CLINICAL STUDIES
Simultaneous intracoronary velocity- and pressure-derived assessment of adenosine-induced collateral hemodynamics in patients with one- to two-vessel coronary artery disease
Christian Seiler, MD, FACCa,
Martin Fleisch, MDa,
Michael Billinger, MDa and
Bernhard Meier, MD, FACCa
a Division of Cardiology, University Hospital, Swiss Cardiovascular Center Bern, Bern, Switzerland
Manuscript received September 10, 1998;
revised manuscript received August 16, 1999,
accepted September 1, 1999.
Reprint requests and correspondence: Dr. Christian Seiler, Division of Cardiology, Swiss Cardiovascular Center Bern, Inselspital, CH-3010 Bern, Switzerland.
christian.seiler.cardio{at}insel.ch
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Abstract
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OBJECTIVES
The purpose of this investigation in patients with poorly and well developed coronary collaterals was to assess the influence of collateral and collateral adjacent vascular resistances and, in part, a stenotic lesion of the collateral supplying vessel on the hemodynamic collateral responses to adenosine.
BACKGROUND
In humans, little is known about the functional behavior of the coronary collateral circulation.
METHODS
In 50 patients with one- and two-vessel coronary artery disease (CAD) undergoing percutaneous transluminal coronary angioplasty (PTCA), collateral flow index (CFI, no unit) changes and vascular resistance index (R, cm/mm Hg) changes of the collateral (Rcoll) and the distal collateral receiving (R4) vessel in response to adenosine (140 µg/min/kg IV) were measured by intracoronary (i.c.) Doppler and pressure guidewires. The variables were determined at baseline and during adenosine in patients with poor (angiographic collateral degree before PTCA <2 of 0 to 3) and good coronary collaterals.
RESULTS
Pressure-derived CFI (CFIp) decreased under adenosine in patients with poor collaterals, and it increased in the group with good collaterals. There were inverse correlations between the adenosine-induced change in CFIp and the change in Rcoll (r = 0.61, p = 0.0001). In the group with good, but not with poor collaterals, there was also a significant correlation between CFIp increase and the decrease in R4, between the severity of the contralateral stenosis and CFIp augmentation and among the left versus right coronary artery as ipsilateral vessel and CFIp change.
CONCLUSIONS
Overall, patients with well, versus poorly developed coronary collaterals do better regarding the capacity to increase collateral flow in response to adenosine. In patients with good, but not poor, collaterals, an adenosine-induced collateral flow increase depends on the ipsilateral distal vascular resistance decrease, but is also directly influenced by the severity of a contralateral stenosis and probably by the size of the collateralized vascular bed.
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Abbreviations and Acronyms
| | ANOVA | = analysis of variance | | CAD | = coronary artery disease | | CFI | = collateral flow index | | CFIp | = pressure-derived collateral flow index | | CFIv | = velocity-derived collateral flow index | | CFVR | = coronary flow velocity reserve | | CVP | = central venous pressure | | ECG | = electrocardiogram | | FFR | = fractional flow reserve | | i.c. | = intracoronary | | LAD | = left anterior descending artery | | LCX | = left circumflex artery | | Pao | = mean aortic pressure | | Poccl | = distal coronary occlusive (wedge) pressure | | PTCA | = percutaneous transluminal coronary angioplasty | | RCA | = right coronary artery | | Rcoll | = collateral resistance index | | R1 | = epicardial vascular resistance | | R3 | = contralateral resistance index | | R4 | = ipsilateral resistance index | | Vioccl | = distal velocity time integral during vessel occlusion | | Viø-occl | = distal velocity time integral during vessel patency |
