Coronary Arterial Flow-Velocity Dynamics in Children With Angiographically Normal Coronary Arteries
Background There have been few reports about coronary hemodynamics in children during the process of growth. In the present study, to assess the characteristics of coronary flow dynamics in children, we examined the phasic coronary flow-velocity (CFV) patterns at rest and during peak hyperemic responses in children with angiographically normal coronary arteries.
Methods and Results Spectral Doppler phasic coronary flow velocity was recorded with a 0.018-in intracoronary Doppler guidewire at rest and during peak responses after intracoronary bolus injection of ATP in 30 patients with Kawasaki’s disease (age, 8.2±5.1 years; 24 boys and 6 girls) without angiographic coronary lesions. Average peak velocity (APV), maximum peak velocity (MPV), and diastolic-to-systolic velocity ratio (DSVR) were evaluated in the left anterior descending coronary artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA). Coronary vasodilator reserve (coronary flow reserve [CFR]) was calculated as the ratio of ATP-induced hyperemic to baseline APV. Flow-velocity parameters in RCA were significantly lower than those in the LAD and LCx in both proximal and distal portions. Although the distal LCx had significantly lower values of APV and MPV than did the proximal LCx, there was no significant difference between the proximal and distal portions of the LAD and RCA for APV and MPV. All three coronary vessels showed a diastolic dominant flow pattern in each segment. This coronary flow pattern was less marked in the RCA than in the LCA. All three coronary vessels showed a significant increase in APV and a significant decrease in DSVR after ATP administration. CFR was significantly lower in the LCx than in the LAD or RCA (P<.01: 1.93±0.34 in LCx versus 2.32±0.42 in LAD and 2.37±0.44 in RCA). From the view of aging, it was revealed that APV values in three vessels were higher in the younger group than in the older group. CFR values in the LAD and LCx were significantly lower in the younger group than in the older group (P<.001 in LAD: 2.01±0.28 in the younger versus 2.53±0.37 in the older; P<.01 in LCx: 1.61±0.15 in the younger versus 2.06±0.31 in the older). In addition, intracoronary injection of ATP did not increase the absolute angiographic coronary luminal diameter.
Conclusions With the use of an intracoronary Doppler guidewire, we demonstrated that there are some characteristic findings in CFV dynamics in childhood. These physiological characteristics in CFV dynamics that occur with aging and occur in each vessel must be taken into consideration in the study of the coronary circulation in children.
Even in childhood, it is important to quantitatively and regionally evaluate coronary flow dynamics for the assessment of the pathological significance of coronary lesions because oxygen supply to myocardial cells is mainly dependent on the volume of coronary blood flow. Although coronary angiography performed routinely in childhood provides some information on coronary flow dynamics, it is an imperfect method for assessing the physiological significance of a variety of coronary lesions or of CFR. Therefore, we functionally evaluated1 2 3 4 5 coronary flow dynamics and CFR in children with a nuclear imaging method such as1 6 7 as 201Tl scintigraphy or positron emission tomography and coronary sinus catheterization via the femoral vein.2 8
Recently, the study of coronary flow dynamics from the view of flow velocity has been advanced. Since Sibley et al10 developed a 3F Doppler catheter with a guidewire lumen in 1986, measurements of coronary flow velocities with Doppler techniques have developed for clinical use.11 12 More recently, Doppler-tipped angioplastic 0.018- and 0.014-in Doppler guidewires have been developed to measure blood flow velocity, even in children. In adults, the clinical application of this Doppler guidewire has advanced evaluation of coronary stenosis, coronary reserve, and the therapeutic effect of interventional therapies, based on many recent clinical studies.13 14 15 16 17 18 19 20 21 22 Although this Doppler guidewire is to be used in pediatric patients with coronary sequelae of Kawasaki’s disease, myocardial disorders, and other anatomic cardiac anomalies, no systematic clinical study in children has been reported. Furthermore, as we reported,2 3 4 compared with adults children have some different coronary hemodynamic characteristics. Therefore, to assess the physiological characteristics of coronary flow-velocity dynamics in children as a preparation for clinical application, we examined phasic coronary flow-velocity patterns at rest and during hyperemic responses (CFR) with a Doppler guidewire in children with angiographically normal coronary arteries. These data provide the basis for future functional assessment of coronary circulation or microvascular lesions in patients with coronary lesions or cardiac disorders.
