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European Journal of Echocardiography 2004 5(4):294-303; doi:10.1016/j.euje.2003.12.002
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Copyright © 2003, The European Society of Cardiology

Reduced coronary flow reserve in the coronary sinus is a predictor of hemodynamically significant stenoses of the left coronary artery territory

Alexander V. Vrublevsky*, Alla A. Boshchenko1 and Rostislav S. Karpov2

Department of Atherosclerosis and Coronary Artery Disease, Cardiology Research Institute, Russian Academy of Medical Sciences, Siberian Branch, Kievskaya Str., 111a, 634012 Tomsk, Russia

Received 19 August 2003; received in revised form 2 December 2003; accepted after revision 17 December 2003.

* Corresponding author. Tel.: +7-382-2-55-34-45; fax: +7-382-2-55-50-57. E-mail address: alexvr{at}mail.tomsknet.ru (A.V. Vrublevsky).

1Tel.: +7-382-2-55-34-45; fax: +7-382-2-55-50-57. E-mail address: cobra{at}mail.tomsknet.ru (A.A. Boshchenko).

2 Tel.: +7-382-2-55-34-49; fax: +7-382-2-55-50-57. E-mail address: administration{at}cardio.tsu.ru (R.S. Karpov).


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Aim and methods: The role of transesophageal Doppler assessment of coronary flow reserve (CFR) in the coronary sinus (CS) in the diagnostics of significant left coronary artery (LCA) stenoses was studied in 65 CAD patients with angiographically proven >50% stenotic atherosclerosis of the LCA territory (38—with isolated left anterior descending artery (LAD) or left circumflex artery (Cx) stenosis; 27—with both LAD and Cx stenoses) and 31 healthy volunteers (all men). Dipyridamole was used as a stress agent. The antegrade phase of coronary flow in the CS moving into the right atrium was analysed. CFR in the CS was calculated in two ways: (1) as ratio of hyperemic to baseline peak antegrade flow velocity (CFRp); (2) as ratio of hyperemic to baseline volumetric blood flow velocity (CFRv). The level of CFR <2.0 in both ways of calculation was diagnosed as reduced.

Results: CAD patients compared with healthy volunteers had significantly lower CFRp (1.51±0.44 and 2.57±0.79; p<0.001) and CFRv (2.21±1.18 and 5.43±2.83; p<0.001) in the CS. CFRp <2.0 in the CS was a predictor of significant stenoses of the LCA with sensitivity of 89% and specificity of 76%, while CFRv <2.0 was a predictor of significant stenoses of the LCA with sensitivity of 49% and specificity of 97%. CFRp <2.0 in the CS was registered in 96% of CAD patients with two-vessel lesion and in 84% of CAD patients with one-vessel lesion, while CFRv <2.0 in the CS was revealed in 85% of CAD patients with two-vessel lesion and only in 26% of CAD patients with one-vessel lesion. Sensitivity and specificity of CFRv <2.0 in the CS in the diagnostics of significant two-vessel lesion of the LCA were 85% and 84%, respectively.

Conclusions: Thus, the reduced CFR in the CS is a sensitive and specific predictor of LCA stenoses. A decrease of both CFRp <2 and CFRv <2.0 in the CS is a predictor of significant two-vessel lesion of the LCA, while a decrease of only CFRp <2.0 in the CS is a predictor of significant one-vessel lesion of the LCA.

Keywords: Coronary flow reserve; Coronary sinus; Transesophageal echocardiography; Coronary atherosclerosis


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Over the last decade the high-frequency intracoronary Doppler, thermodilution and positron-emission tomography studies have demonstrated that pharmacologically mediated vasodilative reserve of coronary blood flow reflects the functional degree of coronary stenoses, revealing their hemodynamically significant varieties.1–3 However, the above-mentioned methods are expensive, most of them require invasive intervention, so they cannot be performed in all patients, and their multiple application is not harmless.