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The often documented benefit of the human coronary collateral circulation on myocardial ischemia (1) depends not only on its anatomical development but also on its vascular function. Moreover, the effect of collaterals is influenced by the vasomotor function of vascular beds adjacent to it. The vascular network of the collaterals together with the surrounding vascular bed with their interdependent and changing vessel resistances (Fig. 1) may determine the beneficial or disadvantageous nature (i.e., collateral steal [2–4]) of collaterals; for example, a drop in the collateral supplying vascular resistance during hyperemia which exceeds that of the collateral receiving bed may induce a steal phenomenon via the collaterals. Analysis of the interrelations of vascular resistances ideally requires simultaneous intracoronary blood flow and perfusion pressure measurements in the ipsi- and contralateral vascular regions during occlusion of the collateral-receiving vessel (angioplasty model). Whereas such studies, particularly those involving pharmacologically induced collateral hemodynamic changes, have not been performed in humans so far, a few similar investigations in patients with naturally developing occlusions (coronary occlusion model) have been done using nuclear cardiology techniques (5–7). Since the first descriptions of collateral flow detection and measurement using intracoronary (i.c.) Doppler guidewires (8,9), there have been a few reports describing the hemodynamics of variably developed collaterals (4,10–12). According to some of those reports comprising patients with one-vessel (12), but also multivessel, coronary artery disease (CAD) (4), it appears that poorly, as well as extensively, developed collaterals tend to function inadequately regarding the adenosine-induced blood supply enhancement to the vascular region in need, whereas intermediate collaterals have a capacity to augment flow. We hypothesized that poor collaterals tend to augment flow during hyperemia inadequately due to their underdevelopment, whereas well developed collaterals may react insufficiently to a hyperemic stimulus because of a hemodynamic interaction among the collateral receiving and supplying bed.
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Figure 1 Diagram showing two coronary arteries with interconnecting collaterals (depicted as one anastomosis). The stenotic lesion on the left side is occluded by an angioplasty balloon. Angioplasty guidewire-based Doppler- and pressure-sensors are positioned distal to the occluded stenosis in order to measure simultaneously occlusive i.c. velocity (i.e., velocity time integral, Vioccl, cm) and pressure (Poccl, mm Hg). At the same time, Pao is determined via the angioplasty guide catheter. A pressure- and velocity-derived collateral flow index (CFIp, mm Hg/mm Hg; CFIv, cm/cm) can be calculated as shown on the right side by additional measurement of the distal i.c. velocity during vessel patency (Viø-occl, cm; CVP = 5 mm Hg). The vascular resistance indexes of the collateral circulation (Rcoll, mm Hg/cm) and of the collateral-receiving (i.e., ipsilateral) microcirculation (R4) can be computed. Resistance indexes of the contralateral side (R1 and R3) cannot be determined. CFIp = pressure-derived collateral flow index; CFIv = velocity-derived collateral flow index; CVP = central venous pressure; i.c. = intracoronary; Pao = mean aortic pressure; Poccl = distal coronary occlusive pressure; Rcoll = collateral resistance index; R1 = epicardial vascular resistance; R3 = contralateral resistance index; R4 = ipsilateral resistance index; Vioccl = distal velocity time integral during vessel occlusion; Viø-occl = distal velocity time integral during vessel patency.
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The purpose of this investigation in patients with both poorly developed and well developed coronary collaterals was, thus, to assess the influence of collateral vascular resistances and, in part, a stenotic lesion of the collateral supplying vessel on the hemodynamic collateral responses to adenosine.
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Methods
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Patients.
Fifty patients (age 59 ± 10 years: 36 men, 14 women) with one- and two-vessel CAD were included in the study. Intracoronary collateral flow velocity data of 38 of the patients have been described previously (4). All 50 patients underwent percutaneous transluminal coronary angioplasty (PTCA) of at least one stenotic lesion because of CAD-related symptoms. No patient included in the study had unstable angina pectoris and none was on heparin. This investigation was approved by the institutional ethics committee, and the patients gave informed consent to participate in the study. The study population was divided into two groups according to the angiographic collateral degree (according to Rentrop [13], obtained before coronary artery occlusion) of <2 (poor collaterals) or  2 (good collaterals).
Cardiac catheterization and coronary angiography.