We studied 30 patients (24 boys and 6 girls; age range, 2 to 17 years; mean age, 8.2±5.1 years) without abnormal findings on selective coronary arterial and left ventricular angiography performed to evaluate cardiac sequelae of Kawasaki’s disease. The duration from the onset of Kawasaki’s disease to study onset ranged from 0.3 to 14 years (mean, 6.3±4.7 years). Patients with myocardial infarction, chest pain, unsuitable anatomy (eg, single coronary artery or significant narrowing of any coronary branch), valvular dysfunction, left ventricular dysfunction, atrioventricular block, or ventricular arrhythmia were excluded. Angiographic findings in these patients were analyzed visually by five experienced pediatric cardiologists. These patients had not received β-adrenergic blockers, calcium channel antagonists, or nitrates. Atropine sulfate (0.01 mg/kg) was given subcutaneously as routine precatheterization medication in all patients, and ketamine (1 mg/kg) and diazepam (0.2 mg/kg) were given as anesthetic medication for younger children. Patients were brought to the catheterization room in a fasting state. Heparin (100 units/kg) was given intravenously before insertion of the coronary catheters. Although all of these patients had had a transient coronary dilatative lesion in the acute or healed stage of Kawasaki’s disease, no patient had a history of ischemic attack or chest pain. The nature of the study was discussed with each patient’s parents, and written informed consent for the research protocol was obtained before cardiac catheterization.
Coronary Flow-Velocity Measurements
After diagnostic coronary angiography and left ventriculography, coronary blood flow velocity was measured with a 175-cm-long, 0.018-in flexible steerable angioplastic guidewire with a 12-mHz piezoelectric ultrasound transducer integrated into the tip (FloWire, Cardiometrics, Inc). Coronary velocity measurement with this Doppler guidewire was reported in detail by Ofili et al,24 Doucette et al,13 and Segal et al.14 The forward directed ultrasound beam diverges in a 28° arc from the long axis. The pulse repetition frequency is >40 KHz, the pulse duration is +0.83 millisecond, and the sampling delay is 6.5 milliseconds. Blood flow velocity is determined from the Doppler frequency shift based on the difference between the transmitted and returning signals, calculated from the following Doppler equation:
where V is velocity of blood flow, c is constant (speed of sound in blood), fo is transmitting (transducer) frequency, θ is angle of incidence, and fD is Doppler frequency shift. The quadra-Doppler audio signals are processed with a real-time spectrum analyzer using on-line fast-Fourier transformation to provide a scrolling gray-scale spectral display. The spectrum of velocity information from all of the red blood cells within the ultrasound region of interest (sample volume) is displayed above the baseline when blood flow is moving away from the transducer and below the baseline when the flow is moving toward the transducer. The coronary flow-velocity spectrum envelope is digitized off-line with a PC/AT computer and a custom-designed software program interfaced with a digitizing tablet. Digitized spectral waveforms from five cardiac cycles are averaged to compute several parameters of intracoronary flow velocity, including instantaneous spectral peak velocity and the time-averaged spectral peak velocity. The DSVR is also computed. Flow-velocity data calculated by analysis of the spectral waveform have been found to correlate with absolute coronary flow measurements in both in vitro and in vivo validation studies.14 16 17
In the present study, the Doppler guidewire was advanced through a 5F guiding Judkins catheter into each target coronary branch. The catheter position was adjusted to obtained a maximal and intense spectral flow-velocity signal within the vessel. The Doppler guidewire was coupled to a real-time spectrum analyzer, videocassette recorder, and video image printer. Simultaneous ECG and arterial pressure signals were also input to the video display (Fig 1⇓).
Average and phasic signals of coronary flow velocity, arterial pressure waveform obtained with the guiding catheter, and lead II ECG waves were also monitored continuously. APV, MPV, and DSVR as coronary flow-velocity parameters were obtained from segments 6 (30 vessels) and 7 (30 vessels) in the LAD, segments 11 (20 vessels) and 13 (12 vessels) in the LCx, and segments 2 (20 vessels) and 3 (20 vessels) in the RCA. APV represents the average of the instantaneous peak velocities in cm/s. MPV represents the maximum of the instantaneous peak velocity in cm/s. DSVR is the ratio of the diastolic to the systolic average peak velocities and provides an indicator of the pulsatility of the flow. Numbers of coronary artery segments indicate the area of coronary arteries according to the reporting system of the American Heart Association committee report (Fig 2⇓).23 The difference between the proximal and distal portions in each coronary vessel in the flow-velocity pattern was also evaluated. Segments 6, 11, and 2 were expressed as the proximal portion and segments 7, 13, and 3 were expressed as the distal portion, respectively, for each of three coronary vessels. After stable baseline signals were obtained in each vessel, ATP (1.0 μg/kg) was injected as a bolus through the guide catheter into each vessel with continuous data recorded throughout the peak hyperemic period. The dose of intracoronary ATP used in the present study was based on our preliminary study of the effects of ATP on the coronary vasodilator response. Hyperemic flow-velocity data were obtained from the LAD (segment 6, n=30), LCx (segment 11, n=20), and RCA (segment 2, n=20). CFR, the maximum change in coronary blood-flow velocity after an intracoronary bolus injection of ATP, was expressed as the ratio of peak hyperemic APV after ATP administration to the baseline value. The change (ΔDSVR) after ATP administration were also analyzed. In addition, in 10 of 30 patients, coronary sinus blood flow was simultaneously measured at baseline and during peak hyperemia by the continuous thermodilution method with coronary sinus catheterization via the femoral vein.2 8 9 Furthermore, to assess age-related characteristics in coronary flow-velocity dynamics at rest and during peak hyperemia, we divided 30 children into two age groups: younger group (≤5 years; 11 patients; mean age, 2.8±1.4 years) and older group (≥6 years; 19 patients; mean age, 11.3±3.8 years).
