Quantification of myocardial blood flow will reform the detection of CAD
- First Online:
- Cite this article as:
- Knuuti, J., Kajander, S., Mäki, M. et al. J. Nucl. Cardiol. (2009) 16: 497. doi:10.1007/s12350-009-9101-1
- 629 Downloads
The detection of functional consequences of epicardial coronary artery disease (CAD) has established role in guiding the therapy of the disease.1 In addition, the assessment of impairment in microcirculatory reactivity has recently gained more interest. Estimates of myocardial perfusion contain independent prognostic information about future major cardiac events and perfusion assessment is also useful in the monitoring of the effectiveness of risk reduction strategies.1
The standard assessment of myocardial perfusion is based on its relative distribution. This approach has obvious limitations since the interpretation is based on the assumption that the best perfused region is normal and can be used as a reference. Using quantification this limitation can be avoided and using absolute parameters instead of relative ones is expected to provide benefits in several clinical scenarios. Despite the recognized potential, the clinical use of absolute quantification has remained scarce.
Recently, several imaging techniques have been studied aiming for the quantitative measurement of perfusion. In addition nuclear imaging, magnetic resonance imaging, and echocardiography have been investigated and shown promising preliminary quantitative results.2,3 Currently, the most robust technique to quantify perfusion noninvasively in human heart is positron emission tomography (PET). However, although the use of PET in cardiac imaging is rapidly increasing, the image interpretation has still been chiefly based on relative distribution of perfusion.4
This review is aiming for brief summary of the current knowledge of quantification of myocardial perfusion for the detection of clinical CAD. The aim is to demonstrate the potential of quantification using several real clinical examples where the additional information gained from quantification has significant impact on the clinical findings.
The Techniques of Myocardial Perfusion Quantification
There are two major determinants that define the potential of imaging technique for quantification of myocardial perfusion. The imaging device and its performance will define how accurate and robust is the measurement of the signal that need to be quantified. The other main factor is the nature of the tracer or the contrast agent. The detailed analysis of different imaging technologies and their performance is beyond the scope of this review.
PET is by nature a quantitative technique and currently the most robust technique to measure perfusion noninvasively in human heart. PET allows very fast and effective imaging protocols with low radiation burden.5-8
Several tracers have been used for the measurement of myocardial perfusion with PET, in particular, 15O-water,9] 13N-ammonia,10 the potassium analog 82Rb.11 Recently also new 18Fluoride-labeled12,13 as well as 68Ga-labeled compounds have been tested.14
Currently, 15O-water and 13N-ammonia are the tracers most widely used for the quantification of myocardial perfusion with PET. Tracer kinetic models for quantification of perfusion have been successfully validated in animals against the radiolabeled microsphere method over a wide flow range for both tracers.9,10
Single-tissue compartment models for an inert freely diffusible tracer are used for calculation of MBF by use of 15O-water.9 For 13N-ammonia a three-compartment model taking into account the myocardial metabolic trapping and whole-body metabolism has been used for calculation of perfusion.10,15 Typically, the models also correct for the partial volume effect and spillover from the left ventricular chamber into the myocardial regions. These two tracers have been found to be equivalent for quantifying myocardial perfusion.16
The most important limitation of perfusion tracers as regard to quantification is the suboptimal myocardial extraction of the tracer. In addition to suboptimal extraction level, even more problematic phenomenon is that the extraction is reduced with increasing perfusion (Figure 1). When extraction fraction is reduced with increasing perfusion the uptake of tracer is not linear with perfusion and higher flows are underestimated. This must be corrected in the mathematical model by increasing the higher range perfusion values using specific equations. However, in the case the extraction is much blunted very high correction factors need to be used or the correction may become impossible. It needs to be noted also that high correction factors also multiplies the noise of the measurements leading to larger scatter of the values with high perfusion rates.
Although kinetic models have been proposed for quantification of perfusion by use of 82Rb, all these models are limited by the dependence of the myocardial extraction fraction on the perfusion rate. The recent animal validation studies with 82Rb has shown reasonable good linearity but as expected the scatter in high flow rates is quite high.11,17 This does not necessarily mean that 82Rb cannot be used to quantify myocardial perfusion in clinical situations but may indicate that different cut-off values for normal and abnormal perfusion need to be used or that the accuracy may not be as good than with other perfusion tracers.
It needs to be noted, however, that this phenomenon is very evident also with other tracers such as SPECT perfusion tracers (Figure 1), MRI, and CT contract agents.
