Pharmacological Modulation of the Human Collateral Vascular Resistance in Acute and Chronic Coronary Occlusion Assessed by Intracoronary Blood Flow Velocity Analysis in an Angioplasty Model
Background The pharmacological responsiveness of the coronary collateral circulation in humans has been studied only by indirect means.
Methods and Results Patients with one-vessel disease and recruitable (n=14) or spontaneously visible (n=24) collateral vessels were studied during coronary angioplasty. Collateral flow in the recipient coronary artery was determined with a 0.014-in Doppler guide wire during balloon coronary occlusion and expressed as the diastolic blood flow velocity integral (dVi). Collateral blood flow velocity, mean aortic pressure (Pao), and coronary wedge pressure (Pw) were used to calculate the collateral vascular resistance index: Rcoll=(Pao−Pw)/dVi (mm Hg/cm) and the peripheral vascular resistance index of the recipient coronary artery: R4=Pw/dVi (mm Hg/cm). Adenosine (12 to 18 μg) and nitroglycerin (0.2 mg) were injected as a bolus in the donor coronary artery during subsequent balloon inflations to assess their effect on these hemodynamic variables. The administration of adenosine or nitroglycerin in patients with recruitable collateral vessels did not induce a change in dVi and Pw/Pao ratio. In patients with spontaneously visible collateral vessels, dVi increased from 8.0±4.5 to 10.8±8.0 cm (P=.01) after adenosine and from 7.4±4.5 to 10.3±6.9 cm (P=.003) after nitroglycerin. The Pw/Pao ratio remained unchanged after adenosine and nitroglycerin. Rcoll decreased from 10.3±9.5 to 8.6±8.5 mm Hg/cm (P=.01) after adenosine and from 11.6±10.4 to 8.3±8.9 mm Hg/cm (P<.001) after nitroglycerin. R4 decreased from 7.7±5.5 to 5.9±5.1 mm Hg/cm (P<.001) after adenosine and from 8.4±6.6 to 7.1±7.2 mm Hg/cm (P=.01) after nitroglycerin.
Conclusions Coronary collateral blood flow can be increased with adenosine and nitroglycerin in patients with one-vessel disease and spontaneously visible collateral vessels, which is in contrast to patients with recruitable collateral vessels. This effect is the result of a reduction in the collateral vascular resistance and peripheral vascular resistance of the recipient coronary artery.
Our current knowledge regarding the protective effect of coronary collateral vessels in clinical studies is based in particular on angiographic studies.1 A limited number of studies have been conducted to express the collateral vascular development in terms of flow and resistance.2 3 4 Moreover, the pharmacological responsiveness of the collateral circulation in humans remains uncertain. Several clinical studies reported improvement in myocardial perfusion due to enhanced collateral flow after the intravenous administration of vasodilators, although this beneficial effect could also be related to the alterations in preload or afterload.5 6 7 The results of studies in which the hemodynamics of collateral circulation were evaluated after intracoronary administration of vasodilators were criticized because of the technique applied to assess collateral flow.8 The introduction of a Doppler guide wire for intracoronary diagnostic purposes provided an alternative method for assessment of collateral flow in the setting of coronary angioplasty.9 These studies measured collateral flow velocity during balloon coronary occlusion in the recipient coronary artery distal to the balloon. The collateral vascular resistance can be assessed with the combined measurement of collateral flow velocity and coronary wedge pressure in the recipient coronary artery. The purpose of the present study was to evaluate the pharmacological responsiveness of the coronary collateral circulation in patients with recruitable or spontaneously visible collateral vessels with the use of this technique in a balloon angioplasty model.
Thirty-eight patients (mean age, 54.6±9.8; range, 35 to 75 years) with one-vessel coronary artery disease who had been referred to our institution for percutaneous transluminal coronary angioplasty were studied prospectively. Inclusion criteria included (1) angina pectoris refractory to medical therapy, (2) coronary narrowing or total coronary occlusion suitable for balloon angioplasty, and (3) the presence of spontaneously visible or recruitable collateral vessels. Exclusion criteria included (1) multilesion one-vessel disease, (2) previous cardiac surgery, and (3) peripheral artery disease that limits arterial access. A total of 21 of the 38 patients underwent cardiac catheterization due to postinfarct angina: 8 patients experienced a Q-wave infarction, and 13 patients experienced a non–Q-wave infarction. Informed consent was given in accordance with the rules of the institutional ethics committee, which approved the study.
