Changes in Phasic Coronary Blood Flow Velocity Profile in Relation to Changes in Hemodynamic Parameters During Stress in Patients With Aortic Valve Stenosis
Background Alterations in phasic coronary flow profile have been demonstrated at rest in patients with aortic valve stenosis (AVS) but have never been studied under conditions of hemodynamic stress.
Methods and Results Thirty-four patients with significant pure AVS (21 with exertional symptoms [group 1], 13 asymptomatic [group 2]) and 9 control subjects (group 3), all with normal coronary arteries, were studied successively at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 μg · kg−1 · min−1 IV) by proximal left anterior descending (LAD) intracoronary Doppler flow velocimetry concomitant with hemodynamic measurements. Systolic retrograde coronary flow velocity (CFV) was recorded only in patients with AVS, and its resting peak value was positively correlated with peak aortic pressure gradient (APG) (r=.63, P<.001). In group 1, there was lower aortic valve area (0.58±0.10 versus 0.75±0.08 cm2, P<.001) and higher resting APG and peak systolic retrograde CFV than in group 2, and also higher resting peak diastolic and mean CFV than in groups 2 and 3. In the two AVS groups, there were no changes from rest in APG and retrograde CFV at peak pacing rate; however, these parameters increased concomitantly and significantly at peak dobutamine stress. The ratio of the resting systolic to diastolic CFV curve area was inversely correlated with mean APG (r=−.54, P<.001); it was significantly lower in group 1 than in groups 2 and 3 (0.19±0.07 versus 0.29±0.10 and 0.30±0.04, respectively, both P<.005) and increased at peak pacing (group 1, to 0.29±0.14; group 2, to 0.39±0.12; group 3, to 0.38±0.07; all P<.001). At peak dobutamine stress, it decreased in patients with AVS (group 1, to 0.05±0.05; group 2, to 0.08±0.03; both P<.001) but did not change in group 3 (0.25±0.05). From rest to peak dobutamine stress, in both AVS groups there was increased retrograde systolic (group 1, 441±483%; group 2, 681±356%; both P<.001), decreased total systolic (group 1, −66±25%, P<.001; group 2, −19±24%; P=NS), and increased diastolic (group 1, 33.4±31.7%; group 2, 197.7±105.1%; both P<.001; group 1 versus group 2, P<.001) CFV curve area. In contrast, group 3 showed comparable increases in both systolic (143.5±44.4%) and diastolic (197.1±75.2%) CFV area (both P<.001). The stress-induced increases in the mean CFV and blood flow exceeded or were comparable with the concomitant increases in the estimated myocardial metabolic demand in groups 2 and 3 but were significantly lower in group 1.
Conclusions Stress-induced changes in LAD phasic CFV profile differ significantly between patients with and without AVS. In AVS, these changes are closely related to the concomitant stress-induced changes in hemodynamic parameters.
Alterations in the resting phasic coronary flow velocity (CFV) and coronary blood flow characteristics have been demonstrated in patients with aortic valve stenosis (AVS),1 2 3 4 5 including the development of an early systolic retrograde component, a reduced systolic component, and an increased diastolic component. Although previous studies demonstrated dependence of the resting phasic CFV profile on hemodynamic changes induced by the valvular obstruction,1 there were no measurements during hemodynamic stress, and all the available data were obtained only at rest. The purpose of this study was to investigate the phasic characteristics of CFV in conscious patients with significant AVS, both symptomatic and asymptomatic, at conditions of rest and, more importantly, during different forms of provoked hemodynamic stress that may (dobutamine) or may not (atrial pacing tachycardia6 ) change transvalvular pressure difference. To the best of our knowledge, such information on the pattern of stress-induced changes in phasic coronary blood flow in AVS would be obtained for the first time in an effort to provide a deeper insight into the mostly unresolved issue of the contribution of these changes, particularly systolic retrograde coronary blood flow, to the development of myocardial ischemia and symptoms.
The study cohort consisted of 34 nonconsecutive patients who were prospectively selected from patients undergoing cardiac catheterization for significant AVS. There were 25 men and 9 women, with a mean age of 63.4±5.7 years (range, 52 to 75 years). Inclusion criteria were (1) significant pure AVS (peak transvalvular pressure gradient >50 mm Hg) with not more than a trace of associated regurgitation, (2) angiographically normal coronary arteries, (3) normal sinus rhythm at the time of the study, (4) no coexistent left ventricular outflow tract obstruction of any type, (5) no coexistent malfunction of any of the other cardiac valves, (6) no clinically overt congestive heart failure, and (7) no underlying hypertension, pulmonary disease, anemia, or peripheral vascular disease. A control group of 9 patients without aortic stenosis (7 men and 2 women; mean age, 54.1±8.2 years) investigated in our hospital for atypical chest pain was also included in the study. In a complete clinical, ECG, echocardiographic, and hemodynamic workup, they had no evidence of heart disease (normal global and segmental left ventricular function, normal coronary arteries) and were selected to serve as control subjects.
