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European Journal of Echocardiography 2005 6(1):31-40; doi:10.1016/j.euje.2004.06.003
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Copyright © 2005, The European Society of Cardiology

Real-time perfusion adenosine stress echocardiography in the coronary care unit: a feasible bedside tool for predicting coronary artery stenosis in patients with acute coronary syndrome

Reidar Winter*, Petri Gudmundsson and Ronnie Willenheimer

Department of Cardiology, Malmö University Hospital, S-205 02 Malmö, Sweden

Received 16 February 2004; received in revised form 26 May 2004; accepted after revision 2 June 2004.

* Corresponding author. Tel.: +46-40-33-10-00; fax: +46-40-33-62-09. reidar.winter{at}skane.se


   Abstract
Top
 Abstract
Introduction
 Objectives
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Myocardial contrast echocardiography using power modulation real-time perfusion (RTP) is an appealing method for bedside risk stratification of patients with acute coronary syndrome. In this study, we aimed to evaluate the accuracy in predicting significant coronary stenosis of a bedside RTP adenosine stress protocol in patients with acute coronary syndrome.

Methods: Prior to coronary angiography, 36 consecutive in-patients with acute coronary syndrome underwent a bedside adenosine stress echocardiography with RTP in the coronary care unit. Visual assessment of both perfusion and wall motion was made, comparing rest and hyperaemia images. Each segment was attributed to one of the three main coronary vessel areas.

Results: The sensitivity of predicting significant stenosis was 87, 83 and 81% for left anterior descending, circumflex and right posterior descending areas, respectively. Specificity was 69, 67 and 60%, respectively. The positive predictive values were 83, 79 and 74%, respectively.

Conclusions: RTP using adenosine is a feasible bedside tool in predicting the area of significant coronary stenosis and could be helpful as a bedside decision-making tool in the clinical setting. More studies are required to assess the clinical value of RTP adenosine stress echocardiography.

Keywords: Real-time perfusion; Coronary artery stenosis; Acute coronary syndrome


   Introduction
Top
 Abstract
 Introduction
Objectives
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Due to the technical development, to recommendations following large clinical studies and to the use of new sensitive cardiac markers,1–8 there has been a rapid increase of invasive and non-invasive treatment options for the acute coronary syndrome. The growing need for invasive procedures creates logistical and financial problems and the increasing number of medical treatment options in this patient category is a clinical challenge. There is an ongoing debate on whether the preferred management in non-ST-segment elevation acute coronary syndromes would be a ‘routine invasive’ or a ‘selective invasive’ approach, as well as an ‘early invasive’ or an ‘ischemia guided’ approach.4,6,9 Either one of these approaches adds to the complexity of the bedside decision-making process, especially in smaller hospitals. The ‘routine invasive’ strategy is simply not possible to apply in many hospitals, due to the limited availability of catheterization resources. On the other hand, given a situation of limited access to the angiography laboratory and a growing number of patients that meet the criteria for coronary angiography and possible PCI, both the ‘selective invasive’ and ‘ischemia guided’ management strategies create a need for difficult priority decisions as well as tools for ischemic evaluation. Many of the acute coronary syndrome patients are at considerable risk due to a substantial myocardial area at risk, a low ischemic threshold, etc., something that often is not evident from the clinical picture. Nevertheless, the physician often has to make priority decisions based on relatively scarce clinical data, which would be simplified by good access to investigational tools with a high negative predictive value. Exercise ECG is widely available, but is probably not accurate enough, and furthermore sometimes not possible to use in the context of the acute coronary syndrome. Myocardial radionuclide examination and stress echocardiography are sufficiently accurate for ischemic evaluation and risk stratification in patients with acute coronary syndrome.10 However, dobutamine stress echocardiography is somewhat risky in the acute situation and sometimes difficult to interpret, and radionuclide examination is often not available. Furthermore, radionuclide examination is not feasible in the bedside setting.

