Improvement of Subendocardial Myocardial Perfusion After Percutaneous Transluminal Coronary Angioplasty
A Myocardial Contrast Echocardiography Study With Correlation Between Myocardial Contrast Reserve and Doppler Coronary Reserve
Background After angioplasty coronary reserve improves but does not normalize in most patients. The purpose of this study was to examine before and after angioplasty coronary reserve and transmural myocardial blood flow distribution using myocardial contrast echocardiography.
Methods and Results Twelve patients with left anterior descending coronary artery stenosis were investigated before and immediately after angioplasty. A Doppler catheter was placed in the proximal segment. Myocardial contrast echocardiography was performed by imaging the septum in M mode in a parasternal view using a 3.0-mL bolus of sonicated amidotrizoate sodium meglumine through the guiding catheter. The gray level before injection was subtracted from the gray level after injection to maximize contrast time-intensity curves. The area under the curve was used as an indicator of myocardial blood flow, and subendocardial/subepicardial ratios were measured. After baseline measurements were obtained, Doppler and echographic data were recorded after a bolus infusion of papaverine into the left main coronary artery. The same protocol was performed in patients after angioplasty and in five control subjects with normal coronary arteries. Before angioplasty, echocardiographic and Doppler coronary reserve were 2.57±0.48 and 2.54±0.57, respectively. Both increased after angioplasty to 3.65±0.57 and 3.36±0.70, respectively (P<.05). Coronary reserve values obtained in patients with these two methods under the different conditions and in control subjects were correlated (r=.81; P=.0001). Before angioplasty, subendocardial/subepicardial septal ratios decreased from 0.80±0.48 to 0.60±0.27 after papaverine (P<.05). However, after angioplasty, these ratios tended to increase, from 0.72±0.27 to 0.92±0.45 after papaverine, but they did not change in control subjects (1.11±0.23 to 0.92±0.11).
Conclusions These results show that myocardial contrast echocardiography yields flow reserve values that correlate with values obtained using intracoronary Doppler. This technique may be considered as an accurate tool to assess coronary reserve in humans.
Experimental studies using radiolabeled microsphere techniques have shown that myocardial ischemia predominantly affects the subendocardial layer of the myocardium.1 2 3 4 5 Recently, myocardial contrast echocardiography (MCE) has been proposed as a new technique for assessing coronary circulation and transmural myocardial perfusion.6 7 8 9 10 11 12 13 14 Experimental studies have demonstrated that in comparison to radiolabeled microspheres, MCE is an accurate technique for assessing coronary reserve in dogs with critical stenoses.12 Moreover, MCE is a sensitive technique for detecting changes in myocardial flow induced by dipyridamole in the various layers of normal segments as well as segments supplied by a critical stenotic coronary artery.15
The intracoronary Doppler technique has shown that in patients with coronary stenoses, the coronary reserve remains abnormal even after successful coronary angioplasty.16 17 18 19 20 21 Recent studies have suggested that myocardial echocardiography could be useful in assessing the functional success of angioplasty.10 12 13 22 Using MCE, Lim et al11 showed that in patients with coronary artery stenosis there was a decrease in the subendocardial/subepicardial gray-level ratio in the segment supplied by a stenotic coronary artery, thus indicating the occurrence of subendocardial myocardial ischemia. However, the effects of angioplasty on the various myocardial layers have not yet been studied in humans.
The present study was designed to assess the accuracy of MCE measurements of coronary reserve compared with intracoronary Doppler measurements and to investigate the effect of angioplasty on transmural blood flow distribution. Accordingly, we examined the effect of angioplasty on myocardial blood flow distribution and coronary reserve in patients with a proximal left anterior descending coronary artery stenosis using MCE. This study was done at rest and after papaverine coronary infusion in order to assess the coronary reserve.23
The study population consisted of 12 patients (10 men and 2 women; mean age, 58±9 years) selected from a population of patients scheduled for percutaneous transluminal coronary balloon angioplasty of proximal left anterior descending coronary artery stenosis. Patients were included if they had ischemia as demonstrated by exercise testing or thallium-201 imaging; a good acoustic window for the visualization of the interventricular septum; single-vessel disease of the proximal left anterior descending coronary artery (stenosis >70%); no angiographic evidence of collateral circulation (grade 0); normal wall motion as assessed by both two-dimensional echocardiography (fractional shortening, 35±6%) and left ventriculography (left ventricular ejection fraction, 64±6%). Patients with unstable angina, recent or previous myocardial infarction, previous percutaneous transluminal coronary angioplasty procedure, or clinical evidence of heart failure were not included. No patient had myocardial hypertrophy or valvular heart disease. Vasoactive therapy, including calcium channel blockers, angiotensin-converting enzyme inhibitors, and long-acting nitrates, was discontinued at least 24 hours before catheterization. No patient received β-adrenergic blockers within 48 hours before the study. All patients received aspirin 100 mg/d for 48 hours before the study, and the use of short-acting sublingual nitroglycerin was allowed up to 1 hour before the study. Written informed consent was obtained from all patients before inclusion. The study protocol was approved by the local ethics committee.