The research protocol was approved by the Ethics Committee of the Institutional Review Board at the Department of Cardiology, Hippokration Athens University Hospital. All patients gave informed written consent for participation in the study.
All patients were premedicated with diazepam 5 mg IM. As is our usual practice during CFV measurements,7 all patients were treated with heparin (10 000 U IV) at the start of the procedure and 5000 U each hour during the procedure. Coronary arteriography and ascending aortography were performed with a standard right femoral approach. After two experienced angiographers had agreed on the presence of a normal epicardial coronary arterial tree, the study protocol was performed as follows. An 8F pigtail catheter was first advanced into the left ventricle via the right femoral sheath (over a straight guide wire, which was used to cross the stenotic valve), pressures were recorded, and a single-plane left ventriculogram was obtained in the right anterior oblique projection. Subsequently, the pigtail catheter was left in place in the left ventricle, a second arterial access was gained by placing an 8F sheath percutaneously into the left femoral artery, and an 8F left Judkins femoral guiding catheter was advanced into the ostium of the left coronary artery. A 2.5F Millar 20-MHz Doppler catheter, model DC-101, was then inserted over a 0.010-in flexible angioplasty guide wire as previously reported8 9 and positioned in the proximal left anterior descending coronary artery (LAD). Right heart catheterization was performed through both the right and left femoral veins with 7F sheaths. A balloon-tipped flow-directed triple-lumen catheter was used for cardiac output determinations, and a pacing wire was positioned in the high lateral right atrial wall for rapid atrial pacing.
To induce hemodynamic stress, rapid right atrial pacing and graded intravenous dobutamine infusion were used sequentially. A bolus of 12 mg papaverine IC was then injected through the guiding catheter to measure coronary vasodilator reserve. All these interventions were used successively only after the hemodynamic and CFV variables had returned to the resting values for at least 5 minutes.
Rapid Atrial Pacing
Rapid atrial pacing was conducted at 90 beats per minute (bpm), followed by subsequent increments in pacing rate of 10 bpm until a final pacing rate of approximately 130 bpm was reached or the rate was limited by the development of Wenckebach-type second-degree atrioventricular block. In control subjects, the maximum pacing rate was prespecified to 125 bpm. Hemodynamic and CFV measurements were continuously monitored and recorded after a 3-minute equilibration period at each particular heart rate.
After the hemodynamic and CFV data had returned to baseline, dobutamine was administered through a peripheral IV line with an infusion pump system in graded doses, starting at a rate of 5 μg · kg−1 · min−1 and increasing the dose by 5 μg · kg−1 · min−1 every 5 minutes to a maximum of 30 μg · kg−1 · min−1. Hemodynamic and CFV measurements were continuously monitored and recorded at the end of the 5-minute equilibration period at each dobutamine dose. The end points for atrial pacing and IV dobutamine were prespecified and included heart rate of 130 bpm, decrease in systolic aortic pressure >20 mm Hg, increase in left ventricular end-diastolic pressure >10 mm Hg, and development of significant arrhythmias, angina, dyspnea, or other intolerable symptoms.
During the study, aortic and left ventricular pressures were recorded simultaneously with thoroughly flushed disposable fluid-filled air reference Statham pressure transducers zeroed to the midchest level. In all cases, recordings were repeated after transducers were switched and reflushed at the start and at the end of the study. In case of even minimal pressure disagreement at the start of the study, transducers were rebalanced and measurements were repeated. Heart rate, pressures, and duration of left ventricular ejection were determined directly from the tracings. Mean systolic aortic blood flow (in milliliters per second) was calculated by dividing cardiac output by systolic ejection time. In patients with AVS, planimetry on the aortic and left ventricular pressure tracings was used to determine the mean pressure difference across the aortic valve. The aortic valve area was calculated according to the formula of Gorlin and Gorlin.10 Estimates of coronary perfusion pressure were calculated as the difference between mean aortic pressure and left ventricular end-diastolic pressure. Diastolic and systolic pressure-time indexes (DPTI and SPTI) were determined by computerized planimetry as previously described11 12 and were converted to appropriate units and multiplied by heart rate [(mm Hg · s)/min]. The ratio DPTI/SPTI was then calculated.