In our previous work4 we demonstrated the possibilities of promising technology—transesophageal Doppler echocardiography—in the diagnostics of stenoses and occlusions of the coronary arteries proximal segments. However, the main methodical disadvantage of this technology is that it is impossible to carry out Doppler assessment of the coronary arteries mid and distal segments stenoses because of their non-visualization. At the same time, visualization of the coronary sinus (CS) through transesophageal approach and registration of its adequate blood flow Doppler spectrum is possible in almost all patients. Zehetgruber et al.5 showed a high correlation of coronary flow reserve (CFR) parameters in the CS, determined by non-invasive transesophageal Doppler echocardiography, with the direct measurements in the left anterior descending coronary artery (LAD) stenotic zone of various localization. We hypothesized that a decrease of vasodilative reserve in the CS as a main venous collector of the left coronary artery (LCA) might be a predictor of significant stenosis of the LCA territory, both its proximal and mid and distal segments.

The aim of our study was to determine the diagnostic role of transesophageal Doppler assessment of CFR in the CS in the diagnostics of significant stenoses of the LCA territory.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusions
 References
 
2.1 Study group
We have assessed 96 men who gave an informed consent to participate in the study. The main group consisted of 65 CAD patients (mean age 51 ± 8 years) with stable angina of I–III functional classes or silent myocardial ischemia and with angiographically proven significant stenosis (>50%) of the LCA territory. All CAD patients had a sinus rhythm, normal wall thickness and function of the left and right ventricles, normal right ventricular systolic pressure, mitral and tricuspid valvular regurgitation less than grade 2, arterial normotension (blood pressure <130/90 mmHg). CAD patients with valvular disease, cardiomyopathy, diabetes mellitus, esophageal, gastric or severe pulmonary diseases were excluded from the study. The control group consisted of 31 healthy volunteers with chest pain (mean age 34±5 years) who had angiographically normal coronary arteries. The research protocol was approved by the Ethical Committee of the Tomsk Cardiology Research Institute, Russia.

2.2 Coronary angiography
Coronary angiography was performed through femoral approach according to Judkins' standard method (1967) using COROSKOP Plus angiographic complex (Siemens, Germany). The number of coronary arteries with significant stenoses, the localization of stenoses and the maximal percentages of stenoses were determined.

2.3 Multiplane transesophageal echocardiography
All patients underwent transesophageal echocardiography within a week after coronary angiography. They had continuous electrocardiographic (ECG) monitoring and every 2 min blood pressure monitoring. A 7–4 MHz multiplane probe with ultrasound diagnostic systems HDI 5000 SonoCT or Ultramark 9 HDI CV (Philips–ATL, Germany–USA) was used. All kinds of medication, except sublingual nitroglycerine, were discontinued 48 h before the study. The investigators were blinded to the coronary angiography data.

Esophageal intubation was made in the left lateral decubitus position after slight sedation (0.5% sibazone in 0.5 ml boluses) and oropharyngeal local anesthesia (2% dicaine). The transducer was advanced to a standard midesophageal position. The CS was imaged in four-chamber plane with the rotation of the transducer array from 0° to 30° (Fig. 1a, b). A good quality image of the CS existed during the entire cardiocycle. The CS diameter was measured at a 1 cm distance from the mouth in the end diastolic phase before the P wave on ECG. The pulsed-wave sample volume was placed at a 1 cm distance from the mouth, and spectral recordings of the flow were made. The Doppler angle between the ultrasound beam and vessels did not exceed 30°. After baseline recording of flows and measurement of diameters, dipyridamole (Persantin, Boehringer Ingelheim, Austria, 0.56 mg/kg) was infused over a 4-min period. An additional infusion of dipyridamole (0.28 mg/kg over a 2-min period) was used if the heart rate (HR) did not exceed a 10% increase from the baseline (Picano et al.6). Two minutes after the end of the infusion, hyperemic spectral profiles in the CS were recorded and the vessel diameter was measured. All images were recorded for playback analysis and were later measured off-line.