Five patients (4 men and 1 woman; mean age, 47±5 years) undergoing coronary angiogram for diagnosis of atypical chest pain and fulfilling the following inclusion criteria were considered as control subjects in this study: normal coronary angiogram with luminal smooth coronary arteries; no evidence of ischemia as demonstrated by exercise testing and thallium-201 imaging; no risk factors for atherosclerosis; no evidence of heart disease and no myocardial hypertrophy on echocardiography; normal left end-diastolic ventricular pressures (<10 mm Hg) assessed before performing coronary angiogram; coronary blood flow reserve above 3 as assessed by intracoronary papaverine administration. None of these patients used medications.
Septal M-mode images were obtained by a commercially available phased-array system (CFM 750 Vingmed) with a 3.25 MHz transducer. MCE was performed by imaging an M-mode parasternal axis view just above the midpapillary muscle level with a proximal depth, focusing only on the right ventricle and interventricular septum during left main intracoronary injection of sonicated amidotrizoate sodium meglumine 76%. Gain settings were adjusted at the beginning of the protocol and were not changed.
Numerical echocardiographic data were directly transferred to a Macintosh IIci microcomputer and stored on an optical hard disk (300 MB). These data had spatial and temporal samplings of Δd=total depth/256 and Δt=5 ms, respectively, on 256 gray levels. The maximum size of each data set was 256 pixels in depth and 2048 pixels in time. Data handling, processing, display, and analysis were performed on the microcomputer by using the echodisp program (Vingmed Sound).
Our aim was to obtain the maximum information (number of pixels) on the interventricular septum. However, it was not possible to analyze the posterior wall with enough spatial precision to explore the subendocardial and subepicardial perfusion.
To quantify the intensity of echocardiographic signals in the septal segments, the cineprobe program (Vingmed Sound) was used with 256 gray levels. On the M-mode septum, end-diastolic bands 10 pixels wide were the regions of interest. End diastole was defined as being coincident with the upstroke of the electrocardiographic R wave. Each segment was divided by the operator into two halves, corresponding to epicardial and endocardial layers, and gray levels were measured for the entire segment as well as for each layer. Epicardial and endocardial septal interfaces were automatically detected on the gray-level profile traced with the cineprobe program (Fig 1⇓).
The four end-diastolic preinjection contrast frames were averaged to produce a mask frame either for the entire septum or for both endocardial and epicardial halves. Digital subtraction was performed by subtracting the gray-level values in the mask frame data points from the corresponding gray levels in all postinjection frames. Subtracted time-intensity curves were then generated by using the diastolic data for the entire septum and for both the endocardial and epicardial layers (Fig 2⇓). Several measurements could be made from the time-intensity curves and used as indices of myocardial perfusion. In agreement with previous studies,9 10 11 12 15 peak intensity and the area under the curve were chosen. Two ratios were used to define myocardial reserve as assessed by MCE: peak intensity after papaverine coronary infusion over the baseline peak intensity and area under the gray-level curve after papaverine infusion over the baseline area. Finally, the subendocardial/subepicardial gray-level ratio was calculated and defined as the ratio of the area under the gray-level curve for the endocardial half over the area under the gray-level curve for the epicardial half.