Cardiac output was determined by thermodilution. Left ventricular volumes and ejection fraction were calculated by the single-plane area-length method.13
Doppler Flow Velocity Studies
CFV was measured in the proximal LAD with the subselective intracoronary Doppler catheter. The use of this device to assess changes in coronary blood flow has been described in detail elsewhere.8 9 Doppler data were processed with a zero-cross velocimeter (Millar Instruments), from which mean and phasic CFV signals were obtained. This pulsed Doppler system has the ability to detect not only the magnitude of CFV but also the direction of coronary flow. Flow toward the tip of the Doppler catheter is recorded below zero line and is assigned a negative value. Before the Doppler catheter was placed in the guiding catheter, the mean and phasic Doppler flow velocity recordings were zeroed and calibrated from an internally set 0- to 100-cm/s signal for full-scale deflection. The Doppler catheter was placed in the center of the vessel in an area free of side branches or vessel overlap, with the guide wire extending from the tip of the catheter so as to obtain a stable CFV signal. Before the study protocol was begun, the position of the Doppler velocity catheter and the range gate control of the 20-MHz pulsed Doppler meter were adjusted to optimize the audio CFV signal and also to record an optimal signal of phasic CFV waveform. The Doppler catheter position was frequently checked by fluoroscopy throughout the study to document its stability. Both phasic and mean Doppler CFV and hemodynamic signals were displayed and recorded on a Honeywell multichannel strip-chart recorder. For data from the zero-crossing velocimeter, the mean CFV was measured from the tracings derived from the recorder in each study cycle (zero-cross frequency analysis).
Measurements of CFV Curve Area
The area under the CFV curve was quantified by computerized planimetry. The percent change in the CFV curve area from rest to each of the hemodynamic interventions was measured during the different portions of the average cardiac cycle and calculated per minute. The CFV curve area during each segment of the cardiac cycle was also expressed as the percentage of the total CFV curve area. The different portions of the cardiac cycle were determined from the recordings of the left ventricular and aortic pressures and the ECG. Systole was defined as the portion between the onset of the initial upstroke of the left ventricular pressure (or the peak of the R wave on the ECG) and the dicrotic notch of the aortic pressure. Diastole was defined as the remainder of the cardiac cycle.
Coronary Vasodilator Reserve
Coronary vasodilator reserve was calculated as the ratio of mean CFV at peak papaverine-induced hyperemia to mean resting CFV.14
Estimates of Changes in Coronary Blood Flow
Estimates of changes in coronary blood flow were made by correcting changes in the mean CFV for changes in the estimated cross-sectional area (CSA) of the LAD.15 16 17 CSA was determined at end diastole just distal to the Doppler velocity catheter tip from a single angiographic view, assuming a circular cross section, as follows: CSA=π×(D/2)2, where D represents the LAD diameter. Coronary arteriography to measure LAD diameter was performed with the use of a power injection of a single bolus of contrast medium at a rate of 6 mL/s for a total of 7 to 9 mL with a digital injection system. The hemodynamic and CFV measurements in each study cycle were always recorded immediately before coronary arteriography. Angiographic determination of the LAD diameter was made by two experienced investigators using a digital computer-assisted method (calipers) as previously described.18 Absolute diameter values were computed with the shaft of the 8F guiding catheter (2.67 mm) used as a scale factor. Coronary blood flow was estimated as the product of the mean CFV times the CSA at the Doppler catheter position. Only relative, not absolute, changes in blood flow were considered for this study.
Acquisition of the Study Data
Throughout the study, the ECG (one lead), the mean and phasic CFV signals, and left ventricular and aortic pressures were continuously monitored, and all measurements were recorded in steady-state conditions at paper speeds of 10, 50, and 100 mm/s. The hemodynamic and CFV data analyzed in this study were those obtained at rest, at peak rapid atrial pacing-induced tachycardia, at peak intravenous dobutamine infusion, and at peak papaverine-induced coronary hyperemia. Furthermore, each individual hemodynamic or CFV measurement included in the final analysis represents the average from 10 consecutive cardiac cycles.
