It has been demonstrated that flow-dependent dilation is abolished in hypertensive patients with angiographically normal coronary arteries (1) and restored immediately after intravenous ACE inhibition (2). Because conductance coronary arteries represent only 5% of the total coronary resistance, maximal coronary blood flow is determined mainly by the maximal area of the coronary microcirculation in the absence of coronary artery stenosis (3). However, large arteries have not only a passive role in the coronary circulation. Normal epicardial coronary arteries dilate in response to increase in blood flow velocity (1,4,5), to physical stimuli such as exercise (6), and to the cold pressor test (7). The flow-dependent coronary artery dilation is mediated by the endothelium (8), which releases vasodilating factors in response to the increase in blood flow velocity and longitudinal shear stress. The factors involved in the flow-mediated coronary vasodilation are nitric oxide (9) and probably endothelium-derived hyperpolarizing factor (10).
The aim of the present study was to evaluate whether restoration of flow-dependent dilation of conductance coronary arteries by angiotensin-converting enzyme (ACE) inhibition in hypertensive patients may alter maximal coronary blood flow and minimal coronary resistance. We measured coronary blood flow produced by maximal dilation of the coronary microcirculation caused by intracoronary papaverine (11) in hypertensive patients with reversible impairment of flow-dependent coronary artery dilation and with angiographically normal coronary arteries.
The study group was composed of 13 patients with essential hypertension undergoing diagnostic coronary angiography for evaluation of chest pain, without a history suggestive of variant angina. All patients had a well-established history of elevated blood pressure >140/90 mm Hg, with at least four sets of readings taken at 1-week intervals. In all patients, an ambulatory blood-pressure monitoring confirmed arterial hypertension. Arterial hypertension was recently diagnosed, and patients had never been treated. Patients were included by consensus of two experienced investigators on immediate review of the angiograms, only if coronary arteries were angiographically normal and completely smooth, without luminal irregularities. Patients with other coronary risk factors were excluded (1). All patients had normal left ventricular systolic function assessed by echocardiography. Left ventricular mass index was calculated at end diastole by use of the Penn convention. Mean value for the group was 96 ± 22 g/m2. Left ventricular mass index was normal in 10 patients and slightly elevated in three patients (139, 111, and 137 g/m2). The study protocol was approved by the institutional review Committee of the University of Kremlin-Bicêtre. Written informed consent was obtained in all patients before cardiac catheterization.
Patients were studied in the fasting state. Nitrate therapy, when given, was withheld 24 h before catheterization. No premedication was administered; 1% lidocaine was used for local anesthesia, and 5,000 U heparin i.v. was administered. After documentation of normal coronary arteries, ≥15 minutes was allowed to elapse. After additional administration of 5,000 U heparin i.v., a 8F guiding catheter was positioned in the ostium of the left coronary artery. Each patient then underwent the following study protocol. A 3F 20-MHz coronary Doppler catheter (Monorail Doppler 3; Schneider Europe AG, Zurich, Switzerland) connected to a single-channel 20-MHz pulsed Doppler velocimeter (model MDV, 20 Single Channel Velocimeter; Millar Instruments, Houston, TX, U.S.A.) was placed in the left anterior descending (LAD) artery, its proximal lumen being placed in the midportion of the artery. The use of this device to assess intracoronary blood flow velocity has been previously discussed in detail (7).
The first hemodynamic measurements and left coronary arteriography (Base 1) were then performed. Five minutes later, two successive boluses of 10 mg papaverine (8 mg papaverine/ml, 0.9% saline solution) were injected in the midportion of the LAD through the proximal lumen of the Doppler catheter, and the flow-dependent dilation was assessed by measuring the diameter of the proximal LAD (LAD1) (1). The first bolus was used to induce flow-dependent coronary dilation. The second bolus, injected immediately after the peak flow induced by the first bolus, was used to maintain a maximal dilation of the microcirculation simultaneous with the delayed flow-dependent dilation of the LAD1. Intracoronary blood flow velocity was measured in the distal LAD (LAD2), near the tip of the Doppler catheter. Coronary angiograms of the left coronary artery were performed at Base 1, and 60 s after the peak flow velocity induced by the first bolus of papaverine (PAP 1). Heart rate, aortic pressure (through the guiding catheter), mean and phasic flow velocities (kilohertz shift), and ECG were continuously monitored throughout the protocol. Measurements of the diameters of the LAD1, LAD2, and circumflex artery (Cx) were made on each angiogram. Estimates of blood flow (F) in LAD2 were calculated from measurements of mean coronary flow velocity in LAD2 (v) and LAD2 cross-sectional area (CSA): F = v×CSA. Cross-sectional area was calculated from measurements of LAD2 diameter (d) assuming a circumferential model: CSA = πd2/4. An index of minimal coronary vascular resistance was calculated by the ratio of the mean aortic pressure at peak coronary blood flow to peak coronary blood flow after papaverine. In all patients, this procedure was repeated (Base 2 and PAP 2) after intravenous infusion over a period of 10 min of 1 mg perindoprilat, the active deesterified form of the oral ACE inhibitor perindopril (Servier, Courbevoie, France). This dosage was chosen because it has been safely prescribed, without significant effect on blood pressure, for patients with acute myocardial infarction and caused an immediate inhibition of plasma ACE activity of >90% (unpublished data from Servier, 1992). Furthermore, it restored a normal flow-dependent coronary vasodilation in hypertensive patients with angiographically normal coronary arteries (2). Last, measurements were repeated 4 min after intracoronary infusion of 2 mg isosorbide dinitrate (ISDN) through the guiding catheter to determine the maximal dimensions of the coronary artery segments, and were followed by a new intracoronary injection of 10 mg papaverine (PAP 3) to evaluate the coronary flow reserve.