Figure 1
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  		Figure 1 Gray-scale and color Doppler images of the coronary sinus. Doppler spectrum of coronary blood flow in the coronary sinus. (a) Gray-scale visualization of the coronary sinus. (b) Color Doppler image of the coronary sinus. (c) Doppler spectrum of coronary blood flow in the coronary sinus. CS, coronary sinus; R, retrograde blood flow; S, systolic wave of the antegrade blood flow; D, diastolic wave of the antegrade blood flow.

 
Systolic (SBP) and diastolic blood pressure (DBP) and HR were automatically measured and digitally displayed by Bosotron 2 (Bosch + Sohn, Germany).

2.4 Analysis of coronary blood flow in the coronary sinus
The antegrade phase of coronary flow in the CS moving into the right atrium was analysed. The peak (Vp, cm/s) and mean (Vm, cm/s) flow velocities and the velocity time integral (VTI, cm) were determined (Fig. 1c). Vp was determined as peak antegrade flow velocity in space. Vm was determined as heartbeat antegrade average velocity. The volumetric blood flow velocity (VBF, ml/min) in the CS was calculated according to the formula, VBF={pi}xD2/4xVTIxHR, where D (cm) is the diameter of the CS.7 The average value of three spectral and planimetric envelopes was used.

2.5 Coronary flow reserve
CFR in the CS was calculated in two ways: 1—as ratio of peak hyperemic blood flow velocity to the peak baseline blood flow velocity (CFRp); 2—as ratio of volumetric hyperemic blood flow velocity to the volumetric baseline blood flow velocity (CFRv).8,9 The level of CFR <2.0 in both ways of calculation was diagnosed as reduced.9

2.6 Statistical analysis
The statistical analysis of the findings was performed by STATISTICA software package, version 6.0 (StatSoft Inc., USA). The data were analysed by one-way analysis of variance (baseline–hyperemia test in the group) and Student–Scheffe post-testing. The data are expressed as mean value ± SD.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusions
 References
 
3.1 Visualization of the coronary sinus
Adequate gray-scale visualization of the CS as well as a good spectral Doppler flow were obtained in 100% CAD patients and 100% healthy volunteers.

3.1.1 Baseline parameters of systemic and coronary sinus hemodynamics
Baseline HR, SBP, DBP, CS diameter and Doppler parameters of coronary blood flow differed significantly in CAD patients and healthy volunteers (Table 1). Baseline Doppler parameters of coronary blood flow in the CS did not depend on SBP and DBP levels. We have revealed a direct correlation between the mean flow velocity, velocity time integral, volumetric blood flow velocity in the CS and the maximum percentage of the LCA territory stenosis (LAD or circumflex artery, Cx), which were: r = 0.24, p<0.05; r = 0.37, p<0.001; and r = 0.31, p<0.01, respectively.


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  		Table 1 Parameters of systemic hemodynamics, coronary blood flow and coronary flow reserve in the coronary sinus at baseline and peak of dipyridamole infusion in CAD patients with significant stenoses of the left coronary artery territory and healthy volunteers

 
3.2 Coronary flow reserve in the coronary sinus in CAD patients and healthy volunteers
At peak of dipyridamole action the HR and SBP changes were uniform in all evaluated individuals, the DBP parameters did not differ significantly (Table 1). A dipyridamole-induced increase of the CS diameter, blood flow linear and volumetric velocities in the CS was revealed in both groups. However, an increase of values was more pronounced in healthy subjects. It was clear from a lower CFRp and CFRv in CAD patients compared with healthy volunteers (Table 1). By individual analysis CFRp <2.0 in the CS was registered in 58 of 65 CAD patients and in 7 of 31 healthy volunteers. CFRv <2.0 was observed in 32 of 65 CAD patients and in 1 of 31 healthy volunteers. Thus, CFRp <2.0 in the CS was a predictor of significant stenoses of the LCA with sensitivity of 89% and specificity of 76%, while CFRv <2 was a predictor of significant stenoses of the LCA with sensitivity of 49% and specificity of 97%.