Echocardiographic Assessment of Left Ventricular Mass
Left ventricular mass was calculated by the previously described “Penn-cube left ventricular mass” formula from measurements made in accordance with American Society of Echocardiography criteria and was indexed by body surface area.19 20
After careful histories were taken, the patients with AVS were classified into two prespecified groups on the basis of their symptomatic state. Twenty-one patients (group 1) reported the presence of exertional symptoms in the form of dyspnea, chest discomfort resembling angina, and alteration in consciousness, whereas 13 patients (group 2) denied the occurrence of any symptoms during exertion. The 9 control subjects were included in the analysis as group 3.
Repeated-measures ANOVA (randomized block two-way ANOVA without replication) was used to compare the study data obtained at rest, at peak atrial pacing-induced tachycardia, and at peak intravenous dobutamine infusion. When results of ANOVA were significant, the Bonferroni inequality was used to isolate the individual significant differences. Comparisons of discrete variables between the three groups of patients were made with one-way ANOVA and Bonferroni t tests. Statistical correlations between CFV and hemodynamic parameters were made by linear regression analysis. Statistical significance was defined as P<.05. All data are expressed as mean±SD.
Clinical characteristics of the study patients are presented in Table 1⇓.
Control subjects had significantly lower left ventricular mass index compared with patients with AVS. Furthermore, the calculated aortic valve area was significantly lower in the symptomatic patients of group 1 than in those of group 2.
The hemodynamic data obtained in the study are summarized in Table 2⇓.
Resting measurements indicated more severe AVS in the symptomatic patients of group 1 than in those of group 2, with a significantly higher transvalvular aortic pressure gradient and a significantly lower cardiac index and aortic valve area.
At peak rapid atrial pacing, in both AVS groups, the left ventricular systolic pressure and the mean aortic pressure gradient were not significantly different from the resting measurements; in contrast, they were significantly increased at peak dobutamine stress. In contrast to atrial pacing–induced tachycardia, the dobutamine-induced tachycardia was accompanied by a significant reduction in systolic ejection time per minute, since the decrease in systolic ejection time per beat exceeded the concomitant increase in heart rate. Importantly, at peak dobutamine stress, aortic systolic and mean pressures declined slightly in both AVS groups; in contrast, they increased significantly in control subjects.
In general, both hemodynamic parameters and CFV returned to (or closely approximated) resting values 3 to 5 minutes after pacing interruption and 10 to 15 minutes after the end of dobutamine infusion.
In all patients in our study, phasic CFV waveform in the proximal LAD showed a predominantly diastolic pattern, with smaller systolic antegrade CFV waves. A systolic retrograde (negative) CFV wave was recorded in early systole (around the point of the peak transvalvular pressure difference) in almost all patients with AVS (except one of group 1) and in none of the control subjects. Measurements of peak phasic and mean CFV at rest and during stress are shown in Table 3⇓.
Resting measurements showed that in patients of group 1, there was a significantly higher peak diastolic and mean CFV than in those of groups 2 and 3. Peak retrograde systolic CFV was higher in group 1 than in group 2.
Atrial pacing–induced tachycardia was accompanied by significant increases in the mean and peak diastolic CFV, but the increases noted in group 1 were significantly lower than those of groups 2 and 3. Peak antegrade systolic CFV did not change in group 1 but increased significantly in groups 2 and 3. Peak retrograde systolic CFV declined slightly (nonsignificantly) in both AVS groups, with the decrease in group 2 being higher than that in group 1.
Dobutamine stress also resulted in significant increases in the mean and peak diastolic CFV, and the increases noted in group 1 were also significantly lower than those in groups 2 and 3. Furthermore, these increases were higher than those observed during pacing tachycardia. Peak antegrade systolic CFV declined significantly in group 1 and remained near resting level (but lower than the respective atrial pacing level) in group 2; it increased significantly in group 3. Impressively, in patients with AVS, peak retrograde systolic CFV increased significantly during dobutamine stress, in sharp contrast to pacing tachycardia, with the increases being comparable in the two AVS groups.
In summary, the two different forms of stress induced different changes in valve hemodynamics and also had different effects on systolic CFV. Overall, pacing tachycardia tended to improve, whereas dobutamine stress tended to depress, systolic coronary flow. Representative tracings from the study patients indicating stress-induced changes in hemodynamic parameters and concomitant changes in phasic CFV in AVS are shown in Figs 1⇓ and 2⇓.
In patients with AVS, the resting peak diastolic and mean CFV were correlated positively with the heart rate–left ventricular systolic pressure product (r=.579, P=.0003 and r=.600, P=.00018, respectively). The resting peak systolic retrograde CFV (measured in absolute values) was correlated positively with the peak systolic aortic pressure gradient (Fig 3⇓), but there were no significant correlations with other hemodynamic parameters.