Quantitative coronary arteriography
Left coronary arteriograms were obtained by ECG-triggered digital subtraction at a rate of six frames per second on a 512-pixel matrix (General Electric CGR DG 300, Iny-les-Moulineaux, France). The angiographic system was set up in the right anterior oblique position with adequate cranial or caudal angulation allowing optimal view of the LAD1, LAD2, and Cx segments on end-diastolic frames without overlap by side branches. Analysis of coronary angiograms was performed by a previously validated technique (7). Each angiogram was analyzed at random without knowledge of the protocol sequence (Base 1, PAP 1, Base 2, PAP 2, and ISDN).
All data are expressed as mean ± SD. Statistical comparisons of hemodynamic parameters, coronary vessel dimensions, and coronary velocity, flow, and resistance under base and papaverine, before and after the administration of the ACE inhibitor perindoprilat, and under post-ISDN conditions were made by two-way analysis of variance (ANOVA) with repeated measures for experimental condition factor, followed by the Fisher protected least significant difference test. Statistical significance was assumed if the null hypothesis could be rejected at the 0.05 probability level.
Heart rate was comparable at Base 1 and Base 2. Intracoronary injection of papaverine was followed by a significant increase in heart rate before perindoprilat [74 ± 10 (Base 1) vs. 79 ± 12 beats/min (PAP 1) (p < 0.05)], and after perindoprilat administration [71 ± 10 (Base 2) vs. 76 ± 13 beats/min (PAP 2) (p < 0.05)]. Changes in heart rate due to papaverine were similar before and after perindoprilat. Conversely, heart rate increase after papaverine injection after ISDN (PAP 3) was significantly higher than after the two former injections of papaverine (86 ± 12, both p < 0.01).
Changes in mean aortic pressure during the procedure are depicted in Fig. 1. There was a significant decrease in mean aortic pressure after each injection of papaverine. Aortic pressure decrease was comparable during PAP 1 and 2, but the pressure decrease was significantly higher than during PAP 1 and 2 when papaverine was administered after ISDN (PAP 3).
Restoration of flow-dependent coronary artery dilation after ACE inhibition
Proximal left anterior descending coronary artery. The cross-sectional area of the proximal LAD was not modified by the injection of papaverine before perindoprilat (PAP 1), indicating the absence of flow-dependent vasodilation (Fig. 2). Conversely, papaverine caused a significant increase in mean LAD1 cross-sectional area (+26.7 ± 11.2%), after perindoprilat (PAP 2) (Fig. 2), indicating the restoration of flow-dependent vasodilation. Isosorbide dinitrate produced a 50.2 ± 16.8% increase in cross-sectional area compared with Base 1. Before perindoprilat, the LAD1 area after papaverine represented 66.9 ± 8.0% of the maximal area caused by ISDN (PAP 1), and 84.0 ± 8.2% after perindoprilat (PAP 2).
Proximal circumflex coronary artery. This segment was used as a reference segment, and cross-sectional area was not altered by papaverine before and after perindoprilat (Fig. 2). ISDN produced a 54.3 ± 24.7% increase in cross-sectional area compared with Base 1.
Coronary blood flow and resistance
Blood flow velocity measured in LAD2 was significantly increased by injection of papaverine in the distal LAD (Fig. 3). Flow velocity increase was slightly but significantly higher during PAP 2 than during PAP 1. Indeed, before perindoprilat, papaverine induced a 405 ± 86% increase in blood flow velocity (from 9.5 ± 2.1 to 38.3 ± 15.2 cm/s). After perindoprilat, papaverine led to a 430 ± 104% increase in blood flow velocity (from 9.4 ± 1.9 to 39.8 ± 15.3 cm/s). Conversely, after maximal vasodilation of the left coronary artery by ISDN, flow velocity increase during PAP 3 was significantly lower than during PAP 1 and 2 (30.7 ± 12.3 cm/s; Fig. 3).