Patients underwent left heart catheterization for diagnostic purposes. Aortic pressure was measured using the PTCA guiding catheter. Biplane left ventricular angiography was performed followed by coronary angiography. Ipsi- as well as contralateral (n = 21) coronary artery stenoses were estimated quantitatively as percent diameter reduction using the guiding catheter for calibration. Angiographic collateral degrees (0 to 3) were determined by two independent observers according to the extent of epicardial coronary artery filling via collaterals with contrast medium from the contralateral side before PTCA: 0 = no filling of the distal vessel via collaterals, 1 = small side branches filled, 2 = major side branches of the main epicardial vessel filled, 3 = main epicardial vessel filled by collaterals (13). The origin of the collaterals (contralateral side) was determined.
Intracoronary Doppler flow velocity.
Intracoronary Doppler flow velocity measurements were performed using a 0.014 in. ( mm in diameter) PTCA Doppler guidewire with a 12-MHz piezoelectric crystal at its tip (FloWire, EndoSonics, Rancho Cordova, California). This Doppler guidewire has been shown to accurately measure phasic flow velocity patterns and to track linear changes in flow rate (14). With regard to the assessment of collaterals, the validation of the Doppler guidewire has been described elsewhere (15).
Coronary flow velocity reserve (CFVR) distal to the stenosis was determined by dividing hyperemic peak flow velocity averaged over three cardiac cycles (i.e., average peak flow velocity, cm/s) by APV at rest. Coronary flow velocity reserve measurements were performed in all ipsilateral stenoses before and after PTCA and in 12 of the contralateral stenoses before PTCA. Hyperemia was induced using an i.c. bolus of 18 µg adenosine for the left and 12 µg adenosine for the right coronary artery (16).
The velocity-derived index of collateral flow to the balloon-occluded vascular region relative to normal resting flow during vessel patency (velocity-derived collateral flow index [CFIv], no unit) was determined as the ratio of flow velocity time integral distal to the occluded stenosis (Vioccl, cm) divided by that obtained at the identical location after PTCA (i.e., not occluded, Viø-occl, cm): Vioccl/Viø-occl (Figs. 1 and 2) (15). Vi represents the integral of flow velocities over time during a cardiac cycle (averaged over two cycles). In patients revealing temporally shifted bidirectional velocity signals, ante- and retrograde Vi were added to obtain Vioccl. The rationale behind this procedure was that even locally retrograde collateral flow (detected as a negative velocity signal) finally reaches the myocardium as antegrade flow via branches originating proximal to the tip of the Doppler wire. Furthermore, unpublished data from our laboratory in 30 patients undergoing PTCA have shown that added bidirectional flow velocity signals as compared with only antegrade, only diastolic signals or to the ratio between ante- and retrograde signals yielded the best correlation coefficients relative to pressure-derived CFIp (slope of the linear, direct regression = 0.85, intercept = 0.02, r = 0.77).
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Figure 2 Simultaneous determination of i.c. distal occlusive velocity (Vioccl = 2.5 cm; upper panel, left side) and wedge pressure (Poccl = 10 mm Hg) together with mean aortic pressure (Pao = 94 mm Hg; right side). The i.c. flow velocity tracing during vessel patency (Viø-occl = 48 cm), i.e., after dilation of the stenosis and following cessation of hyperemia, is shown on the lower left hand side. The flow velocity tracings depict the instantaneous velocity over time (horizontal axis) in the upper, and the flow velocity trend over 90 s in the lower part of the panels. The trend of the lower panel gives also the coronary flow velocity reserve (CFVR, "ratio" = 2.1) measurement. Velocity-derived collateral flow index (CFIv) in this example is equal to 2.5/48 = 0.05. During coronary occlusion, the i.c. ECG shows ST-elevations (right side panel) which disappear after PTCA balloon deflation. APV = average peak flow velocity (cm/s, i.e. maximum flow velocity during a cardiac cycle averaged over three cardiac cycles); B = baseline flow velocity (cm/s) at rest; CFVR = coronary flow velocity reserve; Pra = right atrial or central venous pressure (CVP); P = peak flow velocity during hyperemia; PTCA = percutaneous transluminal coronary angioplasty; S = search mode for peak flow velocity.