Coronary Angiographic Responses
To assess changes in coronary artery dimensions after intracoronary ATP injection, we performed left coronary cineangiography in 6 children (5 boys and 1 girl; mean age, 9.8±2.3 years) without angiographic coronary lesions in a separate patient group. Coronary artery dimensions at baseline and at peak hyperemia were traced from the developed cineangiographic films projected on a projector, and then digital computer-assisted calipers (Digitizer KD4300, Graphtec Co) were used to measure the midportion of segment 6 in LAD. The 5F guiding catheter was used as a reference standard for absolute dimension calculations (in mm).
Statistical analysis for Doppler flow-velocity parameters among three vessels (LAD, LCx, and RCA) was made with ANOVA with the Bonferroni multiple-comparisons test. Comparisons between the proximal and distal portions and between the younger and older groups in each vessel were performed with the Mann-Whitney U test. Coronary flow-velocity data before and after ATP in each vessel were analyzed with the paired t test. Statistical significance was defined as P<.05. All data are given as mean±SD unless otherwise indicated.
Coronary Flow-Velocity Patterns at Rest
The RCA had lower coronary flow-velocity parameter values than the LAD and LCx in both proximal and distal portions (Table 1⇓). In comparison, among the proximal portions in three coronary vessels, RCA had significantly lower values in both APV and MPV than LAD (P<.05 in APV and MPV) and in MPV than LCx (P<.05). The distal portion in RCA had significantly lower values in APV and MPV than in LAD (P<.05 in APV and MPV) and in MPV than in LCx (P<.05). Although the LAD and LCx had similar flow-velocity patterns in APV and MPV, the distal LCx (segment 13) had a significantly lower value in APV than that in the distal LAD (P<.05).
Although there was no significant difference between the proximal and distal portions in LAD and RCA in the flow-velocity parameters, the distal LCx (segment 13) had significantly lower values in APV and MPV than those in the proximal portion (segment 11) (P<.05 in APV and P<.05 in MPV) (Table 1⇑).
The RCA also had significantly lower DSVR values than the LAD and LCx, the same as in APV and MPV (P<.05 in the proximal and distal) (Table 1⇑). Although in the LCA, the distal portions had higher values than the proximal portions in DSVR, there were no statistically significant differences in DSVR between the proximal and distal portions.
In terms of aging in the flow-velocity parameters (Table 2⇓), all three vessels had mildly higher APV values in the younger age group than in the older. Although there was no significant difference in DSVR between two age groups in LAD and LCx, the younger group had significant dominance in the diastolic phase in the distal RCA (P<.005: 2.60±0.42 in the younger versus 1.78±0.26 in the older).
Hyperemic Response to ATP Intracoronary Administration
Intracoronary ATP markedly increased APV in all of the LAD (segment 6), LCx (segment 11), and RCA (segment 2) (P<.001 in each vessel) (Table 3⇓). On the other hand, ATP administration significantly decreased DSVR in all vessels (P<.001 in each vessel) (Table 3⇓). CFR values expressed as the ratio of peak hyperemic to baseline APV were 2.32±0.42 in the LAD, 1.93±0.34 in the LCx, and 2.37±0.44 in the RCA, respectively (Table 3⇓). CFR in the LCx was significantly lower (P<.01) than in the LAD and RCA. There was no significant difference in the change ratio of DSVR (ΔDSVR) among three coronary vessels (Table 3⇓). In addition, CFR assessed as the ratio of peak hyperemic to basal coronary sinus blood flow measured by the continuous thermodilution method was 3.12±0.58 at the ATP (1.0 μg/kg) injection site into the left coronary artery.