The Base 1 and Base 2 estimates of LAD2 blood flow were similar (31.3 ± 10.8 and 31.1 ± 9.8 ml/min, respectively). The cross-sectional area of the distal LAD, which was directly exposed to papaverine, was increased before (PAP 1) as well as after perindoprilat administration (PAP 2; Fig. 2). The increase in cross-sectional area after papaverine was significantly higher after perindoprilat (51.5 ± 23.4%) than before (33.4 ± 20.5%; Fig. 2). Before the administration of perindoprilat, papaverine led to a 422 ± 45% increase in coronary blood flow (to 163.4 ± 73.4 ml/min). After the administration of perindoprilat, papaverine led to a 563 ± 41% increase in coronary blood flow (to 197.8 ± 80.3 ml/min), significantly higher than before restoration of flow-dependent dilation (Fig. 4). This increase in maximal LAD2 blood flow (+21.0 ± 10.3%) was due mainly to the higher increase in area of the LAD2 and also to a slightly higher increase of the LAD2 blood flow velocity after ACE inhibition. The increase in maximal LAD2 blood flow was associated with a 19.3 ± 9.5% decrease in the minimal coronary resistance after restoration of flow-dependent vasodilation (from 0.83 ± 0.31 to 0.67 ± 0.23 mm Hg/ml/min; Fig. 4).
Last, after ISDN administration at the end of the procedure, papaverine (PAP 3) was followed by blood flow increase similar (177.8 ± 72.9 ml/min) to that observed during PAP 1 and significantly lower to that observed during PAP 2 (Fig. 4). Nevertheless, because aortic pressure fall was higher during PAP 3 than during PAP 1 and 2, minimal coronary vascular resistance was still lower during PAP 3 (0.62 ± 0.21) than during PAP 1 and 2.
The present study demonstrates that in hypertensive patients with angiographically normal coronary arteries, restoration of flow-dependent dilation of large coronary arteries by ACE inhibition causes a significant increase in maximal coronary blood flow induced by maximal dilation of the microcirculation and reduction in minimal coronary vascular resistance. These results demonstrate that epicardial coronary arteries are not only conductance vessels, but that they also participate substantially in the total coronary resistance.
Contribution of epicardial coronary arteries to maximal coronary blood flow
Although it is well established that a coronary artery stenosis reduces the maximal flow obtained after dilation of the coronary microcirculation, no study has evaluated the role of nonstenosed conductance vessel dilation on coronary blood flow. Large coronary arteries have been considered to have a predominant role of conductance in the coronary circulation because they impose virtually no resistance to blood flow. According to the Poiseuille law, resistance of a large coronary artery is directly related to the length and inversely related to the fourth power of the radius of the artery, so that small changes in diameter may have large effects on epicardial coronary artery resistance (i.e., the coronary blood flow). Alterations in diameter of large coronary arteries depend on myogenic responses and the vascular tone regulated by the sympathetic nervous system and the endothelium. The direct role of epicardial coronary artery dimensions on maximal coronary blood flow can also be inferred from the results of Groves et al. (12). Although this study was not dedicated to the role of conductance vessels in coronary blood flow, it must be noted that the authors showed a decrease in maximal coronary blood flow induced by papaverine in patients without significant coronary artery stenosis, after administration of a selective bradykinin B2-receptor antagonist, which reduced flow-dependent coronary dilation.
The decrease in minimal coronary vascular resistance we observed after restoration of flow-dependent dilation could be due to an enhancement of microvascular dilation by papaverine after ACE inhibition, which could lead to an improvement of flow-dependent dilation of the epicardial arteries through an increased coronary blood flow. However, it must be pointed out that results of our study show that at baseline, papaverine resulted in an increase in coronary blood flow of 133.0 ± 64.1 ml/min with no change in proximal LAD cross-sectional area (−0.6 ± 3.4%), and after perindoprilat, papaverine resulted in an increase in coronary blood flow of 165.1 ± 71.3 ml/min with a 26.7 ± 11.2% increase in proximal LAD cross-sectional area. It seems unlikely that the former increase in coronary blood flow was unable to evoke any flow-dependent dilation and that flow-dependent dilation was suddenly set up because perindoprilat could have enhanced coronary blood flow through an improvement of endothelium-independent vasodilation due to papaverine at the level of coronary microcirculation. These results demonstrate that there is a true increase in flow-dependent dilation with perindoprilat, irrespective of blood flow increase, and are concordant with those we had previously published (2). Conversely, because coronary microcirculation is heterogeneous, it might be possible that papaverine was unable to vasodilate coronary microcirculation maximally at baseline, and that the increase of coronary blood flow after perindoprilat might result from the recruitment of additional microvessels for vasodilation. However, it must be pointed out that microcirculatory coronary vasodilation was obtained by two successive boluses of 10 mg injected directly in the midportion of the LAD, which feeds a limited microvascular bed, the second one to maintain a maximal dilation of the coronary microvasculature during the assessment of flow-dependent dilation of the epicardial coronary artery. This dose of papaverine is much more higher than the dose of 12 mg injected in the left coronary artery (which feeds a larger microvascular bed) in the study of Wilson and White (11), who have demonstrated that higher doses of papaverine were unable to produce more dilation of the coronary microcirculation when injected in the left coronary artery. Thus, an acute effect of ACE inhibition on endothelium-dependent dilation of the microcirculation could have been suggested only if the microcirculation had not been totally dilated, which is highly improbable with the high dose of papaverine used in this study.