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Intracoronary pressure.
A 0.014 in. fiberoptic pressure monitoring guidewire (Pressureguide, Radi Medical, Uppsala, Sweden) was set at zero, calibrated, advanced through the guiding catheter and positioned distal to the stenosis to be dilated (17,18). The i.c. pressure-derived collateral flow index (CFIp) (no unit) was determined by simultaneous measurement of mean aortic pressure (Pao) (mm Hg, via the angioplasty guiding catheter) and the distal coronary artery pressure during balloon occlusion (Poccl) (mm Hg), Figures 1 and 2. Central venous pressure (CVP) was estimated to be equal to 5 mm Hg. Pressure-derived collateral flow index was calculated as (Poccl-CVP) divided by (Pao-CVP) (19). Pressure-derived collateral flow index expresses collateral flow relative to normal flow through the patent vessel, an index which conceptually corresponds to CFIv (15). Intracoronary distal flow velocity and pressure measurements during balloon occlusion and during vessel patency following PTCA were performed simultaneously.
Study protocol.
Following diagnostic coronary angiography, an interval of at least 10 min was allowed for dissipation of the effect of the nonionic contrast medium (iopamidol 755 mg/mL) on coronary flow velocity and vasomotion. An i.c. bolus of 0.2 mg of nitroglycerin was given in order to maintain epicardial coronary artery calibers constant and, thus, to prevent the influence of changing epicardial vessel diameters on flow indexes (CFVR or CFIv). In 12 patients, the Doppler guidewire was first positioned in the distal part of the contralateral vessel for CFVR measurement. Later, or in the case of no contralateral CFVR assessment, the Doppler and the pressure guidewires were positioned distal to the stenosis to be dilated, and CFVR as well as fractional flow reserve (FFR) (FFR = Poccl/Pao, [19]) measurements were obtained. The Doppler guidewire was used to transport the PTCA balloon. During the entire protocol, an i.c. electrocardiogram (ECG) obtained from the Doppler guidewire and a 3-lead surface ECG were recorded. Following ipsilateral CFVR measurements, distal Vioccl, Pao and Poccl were determined simultaneously and repetitively during balloon occlusion (Figs. 1 and 2). After balloon deflation and cessation of reactive hyperemia, distal nonocclusive Viø-occl, distal i.c. pressure and Pao were determined simultaneously. Occlusive distal Vioccl, Pao and Poccl were then determined during intravenous adenosine infusion (140 µg/kg/min), whereby the measurements were obtained approximately 40 s after the start of the adenosine infusion and 30 s after vessel occlusion during steady state conditions. Blood pressure and heart rate were recorded continuously during all flow velocity measurements including nonocclusive, "normal" flow velocity time integral Viø-occl at the identical distal location as Vioccl, the former of which was recorded after completion of PTCA and after cessation of reactive hyperemia.
Resistance indexes calculations.
The collateral and ipsilateral, distal vascular resistance indexes (Fig. 1, Rcoll and R4, mm Hg/cm) were calculated using an electrical analogue to model the vascular network as depicted in Figure 1 (20). Collateral resistance index (Rcoll) and ipsilateral resistance index (R4) were computed as shown in Figure 1. The proximal epicardial vascular resistance (R1) was assumed to be negligible or small compared with the other resistances in case of a one-vessel or a mild stenosis two-vessel CAD involving the contralateral vessel (i.e.,  50% diameter stenosis at R1), respectively.
Statistical analysis.
Between-group comparisons of demographic, angiographic, hemodynamic, Doppler flow velocity and i.c. pressure data and coronary collateral hemodynamic data during different time points were performed by a two-way repeated measures analysis of variance (ANOVA). A chi-square test was used for comparison of categorial variables among the two study groups. Linear regression analysis was applied for analysis of an association between adenosine-induced collateral flow indexes (CFIs) and coronary resistance index changes as well as contralateral vessel stenotic lesion degrees and CFVR. Statistical significance was defined at a p value of <0.05.