Thus, there is an evolving need for a feasible and accurate bedside tool for the evaluation of myocardial ischemia. Currently ultrasound contrast agent is approved for left ventricular opacification and not for perfusion assessment during stress echocardiography. Myocardial contrast echocardiography is nevertheless a promising tool for assessment of myocardial perfusion11–18 due to the availability of echocardiography and therefore provides an opportunity for bedside applicability. The new power modulation real-time perfusion technique (RTP) allows for combined analysis of myocardial perfusion and contractility bedside.13–16,19,20 RTP can be used during stress echocardiography. Using adenosine as the stressor has the advantage of a very fast elimination and short half time, and could therefore minimize the ischemic burden on the heart from the stress test. Adenosine also has a better tolerability for the patient, while dobutamine-atropine often results in considerable discomfort for the patient.10,20 Using adenosine and a simplified protocol with only apical projections would minimize the stress time and the strain on the potentially ischemic myocardium. Thus, RTP using a simplified protocol and adenosine has the potential to become a bedside tool for risk evaluation of patients having acute coronary syndromes in the coronary care unit (CCU).


   Objectives
Top
 Abstract
 Introduction
 Objectives
Materials and methods
 Results
 Discussion
 Conclusions
 References
 
The aim of this study was to evaluate the feasibility and accuracy of a simplified adenosine RTP protocol, using only apical views, for evaluating myocardial ischemia bedside in the CCU in patients having acute coronary syndrome.


   Materials and methods
Top
 Abstract
 Introduction
 Objectives
 Materials and methods
Results
 Discussion
 Conclusions
 References
 
Patient population
We examined 36 consecutive in-patients with suspected acute coronary syndrome admitted to coronary angiography and possible PCI based on the clinical decision during the hospital stay. The inclusion and exclusion criteria are given in Table 1. Twenty-four of the patients had acute myocardial infarction; two of these had ST elevation infarction, and accordingly 22 patients had non-ST elevation infarction. The mean age was 63±10 years, ranging from 47 to 82 years. Twenty-seven patients (75%) were male, 15 (42%) patients had had a previous myocardial infraction, four patients had done previous PCI, and two had undergone coronary bypass grafting (CABG). Seven patients had diabetes mellitus, 11 had treatment for hypertension, ten were current smokers, and 16 patients were previous smokers. From the resting echocardiography 15 (42%) patients had abnormal global LV function (LVEF <55%), and 16 patients (34%) had regional hypokinesia. The baseline patient characteristics are shown in Table 2.


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  		Table 1 Inclusion and exclusion criteria for the study

 


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  		Table 2 Baseline patient characteristics and number of PCI and CABG during the hospitalization

 
Study protocol
The study protocol was approved by the local Ethics Committee. The echocardiographic equipment used was a Sonos 5500 (Philips, Andover, MA) with real-time perfusion using power modulation (angio mode). Patients were examined in a left lateral recumbent position. The echo contrast used was Optison® or Sonovue®.

The adenosine stress echocardiography was performed in the CCU, prior to coronary angiography. To be able to minimize the patient exposition time to adenosine infusion, we applied a simplified protocol using only apical two-, three- and four-chamber views. The second generation contrast agents Optison® or Sonovue® were used for echo enhancement. The contrast agent was infused in the left decubital vein. For this purpose we used a standard infusion pump (IVAC 200), which was manually rotated during the infusion to avoid sedimentation. The infusion rate was set at 0.5 ml/min for Optison® and 1.0 ml/min for Sonovue®. When the myocardium was visually perfused, an impulse of ten frames was given with a mechanical index of 1.0 and replenishment was visually confirmed. An eventual gain adjustment was made from a visual assessment of over- or under-gain. 2D gain was set at zero and colour gain usually around 65–70% from the visual assessment. When the visual steady state was reached and replenishment was satisfactory after a test impulse, recordings were made at baseline in the three apical views. Digital loops consisting of ten heart cycles were recorded in each projection. After completion of the baseline recording, adenosine infusion was started at an infusion rate of 140 µg/min per kg. Adenosine was given for a minimum of 1 min simultaneously with the contrast infusion, before recording loops of perfusion during adenosine infusion. Recordings were made in a similar manner to baseline, i.e. in apical four-, two- and three-chamber views. The total duration of adenosine infusion was usually less than 4 min and never exceeding 6 min. The infusion of the contrast agent was terminated simultaneously with the adenosine infusion.