Sonification and Injection of the Contrast Solution
Sonification of the contrast solution was done as described by Keller et al12 using an Ultrasonic Atomizer (Model VC50 AT). Briefly, 7 mL of amidotrizoate sodium meglumine 76% was sonicated for approximately 30 seconds until a homogeneous and slightly turbid solution was generated. Before injecting sonicated material, the catheter was purged by opening the distal coronary angioplasty catheter Y connector leading to fill the catheter with blood. Three milliliters were rapidly injected by hand into the catheter, and echocardiographic recordings were obtained simultaneously until the contrast medium disappeared from the myocardium. Because the dead space of the catheter is approximately 1 mL, only 2 mL of sonicated material entered the myocardium. All sonifications and injections were performed manually by the same investigator.
Measurements of septal fractional shortening were made in a cardiac cycle preceding the contrast injection at baseline and at peak papaverine-induced hyperemia.
Intracoronary Doppler Study and Assessment of Coronary Artery Stenosis
An 8.0F guiding catheter was positioned in the ostium of the left coronary artery. A 3.0F Doppler catheter (NuVel, Nu Med Inc) with a side-mounted crystal of 20 MHz was advanced through the guiding catheter into the proximal left anterior descending coronary artery prior to the stenosis. The Doppler signal was transmitted to a velocimeter (MDV 20, Millar Instruments Inc). The position of the catheter and the range of the sample volume were adjusted to obtain a high-quality signal as assessed by both audio and graphic controls. Mean and phasic Doppler velocity signals were recorded, and coronary flow reserve was calculated as the quotient of the peak mean blood flow velocity after papaverine administration over mean resting blood flow velocity.
Coronary stenosis and the results of coronary angioplasty were assessed in two orthogonal views by quantitative coronary angiography as described.24
Since load changes may influence coronary reserve, left ventricular pressures and the first derivative of the left ventricular pressure (peak positive and negative left ventricular dP/dt) were monitored in seven patients with a 5F microtip Millar catheter (Millar Industries) placed through the other femoral artery into the left ventricle. Aortic pressure was monitored through the guiding catheter, and ECG was continuously monitored throughout the study. ECG, Doppler velocity, and pressure tracings as well as derivatives were read on a multichannel recorder and recorded on a Gould recorder (Gould TA 2000).
Before coronary angioplasty, intraventricular and aortic pressures, intracoronary Doppler velocity, septal thickening, and contrast echocardiographic measurements were recorded at rest and 30 to 45 seconds after a bolus infusion of 12 mg papaverine into the left main coronary artery to assess coronary myocardial reserve.
Video frames showing the Doppler catheter placement were recorded to ensure its correct repositioning after angioplasty. The Doppler catheter was then exchanged for a balloon angioplasty catheter, and the lesion was dilated. The size of the balloon was calculated on the basis of the normal segment proximal to the site of the lesion to be dilated. Three inflations of 90 seconds each were performed, and the result of the angioplasty was assessed quantitatively. In case of significant residual stenosis and to obtain the best angiographic result, a larger balloon was used, and repeated inflations were performed until a residual stenosis <30% was obtained.
After coronary angioplasty, a 5-minute period was observed to ensure that angiographic results were stable. At this point, the coronary Doppler catheter was advanced proximal to the dilated region and placed in a position similar to that in the preangioplasty study. The same parameters measured before coronary angioplasty were recorded again at rest and after papaverine infusion. After withdrawal of the intracoronary guidewire and Doppler catheter, angiograms were obtained in the same projections as those taken before the angioplasty to assess the final coronary angioplasty result.
All data are expressed as mean±SD. A paired t test was used to compare reserve values (MCE and intracoronary velocity) before and after angioplasty and the subendocardial/subepicardial gray-level ratios measured before and after papaverine intracoronary bolus injection both before and after angioplasty. Correlations between coronary blood flow reserves as assessed by Doppler analysis and MCE were performed by the linear regression method. Coronary flow reserve using the intracoronary Doppler technique was calculated by an independent investigator unaware of the echocardiographic data. Statistical significance was accepted at P<.05.
Assessment of Reproducibility
The reproducibility for the measurements of peak intensity, area under the curve, and subendocardial/subepicardial gray-level ratio was assessed in six other patients with stenosis of the left anterior descending coronary artery undergoing routine coronary diagnosis angiography. In these patients, injections of sonicated contrast medium were repeated twice. Results are expressed as the mean±SD difference, and correlations were calculated by the linear regression method.
Of the 12 patients initially studied, 3 had noninterpretable MCE data. After angioplasty, a right ventricular contrast enhancement was observed in these patients following the intracoronary injection of microbubbles during the assessment of coronary blood flow reserve. Consequently, since a correct determination of the septal contrast intensity was not possible, these 3 patients were excluded from the current study.