3.3 Differentiation between one- and two-vessel atherosclerotic lesions of the left coronary artery territory
To specify the cause of a lower sensitivity of CFRv <2.0 than CFRp <2.0 in the diagnostics of significant stenoses of the LCA territory the CAD patients were divided into two subgroups. The first subgroup included 38 CAD patients with one-vessel lesion of the LAD or Cx (30—with the LAD stenosis >50%, 8—with the Cx stenosis >50%). The second subgroup consisted of 27 CAD patients with two-vessel lesion of the LCA territory (with the stenosis >50% of the LAD and Cx).

CFRp in the CS was equally reduced in CAD patients with two- and one-vessel LCA lesions, while CFRv in patients with two-vessel LCA lesion was significantly lower than that in patients with one-vessel lesion (Table 2). By individual analysis CFRp < 2.0 was registered in the majority of patients with both two-vessel (26 of 27 pts) and one-vessel lesions (32 of 38 pts). CFRv <2.0 was revealed in the majority of patients with two-vessel lesion (23 of 27 pts) and was rather rarely observed in patients with one-vessel lesion (10 of 38 pts). Thus, sensitivity and specificity of CFRv <2.0 in the diagnostics of the LCA two-vessel lesion were 85% and 84%, respectively.


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  		Table 2 Parameters of coronary blood flow and coronary flow reserve in the coronary sinus at baseline and peak of dipyridamole infusion in CAD patients with one- and two-vessel atherosclerotic lesions of the left coronary artery and healthy volunteers

 
Examples of an adequate CFRp and CFRv in the CS in a healthy volunteer and a reduced CFRv and/or CFRp in the CS in CAD patients with one- and two-vessel lesions of the LCA are shown in Figs. 2–4GoGo.


Figure 2
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  		Figure 2 Normal coronary flow reserve in the coronary sinus in a healthy volunteer. Dipyridamole test. (a) Doppler spectrum of coronary blood flow in the coronary sinus before dipyridamole infusion. (b) Doppler spectrum of coronary blood flow in the coronary sinus after dipyridamole infusion. CFRp, 2.50; CFRv, 4.08. Vp, peak velocity of the antegrade phase of coronary blood flow in the coronary sinus; VBF, volumetric blood flow in the coronary sinus; CFRp, coronary flow reserve by peak velocity of the antegrade phase of blood flow in the coronary sinus; CFRv, coronary flow reserve by volumetric blood flow in the coronary sinus.

 


Figure 3
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  		Figure 3 Coronary flow reserve in the coronary sinus in a CAD patient with one-vessel atherosclerotic lesion of the left coronary artery territory (75% stenosis in proximal segment of the left anterior descending artery). Dipyridamole test. (a) Doppler spectrum of coronary blood flow in the coronary sinus before dipyridamole infusion. (b) Doppler spectrum of coronary blood flow in the coronary sinus after dipyridamole infusion. Reduced CFRp, 1.40; normal CFRv, 3.62. Vp, peak velocity of the antegrade phase of coronary blood flow in the coronary sinus; VBF, volumetric blood flow in the coronary sinus; CFRp, coronary flow reserve by peak velocity of the antegrade phase of blood flow in the coronary sinus; CFRv, coronary flow reserve by volumetric blood flow in the coronary sinus.

 


Figure 4
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  		Figure 4 Coronary flow reserve in the coronary sinus in a CAD patient with two-vessel atherosclerotic lesion of the left coronary artery territory (75% stenoses in proximal and mid segments of the left anterior descending artery and 75% stenoses in proximal, mid and distal segments of the circumflex artery). Dipyridamole test. (a) Doppler spectrum of coronary blood flow in the coronary sinus before dipyridamole infusion. (b) Doppler spectrum of coronary blood flow in the coronary sinus after dipyridamole infusion. Reduced both CFRp, 0.83 and CFRv, 0.88. Vp, peak velocity of the antegrade phase of coronary blood flow in the coronary sinus; VBF, volumetric blood flow in the coronary sinus; CFRp, coronary flow reserve by peak velocity of the antegrade phase of blood flow in the coronary sinus; CFRv, coronary flow reserve by volumetric blood flow in the coronary sinus.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusions
 References
 
In this study we have demonstrated that CFR in the CS can be measured in all CAD patients and healthy volunteers using transesophageal Doppler echocardiography. Besides, we have proven that reduced CFRv and/or CFRp in the CS can be a predictor of significant LCA stenoses and a criterion for differentiation of one-vessel from two-vessel atherosclerotic lesion of the LCA territory.