Coronary angiogram
After the echocardiographic examination, all 36 patients underwent a catheterization procedure with coronary angiography. The coronary angiogram was clinically assessed, using a stenosis degree of ≥50% as significant. Thirteen patients (36%) had one-vessel disease, 11 patients (31%) had two-vessel disease, 11 patients (31%) had three-vessel disease, and only one patient had no significant coronary artery stenosis. The numbers of patients having significant stenosis in LAD, Cx and RCA areas were 21, 21 and 24, respectively.

Image interpretation
Three areas of interest (AOIs) were defined and designated to the three main coronary vessels: the left anterior descending (LAD), the circumflex (Cx) and the right posterior descending (RPD), according to earlier experience in stress echocardiography.21 Each segment was attributed to one of the three main coronary vessel areas of interest, LAD, Cx and RPD, and in two cases the left posterior descending artery. From the 16 segment model, eight segments were contributed to LAD, four to Cx and four to RPD (Fig. 1). Two readers made the interpretation of the images, without knowledge of the coronary angiogram. The reading process was made as a ‘consensus read’, i.e. the two readers carried out the reading process together in a open discussion and decided together in areas of disagreement. Myocardial ischemia was visually evaluated comparing rest and hyperaemia images, looking for both perfusion defects (PDs) and wall motion abnormalities (WMAs).


Figure 1
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  		Figure 1 Distribution areas of the three main coronary vessels.

 
PDs were interpreted at the earliest four beats following the destruction flash at rest and two beats at peak stress. A PD was defined as visually significant slow replenishment as described above or a fixed regional hypoperfusion, either subendocardial, ‘patchy’ or transmural.

Specific reading criteria for assessing ischemia using combined analysis of wall motion and perfusion

  • An AOI having neither PD nor WMA at rest was considered ischemic if there was a visually detectable PD and a WMA at peak stress.
  • A PD with normal WM was considered to be ischemic if the WM was clearly better in the other segments (relative WMA).
  • AOIs with PDs and/or WMAs at rest were considered ischemic if there was a larger PD and/or WMA at peak stress.

Criteria for assessment of artefacts

• A PD at peak stress was considered to be an artefact if the wall motion was better compared to the rest images in any particular AOI.
• PDs were assessed to be artefacts if these were considered to be from contrast shadowing, attenuation defects or artefacts from external shadowing.

An example of an end-systolic still-frame of a patient with LAD stenosis and an ischemic apical area is shown in Fig. 2.


Figure 2
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  		Figure 2 Four-chamber view at rest and during adenosine stress. The rest image is displayed to the left, and the adenosine stress image in the right panel. An apical perfusion defect is clearly seen during adenosine stress. This particular patient had an isolated LAD stenosis.

 
To assess if there was an additional value of combining perfusion and wall motion according to the pre-specified criteria above we made an additional analysis using only worsened wall motion or perfusion at peak stress in two separate analyses.

Separate wall motion analysis
Relative WMA at peak stress according to our definition in the combined analysis above was used as the criteria ischemia, regardless of perfusion, in the separate wall motion analysis.

Separate perfusion analysis
AOIs with PDs at peak stress or AOIs with resting PD that appeared larger at peak stress were considered ischemic, regardless of the wall motion. Thus, PDs that were considered to be artefacts due to lack of at least relative WMA at peak stress according to the criteria for the combined analysis above were in this analysis considered to be ischemic. Our interpretation criteria for ischemia are summarized in Fig. 3.


Figure 3
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  		Figure 3 Reading criteria for assessment of ischemia using three different criteria, combined perfusion and wall motion and wall motion and perfusion separately. WMA, wall motion abnormality; PD, perfusion defect.