In terms of age-related hyperemic characteristics (Table 4⇓), although there was no significant difference in CFR between two age groups in RCA, the younger group had significantly lower values in CFR than the older in LAD and LCx (P<.01 in LAD: 2.01±0.28 in the younger versus 2.53±0.37 in the older, P<.01 in LCx: 1.61±0.15 in the younger versus 2.06±0.31 in the older, respectively) (Fig 3⇓). The younger group had mildly lower values, but they were not statistically significant, in the change ratio (ΔDSVR) of DSVR than the older in all three vessels (Fig 3⇓).
Coronary Angiographic Responses
Intracoronary injection of ATP did not increase the absolute angiographic coronary luminal diameter in 6 children. There was no significant change in the diameter of segment 6 in the LAD (3.00±0.31 mm at baseline to 3.03±0.28 mm at hyperemia after ATP injection; percent change, 0.8±2.6%).
Hemodynamic and ECG Responses to Intracoronary ATP
Intracoronary ATP produced brief increases in heart rate (from 100.5±21.6 to 104.0±20.7 min−1) and decreases in systolic (from 100.7±13.5 to 98.2±13.5 mm Hg), mean (from 83.8±13.5 to 75.6±12.2 mm Hg), and diastolic (from 66.4±13.3 to 56.1±13.1 mm Hg) arterial pressures. These changes were slightly significant statistically but not clinically. There were no significant alterations in PR, QRS, or QT intervals on the ECG after ATP administration in each vessel. Transient (<5 seconds) second-degree atrioventricular block occurred in 2 patients after intracoronary injection of ATP; these resolved spontaneously. No patient required atropine or had a complication requiring premature study termination.
In the present study, there was no significant difference between the LAD and LCx in most of the physiological coronary flow-velocity patterns at rest in children. However, it was observed that both the APV and the MPV in the RCA were significantly lower than those in the LCA. These were the same findings as reported in adult population.24 As has been previously suggested from data on DSVR, this study also demonstrated that coronary blood flow was greater during the diastole phase. In addition, based on a comparison among three vessels for DSVR, it was revealed that coronary blood flow in LCA was more dominant in the diastolic phase than in RCA and that the RCA had relatively systolic dominance in coronary blood flow compared with the LCA. Furthermore, in the LAD and LCx, coronary blood flow in the distal portion was more dominant in the diastolic phase than in the proximal portion. These differences in the physiological coronary flow-velocity patterns that were observed between the right and the left coronary arteries suggest that the differences in the APV and MPV reflect the difference in the coronary blood flow based on the work load of the right and left ventricles, ie, the oxygen demand level, and that the difference in DSVR reflects the difference in coronary flow resistance during systole inside the wall of the right and left ventricles that was observed as different systolic pressures in the right and left ventricles. The clinical application of the Doppler guidewire made it possible to analyze such phasic blood flow-velocity patterns very easily, even in children. Although there was no significant difference between children and adult concerning these flow patterns in APV, MPV, and DSVR at rest, the higher values in DSVR indicated more diastolic predominance in the pediatric population than in adults.
Intracoronary administration of ATP caused a marked increase in APV in three coronary vessels. However, when a comparison was made in the coronary vasodilator reserve (CFR) expressed as the ratio of APVs before and after ATP administration, CFR in the LAD was nearly the same as that in the RCA, whereas CFR in the LCx was characterized as being significantly lower than that in the LAD and RCA. This lower CFR in the LCx may be characteristic in childhood because it has been reported that there was no significant difference in CFR among three vessels in an adult population.24 The cause of these differences has not been determined, but a low oxygen demand in the coronary perfusion area of the LCx or an additional supply of blood from the RCA into the coronary perfusion area of the LCx could be a possible cause. In terms of angiographic coronary dominance, 16 of 30 patients (53%) showed right dominancy, 8 of 30 (27%) showed balanced dominancy, and 6 of 30 (20%) showed left dominancy. This result suggested that poor development of the LCx could be a possible cause of lower CFR. Furthermore, when changes in the phasic flow patterns in both diastole and systole during coronary hyperemia were indicated by changes in DSVR, it was found that the ratios in the three vessels (LAD, LCx, and RCA) became significantly lower. This indicates that the increase in the coronary blood flow is not just the result of the increased flow during diastole but rather to a great extent is due to the increased coronary blood flow during systole, which was induced by a decrease in coronary resistance.