All antianginal medications and aspirin (100 mg) were continued until cardiac catheterization. Lorazepam (1 mg) was administered orally before the procedure. At the beginning of the catheterization, all patients received heparin intravenously (5000 U) as a bolus. Additional heparin was administered if the procedure lasted >90 minutes. Nitroglycerin (0.1 mg IC) was administered only for the occurrence of coronary spasm. Cardiac catheterization was performed using the percutaneous femoral approach. A 6F or 7F sheath was inserted into both the right and left femoral arteries. One guiding catheter was used for the introduction of a Doppler guide wire and the balloon catheter in the recipient coronary artery, and one guiding catheter was used for angiography of the donor coronary artery and the administration of vasodilators.
Quantitative Coronary Angiography
Angiography of the donor artery was performed before angioplasty with automatic contrast injection (Angiomat 3000, Liebel-Flarsheim Co; right coronary artery, 4 to 6 mL, 7 mL/s; left coronary artery, 6 to 8 mL, 9 mL/s). Cineangiography was continued until there was no further opacification of the injected vascular bed. A repeat arteriogram of the donor artery was obtained at 30 seconds during the first balloon inflation. The severity of the coronary narrowings was assessed with an automated contour detection algorithm (ARTREK, ADAC Laboratories) in two orthogonal projections, using the guiding catheter as a reference, to determine the percentage diameter stenosis and minimal luminal diameter. A stenosis was considered subtotal (95% diameter stenosis) if there was an interruption of contrast medium but complete and brisk filling of the distal part of the stenosed artery. A stenosis was considered a functional occlusion (99% diameter stenosis) if there was an interruption of contrast medium with a slow filling of the distal part of the coronary artery (TIMI 1). A total coronary occlusion was defined as an interruption of contrast medium without antegrade filling of the distal part of the artery (TIMI 0).
Collateral vessels were graded according to Rentrop’s classification: 0 indicates no filling of collateral vessels; 1, filling of collateral vessels without any epicardial filling of the artery to be dilated; 2, partial epicardial filling by collateral vessels of the artery to be dilated; and 3, complete epicardial filling by collateral vessels of the artery to be dilated. The grading of the collateral vessels was performed independently by two angiographers, and a consensus was reached in the event of disagreement. Collateral vessels were considered recruitable when they were absent before coronary occlusion (grade 0 or 1) and present during coronary occlusion (grade 2 or 3). Collateral vessels were classified spontaneously visible when they were grade 2 or 3 before angioplasty.
Aortic pressure was measured at the tip of the guiding catheter. The coronary occlusion wedge pressure was measured at the tip of the balloon catheter through the fluid-filled lumen during balloon inflation. The heart rate was obtained from the ECG and monitored throughout the procedure.
Collateral Flow Velocity
A 0.014-in Doppler guide wire equipped with a Doppler crystal at its tip (Flowire, Cardiometrics) was inserted in the recipient coronary artery to assess collateral blood flow velocity distal to the balloon during coronary occlusion. Coronary blood flow velocity in the recipient artery was assessed during the first and subsequent balloon inflations of ≈1-minute duration. Collateral flow was considered present in the case of a partial or complete diastolic blood flow velocity signal of >5 cm/s. The Doppler signals of the Doppler guide wire were generated with a 12-MHz pulsed Doppler velocimeter and processed with a real-time spectral analyzer using fast Fourier transformation (Flowmap, Cardiometrics). Collateral flow in the recipient coronary artery was determined on the basis of Vi, dVi, and dMPV. These collateral blood flow velocity parameters were assessed off-line through manual tracing of the peak blood flow velocity pattern from a digitized video frame, averaged over three consecutive beats, and corrected for heart rate by using a software program available on the Internet (NIH Images 1.58, National Institutes of Health). The blood flow velocity signals (retrograde or antegrade) were expressed as an absolute value. Rcoll was assessed by relating dVi measured during balloon inflation in the recipient coronary artery to the pressure gradient on the collateral vascular bed: Rcoll=(Pao−Pw)/dVi (mm Hg/cm). R4 was calculated with the following equation: R4=Pw/dVi (mm Hg/cm).
Pw/Pao can be expressed with the following equation (see “Appendix”): Pw/Pao=R4/(Rcoll+R4).
Adenosine (12 to 18 μg) or nitroglycerin (0.2 mg) was injected as a bolus in the donor coronary artery during the second and third balloon inflations, respectively, to determine the effect on the collateral blood flow velocity parameters and the ratio of hyperemic to baseline dVi. The blood flow velocity signals (retrograde or antegrade) during hyperemia were expressed as an absolute value. The effect of the adenosine or nitroglycerin on Pw/Pao was assessed during subsequent, separate balloon inflations after withdrawal of the guide wire.