 
Statistical analysis
The StatView statistical program (SAS Institute, Cary, NC) was used for the statistical analysis. We calculated sensitivity, specificity, positive and negative predictive values, and accuracy for predicting significant coronary stenosis at the coronary angiogram in the three predefined distribution areas of the three main coronary vessels.


   Results
Top
 Abstract
 Introduction
 Objectives
 Materials and methods
 Results
Discussion
 Conclusions
 References
 
We assessed 108 AOIs; 69 areas had significant stenosis at coronary angiogram and 69 areas were considered ischemic at the echocardiographic examination. Using the combined perfusion and wall motion analysis, the accuracy, sensitivity, specificity and predictive values of predicting significant stenosis in any specific AOI and AOIs contributed to respectively LAD, Cx and PCA distribution areas as shown in Table 3. Generally, the highest accuracy was found for the LAD territory, and the lowest for the RPD territory. Twelve patients (33%) were assessed to be ischemic in one AOI, 12 in two AOIs and 11 patients were assessed to be ischemic in all three AOIs (Tables 4 and 5Go). The relation between the number of ischemic AOIs and the number of vessels having significant stenosis is displayed in Table 4. All three-vessel diseased patients were assessed to be ischemic in at least two AOIs and the majority of these (58%) in all three AOIs. There was approximately the same relation the other way around; patients that were assessed to have ischemia in all three AOIs were mostly three-vessel diseased (64%), however there was one patient having no significant stenosis but ischemia in all three AOIs. This particular patient was a diabetic who had atherosclerotic lesions in all coronary arteries, but no single significant stenosis (Table 4).


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  		Table 3 The accuracy, positive and negative predictive values (PPV, NPV), sensitivity and specificity of RTP using significant stenosis as the angiogram as the ‘gold standard’

 


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  		Table 4 Distribution of number of areas of interest (AOIs) in comparison of one-, two- and three-vessel disease

 


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  		Table 5 The distribution of perfusion defects (PDs) and wall motion abnormalities (WMAs) in areas of interest (AOIs) assessed to be ischemic on the adenosine stress echocardiography

 
According to our definition of ischemia above, a majority of ischemic AOIs (without resting defects (WMA and/or PD)) had both PDs and clear WMAs at peak stress, as displayed in Table 5. Patients having resting defects (infarctions or scars) had less clear WMAs during peak stress in the ischemic AOIs. The majority in this group had PD but only relative WMAs. There was an inverse relationship between WMA and PD in these two groups, where patients having resting PDs and WMAs had less detectable worsening of WMA during adenosine provocation, while there were more pronounced WMAs at peak stress in the group without resting defects. This relation was more pronounced the more ischemic the patient was, both in terms of the number of ischemic AOIs and the number of vessels with significant stenosis (Tables 5 and 6Go).


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  		Table 6 The relation of perfusion defects (PDs) and wall motion abnormalities (WMAs) in ischemic areas of interest (AOIs) in patients having one, two and three vessel diseases (vd) on the angiogram

 
Sensitivity, specificity, predictive values and accuracy for the separate analyses of perfusion and wall motion in comparison to the combined analysis are displayed in Table 7. Only marginal differences are seen comparing perfusion defects with or without using simultaneous wall motion analysis. Accuracy is virtually the same (78% for perfusion analysis compared to 79% for the combined analysis), whilst the sensitivity is slightly better for perfusion analysis but having a slightly inferior specificity (62% compared to 67%). The accuracy is markedly lower for the wall motion analysis (59%) but having the best specificity (72%).


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  		Table 7 The accuracy, positive and negative predictive values (PPV, NPV), sensitivity and specificity of RTP comparing three different reading criteria: (1) based on the predefined combined analysis of both perfusion and wall motion abnormalities (PD and WMA); (2) PD only; or (3) WMA only using significant stenosis from the angiogram as the ‘gold standard’

 

   Discussion
Top
 Abstract
 Introduction
 Objectives
 Materials and methods
 Results
 Discussion
Conclusions
 References
 
The present study shows that it is possible to use RTP and a simplified adenosine stress echocardiography protocol bedside in the CCU, using simple visual assessment, for a reasonably accurate prediction of significant coronary artery stenosis in the three main vessel areas. This demonstrates the potential of a new real-time myocardial contrast echocardiographic technique as a bedside tool for guidance in the bedside decision-making process in patients with acute coronary syndrome.