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Results
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Patient characteristics and clinical data.
The study population comprised 50 patients, 29 in the group having poor collaterals and 21 in the group having good collaterals. There were no statistically significant differences among the two groups regarding age of the patients, gender, hemodynamic variables during diagnostic cardiac catheterization, left ventricular ejection fraction, the frequency of cardiovascular risk factors, the number of non–Q-wave myocardial infarctions and the use of vasoactive substances (Table 1).
Angiographic data, stenoses severities and collateral assessment.
The occurrence of one- and two-vessel CAD, and the distribution of the coronary arteries undergoing PTCA (i.e., the ipsilateral vessels) were similar between the study groups (Table 2). Patients with poor collaterals had significantly less severe stenoses of the ipsilateral vessels than those with good collaterals. The contralateral coronary artery in patients with poor collaterals was the left anterior descending (LAD), the left circumflex (LCX) and the right coronary artery (RCA) in 21%, 10% and 14%, respectively (not determinable in 55%, p = 0.004 vs. visible collaterals); in patients with good collaterals, it was the LAD, LCX and RCA in 43%, 14% and 43%, respectively. Ten of the patients with poor and 11 of those with good collaterals had stenotic lesions of the collateral supplying vessel. The stenosis severities of the contralateral vessels (ranging from 20% to 90% in diameter) were similar among the groups (Table 2). The functional stenosis severity expressed in CFVR or FFR of the vessel undergoing PTCA was not different before or after the intervention. Coronary flow velocity reserve of the contralateral vessel was higher in the group with poor than in patients with good collaterals.
During balloon occlusion of the stenosis to be dilated, patients with poor versus good collaterals suffered more often from angina pectoris and more often showed signs of myocardial ischemia on i.c. ECG (Table 2). In patients with angiographically poor collaterals, i.c. Doppler- and pressure-derived CFIs amounted to approximately 20%, whereas in patients with good collaterals they were equal to about 29% as expressed in terms of normal flow during vessel patency (Table 2).
The correlation between velocity- and pressure-derived CFI in the present study was as follows: CFIv = 0.52 CFIp + 0.11; r = 0.54, p = 0.0001, standard error of estimate = 0.14, n = 100 (i.e. baseline and adenosine measurements).
Adenosine-induced coronary collateral flow changes.
Table 3 illustrates that Pao and the heart rate did not change significantly during adenosine infusion in either group. They were not significantly different between the groups either. Distal velocity time integral during vessel occlusion showed a tendency to decrease in the group with poor collaterals, and, overall, it increased in the group with good collaterals. Coronary wedge pressure did not change significantly in either study group. Velocity-derived CFI and CFIp both revealed a decrease during adenosine in patients with poor collaterals, whereas both increased significantly in individuals with good collaterals (Table 3, Fig. 3). In accordance with an adenosine-induced decrease and increase of CFI in the group with poor and good collaterals, respectively, Rcoll increased and decreased in the groups with poor and good collaterals, respectively (Table 3). The distal resistance index of the ipsilateral vessel (R4) showed a tendency to increase and to decrease during adenosine in the group with poor and good collaterals, respectively (Table 3). There was a significant, inverse relation between the adenosine-induced change in collateral flow and the change in the Rcoll (poor collaterals: delta Rcoll = 1.3–176 delta CFIp; r = 0.52, p = 0.007; good collaterals: delta Rcoll = 1.7–103 delta CFIp; r = 0.67, p = 0.001). There was an inverse relation between collateral flow change and ipsilateral distal vascular resistance change only in the case of good collaterals: delta R4 = 0.3–24 delta CFIp; r = 0.41, p = 0.05.