Maximal coronary blood flow caused by papaverine depends also on maximal cross-sectional area of the coronary circulation and on coronary perfusion pressure (13). Maximal lumen cross-sectional area of the coronary microcirculation is frequently reduced in patients with hypertension (14,15), but cannot be acutely increased by ACE inhibition. Indeed, it depends on intima-media thickness, perivascular fibrosis, and extravascular compressive forces if they are severely elevated; that was not the case in the studied patients.
In our study, coronary blood flow was also derived from measurements of flow velocity. When a vessel dilates, Doppler position is more unstable, which makes measurements more difficult. In our study, we always paid special attention to get the better signal in each condition to detect changes in flow velocity accurately.
Last, increase in maximal coronary blood flow cannot be explained by an elevation of coronary perfusion pressure, because there was no difference between postpapaverine mean aortic pressure measured before and after ACE inhibition. Conversely, coronary blood flow after ISDN and papaverine (PAP 3) was lower than after papaverine after perindoprilat administration (PAP 2; Fig. 4). However, mean aortic pressure was more reduced during PAP 3 than during PAP 2 (Fig. 1), which results in a decrease in minimal coronary vascular resistance during PAP 3 (Fig. 4). As ISDN dilates only conductance vessels, this result could be explained by the dilation of the whole LAD, as shown in Fig. 2. Thus, we can conclude that changes in minimal coronary vascular resistance and maximal coronary blood flow were due to changes in large coronary artery dimension and resistance.
Endothelium-mediated flow-dependent dilation has been shown in normal human coronary circulation, and is substantial, resulting in about 10-17% mean diameter increase (1,4,5), and 25-35% mean cross-sectional area increase (1,12). Thus, physiologic participation of large coronary arteries in coronary resistance may have some clinical implications. Indeed, flow-dependent dilation has been evidenced when myocardial metabolic demand increases (16). We had previously shown that epicardial coronary artery flow-dependent dilation is abolished in patients with essential hypertension (4) and restored after ACE inhibition (2). Although the role of large coronary arteries on coronary resistance could be studied with other vasodilators such as calcium antagonists or nitrates, it must be pointed out that ACE inhibition does not alter coronary artery diameter at baseline and allows dilation of epicardial coronary arteries only when coronary blood flow increases. This effect is quite different from those of nitrates or calcium antagonists that dilate coronary arteries at baseline (17). Thus, ACE inhibition reestablishes a normal regulation of coronary vasomotion in hypertensive patients.
Coronary flow-dependent dilation is also impaired in patients with atherosclerosis (5,18), diabetes mellitus (19), as well as epicardial coronary vasomotor response to dynamic exercise in patients with atherosclerosis with or without hypertension (17). Impaired endothelium-dependent epicardial coronary artery dilation may limit the ability of coronary circulation to deliver an adequate blood flow to the myocardium when myocardial metabolic demand increases. However, the results shown in our study are now only applicable to hypertensive patients whose flow-dependent coronary dilation can be restored by ACE inhibition. The improvement of endothelium-dependent coronary vasodilation by other compounds such as antioxidants (20) or cholesterol-lowering agents (21) might also decrease coronary resistance and improve myocardial perfusion, but it must be demonstrated.
The present study shows that ACE inhibition, by restoring flow-dependent epicardial coronary artery dilation, results in a significant increase in maximal coronary blood flow caused by maximal dilation of the coronary microcirculation in hypertensive patients with angiographically normal coronary arteries. In these patients, the contribution of epicardial coronary arteries to the total coronary resistance may be relevant, and the improvement of conductance vessel dilation by ACE inhibition may participate in the enhancement of blood flow delivery to the myocardium when myocardial oxygen demand is importantly increased.
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