There was some mismatch in which AOIs were considered ischemic in comparison to which vessel area had significant stenosis. However, the sensitivity for detecting significant coronary stenosis in the different territories is quite good, especially considering that we did not test the accuracy for ‘only’ detecting significant coronary artery disease, as in many earlier stress echocardiography studies, but actually tested the accuracy of detecting coronary disease in individual territories. The accuracy in detecting the location of the stenosis is addressed in some earlier studies,21 and the accuracy in this study is comparable, despite the fact that we included 15 patients with earlier MI, in some cases probably with old stenosis and/or fixed PD and WMA. In the present study, it is not appropriate to test for accuracy for detecting coronary stenosis in general, since only one patient did not have significant stenosis. The accuracy was, not surprisingly, best in the LAD territory. This is to be expected from the well-known anatomical fact that the LAD territory is predominantly in the echocardiographic ‘near-field’ and, therefore, also produces the best ultrasound images.

There seems to be relatively little to gain from using the combination of perfusion and wall motion, as the result from using only perfusion had virtually the same accuracy in this study. The sensitivity seems to be somewhat higher looking at only perfusion. On the other hand specificity is lower. This could be indicative for using combined analysis of perfusion and wall motion in adenosine stress echo. The difference is however not statistically significant and further studies should address this specific question. Using solely wall motion criteria was in this study markedly less accurate, which is to be expected from the use of a vasodilator as the stressor.

Some ischemic regions are situated in or near border zones. Therefore, perfusion–angiogram mismatch may arise simply due to projection errors or anatomical variations in the coronary artery distribution areas. Consequently, it is impossible to establish in which cases there is a true perfusion–angiogram mismatch and in which cases there is mismatch due to anatomical reasons, incorrect projections, artefacts, or misinterpretations due to sub-optimal image quality. Assessment of the true perfusion–angiogram mismatch would require some kind of thorough anatomical matching of the angiogram and the echocardiographic projections, which is not possible in this study.

The specificity was generally considerably lower than the sensitivity. This is presumably partly due to the reasons mentioned above. However, the main reason probably is the fact that vasodilator stress echocardiography and coronary angiography measure different things. Coronary angiography is merely giving a rough picture of the inner lumen of the vessel, which tells us little about the actual myocardial ischemia. This is illustrated by the patient having the most extreme perfusion–angiogram mismatch. This was a diabetic 49-year-old male who was overweight, had recently quit smoking and had a father who had had a myocardial infarction in his 40s. He was admitted due to chest pain and had some dynamic ECG changes, but normal Troponin. The coronary angiogram showed several non-significant stenoses, i.e. widespread atheromatosis. Clearly this patient has a high-risk profile and should be treated aggressively with statins, aspirin, a betablocker, an angiotensin-converting enzyme inhibitor and perhaps clopidogrel. Most likely this patient has endothelial dysfunction and a non-optimal coronary flow reserve due to his atheromatosis, and probably also microvascular disease. This particular patient was considered ischemic in all three areas using adenosine RTP stress echocardiography, but was nevertheless classified as having no significant stenosis in all of the three coronary artery territories. Most likely, this patient is truly ischemic and the perfusion–angiogram mismatch is a consequence of the fact that coronary angiography and RTP are measuring different things. The lower specificity is also to be expected considering findings of studies comparing stress echocardiography and SPECT, showing in general a slightly higher sensitivity but on the other hand lower specificity,10 considered to be a consequence of the ischemic cascade.22

Much effort has been made to quantify stress echocardiography,23,24 and much work is also currently being done to make it possible to quantify perfusion studies.25 It is likely that in the relatively near future we will have access to feasible quantitative methods to evaluate myocardial perfusion. However, the present study demonstrates that it is feasible and reasonably accurate to evaluate ischemia bedside in a qualitative manner, using real-time perfusion myocardial contrast echocardiography. A considerable disadvantage of vasodilator (adenosine or dipyridamole) stress echocardiography is the seemingly lower accuracy,10,20 compared to dobutamine stress echocardiography. However, adenosine stress echocardiography using an infusion of a second-generation contrast agent and RTP, as in this study, seems to be accurate enough in this clinical setting. Using only apical projections has the dual benefit of minimizing the ischemic burden due to a shorter examination time, and also creating less shadowing from contrast in the right ventricle.