Wall Motion Score
The regional wall motion of the perfusion territory of the narrowed or occluded coronary artery in patients with spontaneously visible collateral vessels were scored as hyperkinetic (−1), normal (0), hypokinetic (1), akinetic (2), dyskinetic (3), or aneurysmatic (4) based on the findings of echocardiography or contrast left ventriculography. To determine the relationship with pharmacological modulation of collateral blood flow velocity, patients with a normal or hypokinetic wall motion were classified as having normal wall motion (n=13) and patients with an akinetic, a dyskinetic, or an aneurysmal wall motion were classified as having abnormal wall motion (n=11).
Continuous variables are expressed as mean±SD and were compared with the use of the unpaired Student’s t test. The two-tailed paired t test was used to determine the effect of adenosine or nitroglycerin on the hemodynamic and blood flow velocity parameters. The degree of association between variables was evaluated with the correlation coefficient. A value of P<.05 was considered statistically significant.
A total of 38 patients were included in the study and divided into two patient categories (ie, patients with recruitable collateral vessels during balloon coronary occlusion [group 1, n=14] or patients with spontaneously visible collateral vessels before balloon angioplasty [group 2, n=24]). Three of the 14 patients with recruitable collateral vessels were excluded from further analysis because a collateral blood flow velocity signal could not be detected. The clinical and angiographic characteristics of the study patients are depicted in Table 1⇓. Coronary angiography in patients with spontaneously visible collateral vessels (group 2) revealed a total coronary occlusion in 13 patients, a functional coronary occlusion in 8 patients, a subtotal coronary occlusion in 2 patients, and a 65% diameter stenosis in 1 patient.
Angiography of Collateral Vessels
In the 11 patients with recruitable collateral vessels (group 1), collateral vessels were graded 0 in 6 patients and graded 1 in 5 patients, and during balloon coronary occlusion, vessels were graded 2 in 8 patients and 3 in 3 patients. A total of 6 patients with spontaneously visible collateral vessels (group 2) were graded 2 and 18 patients were graded 3 before the balloon coronary occlusion. During balloon coronary occlusion, 4 patients were graded 2 and 20 patients were graded 3. Collateral vessels were fully absent (grade 0) after the successful completion of the procedure in all patients.
Wall Motion Score
The regional wall motion of the narrowed or occluded vascular bed of the patients with spontaneously visible collateral vessels was graded as hyperkinetic (n=0), normal (n=10), hypokinetic (n=3), akinetic (n=7), dyskinetic (n=2), or aneurysmal (n=2).
Collateral Blood Flow Velocity
A complete diastolic collateral blood flow velocity signal of >5 cm/s was noted in 36% of the patients with recruitable collateral vessels, whereas a complete diastolic collateral blood flow velocity signal was obtained in 88% of the patients with spontaneously visible collateral vessels (P<.01). dVi of the patients with spontaneously visible collateral vessels (group 2) was larger compared with the patients with recruitable collateral vessels (group 1) before the administration of adenosine and nitroglycerin (8.0±4.5 versus 3.8±2.9 cm, P<.01; 7.4±4.5 versus 4.2±3.8 cm, P<.05, respectively; Table 2⇓). The other blood flow velocity parameters did not demonstrate a difference between group 1 and group 2 before the administration of the vasodilators.
Coronary Wedge Pressure
Pw/Pao values before the administration of adenosine or nitroglycerin were lower in the patients with recruitable collateral vessels than in the patients with spontaneously visible collateral vessels (0.36±0.13 versus 0.45±0.12, P=.04; 0.36±0.15 versus 0.44±0.11, P=.05, respectively).
Rcoll of the patients with recruitable collateral vessels was higher compared with the patients with spontaneously visible collateral vessels before the administration of adenosine and nitroglycerin (29.0±27.5 versus 10.3±9.5 mm Hg/cm, P=.005; 35.8±44.8 versus 11.6±10.4 mm Hg/cm, P=.02, respectively). R4 was higher in patients with recruitable collateral vessels compared with patients with spontaneously visible collateral vessels before the administration of adenosine (12.7±7.4 versus 7.7±5.5 mm Hg/cm, P=.03). There was no difference between the baseline values before the administration of nitroglycerin (Table 2⇑).