When the aging factor was investigated in terms of coronary flow-velocity dynamics, it was found that in the younger children the three vessels showed slightly higher APVs than in the older children, although this difference was not statistically significant. On the other hand, in terms of DSVR, although there were no significant differences between the younger and older children in the LAD and LCx, the younger children tended to show higher values than the older children in the RCA and this difference was statistically significant in the distal RCA. This means that in the RCA, the younger children tended to have relatively greater coronary blood flow during diastole than the older children. This reflects the fact that the younger children had higher coronary resistance during systole than the older children. This suggests from the viewpoint of coronary flow velocity that the effect of the right ventricular predominance observed in the hemodynamics as the embryonal and neonatal periods remains during early childhood.
In terms of CFR expressed as the ratio of APV before and after ATP administration, the younger children showed significantly lower values than the older children in the LAD and LCx. The cause of the lower coronary reserve value in the younger age group has not been determined, but any developmental immaturity of the coronary arteries could be a possible cause. In the past, we reported on a study concerning increasing patterns of coronary sinus blood flow in children that were quantitatively measured with the continuous thermodilution method and showed that the lower the coronary reserve, the lower is the age.2 4 The results of the present study reconfirmed this previous conclusion from the viewpoint of coronary flow-velocity dynamics. Furthermore, this study also revealed that the phenomenon of the younger children having lower coronary flow reserves was seen only in the left coronary artery and not in the RCA. Therefore, we believe that the clinical significance of evaluating coronary flow velocity using Doppler guidewire lies in the fact that it is possible to determine the localization of the lesions.
Although the Doppler flow guidewire provides a convenient method of obtaining phasic flow-velocity data in coronary arteries, the limitations of intracoronary Doppler catheter techniques have been described in detail.25 26 27 28 29 Flow-velocity measurements do not provide an absolute value but are linearly related to changes in absolute flow when vessel area remains unchanged.27 In this study, the changes of flow-velocity signal can be used to indicate important volumetric alterations from baseline conditions because the vessel diameter was angiographically unchanged before and after ATP injection and, in addition, the significant increase of coronary sinus blood flow volume by intracoronary ATP was quantitatively revealed with the continuous thermodilution method. Optimal placement of the transducer approximately parallel to blood flow is necessary to detect accurate peak velocity because this is a Doppler-based technology. We always directed the distal tip of the Doppler guidewire to identify the maximal and most intense spectral flow-velocity signal. Doppler velocity signal artifact could have been produced by movement of the guidewire tip with a changing angle of the Doppler beam related to the axis of the blood flow, especially in children with unexpected body and respiratory movements. However, in this study, a relatively stationary placement of the Doppler guidewire was observed in all patients, and satisfactory velocity signals were obtained without repositioning or manipulating the guidewire, even during ATP injection. Although several factors, such as change in heart rate or emotional stimuli, can influence coronary blood flow and, possibly, pharmacologically induced hyperemia, these factors remained relatively constant during the study. Coronary flow-velocity and flow reserve measurements were performed with the guiding catheter positioned in the coronary ostium. However, in our study, the guiding catheter obstruction at the ostium of the coronary artery that interfered with coronary flow was minimized in all cases by using 5F guiding catheters. In addition, in our preliminary study, coronary sinus blood flow measured with the continuous thermodilution method did not change before and after insertion of the 5F guiding catheter into the left coronary artery. No patients had complications related to cannulation or a guidewire.
Despite these study limitations, it was revealed that there were some differences in each vessel in the coronary flow-velocity patterns and coronary vasodilator reserves (CFR), which also exhibited different characteristics depending on age. Therefore, as this study revealed, when functional evaluations of coronary lesions and coronary microcirculation are conducted in children, it is necessary to take into consideration the physiological characteristics of flow-velocity dynamics. In addition, the investigation of coronary flow-velocity dynamics with a Doppler guidewire was not only technically easy and safe but also useful for functional assessment of localized coronary lesion, even in children. Thus, they have considerable clinical application in a pediatric population in the future.
Selected Abbreviations and Acronyms
|APV||=||average peak velocity|
|CFR||=||coronary flow reserve|
|DSVR||=||ratio of diastolic to systolic peak velocity|
|LAD||=||left anterior descending coronary artery|
|LCX||=||left circumflex artery|
|MPV||=||maximum peak velocity|
|RCA||=||right coronary artery|
This study was supported by a grant-in-aid (C-06670816, 1994) from the Ministry of Education, Science and Culture in Japan. We thank Dr Morton J Kern (Director and Professor, The J. Mudd Garard Cardiac Catheterization Laboratory, St Louis University Hospital) for his valuable advice for this study.
- Received January 23, 1995.
- Revision received April 24, 1995.
- Accepted May 25, 1995.
- Copyright © 1995 by American Heart Association
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