In groups 2 and 3, the stress-induced increases in the mean CFV were comparable to or exceeded the respective increases in the heart rate–left ventricular systolic pressure product at both peak pacing and peak dobutamine stress, whereas in group 1, they were significantly lower (Tables 3⇑ and 4⇓). These data suggest that in patients of group 1, there was an inadequate CFV response relative to the increase in myocardial metabolic demand and a worse myocardial oxygen supply-to-demand ratio during hemodynamic stress than in patients of groups 2 and 3.
Indexes of Myocardial Metabolic Supply and Demand
The resting heart rate–left ventricular systolic pressure product and SPTI were higher in patients with AVS than in control subjects (Table 4⇑). These indexes of the resting myocardial metabolic demand were also higher in group 1 than in group 2. The resting DPTI/SPTI ratio was lower in patients with AVS than in control subjects and lower in group 1 than in group 2, indicating a worse resting myocardial metabolic supply-to-demand imbalance with the presence and increasing severity of AVS. In all patient groups, the DPTI/SPTI ratio declined with pacing tachycardia (significantly decreased DPTI and unchanged or increased SPTI). In contrast, it did not change significantly with dobutamine stress because of significant and relatively comparable increases in both DPTI and SPTI.
In all study groups, the coronary perfusion pressure increased slightly with rapid atrial pacing–induced tachycardia. At peak dobutamine stress, it was not different from the resting level in both AVS groups (decreases in both mean aortic and left ventricular end-diastolic pressures), but it was significantly increased in control subjects (significantly increased mean aortic pressure).
Changes in CFV Curve Area
In group 1 (Fig 4⇓), from rest to peak paced heart rate, total systolic and antegrade systolic CFV area per minute increased significantly (by 58.2±69.9% and 52.7±53.7%, respectively). Retrograde systolic area increased insignificantly (by 26.6±54.8%, P=NS), and diastolic CFV area did not change (0.32±11.9%, P=NS). In the same group, from rest to peak dobutamine stress, there was a significant decrease in total systolic CFV area (−66.3±25.0%), mainly due to a highly significant increase (441.4±483.1%) in retrograde systolic CFV area per minute. Antegrade systolic area per minute did not change (3.82±9.2%, P=NS), whereas diastolic area increased slightly (33.4±31.7%).
In group 2 (Fig 5⇓), from rest to peak paced heart rate, there were also significant increases (but higher than those observed in group 1) in total systolic and antegrade systolic CFV area per minute (by 138.0±67.6% and 124.5±64.1%, respectively). In contrast to group 1, diastolic CFV area also increased (by 71.9±47.8%), and retrograde systolic area decreased slightly (by −15.0±64.9%, P=NS). As in group 1, from rest to peak dobutamine stress, there was also a highly significant increase in retrograde systolic CFV area per minute (680.9±355.9%), concomitant with a slight increase in antegrade systolic area (34.5±37.5%, P=NS), and as a result, total systolic area declined slightly (−19.3±24.2%, P=NS). Diastolic CFV area per minute increased significantly (197.7±105.1%), and this increase was higher than that of group 1 (P<.001). A representative recording to indicate the influence of the dobutamine-induced increase in pressure gradient on the phasic CFV waveform and particularly on the retrograde CFV wave in patients with AVS is shown in Fig 6⇓.
In group 3 (Fig 7⇓), from rest to peak paced heart rate, there were significant increases (slightly higher than but comparable to those of group 2) in total (antegrade) systolic and diastolic CFV area per minute (by 146.8±51.2% and 90.4±28.6%, respectively). From rest to peak dobutamine stress, in sharp contrast to both AVS groups, there was a significant increase in total (antegrade) systolic CFV area per minute (143.5±44.4%), concomitant with the significant increase in diastolic CFV area (197.1±75.2%), which was again higher than that of group 1 (P<.001).
Ratio of Systolic to Diastolic CFV Curve Area
Resting measurements of the percentage of the CFV curve area in different segments of the cardiac cycle showed that patients of group 1, in comparison with those of groups 2 and 3, had lower total systolic (15.5±5.2% versus 22.0±6.1% and 22.8±2.4%, respectively, both P<.005) and higher diastolic (84.5±5.2% versus 78.0±6.1% and 77.2±2.4%, both P<.005) percent area of the CFV curve. Between the two AVS groups, there was lower antegrade systolic (18.4±4.7% versus 23.9±5.9%, P=.005) and higher (in absolute values) retrograde systolic (−2.9±1.2% versus −1.9±0.9%, P=.019) percent CFV curve area in group 1 than in group 2. Among all patients with AVS, significant inverse correlations were found between the ratio of resting systolic to diastolic CFV area and the resting peak and mean transvalvular pressure gradient (r=−.722, P=.0000014 and r=−.538, P=.001, respectively) (Fig 3⇑).