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Figure 3 Individual, collateral flow index values (CFIp, vertical axis, left side panel) at baseline and during adenosine infusion (top panel, horizontal axis). The triangles indicate mean values (± standard deviation). The bottom panel depicts individual, absolute CFIp changes in response to adenosine (i.e. CFIp during hyperemia – CFIp at rest). They were significantly lower in patients with angiographic collateral degree <2 than in those with 2 (horizontal axis). CFIp = pressure derived collateral flow index.
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Overall, there was a direct and inverse correlation between the contralateral stenosis severity or CFVR, respectively, and the adenosine-induced collateral flow change (Fig. 4). However, those relations were not statistically significant in the case of poor collaterals, but only in the group with good collaterals. In patients with poor collaterals, there was no association between the ipsilateral vessel and the adenosine-induced collateral flow change. In patients with good collaterals, collateral flow changes were significantly higher in cases of left as opposed to those of right collateralized coronary arteries: +0.12 ± 0.15 versus –0.07 ± 0.14, respectively (p < 0.05). The frequency of different stenosis locations (proximal, mid, distal portion) were not different between the study groups.
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Figure 4 Correlations between the structural (% diameter stenosis, n = 50; horizontal axis; top panel) and the functional (distal coronary flow velocity reserve, n = 12; horizontal axis; bottom panel) stenosis severity of the contralateral coronary artery and the adenosine-induced collateral flow index change (delta CFIp, vertical axis). The regression equations provided describe the mentioned relations in patients with good collaterals. There were no respective associations in patients with poor collaterals. Closed symbols: patients with good collaterals (angiographic degree 2); crossed symbols: patients with poor collaterals (degree <2).
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Discussion
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Simultaneous Doppler and pressure measurements in patients with one-vessel CAD documented an adenosine-induced decrease in individuals with poorly grown collaterals and an overall increase in collateral flow in those with angiographically well developed collaterals. These hyperemic collateral flow changes were accompanied by concordant, inverse shifts in the Rcoll. In patients with good, but not poor, collaterals, collateral flow changes were also influenced by the resistance in the collateral receiving vascular bed by a stenotic lesion of the collateral supplying vessel and by the bed size of the collateralized vessel.
Coronary collateral function studies.
A number of experimental papers have been published examining the effect of various neurohumoral and pharmacological agents on collateral perfusion (21). However, many of them have not used experimental preparations that account for the fact that coronary collaterals exist in a series of adjacent vascular resistances, i.e. they have not been able to permit discrimination between changes in true collateral tone versus changes in the vasomotor tone of up- or downstream resistances (Fig. 1). Investigations in experimental animal models considering these interactions have included studies on the alpha-adrenergic regulation of collateral vasomotion which appears not to be present in the dog (22–25); they have contained studies on beta-adrenergic receptors (26), collateral vasomotor responses to vasopressin (27,28) and on the relevance of nitric oxide production to maintain collateral blood flow at rest and during exercise in dogs (29).
Only a few clinical studies using nuclear cardiologic techniques in patients with single coronary artery occlusions in the absence of a myocardial infarction have examined the coronary collateral vasodilator response (5,7,30). The recently published study by Piek et al. (12) and this investigation are the first to directly and simultaneously examine collateral flow and vascular resistance changes in response to pharmacologic agents by i.c. wedge pressure and occlusive flow velocity measurements. In contrast with the study by Piek et al. (12), the measurement of the distal occlusive i.c. pressure in this study occurred via an independent pressure sensor, and patients with a broader range of CFIs (CFI 0 to 0.8) were included as well as 21 individuals with stenotic lesions of the contralateral vessel. The principal findings of the study by Piek et al. (12) were reproduced, by demonstrating that adenosine-induced enhanced CFIs in patients with well developed collaterals were due to reductions in both collateral and distal ipsilateral vascular resistance indexes, and conversely, diminished collateral flow in the presence of poorly developed collaterals was due to a more pronounced collateral resistance. Collateral and ipsilateral resistance indexes were of the same magnitude in both studies, but measures for collateral flow in Piek’s (12) and this study are only partly comparable. Diastolic flow velocity time integral values and the ratio between wedge and Pao have been used as a collateral index, whereas we expressed collateral flow during occlusion in terms of normal antegrade flow during vessel patency. However, this difference in determining CFIs probably does not account for the more pronounced variability in collateral vascular responses to adenosine in this study versus the aforementioned study.
