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1Department of Cardiology and 2Department of Medical Physics, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands
Submitted 10 December 2002 ; accepted in final form 18 June 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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microcirculation; coronary disease; physiology; blood flow; blood pressure
The ratio of mean distal pressure to average peak blood flow velocity can be used as an index of microvascular resistance (MRv) (14, 18). The purpose of this study was to investigate the influence of epicardial stenosis on the resistance of the downstream microcirculation assessed by intracoronary-derived pressure and Doppler flow velocity measurements in patients with coronary artery disease.
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METHODS |
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Study protocol. Twenty-seven patients underwent routine coronary angiography during which intracoronary measurements were performed. All oral (antianginal) medication was continued before this study. Coronary lesion severity was determined by quantitative coronary angiography (QCA). Main coronary arteries [i.e., right coronary artery (RCA), left anterior descending coronary artery (LAD), and the left circumflex artery (LCx)] were functionally divided per patient into the following: an angiographically normal reference artery (artery 1); an artery with the less severe narrowing (artery 2); and an artery with the more severe narrowing (artery 3). Thus measurements in each artery represented a different myocardial perfusion area. Flow velocity and pressure were measured sequentially distal to the coronary narrowings and in the reference artery in all patients. Furthermore, all lesions in artery 3 (with a severe coronary narrowing) were treated with PTCA; Doppler flow measurements were repeated afterwards. The study protocol was approved by the Medical Ethics Committee of our institution; all patients gave written informed consent.
Quantitative coronary angiography. Coronary angiography was performed according to standard procedure as previously described (3). Coronary lesion severity was measured by QCA using the CMS-QCA software version 3.32 (MEDIS, Leiden, The Netherlands) (23). Coronary lesion severity was expressed as the percent diameter stenosis (%DS) and minimal lumen diameter (in mm; MLD) using an automated contour detection algorithm, and the reference diameter was measured (in mm). Coronary lesion severity was assessed on a end-diastolic frame in two, if possible, orthogonal views. The projection showing the most severe coronary narrowing in %DS was used.
Intracoronary hemodynamic measurements. Measurements were performed in all patients in the LAD, LCx, and RCA. An intracoronary bolus of 0.1 mg nitroglycerin was administered every 30 min to ensure maximal epicardial vasodilation. All measurements were performed at baseline and during hyperemia and repeated two or three times to test reproducibility. Hyperemia was induced by administering an intracoronary bolus of adenosine (15 µg in the RCA and 20 µg in the LCx).
Translesional blood flow velocity was measured with a 0.014-in. Doppler guide wire (FloWire, JOMED; Rancho Cordova, CA). The Doppler guide wire was advanced distal to the stenosis; care was taken to avoid poststenotic turbulent flow, and the distal tip was not placed adjacent to side branches. Distal baseline and hyperemic blood flow velocity data were obtained, and the Doppler signals were processed by a real-time spectral analyzer (9).
Intracoronary pressure was measured with a 0.014-in. pressure guide wire connected to the pressure console (RADI Medical Systems; Uppsala, Sweden). After calibration with the pressure console, the accuracy of the signal was verified using the aortic pressure as measured through the guiding catheter. The wire was advanced with the pressure sensor at least 3 cm distal to the lesion. No pressure wire was introduced in the reference vessels and post-PTCA; the pressure as measured through the guiding catheter was used to calculate the MRv.
An index of minimal microvascular resistance (in mmHg · cm–1 · s–1) during baseline (bMRv) and maximum hyperemia (hMRv) was defined as the ratio of mean distal pressure to average peak blood flow velocity (14). Pressure and blood flow velocity data were obtained sequentially using two guide wires. The ability of the resistance vessels to dilate under maximal hyperemic conditions was expressed as bMRv minus hMRv; this ability was also expressed as a percentage of baseline.
The coronary circulation was modeled as a series of three of resistances, each reflecting a certain behavior: the stenosis resistance (Rs) in the epicardial conduit artery, the variable arteriolar resistance vessels (Rres), and the minimal microvascular resistance (Rmin) present during maximal hyperemia (22). By definition, the microvascular resistance is defined as the sum of the two resistances present distal of an epicardial coronary narrowing. Therefore, as indicated in Fig. 1, bMRv represents the sum of the latter two, whereas hMRv is minimum microvascular resistance during hyperemia (assuming that the resistance vessels are maximally dilated), and thus bMRv-hMRv represents the resistance vessels during baseline conditions.