The effect of adenosine administration on resting hemodynamics varied between the patient groups. In the patients with recruitable collateral vessels, aortic pressure and heart rate remained unchanged after the administration of adenosine (91±9 versus 90±13 mm Hg, P=.58; 63±11 versus 65±10 bpm, P=.19). In the patients with spontaneously visible collateral vessels, heart rate increased from 67±12 to 69±13 bpm after the administration of adenosine (P=.07). The aortic pressure decreased from 99±11 to 95±11 mm Hg after the administration of adenosine (P<.01).
Intracoronary administration of nitroglycerin induced a decrease in the aortic pressure in the patients with recruitable collateral vessels and patients with spontaneously visible collateral vessels (93±10 versus 90±12 mm Hg, P<.05; 99±11 versus 96±11 mm Hg, P<.005, respectively). Heart rate did not change in the patients with recruitable collateral vessels (62±10 versus 64±9 bpm, P=.15) but increased in the patients with spontaneously visible collateral vessels (66±13 versus 68±13 bpm, P<.005).
Collateral Blood Flow Velocity
The administration of adenosine or nitroglycerin did not induce an increase in collateral blood flow velocity in patients with recruitable collateral vessels (Table 2⇑). All blood flow velocity parameters increased significantly after the administration of adenosine or nitroglycerin in patients with spontaneously visible collateral vessels (Table 2⇑ and Fig 1⇓). A positive signal becoming negative or a negative signal becoming positive after the administration of vasodilators was not noted in any of the patients. The majority of the patients with spontaneously visible collateral vessels demonstrated an increase in dVi. However, in a few patients, dVi remained unchanged or decreased during hyperemia (Table 3⇓ and Fig 2A⇓ and 2B⇓). Fig 3A⇓ shows the correlation between the effect of adenosine and nitroglycerin on dVi (r=.76, P<.001).
The ratio of the hyperemic versus baseline dVi in patients with spontaneously visible collateral vessels was higher than that in patients with recruitable collateral vessels after the administration of adenosine (1.3±0.5 versus 1.0±0.2, P=.02) and nitroglycerin (1.4±0.6 versus 1.0±0.2, P=.03). Furthermore, there was no significant difference in the ratio of dVi in patients with spontaneously visible collateral vessels and a normal wall motion (n=13) compared with patients with an abnormal wall motion (n=11) after the administration of adenosine (1.2±0.4 versus 1.5±0.6, P=.25) or nitroglycerin (1.3±0.4 versus 1.5±0.8, P=.43).
Coronary Wedge Pressure
The administration of vasodilators did not induce a significant difference in overall Pw/Pao in patients with recruitable or spontaneously visible collateral vessels (Table 2⇑). The variability of the change in Pw/Pao in the individual patient with spontaneously visible collateral vessels is illustrated in Fig 2A⇑ and 2B⇑. Baseline Pw/Pao was higher in patients demonstrating a decrease in Pw/Pao after the administration of vasodilators compared with patients showing an increase in Pw/Pao (adenosine, 0.53±0.11 versus 0.38±0.07, P=.001; nitroglycerin, 0.50±0.15 versus 0.41±0.07, P=.05). The correlation between the effect of adenosine and nitroglycerin on Pw/Pao is depicted in Fig 3B⇑ (r=.64, P=.001).
The administration of adenosine and nitroglycerin did not reduce Rcoll and R4 in patients with recruitable collateral vessels (Table 2⇑). In patients with spontaneously visible collateral vessels, both Rcoll and R4 decreased after the administration of the vasodilators (Table 2⇑). The correlation between the effects of adenosine and nitroglycerin on Rcoll and R4 is shown in Fig 3C⇑ and 3D⇑ (r=.76, P<.001; and r=.53, P=.007, respectively). Patients with an increase in Pw/Pao after the administration of vasodilators were characterized with a predominant reduction of Rcoll compared with the reduction in R4 (after adenosine, −16±28% versus −5±32%, P=.004; after nitroglycerin, −31±28% versus −9±36%, P<.001, respectively). On the other hand, patients with a decrease in Pw/Pao after the administration of vasodilators showed a more pronounced reduction in R4 compared with the reduction in Rcoll (after adenosine, −29±24% versus 5±32%, P<.001; after nitroglycerin, −17±24% versus 17±38%, P=.002, respectively).