The assessment of coronary blood flow at rest is not known to provide information about the degree of coronary vessel atherosclerotic lesion as the parameters of coronary hemodynamics in CAD patients and healthy subjects can be similar even in marked stenosis due to compensatory ability of the coronary vascular bed.10 One of the most accurate indices, showing the total atherosclerotic lesion of the coronary arteries, is CFR which is defined as an ability of the coronary vascular bed to increase the volumetric blood flow according to the myocardium demands in a certain hemodynamic situation.1,3,8,9

It is well known that the most accurate methods of CFR measurement are intracoronary Doppler techniques, thermodilution and positron-emission tomography.1,2,11 Using intracoronary Doppler wires during dipyridamole and adenosine stress tests it has been shown that in adequate vasodilatation in healthy arterial coronary system the level of CFR is over 2.0.1,3,8,9 However, up-to-date clinical cardiology needs the development of new technologies and methodical approaches for the study of CFR level. On the one hand, it is due to the invasiveness and/or high cost of angiographic and tomographic techniques, on the other hand, it is due to the fact that practical cardiologists need an available informative technique allowing them not only to determine the baseline level of the coronary arteries lesion but also to evaluate in dynamics the efficacy of therapeutical and cardiosurgical treatment. Besides, unlike stress-exercise tests, which evaluate the degree of coronary circulation impairment indirectly, this technique is expected to analyse the coronary hemodynamic parameters directly as all the efforts of clinicians are aimed at their restoration.

Recent studies have reported the usefulness of transesophageal Doppler measurements of CFR in proximal significant LAD stenoses.5,12 However, transesophageal echocardiography fails to visualize the mid and distal segments of the coronary tree. It has been reported that transthoracic Doppler assessment of CFR in the distal third of the LAD and RCA is significantly correlated with the results obtained with intracoronary Doppler wire for the LAD and RCA stenoses.13–15 Caiati et al.16 have demonstrated that contrast-enhanced second harmonic Doppler measurements of CFR in the LAD is an effective method for detection of LAD territory stenoses >75%. However, CFR assessment by transthoracic Doppler echocardiography does not provide information about the total atherosclerotic lesion of the coronary vascular territory because it does not register the reserve in the Cx and arteries of smaller diameter.

The whole complex of the above-mentioned limitations of transesophageal and transthoracic Doppler echocardiography of the coronary arteries made the researchers pay attention to the CS, the main venous collector of the LCA, which is adequately visualized through transesophageal approach in almost all patients.5,17–19 Our study has confirmed the possibility of getting the image of the coronary sinus through transesophageal approach and availability of its location for an adequate registration of coronary blood flow Doppler spectrum in all studied subjects. Yamagishi et al.20 have demonstrated that assessment of the great cardiac vein flow during stress test reflects the flow velocity in the LAD. Later Zehetgruber et al.5 have shown a moderate correlation between intracoronary flow velocity reserve measurements in the left anterior descending coronary artery stenotic zone of various localization and the assessment of coronary sinus CFR using transesophageal Doppler measurements.

Zehetgruber et al.5 and Filho et al.21 using transesophageal Doppler echocardiography have established that the CS blood flow has a two-phase character. During atrial systole, when the pressure in the right atrium becomes higher than that in the CS, a retrograde blood flow moving from the right atrium into the CS is registered. During ventricular systole the first antegrade (systolic) wave of the blood flow in the CS moving into the right atrial cavity can be observed. During ventricular diastole—a period of maximal myocardium relaxation—the second antegrade (diastolic) wave of the blood flow in the CS is registered. That is why for CFR assessment in the CS we used the parameters of the antegrade blood flow phase (systolic and diastolic waves).