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Statistical considerations. Data are expressed as means ± SD. Skewed data distributions are presented as median and range, and nonparametric statistical tests were performed: the Wilcoxon-signed rank test was used for paired comparisons within patients, i.e., comparison of bMRv and hMRv values in all three arteries, and pre-PTCA and post-PTCA comparison of MRv in artery 3. The Page test for ordered alternatives (19) was applied to compare the MRv value for the three different perfusion areas within patients based on their division in artery 1, artery 2, and artery 3. Data analysis was performed using the SPSS 10.0.5 software package for Windows (SPSS 1999; Arlington, VA). A P value of <0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Microvascular resistance index. Hemodynamic data of all patients during baseline and hyperemic conditions are summarized in Table 2. Variability of the repeated measurements of the indexes was 2.6–4.9% for pressure and 7.9–9.8% for Doppler flow velocity measurements. The MRv was significantly lower during hyperemia compared with baseline conditions for all three vessels (median values for artery 1, 1.69 vs. 6.50, P < 0.001; artery 2, 2.08 vs. 6.38, P < 0.001; artery 3, 2.56 vs. 4.94, P < 0.001; respectively). The mean ability of resistance vessels (expressed as a percent decrease of baseline value) to reduce microvascular resistance during maximal hyperemia was 74% for artery 1, 67% for artery 2, and 48% for artery 3.
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MRv data are represented in histograms in Fig. 3. No significant trend was detected between the bMRv of the three arteries (Page test: Z score –1.225; P = 0.11). However, the bMRv of artery 3 is lower than that of artery 2 (P = 0.022) and tended to be lower than that for artery 1 (P = 0.075), although this difference did not reach significance (Fig. 3A). In contrast, a statistically significant difference was found between the hMRv values of the different arteries (Page test: Z score 2.041; P = 0.021), which was confirmed by pair-wise comparisons (Fig. 3B); hMRv of artery 3 was significantly higher than the hMRv of artery 1 (P = 0.001) and artery 2 (P = 0.029). The difference between bMRv and hMRv, representing the resistance of the arterioles at baseline (Rres), was significantly higher for artery 1 and artery 2 than for artery 3 (Page test: Z score –3.402; P < 0.0001), which was confirmed by pair-wise comparisons: bMRv – hMRv of artery 3 is significantly lower than those for artery 1 (P = 0.001) and for artery 2 (P = 0.001), as illustrated in Fig. 3C. Hence, the effect of the compensatory vasodilatation at baseline induced by the pressure drop resulting from a stenosis was noticeable in this patient group.
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Furthermore, from Fig. 3 it can be appreciated that the resistance distributions in the different perfusion areas show a considerable variation within each group but also between groups at the same conditions of baseline versus hyperemia.
MRv pre- and post-PTCA. All lesions in artery 3 underwent a PTCA procedure. In two patients, no-flow velocity measurements were performed post-PTCA because the PTCA procedure was not successful. Therefore, the MRv of artery 3 obtained post-PTCA was calculated in 25 patients (93%). The median MRv value during hyperemia declined from 2.56 pre-PTCA to 1.85 post-PTCA (P < 0.009). In total, 19 of 25 patients (76%) showed a decline of the MRv. In Fig. 4, pre- and post-PTCA MRv distributions are plotted below the distribution of the reference vessels (artery 1). The minimal microvascular resistance after PTCA was significantly reduced to values comparable to those of artery 1. Moreover, there was no statistical difference between the MRv value of artery 1 and post-PTCA in artery 3 (median value 1.69 and 1.85, respectively; P = 0.67), suggesting that treating the epicardial stenosis also influences the microvascular resistance toward normal values.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Relation between severity of coronary artery disease and microvascular resistance. The present results demonstrate that minimal microvascular resistance is higher distal to hemodynamically significant stenosis compared with vessels without stenosis in the same patient. These results are in accordance with the work of Sambuceti and others (17), who also found a paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease that was reversed by angioplasty. We hypothesize that the pressure dependence of the microvascular resistance vessels is an explanation for the found higher hMRv distally of epicardial narrowings (5, 12, 17, 20). It is obvious that the distal pressure depends on the severity of coronary narrowing in the epicardial conduit artery (see Table 2). A higher MRv can be explained by a paradoxical vasoconstriction as a result of passive collapse of larger-sized (>100 µm) arterial microvessels due to reduced distending pressure (12). This suggestion is supported by the effect of angioplasty, which restored distal pressure and resulted in MRv values that did not significantly differ from values in the reference vessels without focal coronary narrowings (artery 1). Further research is mandatory to elucidate the underlying mechanism.
Spatial heterogeneity of the resistance in the coronary microcirculation. The present study showed spatial heterogeneity of the MRv during hyperemic conditions (see Fig. 3B) representing Rmin. Despite the large variability between the groups, the hMRv downstream of the most severely diseased vessel (artery 3) was demonstrated to be significantly higher. This suggests that the differences in hMRv are modulated by the pressure changes as a result of epicardial coronary artery disease. This finding is independent of the autoregulatory mechanism that acts solely on the Rres, represented by bMRv – hMRv, whose value was lower in the narrowed arteries (Fig. 3B). These results are important in view of the concepts of intracoronary-derived hemodynamic parameters that assume homogeneity in the behavior of the myocardial resistance beds of the major perfusion areas within the same heart.