Angioplasty was successful for the remaining 9 patients, with a mean decrease in coronary stenosis from 84±21% to 27±18%, P<.01.
Hemodynamic Conditions and Septal Thickening
Systemic hemodynamic parameters at rest and 30 to 45 seconds after papaverine administration (peak effect on coronary blood flow) both before and after coronary angioplasty are shown in Table 1⇓. No significant hemodynamic changes occurred after papaverine infusion. End-diastolic pressure tended to increase after papaverine, but the trend was similar before and after angioplasty. Before angioplasty, septal thickening decreased from 43±6% to 30±6% after papaverine administration (P<.05) and tended to increase after angioplasty (39±6% to 42±9%, P=NS).
Coronary Reserve After Angioplasty
Individual values of coronary reserve assessed either by Doppler or MCE before angioplasty are shown in Table 2⇓. Coronary blood flow velocity at baseline (before coronary reserve assessment) was similar before and after coronary angioplasty (4.23±0.3 versus 4.34±0.45 kHz, P=NS). Compared with values measured before angioplasty, coronary reserve as assessed by Doppler and transmural MCE (area under the curve) increased by 33±21% and 42±15%, respectively (both P<.05).
Regional Assessment of Coronary Blood Flow
Before angioplasty, subendocardial coronary reserve (2.23±0.36) was lower than subepicardial coronary reserve (2.99±0.87, P<.05) (Table 3⇓). Subendocardial/subepicardial gray-level ratio was 0.80±0.48 at rest and decreased to 0.60±0.27 (P<.05) after papaverine infusion (Fig 3⇓). After angioplasty, subendocardial coronary reserve increased significantly, but no change was observed in subepicardial coronary reserve. In contrast to conditions before angioplasty, subendocardial coronary reserve was higher than the subepicardial reserve. At rest, the subendocardial/subepicardial gray-level ratio was 0.72±0.27 and tended to increase (0.92±0.45, P=NS) after papaverine infusion in contrast to conditions before angioplasty. Individual data are given in Fig 3⇓.
Coronary Blood Flow Reserve in Control Subjects
At baseline, heart rate and mean aortic blood pressure were 67±18 beats per minute and 95±12 mm Hg, respectively. No significant changes in these parameters were observed after papaverine administration, and septal thickening remained unchanged (46±7% versus 45±7% at baseline, P=NS). Coronary blood flow reserve as assessed by Doppler and transmural MCE of the entire septum (area under the curve) were 3.78±0.63 (range, 3.1 to 3.9) and 3.58±0.28 (range, 3.3 to 4), respectively.
Subendocardial coronary reserve (3.14±0.11) was significantly (P<.05) lower than subepicardial coronary reserve (4.35±0.84).
The subendocardial/subepicardial level ratio at rest was 1.11±0.12, a value not significantly different from patients before angioplasty (P=.12). After papaverine infusion, the subendocardial/subepicardial level ratio did not change significantly (0.91±0.09, P=NS). Individual data are shown in Fig 3⇑.
Relation Between Coronary Reserve As Assessed by MCE and Doppler Measurements
Coronary reserve values obtained at rest and after papaverine administration using both methods were correlated (r=.81, P=.0001; Fig 4⇓). No correlation was found with data from peak intensity (r=.39, P=.11) and Doppler coronary reserve.
Correlations between the coronary reserve of the subepicardium and subendocardium as assessed by MCE and the coronary reserve as assessed by Doppler were r=.77, P=.0001 and r=.55, P=.0064, respectively (all P<.05).
Reproducibility of Results
Peak intensity curve, area under the curve, and subendocardial/subepicardial gray-level ratio showed reproducible results between the same observer. The mean differences for the two analyses were 0.035±0.199 (2.7%) for peak intensity and 0.092±0.229 (3.5%) for area under the curve. The mean subendocardial/subepicardial gray-level ratios measured in the two sequential injections were 0.83±0.044 and 0.88±0.052. The mean differences for the two analyses were 0.052±0.021 (6.2%). For each variable, the two serial measurements were correlated: r=.92 (P=.002), r=.91 (P=.003), and r=0.93 (P=.008) for peak intensity, area under the curve, and subendocardial/subepicardial gray-level ratio, respectively.
