl xanthine–containing medications, food, or drinks were withheld for >48 hours before both studies. Sublingual nitroglycerin and parenteral aminophylline were available but were not required to reverse dipyridamole side effects.
[15O]H2O Myocardial PET Studies
A validated [15O]H2O PET myocardial perfusion imaging protocol was used (Fig 1⇓).12 28 After the patient was positioned in the SP-3000E whole-body time-of-flight PET imaging system,29 a transmission scan of the chest was obtained with a 68Ge/68Ga ring source to correct for photon attenuation of the emitted radiation and to ensure that four to six of the seven cross-sectional imaging planes intersected the myocardium.
After collection of attenuation data, 40 to 50 mCi of [15O]CO was administered by inhalation to label red cells in the blood pool. After 30 to 60 seconds for clearance of labeled [15O]CO from the lungs, emission data were collected for 5 minutes under basal conditions. [15O]H2O (0.4 mCi/kg) was then injected as a bolus through a large-bore antecubital vein catheter, with data collected for 150 seconds after the onset of tracer administration in list mode. After a 5- to 10-minute interval for decay of activity to baseline levels, dipyridamole (0.56 mg/kg IV) was administered over a period of 4 minutes (in a manner identical to that used for the Doppler flow velocity study), and the [15O]H2O PET imaging sequence was repeated beginning 4 to 6 minutes after cessation of dipyridamole infusion to assess the maximal hyperemic myocardial blood flow response. [15O]CO (40 to 50 mCi) was then readministered.
Transaxial slices were reconstructed with a center-to-center slice separation of 1.5 cm and slice thickness of 1.14 cm. Filtered reconstructions of these high-resolution emission data provide resolution within the plane of reconstruction of 13.5 mm. A single 120-second [15O]H2O data acquisition was reconstructed for ROI placement. Data obtained in the 120-second composite acquisition after administration of [15O]H2O were corrected on a pixel-by-pixel basis for [15O]H2O remaining in the vasculature. Unsubtracted [15O]H2O data were reconstructed into eighteen 5-second frames (total of 90 seconds) after the appearance of activity in the left atrial blood pool. Decay-corrected counts per data point were then computed from each 5-second frame. Calculation of RMBF within each myocardial ROI requires knowledge of the arterial input function (obtained from an ROI) and the myocardial time-activity profile of [15O]H2O. Absolute RMBF (mL·g−1·min−1) was calculated by use of a previously validated one-compartment kinetic model, with data corrected for attenuation, tracer decay, partial volume effect, and count spillover.
A total of seven transverse images were available for the analysis of RMBF. From these images, the three transverse slices in which septal, anterior, lateral, and posterior myocardial activity could all be identified were selected for the placement of ROIs. The averages of those PET perfusion data derived from midventricular and apical ROIs found distal to the index coronary stenosis were compared with corresponding distal intracoronary Doppler flow data.
Myocardial ROIs of ≈3 cm3 (1×3×1 cm) were placed within predefined vascular distributions subtending the left anterior descending (anterior ROI) and left circumflex (lateral ROI) coronary beds. The septal ROI was placed in the most anterior and apical part of the septal myocardial activity but was not analyzed so as to minimize the chances of including basal-inferoseptal myocardium supplied by the right coronary artery. Posterior wall measurements demonstrated RMBF interstudy measurement variability comparable to those obtained from the other vascular territories; these were used in the normal reference RMBF calculation of one patient (patient 1).
Group values (mean±SD) are reported for the clinical, angiographic, intracoronary Doppler, and PET myocardial perfusion parameters. Correlations between continuous angiographic, intracoronary hemodynamic, and PET imaging data were performed by linear regression (Pearson product moment) with commercially available statistical software. Two-way ANOVA was used to compare multiple subgroups of continuous variables. Intergroup differences were considered significant at a probability value of P<.05 to reject the null hypothesis.
The mean %DS reduction was 59±23% (range, 10% to 98%), and the mean %AS was 80±24% (range, 17% to 99%) (Table 1⇓). Mean luminal diameter of the stenotic segment of the index artery was 1.32±1.08 mm, and minimal luminal diameter of the normal reference artery was 2.76±0.57 mm.
Hemodynamics During Dipyridamole
The basal heart rate did not differ between Doppler and PET studies (81±21 versus 71±14 bpm; P=NS) (Table 2⇓). Peak dipyridamole heart rates were also similar (94±17 versus 87±14 bpm; P=NS). Systolic blood pressure was comparable under basal conditions (141±23 versus 138±21 mm Hg; P=NS) and at peak stress (128±22 versus 137±17 mm Hg; P=NS).