The pharmacological responsiveness of the collateral circulation in conscious humans has been studied only indirectly.4 10 11 Collateral flow was determined directly in the present study through blood flow velocity analysis of the recipient coronary artery during balloon coronary occlusion. Coronary collateral blood flow can be increased with adenosine and nitroglycerin in a selected cohort of patients with one-vessel disease and spontaneously visible collateral vessels, which is in contrast to patients with recruitable collateral vessels. This effect of these vasodilators is a result of a reduction in the collateral vascular resistance and peripheral vascular resistance of the recipient coronary artery.
Intracoronary Blood Flow Velocity Analysis for Assessment of Collateral Flow
Collateral blood flow can be assessed in the setting of coronary angioplasty through intracoronary blood flow velocity analysis in the donor or recipient coronary artery.9 12 13 This study is the first report of a cohort of patients concerning the application of intracoronary blood flow velocity analysis in humans for evaluation of the pharmacological modulation of Rcoll. These observations were performed in patients with one-vessel disease to avoid unpredictable effects on coronary hemodynamics related to the presence of multivessel disease.
Only a limited number of studies have been reported regarding the assessment of collateral flow with a Doppler guide wire during balloon coronary occlusion. Recent studies by Yamada et al14 and Bach et al15 involve the assessment of collateral flow in patients in whom half had spontaneously visible collateral vessels in the presence of subtotal or total coronary occlusions. The magnitude of a collateral peak velocity integral of ≈10 cm in the presence of spontaneously visible collateral vessels in these studies is in accordance with our results. These investigations demonstrate the feasibility of studying the physiology of the collateral circulation during brief balloon coronary occlusion. However, recruitability of collateral vessels was not evaluated, and pharmacological modulation of collateral vascular resistance was not studied.
Pharmacological Modulation of Collateral Flow in Humans
Collateral flow and its pharmacological responsiveness in conscious humans have been measured in the setting of coronary angioplasty through measurement of the great cardiac vein flow during balloon occlusion of the left anterior descending coronary artery.3 4 10 11 However, experimental data have led to questioning of the accuracy of the use of the great cardiac vein flow to assess collateral flow to the left anterior descending vascular bed.8
A noninvasive study using perfusion scintigraphy by Aoki et al5 in patients with a chronic coronary occlusion reported an improvement in flow to collateral-dependent vascular regions after the intravenous administration of nitroglycerin. These observations coincide with more recent studies in patients with a chronic coronary occlusion who were evaluated with the use of positron emission tomography after the intravenous administration of dipyridamole.6 7 The ratio of hyperemic to baseline myocardial blood flow to the collateral-dependent areas varied in these studies from 1.4±0.6 to 1.9±1.0, respectively. However, the improvement in myocardial perfusion after the administration of vasodilators may have been the result of alterations in preload or afterload as well as a direct vasodilating effect on collateral vessels. To minimize its influence on preload or afterload, the effect of vasodilators on collateral blood flow velocity was studied in the present study after intracoronary administration. Although in the present study, changes in blood pressure and heart rate were noted after the intracoronary administration of either nitroglycerin or adenosine, these hemodynamic effects were less pronounced than those reported after the intravenous administration of dipyridamole.6 Nevertheless, the increase in collateral blood flow velocity in the present study is surprisingly similar to the increase in myocardial perfusion of the collateral-dependent vascular areas as determined with positron emission tomography.
Although the magnitude of collateral flow velocity response in our study was in accordance with that of Vanoverschelde et al,7 we were unable to confirm their observation that a larger ratio of hyperemic to baseline collateral blood flow velocity was noted in patients with a normal left ventricular function. This nonuniformity of study results and the small number of patients (n=11) reported in the study of Vanoverschelde et al indicate that the factors influencing the collateral blood flow velocity response require further study in a larger cohort of patients.