The present study shows that coronary reserve measured by the area under the curve as assessed by MCE is correlated to coronary reserve as measured by the Doppler technique. This study also shows that percutaneous transluminal coronary angioplasty improves the coronary reserve of the subendocardial region and increases the subendocardial/subepicardial gray-level ratio. These results suggest that coronary angioplasty improves the perfusion of the subendocardial region.
Assessment of Regional Blood Flow by MCE
MCE was initially proposed as a method of identifying myocardial regions supplied by the injected coronary artery. Experimental data first demonstrated the ability of this method to visualize accurately myocardial segments perfused by the vessels filled with the contrast solution.6 7 8 MCE can also be successfully applied to estimate perfusion zones of coronary artery during cardiac catheterization.9 10 11 12 13 14 Quantification rather than the presence or absence of enhanced contrast was investigated, showing that MCE allowed the assessment of coronary blood flow reserve and transmural myocardial blood flow distribution. Indeed, this technique was validated for the measurement of blood flow reserve against the method of radiolabeled microspheres in dogs. In particular, Keller et al12 showed that the ratios of areas under the curves derived from time-intensity plots generated during MCE were well correlated with coronary blood flow reserve using radiolabeled microspheres. Cheirif et al15 showed that MCE was a sensitive technique to detect changes in myocardial flow induced by dipyridamole in the various layers of normal segments as well as in segments supplied by a critically stenotic coronary artery. In humans, regional measurements of myocardial contrast intensity before and after papaverine infusion were obtained, showing that MCE was able to differentiate regions with normal hyperemic response from those with abnormal response due to the presence of an obstructive lesion as determined angiographically.10 Recently, Lim et al11 measured transmural myocardial blood flow distribution in patients with or without coronary artery stenosis using MCE. They found no significant difference in the subendocardial/subepicardial gray-level ratio before rapid pacing among anteroseptal, posterolateral, and inferior segments in patients without coronary artery disease, indicating that transmural myocardial blood flow distribution was homogeneous from endocardium to epicardium in all areas of the left ventricular short-axis image. However, the subendocardial/subepicardial gray-level ratio significantly decreased after rapid pacing in segments supplied by stenotic coronary artery, indicating a subendocardial ischemia after pacing but not at rest.
In the present study, another methodology was used to detect regional myocardial blood flow perfusion. M mode was chosen to focus on an accurate temporal resolution. To avoid or to minimize translation between end-diastolic frames, patients were asked to hold their breath during the injections and the echographic data acquisition. On-line digital capture of scan line echo data avoided many problems of image degradation. Furthermore, subsequent digital subtraction processing seemed to reduce the effects of instrument settings and facilitated the study of spatial distribution of perfusion. The ability of digital subtraction echocardiography to provide high-quality and contrast-enhanced radiographic images is accepted. The digital subtraction processing techniques applied to echocardiography in this study were similar. In studies in which coronary flow was reduced, measurements from the washout phase of the curve, such as T, were well correlated with changes in coronary artery blood flow and not myocardial perfusion.8 25 However, when the experimental protocol included a hyperemic stimulation, the results were more accurate with peak intensity9 10 11 15 and area under the curve12 15 than with measurements of the T. In the present study and in agreement with other human studies, correlation with Doppler coronary blood flow velocity was found using area under the curve and not peak intensity.26 However, using the area under the curve, a coefficient correlation of only .81 indicates that echocardiographic measurements account for 65% of the variability of the Doppler measurement.
Coronary Blood Flow Reserve After Coronary Angioplasty
Several investigators have reported an improvement of the coronary blood flow reserve after percutaneous transluminal coronary angioplasty. However, it has been shown that coronary blood flow reserve remains depressed in approximately half of the patients despite angiographic and hemodynamic improvement in the epicardial artery.13 16 21 27 Recovery of normal coronary reserve responses may be expected in most patients some months later. Previous studies have demonstrated good correlation between the measurements of coronary flow reserve as assessed by Doppler technique and MCE.9 Additionally, using MCE, Reisner et al27 showed a marked improvement in peak contrast intensity after coronary angioplasty, and Porter et al28 found a marked improvement in area under the curve, demonstrating that MCE was able to assess quantitatively the immediate results of coronary angioplasty. However, no study comparing the results of coronary angioplasty with both Doppler and MCE techniques had been made. In the present study, after coronary angioplasty, both techniques showed an increase in coronary blood flow reserve, which tends to normalize. In agreement with a previous report,9 the present study shows that changes in Doppler epicardial flow velocity after papaverine administration are correlated with the changes in area under the curve in the entire septum as measured by MCE. Interestingly, analysis of regional reserve showed that in contrast to conditions before coronary angioplasty, coronary reserve of the subendocardium increased after coronary angioplasty. However, if an improvement of subendocardial perfusion is expected after coronary angioplasty, the reasons why coronary reserve was higher after coronary angioplasty in the subendocardium compared with the subepicardium remain unclear. We cannot exclude that regional wall-motion changes may have participated in changing regional blood flow since septal thickening was different after angioplasty during the measurement of coronary blood flow.