We revealed an increase of antegrade linear and volumetric velocities in CAD patients in comparison with healthy volunteers already at rest, which is due to the LCA territory stenosis. However, it is impossible to diagnose stenosis by measuring the velocities at rest since there are no accurate quantitative criteria for normal parameters of the CS blood flow. High volumetric blood flow velocity at rest in groups and differentiation of coronary blood flow velocities at rest between the groups were the main cause of the fact that in dipyridamole stress test we were guided not so much by the absolute values of the parameters as by their change with respect to the baseline level ({Delta}% and CFR).

In our study an increase of VBF in the CS during stress test in healthy volunteers was caused, to a greater extent, by vasodilatation and, to a lesser extent, by acceleration of blood flow: {Delta}% of VBF 442±283% versus {Delta}% of Vp 157±79%, p<0.001. It is clear from much greater CFRv than CFRp in the CS in the group of healthy individuals. This fact also caused a reduced CFRp in seven healthy volunteers but reduced CFRv was registered in one healthy volunteer only.

Coronary blood flow analysis in the CS after dipyridamole infusion showed that both significant LAD and CA stenoses limited an increase of coronary blood flow velocity distally beyond the impairment. This fact accounts for a significantly lower CFRp in the CS in CAD patients of both single- and two-vessel lesion groups in comparison with healthy volunteers. A decrease of CFRp <2.0 in the CS was a reliable marker of the LCA territory stenosis of any localization.

The analysis of CFR parameters in the CS in CAD patient subgroups has shown that in one-vessel lesion of the LCA territory a CFRp decrease was compensated by an adequate increase of the CS diameter evidently due to the compensating increase of the volumetric blood flow in the unaffected vessel of the LCA territory. Hence, there was no marked decrease of CFRv in the majority of patients with one-vessel lesion. In seven of nine CAD patients with one-vessel lesion who had a decreased CFRv, LAD or Cx stenoses >75% and predominant left-artery blood supply were revealed by coronary angiography. In two-vessel lesion the vasodilative reserve of the coronary vascular bed in both the LAD and Cx was practically entirely exhausted; that is why a decrease of both CFRp and CFRv in the CS was observed. Thus, a decrease of CFRv <2.0 was an accurate marker of severe two-vessel atherosclerotic lesion of the LCA territory.

4.1 Study limitations
First, a considerably greater age of CAD patients compared with that of healthy volunteers which might result in an increase of blood flow velocities in the CS at rest in CAD patients should be considered a study limitation. Second, this study did not include intracoronary velocity measurements distal to the lesions because many patients had very distal lesions of coronary arteries and the Doppler wire might change the blood flow parameters in the vessel. A cut-off value of CFR for ischemia in the venous part of coronary vascular tree is not elaborated, that is why we used the arterial number 2.0 as a cut-off value for ischemia. Third, this study included a highly selective group of CAD patients without heart valve failure, microvascular disease, arterial hypertension, etc., which restrict the use of the obtained results in all CAD patients. Fourth, in case of diagnosing one-vessel lesion of the LCA territory on the basis of decreased CFRp in the CS it is impossible to determine which artery LAD or Cx is affected.

4.2 Clinical implication
This method, being rapid, reliable, non-expensive and semi-invasive in the assessment of coronary flow reserve, has potential for clinical implication, especially in the following cases:

(a) as an additional method to a simple exercise ECG test and stress echocardiography for evaluation of total atherosclerotic lesion of the LCA territory;
(b) as a method differentiating patients with one- and two-vessel significant stenosis of the LCA territory without CAD site detection;
(c) as a method for serial measurements of CFR in patients after bypass grafting, coronary angioplasty and stenting performed on the LCA territory.


   5 Conclusions
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
References
 

1. A decrease of coronary flow reserve <2.0 by peak and volumetric velocities of coronary blood flow in the coronary sinus is an evidence of two-vessel atherosclerotic lesion of the left coronary artery territory.
2. A decrease of coronary flow reserve <2.0 by peak velocity of coronary blood flow in the coronary sinus and normal (≥2.0) coronary flow reserve by volumetric velocity of coronary blood flow in the coronary sinus are representative of one-vessel atherosclerotic lesion of the left coronary artery territory.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 

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