Pharmacological Modulation of Collateral Vascular Resistance Index in Humans
Several studies with the coronary angioplasty model demonstrated that the angiographic development of collateral vessels is positively associated with Pw/Pao, presumably related to a reduction in collateral vascular resistance.16 17 18 19 In a recent study by Pijls et al,20 the development of collateral circulation was expressed as a pressure-derived fractional collateral blood flow index (ie, Pw/Pao after correction for the central venous pressure). Rcoll was determined in the present study through measurement of collateral blood flow velocity in combination with assessment of Pw/Pao. The results of this study illustrate that the combined measurements provide additional information on the effect of vasodilators on Rcoll as it would be concealed through measurement of Pw/Pao only (Table 2⇑). For example, the patient depicted in Fig 1⇑ demonstrated a marked increase in blood flow velocity and a reduction in Rcoll and R4 after the administration of adenosine, whereas Pw/Pao remained unchanged (Table 4⇓, patient 21). It should be emphasized that the diameter of the recipient coronary artery was considered to remain constant for the calculation of Rcoll. This limitation of the technique may explain why an increase or a decrease in Pw/Pao was noted in some patients in the presence of minimal blood flow velocity changes as a result of underestimation of alterations in volume blood flow due to vasodilation (Fig 2A⇑ and 2B⇑). The results of the present study indicate that the resistance of recruitable collateral vessels does not respond to vasodilators, which coincides with experimental studies showing that the vascular wall of collateral vessels in recent coronary occlusion consists of a small layer of smooth muscle cells.21 This contrasts with the vascular wall alterations in chronic coronary occlusion showing multiple layers of smooth muscle cells oriented in longitudinal and circular layers.21 These morphological alterations may provide an explanation for the observations in the present study of a pharmacological responsiveness of recruitable collateral vessels that contrasts with that of spontaneously visible collateral vessels.
The increase in the collateral blood flow velocity after the administration of adenosine or nitroglycerin is the result of a reduction in both Rcoll and R4. There is a good agreement between the effects on adenosine and nitroglycerin on the Rcoll, whereas there is a variable response for R4 (Fig 3C⇑ and 3D⇑). This effect on R4 explains in part the variability of the response of adenosine and nitroglycerin on Pw/Pao (Fig 3B⇑ and Equation 5). An increase or decrease in Pw/Pao during the administration of vasodilators relates to the baseline Pw/Pao. A high Pw/Pao predisposes to a reduction in this ratio during hyperemia, presumably as a result of a recovery of autoregulation of the resistance vessels due to marked collateral vascular development.
It is noteworthy that the induction of hyperemia in the donor artery did not result in general in a decrease in collateral blood flow velocity in the recipient coronary artery and reduction in Pw/Pao due to a “steal” phenomenon.22 23 This suggests that the hyperemia in the donor vascular bed does not result in a decrease in collateral driving pressure due to a pressure drop in the epicardial donor coronary artery (see “Appendix”). It is conceivable that the rare occurrence of this phenomenon in the patients studied is related to the selection criterion (one-vessel disease) of the patients.
The present study concerns a selected cohort of patients with one-vessel disease, and the findings of this study cannot be extrapolated to the general category of patients with collateral vessels associated with multivessel disease or diffuse coronary artery disease that may or may not be apparent on coronary angiography. Coronary steal is a well-documented phenomenon in coronary artery disease, and the beneficial effects of vasodilators in the patients studied are potentially harmful in other categories of patients.22 23
Collateral flow in this study was evaluated through intracoronary blood flow velocity analysis. Angiographic studies have reported that the intracoronary administration of nitroglycerin may result in a 30% to 50% increase in the diameter of the donor and recipient coronary artery.24 This indicates that the observed changes of collateral blood flow velocity in spontaneously visible collateral vessels after the administration of nitroglycerin may underestimate the true alterations in volume flow. On the contrary, our observations do not exclude the possibility that some changes in collateral volume flow may have occurred in the presence of recruitable collateral flow that was concealed due to vasodilation of the recipient coronary artery. Moreover, the epicardial blood flow velocity analysis in the setting of recruitability of collateral vessels may be unable to detect alterations in collateral flow at the myocardial level and therefore may obscure the effect of vasodilators in this situation. The effect of vasodilators was determined with the alterations in coronary hemodynamics and was not extended to the evaluation of improvement of global or regional left ventricular function. The present study was not designed to evaluate the relation between the hemodynamics of the collateral circulation and the restoration of left ventricular function after successful recanalization.
The patients studied represent a selection of symptomatic patients, and this potentially introduces selection bias with respect to potential functional capacity of the coronary collateral circulation. Finally, the limited number of studies conducted on this subject requires further confirmation by other investigators.
Numerous studies have indicated that collateral vessels play an important role in the outcome of acute coronary syndromes. The presence of collateral vessels during abrupt coronary occlusion in acute myocardial infarction results in a reduction in infarct size, exerts an additional beneficial effect on preservation of left ventricular function after thrombolytic therapy, and prevents aneurysm formation in patients with sustained coronary occlusion.25 26 27 28 29 It is possible that the pharmacological responsiveness of spontaneously visible collateral vessels, as documented in the present study, constitutes the background for the observed endorsement of thrombolytic therapy with nitroglycerin treatment in the presence of collateral vessels.30 Although the present study indicates that recruitable collateral vessels are not responsive to vasodilatory therapy, these vessels become spontaneously visible, and potentially responsive to pharmacological modulation in the relatively short time span of 10 to 14 days in sustained coronary occlusion.31 Consequently, the pharmacological responsiveness of collateral vessels in this situation may alleviate cardiac symptoms or improve left ventricular function. These findings may stimulate further research for evaluation of other pharmacological agents that are effective in modulating coronary collateral vascular resistance.