At rest, there was a significantly lower ratio of systolic to diastolic area in group 1 than in groups 2 and 3 (0.188±0.074 versus 0.289±0.099 and 0.297±0.041, respectively) (Fig 8⇓). In all patient groups (with and without AVS), this ratio increased significantly at peak pacing tachycardia (group 1, to 0.290±0.142; group 2, to 0.395±0.120; group 3, to 0.383±0.068). In contrast, at peak dobutamine stress, it decreased significantly in both AVS groups (group 1, to 0.052±0.049; group 2, to 0.079±0.029) but was not different from rest in control subjects (0.249±0.053) (Fig 8⇓). The above CFV data indicate that the pattern of the response of phasic coronary flow (systolic and diastolic component) to a stress-induced increase in myocardial metabolic demand differs considerably between patients with and without AVS. In the presence of AVS, this response (particularly the systolic component) depends heavily not only on the existing vasodilator capacity but also on the simultaneous stress-induced changes in transvalvular pressure difference and intramyocardial compressive forces.
Coronary Cross-Sectional Area Measurements
At rest, the measured CSA of the interrogated LAD was significantly lower in group 3 (9.74±1.99 mm2) than in groups 1 (13.86±2.62 mm2, P<.001) and 2 (12.52±2.30 mm2, P<.05). In all groups, the CSA measured at peak pacing tachycardia (group 1, 13.98±2.58 mm2; group 2, 12.87±2.26 mm2; group 3, 10.11±2.10 mm2) and at peak dobutamine stress (group 1, 14.04±2.60 mm2; group 2, 13.13±2.26 mm2; group 3, 10.43±2.20 mm2) was slightly but significantly higher compared with the resting measurements (all P<.05).
Coronary Blood Flow Changes
From rest to peak pacing and peak dobutamine tachycardia, the calculated coronary blood flow increased in group 1 by 17.6±16.8%, P<.005, and 30.7±31.0%, P<.001, respectively; in group 2 by 94.9±54.9%, P<.001, and 168.7±93.6%, P<.001; and in group 3 by 111.7±58.1%, P<.005, and 215.8±115.7%, P<.001. Again, the increases observed in groups 2 and 3 were higher than those of group 1 (all P<.001).
Coronary Vasodilator Reserve Measurements
The intracoronary injection of papaverine significantly increased the mean CFV (group 1, 57.1±34.2%, from 30.3±8.2 to 46.6±7.2 cm/s; group 2, 180.0±71.4%, from 14.2±5.8 to 37.7±5.0 cm/s; group 3, 317.6±58.5%, from 9.7±2.6 to 39.5±7.2 cm/s), the coronary CSA (group 1, 2.0±1.6%, from 13.82±2.67 to 14.12±2.60 mm2; group 2, 6.6±4.8%, from 12.48±2.41 to 13.29±2.19 mm2; group 3, 8.7±3.6%, from 9.81±2.15 to 10.63±2.18 mm2), and the calculated coronary blood flow (group 1, 60.6±36.8%; group 2, 200.6±86.7%; group 3, 353.2±58.7%) (all P<.001). The respective increases were lower in group 1 than in group 2 and also lower in group 2 than in group 3. The calculated coronary vasodilator reserve ratio was significantly lower in group 1 (1.57±0.34) than in group 2 (2.8±0.71) and also lower in group 2 than in group 3 (4.18±0.58) (all P<.001).
Side Effects of Hemodynamic Stress Interventions
Rapid atrial pacing and intravenous dobutamine infusion were not limited by the development of significant arrhythmias, chest pain, dyspnea, and significant (<90 mm Hg systolic aortic pressure) or symptomatic hypotension. Importantly, intravenous dobutamine infusion was generally well tolerated by all patients with significant AVS. The majority of these patients (32 patients, 94%) tolerated a dose of at least 20 μg · kg−1 · min−1, and 29 patients (85%) tolerated the maximum dose of 30 μg · kg−1 · min−1. Specific reasons for terminating dobutamine infusion in AVS were an achieved maximal dose of 30 μg · kg−1 · min−1 (29 patients, 85%), a patient’s demand (3 patients, 9%), and a decrease in aortic pressure >20 mm Hg (6 patients, 18%).