Whereas adenosine has been shown to be a profound microvascular coronary artery dilator (16), it may have been documented more often to decrease than to enhance collateral perfusion (4,9,21). At first sight, there seemed to be discrepant collateral responses to IV adenosine between our recently published (4) and the present data: coronary collateral steal occurred in patients with well developed collaterals in the study mentioned first, but in this one, individuals with good collaterals showed an overall increase in hyperemic collateral flow. The reason for the apparent incompatibility is related to the fact that a reduced hyperemic ipsilateral flow during vessel patency (steal, i.e., CFVR < 1) is not the same as a diminished hyperemic collateral flow during occlusion of the collateral-receiving vessel. Although all the cases with hyperemic flow diversion via collaterals have manifested a diminished hyperemic collateral flow during vessel occlusion, most of the patients with good collaterals revealing diminished hyperemic collateral flow during occlusion in that study did not exhibit steal (4). Since well developed collaterals are a necessary, but not sufficient, condition for steal to occur, the relation between reduced hyperemic ipsilateral flow (measured during vessel patency) and extensive collaterals is not invertable, i.e., well-grown collaterals are not automatically linked to impeded hyperemic flow. Therefore, the fact that patients with good collaterals in this study overall revealed an increased adenosine-induced flow via collaterals is compatible with the data on steal just mentioned. Still, there were variable reactions of the collateral flow to adenosine in this study, and it was the purpose of this study to elucidate possible factors and mechanisms accountable for those variable collateral hyperemic responses.
Sources of variable collateral hyperemic response and study limitations.
Figure 1 provides a simplified schematic of the coronary collateral circulation between two vascular regions, which should illustrate that only a certain change in the interplay between the vascular resistances of the anastomoses itself (Rcoll), the occluded collateral receiving and the supplying vessel finally leads to collateral flow increase in response to pharmacologic or physicochemical stimuli. For example, reducing the collateral resistance itself will not result in increased collateral perfusion unless there is a concomitant resistance decrease in the ipsilateral distal vasomotor tone. Furthermore, this constellation itself is necessary but may still not be sufficient to positively affect collateral flow because a simultaneous overproportional reduction in the contralateral distal resistance may even lead to collateral flow decrease. The scenario becomes more complicated in the situation of a proximal resistance added to the contralateral vessel (R1) as a hemodynamically relevant epicardial stenotic lesion, and the physical consequences of different vascular resistance interactions become difficult to grasp perceptively. Using Ohm’s law and an electrical analogue, the situation illustrated in Figure 1 has been modeled in order to overcome the mentioned intuitive difficulties (20), but in the beating heart, the model has not been evaluated directly in its entirety because, optimally, four i.c. measurement sites of pressure and flow velocity would be required to compute all the mentioned resistances. Thus, the setting of i.c. measurement devices used in this study is unique but also crude since it does not allow calculation of a contralateral distal, let alone a proximal, resistance index.
Despite these shortcomings, it can be demonstrated on the basis of the present data that the mentioned interactions of vascular resistances in regions adjacent to the collaterals play an important role in patients with well developed collaterals, whereas they do not in those with poorly grown collaterals. It can be speculated that a poor collateral flow response to adenosine (Fig. 3) is exclusively related to collateral vasoconstriction in structurally underdeveloped collaterals. On the other hand, among the 11 of 21 patients with good collaterals showing a hyperemic flow decrease, this response, in contrast to the average, was codetermined by an insufficient collateral resistance decrease, but also by an overproportional resistance decline in the collateral-supplying bed or by an elevated ipsilateral vascular resistance. This concept is supported by the present data as follows (Table 4): the adenosine-induced collateral flow change was inversely related to collateral resistance shifts irrespective of the study group. The contralateral stenosis severity (Fig. 4), and the ipsilateral vessel, as well as its distal resistance, were associated with the hyperemic collateral flow change only in patients with good collaterals. Obviously, the vascular resistance of the poorly developed collaterals was too predominant to allow for an interaction between the vascular resistances of the collateral supplying and receiving beds. In patients with well developed collaterals, a contralateral stenosis likely caused a predilation of the dependent myocardial bed at rest and, thus, less vasodilator capacity with less lowered resistance shift towards the contralateral side under adenosine and, therefore, less collateral flow diversion. The vasodilator capacity of the relatively small ipsilateral right coronary artery territory may have been less pronounced than that of the large left coronary artery region, and, hence, there was less collateral flow increase in receiving right than left coronary arteries.