Furthermore, a recent study suggests that the collateral flow increase after the administration of vasodilators in patients with a chronic coronary occlusion may be positively related to the functional integrity of the myocardium, as reflected by the left ventricular function.7 Although this relationship was evaluated in a limited number of patients, the potential impact requires further analysis before and after revascularization. In addition, the observed large variation in the collateral flow response in patients with spontaneously visible collateral vessels requires further study because it may be important to select patients who might benefit from conservative therapy or who are candidates for revascularization.
Selected Abbreviations and Acronyms
|dMPV||=||diastolic maximal peak blood flow velocity|
|dVi||=||diastolic blood flow velocity integral|
|Pw/Pao||=||coronary wedge/aortic pressure ratio|
|R4||=||peripheral vascular resistance index of the recipient coronary artery|
|Rcoll||=||collateral vascular resistance index|
|Vi||=||total blood flow velocity integral|
The coronary arterial circulation is schematically depicted in an electric analog model (Fig 4⇓).
The coronary vasculature is represented as resistors exhibiting ideal current-voltage behavior: V=I*R (Fig 2⇑). The voltage (V) is expressed as the pressure gradient, and the current (I) is the diastolic blood flow velocity integral. The central venous pressure is assumed to be zero. where Pao can also be expressed according to the following equation: The Pw/Pao can be expressed by eliminating dVi and dVitot from Equations 1, 2, and 3, which provides the following equation32 : The assumption that R1 is negligible compared with all other resistances in patients with one-vessel disease yields the following equation: Rcoll and R4 can be expressed according to the following equations:
The interaction among Rcoll, R4, and Pw/Pao is illustrated in two patients. Equation 5 indicates that an increase in Pw/Pao can be accounted for by a pronounced reduction in Rcoll compared with R4. This is demonstrated in patient No 21 (Table 4⇑). In this patient, the effect of nitroglycerin on Rcoll was more pronounced (87% reduction) than that on R4 (65% reduction), resulting in an increase in Pw/Pao. The same patient showed a similar reduction in Rcoll (63%) compared with R4 (60%) after the administration of adenosine, resulting in a Pw/Pao that remained unchanged.
On the other hand, an increase in blood flow velocity due to a pronounced reduction in R4 compared with Rcoll results in a decrease in Pw/Pao. For example, in patient 10, Rcoll demonstrated a reduction of 4% and R4 demonstrated a reduction of 45% after the administration of adenosine, resulting in a decrease of Pw/Pao from 0.51 to 0.38. The same patient demonstrated a decrease in Pw/Pao from 0.50 to 0.34 after the administration of nitroglycerin due to a pronounced reduction in R4 (58%) compared with Rcoll (17%).
Coronary steal phenomenon, which is defined as a reduction in collateral blood flow (velocity) in the recipient coronary artery after the administration of vasodilators in the donor coronary artery, can be explained by the presence of a resistance in the epicardial donor coronary artery (R1). The electric analog model illustrates that coronary steal may occur as a result of a reduction in collateral driving pressure due to a pressure drop across a resistance (R1). In that case, we cannot eliminate R1 from Equation 4.
This study was supported in part by the Dutch Heart Foundation, The Hague, Netherlands (grant number 90.270). We gratefully acknowledge the skilled assistance of the technical and nursing staff of our Cardiac Catheterization Laboratory (chief, Peter J. Belgraver). We thank Alexander C. Metting van Rijn, PhD; Jos A.E. Spaan, PhD (Department of Medical Physics, University of Amsterdam); and Morton J. Kern, MD (J.G. Mudd Cardiac Catheterization Laboratory, St Louis University Hospital) for critical review of the manuscript.
- Received November 12, 1996.
- Revision received January 16, 1997.
- Accepted January 29, 1997.
- Copyright © 1997 by American Heart Association
Cohen MV. Functional significance of coronary collaterals in man. In Coronary Collaterals: Clinical and Experimental Observations. Armonk, NY: Futura; 1985:93-114.
Goldstein RE, Stinson EB, Scherer JL, Seningen RP, Grehl TD, Epstein SE. Intraoperative coronary collateral function in patients with coronary occlusive disease. Circulation.. 1974;49:298-308.