RTP contrast echocardiography should in fact be more sensitive than regular stress echocardiography, due to the simultaneous wall motion and perfusion assessment, and could also therefore be easier to learn, with a steeper learning curve. Thus, the technique could possibly be used in any hospital with echocardiographic facilities, without the need for large volumes or great expertise. This would however need to be shown in further studies before implementing a bedside assessment of the acute coronary syndrome using adenosine power modulation real-time contrast echocardiography in any kind of clinical routine.

Study limitations
There is an obvious limitation in collecting images solely in RTP mode making it more difficult to separate perfusion and wall motion. Due to this limitation and the qualitative reading, it is difficult to assess the additional value of combining perfusion and wall motion. The subjectivity in our reading criteria, especially ‘relative wall motion abnormality’, is obvious and it is really not possible to read wall motion without somehow being affected by the perfusion, since the perfusion information is seen in the same image.

This is however also a simplification of the image collection making the ischemic burden minimal and the test more cost-effective to the simple protocol of only three projections at rest and during adenosine infusion. Only collecting apical projections and no parasternal projections and having a confirming projection, as the parasternal short axis often becomes, could also be a problem, creating some degree of uncertainty for the test. Due to this there is probably some ‘trade off’ in accuracy for the test.

One major limitation of the study is the fact that the vast majority of the patients had significant CAD, and for this reason it was impossible to test the overall negative predictive value for RTP adenosine stress echo.

Compared to other myocardial segments, left ventricular basal segments and the lateral wall segments are more often sub-optimally visualized. In particular, the basal lateral wall is likely to produce artefacts from shadowing and attenuation. This is the reason why the LAD region has the best accuracy using this technique. Nevertheless, anterior infarctions are often the largest with the poorest prognosis and, therefore, also clinically most important. From this point of view it is an advantage that the LAD region has the best accuracy using this technique.

The use of the coronary angiogram as the gold standard for ischemia is an obvious limitation. It is well known that it is possible to have ischemia in specific areas without angiographically significant stenosis in the epicardial arteries supplying that area. This can be due to microvascular disease, diffuse atherosclerosis or coronary vasospasm, etc. Furthermore, there were a large number of previous myocardial infarctions in the study population, and a certain number of stenoses seen in this study would be expected to have a distribution area consisting of infarcted myocardium without ischemia, thus giving a false negative result from the RTP analysis.

There is also a limitation in the visual qualitative assessment. This means that the technique has a certain limitation due to subjectivity and is bound to require at least some expertise and, therefore, has a learning curve. This could be steeper due to the dual assessment of wall motion and perfusion, but this particular question needs to be addressed in further studies.


   Conclusions
Top
 Abstract
 Introduction
 Objectives
 Materials and methods
 Results
 Discussion
 Conclusions
References
 
RTP using adenosine and a simplified protocol is a feasible tool in predicting the area of significant coronary stenosis and could be helpful as a bedside decision-making tool in the clinical setting. Since myocardial ischemia may be present despite the absence of significant coronary stenosis, the actual accuracy of RTP in detecting myocardial ischemia may be underestimated in this study. This will have to be further evaluated in future studies.


   References
Top
 Abstract
 Introduction
 Objectives
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 

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P. A. Dijkmans, R. Senior, H. Becher, T. R. Porter, K. Wei, C. A. Visser, and O. Kamp
Myocardial Contrast Echocardiography Evolving as a Clinically Feasible Technique for Accurate, Rapid, and Safe Assessment of Myocardial Perfusion: The Evidence So Far
J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2168 - 2177.
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