Basal cardiac double product between Doppler and PET studies (10 700±3900 versus 9500±2200; P=NS) and peak dipyridamole stress cardiac double product were also comparable (12 200±4300 versus 11 500±1700; P=NS). There were no serious adverse reactions during dipyridamole infusion.
Doppler Coronary Blood Flow
The APV increased significantly during hyperemia in both the index vessel (19±6 to 45±19 cm/s; P<.01) and the reference vessel (22±10 to 58±22 cm/s; P<.01) (Table 3⇓). The CFR increased to an average of 2.3±0.7 in the index vessel, compared with 2.8±0.7 in the reference vessel (P<.03). The relative Doppler CFR was 0.86±0.21.
Index coronary artery volumetric flow increased from a mean value of 49±26 to 120±85 mL/min during hyperemia (P<.05). Volumetric flow in the reference vessel increased to a greater mean level during hyperemia (54±28 versus 150±97 mL/min; P<.05).
PET Myocardial Blood Flow
RMBF in the index vessel increased from 1.3±0.4 to 2.7±0.9 mL·g−1·min−1 during hyperemia (P<.05) (Table 4⇓). In the reference artery, PET RMBF increased from 1.3±0.4 to 2.8±0.7 mL·g−1·min−1 during hyperemia (P<.05).
The mean MPR in the index vessel was 2.1±0.8, compared with 2.4±0.9 in the reference vessel (P=NS). Relative MPR, the ratio of PET perfusion reserve between the index and reference arteries, averaged 0.83±0.25.
Correlation of Doppler Flow and PET Myocardial Perfusion
There was a significant correlation between Doppler coronary APV and PET RMBF (r=.60; P<.001; Fig 4⇓). A highly significant linear correlation was observed between Doppler-derived CFR and PET-derived MPR over a wide range of flows in the index and reference vessels (r=.76; P<.0002; Fig 5⇓).
A trend toward a correlation existed between Doppler-derived CFR and minimal luminal diameter (r=.41; P<.07). No correlation was obtained between PET-derived perfusion reserve and minimal luminal diameter, %DS, stenosis length, or %AS.
This study shows that in a small but well-defined population with a range of proximal stenoses of the left coronary artery, quantitative [15O]H2O myocardial PET RMBF and poststenotic Doppler coronary APV were correlated under basal and hyperemic conditions. A stronger correlation occurred between poststenotic Doppler-derived CFR and PET MPR. Significant correlations were not obtained when isolated quantitative angiographic lesional data were compared with these physiological data; an analysis of the integrated effects of multiple stenosis dimensions and determination of angiographic flow reserve was not performed. Future studies with more complete geometric analysis integrating all dimensions may improve the correlation between stenosis geometry and CFR obtained by the PET and/or Doppler wire techniques.30
Previous PET Correlations of Stenosis Severity
The Doppler coronary blood flow velocity technique measures normal and poststenotic flows under varied physiological conditions,20 21 22 23 supplying information previously restricted to noninvasive myocardial perfusion imaging.11 12 16 31 32 33 The relative MPR values obtained with [15O]H2O PET and Doppler coronary flow analysis in the present study were comparable to those derived by Goldstein et al,10 who used 82Rb or [13N]NH3 PET. In these studies, considerable scatter was noted about curves correlating angiographic and physiological parameters, reinforcing the known limitations of coronary angiography in comparing two-dimensional geometric descriptors of coronary anatomy with functional measures of coronary physiology, especially in the intermediate range of stenosis severity.30 The correlation of two physiological end points of coronary blood flow more accurately reflects the functional severity of coronary stenoses than angiography alone.8 9 31
PET myocardial imaging during dipyridamole-induced coronary vasodilation with either [13N]NH3 or 82Rb (References 7 and 8, respectively) has been used to derive MPR. Although PET imaging is 95% sensitive for coronary lesions with an angiographically determined flow reserve <3.0, the diagnostic accuracy of PET imaging decreases when angiographically less severe (ie, intermediate) lesions of ≈50% diameter stenosis (versus >70%) are considered significant.15 33
The absolute quantification of RMBF can be achieved by use of PET with either [13N]NH3 or [15O]H2O (References 13, 31, and 34, and 11 and 12, respectively). [15O]H2O has several advantages as a PET blood flow tracer, including the properties of being a readily diffusible, nonmetabolized tracer with purely flow-dependent myocardial kinetics35 and a short physical half-life. Techniques for the conversion of regional [15O]H2O tomographic myocardial distribution to quantify RMBF have been validated in humans over a wide range of flows.11 12 16 28
Intermediate Coronary Stenosis Assessment
Variations in [15O]H2O PET image homogeneity and derived perfusion measurements reflect regional differences in myocardial tracer uptake. A relative PET MPR of 1.0 has been reported when vessels with stenoses ranging from 21%DS to 60%DS (mean, 46±12%DS) are compared with normal reference vessel beds.10 This suggests that angiographically normal vessels and vessels with intermediate stenoses may respond similarly to hyperemic stress, because of either a limited vasodilatory response of the normal reference bed, inaccuracy (ie, overestimation) of angiographic lesion severity in the diseased bed, or underestimation of angiographic disease severity in the normal reference bed.