The fact that occlusive flow velocity and pressure are terms used to calculate resistance indexes leads to the situation of some inherent association among adenosine-induced collateral flow and resistance alterations. However, the hyperemia-induced altering flow velocity term is applied only in the equations for the resistance calculations (Fig. 1), and thus renders the associations between collateral flow and resistance changes feasible. The relation between collateral flow changes and the contralateral stenosis severity (Fig. 4) is, furthermore, entirely independent of pressure measurements in the second variable and can only be operative via collateral resistance changes.
Even in the presence of more extensive simultaneous i.c. Doppler and pressure determinations, unprecise measurement of the Doppler and the pressure guidewire would have to be considered as a source of variable results of collateral flow responses to adenosine. This problem becomes evident in that CFIps did not agree exactly with Doppler-derived values regarding the hyperemic changes in both groups (Table 3). A recent validation of the i.c. Doppler and pressure sensors (15) has provided a reasonably good agreement between respective CFIs that should be interchangeable (regression coefficient r = 0.8, p = 0.0001, SEE = 0.08, n = 100). However, the agreement among the two i.c. sensors in this study was worse (r = 0.54, p = 0.0001, SEE = 0.14, n = 100) indicating that the i.c. sensor methods may be less predictive of sufficient collateral flow than recently indicated. In the case of CFIp, extravascular transmyocardial forces due to increased left ventricular filling pressure during coronary occlusion can theoretically lead to an overestimation of the coronary wedge pressure in patients with few collaterals and large ischemic areas. In this group of patients (n = 20), CFIp should not be lower than  0.15 supposed that the ventricular filling pressure was at least 20 mm Hg and Pao = 100 mm Hg; 14 of the 20 patients mentioned actually had a CFIp < 0.15, which makes it unlikely that CFIp was overestimated by elevated filling pressures.
In the case of i.c. velocity measurements, there are other technical limitations of obtaining satisfactory signals such as the recording of vessel wall artifacts or insufficient Doppler spectra (31). We tried to avoid them by careful patient selection (no patients with tortuous vessels or multiple stenoses in series) and by appropriate positioning of the Doppler guidewire away from regions of turbulent flow. Pressure guidewire measurements are more robust to positional influence than velocity measurements, and satisfactory tracings can be obtained almost always, unless the wire is located too proximally in the vicinity of the stenosis.
Since it is difficult to determine the complete source of collaterals on angiography, considerable variability in the relation between contralateral stenosis severity and hyperemic collateral flow change (Fig. 4) may be the result of collaterals originating from vessels other than the "contralateral" artery. Also, the observed poor correlation between resting angiographic collateral grade and recruitable collateral degree during PTCA as well as pressure-derived CFI are sources of variability in our study results.
It is concluded that patients with well versus poorly developed coronary collaterals do better regarding the capacity of increasing collateral flow in response to adenosine. In patients with angiographically good, but not with poor, collaterals, an adenosine-induced collateral flow increase depends on the ipsilateral distal vascular resistance decrease but is also directly influenced by the severity of a contralateral stenosis and by the size of the collateralized vascular bed.
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Footnotes
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This study was supported by a grant from the Swiss Heart Foundation and by a grant from the Swiss National Science Foundation, grant #32-49623.96.
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References
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