At baseline, a difference in arteriolar resistance (bMRv – hMRv) was found between arteries 3 and 2 and between arteries 3 and 1, but not between arteries 2 and 1, because the difference in distal pressure (Pd) between artery 1 and 2 is small under resting conditions. Hence, MRv is only marginally different in those conditions where MRv is reduced to compensate for the pressure gradient over the stenosis (autoregulation). However, because of the nonlinear relation between pressure gradient and flow velocity, this difference in Pd between artery 1 and artery 2 is larger during hyperemia when autoregulation is abolished by definition. Artery 2 can thus be considered a "hybrid" of artery 1 and artery 3.
Comparison with other studies. In 1990, a study in dogs found that coronary flow reserve is spatially heterogeneous and determined by two distinct perfusion patterns: the resting (control) pattern and the maximal perfusion pattern (1). Normal hearts, therefore, contain small regions that may be relatively more vulnerable to ischemia. This may explain the patchy nature of infarction with hypoxia and at reduced perfusion pressures as well as the difficulty of using global parameters to predict regional ischemia (1).
Recently, Chareonthaitawee et al. (4) showed that there is variability of myocardial blood flow as measured with PET, both between and within 169 healthy volunteers. They demonstrated spatial flow heterogeneity among four perfusion regions (anterior, septal, inferior, and lateral) within each individual during hyperemic conditions. These data are in accordance with previous reports (8) and describe naturally occurring flow heterogeneity in normal hearts. Our data show in addition that the presence of a stenosis leads to a more organized heterogeneity of microvascular resistance that is associated with the severity of a lesion in a proximal segment and is induced by another mechanism most likely related to passive collapse of distal vessels (11, 20).
Limitations. Flow velocity and pressure were sequentially measured after exchanging the Flowire for the pressure wire. No significant hemodynamic changes in blood pressure and heart rate occurred between the measurements. For practical reasons, we used the aortic pressure as measured through the guiding catheter to determine MRv in the reference vessel and post-PTCA in artery 3. However, an angiographically apparently normal reference artery does not exclude the presence of atherosclerotic disease (15). Our QCA data showed a median diameter stenosis of 16% in the reference vessels. It was suggested that a decline in pressure might be present in these diffusely diseased vessels without a focal stenosis (7, 10). It was demonstrated that this decline is most likely no more than 0.12–0.25 mmHg/cm during maximal hyperemia (2, 6). Therefore, it is conceivable that this limitation of the protocol did not influence the main conclusions drawn from this study.
We used a Doppler guide wire to assess blood flow velocity in the three coronary arteries, whereas coronary blood flow may be dependent on arterial dimensions. Vessel diameter in the coronary circulation is scaled to the perfusion area of the vessel, and velocity normalizes flow for differences in coronary arterial diameter due to branching (16). Blood flow velocity may thus well be more appropriate for calculating an index of microvascular resistance than volume flow. The use of velocity to calculate the resistance index would be limited in a setting of variable area. However, active changes in vessel area during the procedure were minimized by administration of intracoronary nitroglycerin.
It is known that coronary flow occurs mainly during diastole, and the pressure amplitude can significantly increase at the distal site of a coronary stenosis (21). The magnitude of the distal pressure amplitude depends on the severity of coronary stenosis. We did not record pulsatile pressure in the present study, but mean values were obtained online in the catheterization laboratory. Mean flow (velocity) at a given mean distal pressure was used to calculate the mean resistance value. This is appropriate because mean and not diastolic pressure is regarded as the driving pressure for the coronary circulation (21).
Variability in flow velocity or pressure measurements may contribute to the detected heterogeneity in hMRv. However, this variability varied between 2% and 5% for pressure, 8% and 10% for flow velocity measurements, and 7% and 13% for the hMRv. This indicates that the observed heterogeneity in hMRv cannot be explained by the variability of the pressure or flow velocity measurements.
Although no visible collaterals were present in these patients (according to Rentrop classification), we cannot exclude a confounding effect of recruitable collateral flow, especially in areas supplied by the severely narrowed coronary arteries.
Clinical implications. For clinical practice, the fact that the spatial heterogeneity in MRv exists during hyperemia indicates that the role of relative CFVR for patient management is of limited value considering the more extensive acquisition requirements (both stenotic and reference vessel must be instrumented with a Doppler guide wire) because homogeneity of microvascular resistances in the adjacent perfusion regions is a prerequisite for this index. In addition to previous reports (4), these findings are also relevant for the interpretation of the results of regional myocardial perfusion for all stress test modalities using imaging techniques in this patient cohort that warrants testing in a direct comparative study.
Our results provide novel insight into the dynamic behavior of the coronary microcirculation in the presence of epicardial narrowings that is relevant for the interpretation of diagnostic noninvasive and invasive tests as well as the evaluation of pharmacological or mechanical coronary interventions.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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