Subendocardial/Subepicardial Gray-Level Ratio
In addition to regional coronary reserve assessment, MCE allows the measurement of endocardial/epicardial gray-level ratios. In the present study, the subendocardial/subepicardial ratio at rest was below 1 and lower than the findings of Lim et al,11 who had an at-rest subendocardial/subepicardial ratio nearly equal to 1 in patients with coronary artery stenosis. However, since there was no significant difference of the subendocardial/subepicardial ratio compared with that found in our control population, we cannot ascertain that there was a subendocardial ischemia at rest. Indeed, experimental studies have demonstrated that severe coronary stenosis produces myocardial underperfusion or perfusion defect even at rest.13 During papaverine infusion, a significant decrease in subendocardial/subepicardial ratio was shown before angioplasty in patients with coronary stenosis, but no change was observed in control subjects. After coronary angioplasty, this ratio tended to increase. These results suggest that patients with coronary artery stenosis may have subendocardial hypoperfusion without at-rest wall-motion dysfunction. These data agree with experimental data that show subendocardial ischemia.17 19 Recently, using both the microsphere method and MCE, Cheirif et al15 showed that dipyridamole administration resulted in a significant reduction in endocardial/epicardial flow ratio in an ischemic region due to a critical stenosis of the circumflex artery. A similar change in the subendocardial/subepicardial ratio was observed by contrast echocardiography with the use of the area under the curves of the subendocardial and subepicardial layers. These data are also consistent with those of Lim et al,11 who demonstrated that the subendocardial/subepicardial ratio decreased after pacing in patients with coronary stenosis.
Limitations of the Study
All injections and sonifications were performed by the same investigator to decrease the variability in the rate of injection and in the number and size of the bubbles generated. Nevertheless, limitations included the absolute size and number of microbubbles injected and their volume of distribution, gain and reject settings in the echocardiographic system, depth of penetration, degree of attenuation, exact angle of incidence, axial resolution, and gray-scale compression settings. Therefore, although relative blood flow could be measured, it might not be feasible to measure absolute myocardial blood flow. For these reasons, it seems important to focus on the results of subendocardial/subepicardial ratios calculated during the same injection.
We used amidotrizoate sodium meglumine because of the current use of this agent in other studies,10 12 22 although this contrast medium may influence myocardial contractility and consequently coronary blood flow. However, we monitored ventricular pressure and derivatives, and we did not observe any significant negative inotropic effect during contrast medium injections. This is probably due to the small quantities of contrast agent injected into the coronary circulation. Although new contrast agents appear promising,29 the results found in the present study are unlikely to have been affected by the choice of meglumine.
The present results concerning transmural blood flow distribution must be considered very carefully since we could not validate this technique with microspheres in humans. However, animal studies have validated MCE as a tool for assessing transmural blood flow, and our findings concerning the effect of angioplasty on transmural blood flow distribution agree with other studies.30 Additionally, there is indeed no “gold standard” for assessing transmural coronary flow reserve in humans, and other promising techniques, such as nuclear studies, have not yet been validated.31
The ability to assess changes in blood flow in the different myocardial layers is a major advantage of MCE. In patients with coronary stenosis, MCE shows that perfusion of the subendocardium was altered, and our data suggest that it may be reversed by angioplasty. Application of this technique could be considered for patients with known altered coronary reserve, as in hypertrophy, and the results may improve our understanding of myocardial perfusion in different pathological states.
This study was supported in part by a grant of the Fédération Française de Cardiologie.
- Received June 20, 1994.
- Revision received September 20, 1994.
- Accepted October 3, 1994.
- Copyright © 1995 by American Heart Association
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