In this work, we measured mean and phasic CFV and blood flow concomitant with hemodynamic parameters in control subjects and in patients with significant pure AVS. We must emphasize that the major point in this study is the evidence, for the first time, about the changes in phasic coronary blood flow profile in the major epicardial coronary arteries of patients with AVS during hemodynamic stress and the association between these changes and the concomitant stress-induced changes in hemodynamic parameters. The resting phasic CFV profile in patients with AVS was predominantly diastolic, as it was in control subjects. Furthermore, an early systolic retrograde CFV wave was recorded below zero line only in patients with AVS, and the resting magnitude of this wave was related to the magnitude of the transvalvular aortic pressure gradient. In control subjects, systolic and diastolic CFV increased concomitantly and comparably in response to stress. In AVS, the dobutamine-induced increase in transvalvular pressure gradient resulted in increased retrograde systolic and decreased total systolic CFV, indicating depression of systolic coronary flow with increasing intramyocardial coronary compression. The increases in systolic retrograde and the reduction in total systolic CFV waves occurred similarly and were relatively comparable in magnitude in both the symptomatic and asymptomatic patients with higher and lower degrees of valvular obstructive disease. In contrast, the concomitant increases in the diastolic and mean CFV were significantly lower in the symptomatic than in the asymptomatic patients or the control subjects and were also inadequate relative to the estimated stress-induced increase in myocardial metabolic demand. This blunted response of the coronary circulation was also associated with a higher resting CFV and blood flow, which in turn was closely related to a higher estimated resting myocardial metabolic demand.
Chilian and Marcus21 studied the phasic character of CFV in open-chest anesthetized dogs, recorded retrograde systolic CFV in the septal and small epicardial arteries concomitant with persistence of antegrade CFV in the LAD, and concluded that the epicardial coronary systolic capacitance is of sufficient magnitude to obscure phasic intramyocardial blood flow in the large epicardial coronary arteries. In the same study,21 the increase in systolic tissue pressure without concomitant changes in coronary perfusion pressure increased retrograde (negative) flow in intramyocardial arteries. In accordance with these experimental findings, our study suggests that in patients with AVS, the systolic difference between intraventricular and aortic blood pressure results in increased intramyocardial compressive forces, which far exceed the systolic capacitance of the large epicardial coronary arteries even at rest, with the appearance of resting systolic retrograde (negative) epicardial CFV. Similarly, conditions of stress increasing transvalvular pressure gradient and intramyocardial compression increase further the resting retrograde epicardial CFV. Since almost all patients included in the study had significant AVS and clearly evident resting systolic retrograde CFV waves, we could not define the lower cutoff value of transvalvular pressure difference, which results in increased extravascular coronary compression to a degree exceeding epicardial systolic capacitance and producing retrograde flow. However, in a recent publication, Hongo et al1 studied patients with a wide range of aortic stenosis severity and reported resting systolic retrograde flow only in those with pressure gradients >49 mm Hg, whereas systolic flow reversal was absent with gradients <35 mm Hg.
In the present study, as in previous ones,1 2 4 5 the resting systolic retrograde CFV wave represented only a small fraction of the total (systolic and diastolic) CFV curve; thus, it could be considered a negligible quantity that could not significantly influence coronary myocardial blood supply and contribute to the development of ischemia. However, experimental data from the study of Sabbah and Stein4 suggested that the increase in coronary extravascular pressure and the development of systolic retrograde blood flow during conditions of maximal pharmacological coronary vasodilation reduce total systolic coronary flow and result in decreased total coronary flow at maximal hyperemia. These experimental data provide a strong basis to speculate that the increase in systolic retrograde coronary blood flow during hemodynamic stress, as noted in our study, may reduce the maximal stress-induced increase in total coronary flow to a level lower than that predicted from the residual vasodilatory capacity and thus contribute (to a small but not precisely known degree) to the development of ischemia. This speculation seems to apply principally to symptomatic patients with significant AVS, high resting myocardial metabolic demand, near-maximal resting coronary vasodilatation, and impaired vasodilatory capacity, in which the compensatory increase in diastolic coronary flow may not be adequate to meet the stress-induced increased myocardial metabolic demands and simultaneously to cover the increase in retrograde and the worsening of total systolic flow. Although the same mechanism could also work in asymptomatic patients with less severe AVS, it would obviously require a much more intense stress to deplete the relatively preserved coronary vasodilatory capacity and unmask the adverse effect of systolic coronary flow reversal. Relevant to these considerations were our findings in the symptomatic patients with AVS and normal coronary arteries of an elevated resting coronary flow and a reduced coronary flow reserve, which have been considered in previous reports1 22 23 to represent the principal mechanism for the development of ischemia and symptoms in this clinical setting.