Although Uren et al15 were able to clearly distinguish severe (>70%DS) from mild (<30%DS) stenoses with [15O]H2O PET (MPR, 1.3±0.8 versus 4.6±0.8; P<.05), a larger subset of their population (19 of 35 patients) with intermediate severity (30%DS to 70%DS) lesions had a mean stenosis severity and a perfusion reserve that did not differ from a control population (52±11%DS versus 56±20%DS and 2.0±1.0 versus 2.1±1.3, respectively).
Recent studies from our own laboratory8 22 using poststenotic intracoronary flow velocity data have demonstrated a wide range of poststenotic CFR responses in patients with intermediate coronary artery stenosis severity (56±14%DS). PET imaging data derived by other investigators indicate that considerable variability also exists in flow and perfusion in angiographically normal vascular beds.15 31 34
The limitations of using isolated quantitative angiographic lesional parameters for determining the physiological characteristics of a coronary lesion are well known,24 36 37 especially in the setting of intermediate-severity coronary stenoses as encountered in this study.9 30 The administration of nitrates before angiography reduces the potential for interstudy lesion variability secondary to alterations in vasomotor tone.38 This procedure was not routinely applied in our study so as to reduce variation in coronary flow velocity data by persisting nitrate vasodilating effects occurring over the hyperemic period. The volumetric flow data could theoretically have been modified by pretreatment with nitrates or dipyridamole or at high flow rates, all of which may affect vessel cross-sectional area.
[15O]H2O PET perfusion imaging has some limitations. After blood pool activity subtraction using [15O]CO in the blood pool, [15O]H2O PET myocardial images are not as smooth as those observed with 82Rb or [13N]NH3. Quantification of RMBF from transverse PET images is not ideal and requires meticulous correction for cardiac motion and partial volume effects and an accurate determination of the arterial input function.12 14 Previous studies have reported higher than optimal variability in normal resting/basal (35±10%) and hyperemic (29±15%) RMBF,16 which may limit the ability of [15O]H2O PET to independently differentiate subtle RMBF differences in serial studies.
This and previous studies15 16 have preferentially excluded populations with multivessel CAD, reducing the potential complexities associated with balanced coronary disease (ie, absence of a true normal reference vascular bed), coronary collateral flow effects, and the need for measurements of Doppler flow and perfusion in all arterial beds. However, the potential for false-negative myocardial imaging studies in patients with balanced multivessel CAD that reduces the flow heterogeneity required for standard perfusion defect visualization is theoretically reduced by absolute RMBF determinations derived with [15O]H2O PET.
Finally, relatively simple techniques39 40 and more sophisticated methods for the quantification of left ventricular mass41 and of coronary vascular bed size42 have been reported, but these were not applied to correct regional coronary flow data for the size of the vascular bed in the present study.
Quantitative PET myocardial perfusion and poststenotic Doppler flow velocity are correlated and can be used clinically to distinguish the physiological significance of coronary lesions in humans. The application of these quantitative physiological techniques in the clinical assessment of coronary artery disease provides objective evidence of lesion significance, which may also be useful to support the decision for coronary revascularization interventions, especially in patients with angiographically intermediate coronary stenoses in which a range of flow reserve abnormalities exists.
Selected Abbreviations and Acronyms
|%AS||=||percent cross-sectional area stenosis|
|%DS||=||percent diameter stenosis|
|APV||=||average peak flow velocity|
|CFR||=||coronary flow velocity reserve|
|MPR||=||myocardial perfusion reserve|
|PET||=||positron emission tomography|
|RMBF||=||regional myocardial blood flow|
|ROI||=||region of interest|
This study was funded in part by grant HL-46895 from the National Institutes of Health. The authors would like to thank Lori Gallini for her secretarial assistance.
Presented in part at the 41st Society of Nuclear Medicine Meeting, Orlando, Fla, June 5-8, 1994, and at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90[pt 2]:I-447).
- Received January 9, 1996.
- Revision received May 31, 1996.
- Accepted June 10, 1996.
- Copyright © 1996 by American Heart Association
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