McFalls EO, Araujo LI, Lammertsma A, Rhodes CG, Bloomfield P, Pupita G, Jones T, Maseri A. Vasodilator reserve in collateral-dependent myocardium as measured by positron emission tomography. Eur Heart J.. 1993;14:336-343.
Vanoverschelde J, Wijns W, Depre C, Essamri B, Heyndrickx GR, Borgers M, Bol A, Melin JA. Mechanisms of chronic regional postischemic dysfunction in humans: new insights from the study of noninfarcted collateral-dependent myocardium. Circulation.. 1993;87:1513-1523.
Cohen MV, Matsuki T, Downey JM. Pressure-flow characteristics and nutritional capacity of coronary veins in dogs. Am J Physiol.. 1988;255:H834-H846.
Feldman RL, Macdonald RG, Hill JA, Limacher MC, Conti CR, Pepine CJ. Effect of propranolol on myocardial ischemia occurring during acute coronary occlusion. Circulation.. 1986;73:727-733.
Piek JJ, Koolen JJ, Metting van Rijn AC, Bot H, Hoedemaker G, David GK, Dunning AJ, Spaan JAE, Visser CA. Spectral analysis of flow velocity in the contralateral artery during coronary angioplasty: a new method for assessing collateral flow. J Am Coll Cardiol.. 1993;21:1574-1582.
Kyriakidis MK, Petropoulakis PN, Tentolouris CA, Marakas SA, Antonopoulos AG, Kourouclis CV, Toutouzas PK. Relation between changes in blood flow of the contralateral coronary artery and the angiographic extent and function of recruitable collateral vessels arising from this artery during balloon coronary occlusion. J Am Coll Cardiol.. 1994;23:869-878.
Bach RG, Donohue TJ, Caracciolo EA, Wolford T, Aguirre FV, Kern MJ. Quantification of collateral blood flow during PTCA by intravascular Doppler. Eur Heart J.. 1995;16:74-77.
Meier B, Luethy P, Finci L, Steffenino GD, Rutishauser W. Coronary wedge pressure in relation to spontaneously visible and recruitable collaterals. Circulation.. 1987;75:906-913.
Schaper W. The microscopic structure of developing collaterals. In: Black DAK, ed. The Collateral Circulation of the Heart. Amsterdam, Netherlands: North Holland Publishing Co; 1971:51-65.
Becker LC. Conditions for vasodilator-induced coronary steal in experimental myocardial ischemia. Circulation.. 1978;57:1103-1110.
Schwartz H, Leiboff RL, Katz RJ, Wasserman AG, Bren GB, Varghese PJ, Ross AM. Arteriographic predictors of spontaneous improvement in left ventricular function after myocardial infarction. Circulation.. 1985;71:466-472.
Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Natte P, Passamani ER, Williams DO, Zaret B. The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial. Circulation.. 1987;75:817-829.
Hirai T, Fujita M, Nakajima H, Asanoi H, Yamanishi K, Ohno A, Sasayama S. Importance of collateral circulation for prevention of left ventricular aneurysm formation in acute myocardial infarction. Circulation.. 1989;79:791-796.
Habib GB, Heibig J, Forman SA, Brown BG, Roberts R, Terrin ML, Bolli R, and the TIMI Investigators. Influence of coronary collateral vessels on myocardial infarct size in humans: results of phase I Thrombolysis in Myocardial Infarction (TIMI) trial. Circulation.. 1991;83:739-746.
Rentrop KP, Feit F, Sherman W, Stecy P, Hosat S, Cohen M, Rey M, Ambrose J, Nachamie M, Schwartz W, Cole W, Perdoncin R, Thornton JC. Late thrombolytic therapy preserves left ventricular function in patients with collateralized total coronary occlusion: primary end point findings of the second Mount Sinai-New York University Reperfusion Trial. J Am Coll Cardiol.. 1989;14:58-64.
Rentrop KP, Feit F, Sherman W, Thornton JC. Serial angiographic assessment of coronary artery obstruction and collateral flow in acute myocardial infarction: report from the Second Mount Sinai-New York University Reperfusion Trial. Circulation.. 1989;80:1166-1175.
Schaper W, Winkler B. Determinants of peripheral coronary pressure in coronary artery occlusion. In: Maseri A, Klassen GA, Lesh M, eds. Primary and Secondary Angina Pectoris. New York/San Francisco/London: Grune & Stratton; 1978:351-361.