In this study, cardiovascular stress induced by rapid atrial pacing did not change transvalvular pressure difference (in agreement with a previous report6 ) and systolic retrograde CFV. Dobutamine was used for the first time in patients with AVS and was found to mimic closely the hemodynamic changes induced by exercise,24 25 increasing heart rate, left ventricular systolic pressure, and transvalvular pressure gradient. In previous studies of patients with AVS, hemodynamic stress provoked by rapid atrial pacing, exercise testing, or intravenous isoproterenol infusion has been shown to decrease the ratio DPTI/SPTI (which is related to the balance between myocardial oxygen supply and demand11 12 ) and induce myocardial ischemia.26 27 28 29 30 31 This effect has been attributed to the hemodynamic consequences of aortic stenosis11 12 28 29 30 31 and has been considered one of the mechanisms causing myocardial ischemia during hemodynamic stress. In agreement with these data, rapid atrial pacing decreased DPTI/SPTI in patients with AVS; however, this ratio remained unchanged during dobutamine stress. Thus, in contrast to what was reported by Smucker et al29 for isoproterenol stress, intravenous dobutamine overall did not seem to adversely affect coronary hemodynamics.
Stress-induced alterations in phasic CFV variables in the proximal LAD of patients with significant pure AVS differ from those of patients without AVS and are closely related to concomitant changes in hemodynamic parameters. Systolic retrograde coronary flow is present at rest and increases during conditions of stress in relation to the increase in transvalvular pressure gradient, with resultant depression of total systolic flow. In asymptomatic patients with less severe AVS, lower resting coronary flow, and relatively preserved coronary autoregulation, the increase in myocardial oxygen demand and in retrograde flow that occur during stress are well compensated for by the concomitant increase in diastolic antegrade flow. In symptomatic patients with severe AVS, higher resting coronary flow, and depleted coronary flow reserve, the increase in retrograde flow may interfere with an adequate increase in coronary flow under stress and further worsen the myocardial oxygen supply-to-demand ratio beyond the residual vasodilatory capacity.
Although great care was taken to obtain and analyze only optimal, undisturbed, and stable CFV signals, some potential limitations to the presented CFV data must be considered.
1. A Doppler angioplasty guide wire with a 12-MHz Doppler transducer has recently been developed and validated in which the CFV signals are processed with fast Fourier transformation and displayed in a spectral format.32 33 34 This technique seems to lack some of the limitations inherent in the older zero-crossing technique, and it must be emphasized that significant differences in CFV measurements have recently been reported between the fast Fourier and the zero-cross frequency analysis.35 On the other hand, recent experimental and clinical studies34 36 found a high degree of correlation between the CFV and flow reserve data that were obtained in proximal segments of normal coronary arteries using both the Doppler catheter (with the zero-crossing detector) and the guide wire (with fast Fourier analysis), which was not yet available in our center at the time of this study.
2. Results of this study suggested that intravenous dobutamine infusion is generally well tolerated and can be safely used as a pharmacological alternative to exercise testing in patients with AVS. However, these conclusions cannot be extrapolated to the general population of patients with AVS, particularly since patients with obstructive epicardial coronary artery disease were not included in the study.
3. It has been shown that in the presence of significant positive inotropic stimulation, both the heart rate–left ventricular systolic pressure product and the SPTI imperfectly reflect myocardial contractility and oxygen demand.12 Since direct measurements of myocardial contractility were not obtained in the study, this limitation should be taken into account in the interpretation of study data when these indexes are used to quantify myocardial oxygen demand under the potent inotropic action of dobutamine.
4. In our study, dobutamine was used as an appropriate alternative to exercise stress to study the effects of stress-induced changes in intramyocardial compressive forces on the phasic CFV waveform. Although there are some important differences between the hemodynamic effects of intravenous dobutamine, as noted in this study, and those of supine leg exercise, as have been reported previously,24 25 the common principal hemodynamic effect of both dobutamine and exercise stress appears to be the increase in systolic blood flow through the stenotic aortic valve and the increase in pressure gradient.
- Received January 25, 1995.
- Revision received March 20, 1995.
- Accepted March 26, 1995.
- Copyright © 1995 by American Heart Association
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