Quantitative Perfusion Imaging Protocols
The perfusion imaging protocol depends on which tracer is used. With PET imaging the stress study is performed using pharmacologic stressors such as adenosine, dipyridamole, or dobutamine. The dynamic imaging protocols have been standardized.1,18 With PET tracers such as 82Rb and 15O-water studies (half-lives 76 seconds and 112 seconds) the stress study can be performed practically without delay after the rest study. With 13N-ammonia stress testing is delayed for about 30 minutes to allow tracer decay. If method to correct patient motion between stress and rest studies is not available, second low-dose attenuation is needed. In all studies quality control process is needed to ensure optimal alignment of the attenuation and PET emission scans and, if necessary, misalignment needs to be corrected.19,20
If the system is capable to list mode acquisition, the data can be collected as ECG gated mode that allows the simultaneous assessment of regional and global left ventricular wall motion from the same scan data. This is particularly practical when 82Rb is used as tracer. The total time required for whole study session depends on the tracer used. With 15O-water and 82Rb the whole session can be finished in 30 minutes and with 13N-ammonia in 80 minutes. The protocols can be further shortened significantly since in hybrid approaches only single stress perfusion imaging may be needed especially when using quantification21 and the protocols with all tracers can be as short as 15 minutes.
Interpretation of Absolute Myocardial Perfusion Results
When quantitative results are obtained, the criteria for interpretation must be redefined. As regard to perfusion reserve typically values above 2.5-2.7 have been regarded as normal.5
As regard to absolute perfusion in mL/g/minute, a little clinical evidence is available and it also appears that different traces may provide different cutoffs.15,21-23 In the study by Muzik et al5 using 13N-ammonia as tracer, the optimal cutoff value was found to be quite low (1.52 mL/g/minute) to separate ischemic from noninschemic regions. In our recent analysis using 15O-water the ideal cutoff for absolute stress perfusion was 2.5 mL/g/minute, the range from 2.0 to 2.5 being mildly reduced.23 Naturally the more severe is ischemia the lower is the stress perfusion and in clearly ischemic regions the stress perfusion is just above resting values (1.0-2.0 mL/g/minute).
With 82Rb very limited clinical data is available. In the study by Anagnostopoulos et al22 linearity with the perfusion or perfusion reserve versus coronary diameter stenosis was detected but the cutoffs for perfusion reserve and absolute stress perfusion values seem to be lower than the numbers reported for 13N-ammonia or 15O-water earlier. More studies are warranted.
It needs to be acknowledged that there is still limited clinical data about the optimal cut-off perfusion reserve or stress perfusion values to distinguish ischemic from nonischemic regions. Furthermore, display of quantified parametric perfusion images needs to be standardized. One option used in the clinical examples of this article is to display the images using fixed scale so that each color or gray zone represents specific absolute number in quantification. All examples shown in this article have been displayed in this way by choosing the maximum value as 3.5 mL/g/minute.
Clinical Scenarios Where Quantification is Beneficial
The incremental value of quantitative analysis for the clinical decision making has been sparsely studied. In those few studies it was found that the accuracy was further improved by quantitative analysis.5-7,21 Based on the currently available information there are several clinical scenarios where the quantification is likely changing the clinical interpretation.
This problem can be solved immediately by quantification since it provides independent information about all myocardial territories.5-7,21 Also determination of the response of left ventricular ejection fraction to stress from gated perfusion data will help.24
Balanced Multivessel CAD
Earlier this problem has been regarded as clinically uncommon but in recent preliminary analysis 5-10% of patients with suspected CAD will display balanced CAD pattern.21
The Exclusion of CAD in Symptomatic Patients
Although the normalcy rate of perfusion imaging has been reported to be quite high (around 90%) subtle irregularities are commonly classified as equivocal findings. In addition, in recent clinical studies the specificity of perfusion imaging has been quite low (50-70%) but sensitivity has remained high. Although, this phenomenon can be partly explained by referral bias, part of the explanation lays on the interpretation of subtle perfusion irregularities as suspicious findings.
It has been also documented that PET is more accurate than SPECT in traditionally difficult patient populations such as obese and diabetic subjects25 and this phenomenon may be linked with the more quantitative nature of PET imaging.
Patients with Microvascular Disease
Limitations of Perfusion Quantification
Although quantification of myocardial perfusion has obviously a great clinical potential there are several limitations that need to be recognized.
The knowledge of optimal cut-off values for absolute perfusion needs to be studied in larger populations and in various tracers. Furthermore, the quantification process using each tracer and the interpretation needs to be standardized. More information is needed about different subpopulations such as diabetic and obese patients, patients with heart failure, and revascularized patients.
Even with optimized techniques it remains the fact that perfusion imaging does not provide morphological information. The perfusion imaging only provides information about existence and severity of perfusion abnormalities but not about the mechanism, e.g. the patients with diffuse balanced coronary heart disease and those with microvascular dysfunction leading to globally compromised perfusion cannot be separated by perfusion imaging. Therefore, the combined or hybrid imaging with CT angiography is believed to provide incremental information in patients with suspected CAD.26
Myocardial perfusion imaging provides a simple and accurate integrated measure of the effect of all parameters on coronary resistance and tissue perfusion, but at the same time it cannot dissect the effect of specific coronary plaque in the case of serial changes or when combined with microvascular disease (Figure 7).
A special group of patients where perfusion is difficult to interpret are patients with heart failure. In heart failure absolute perfusion and perfusion are commonly reduced and also heterogeneous. This makes the interpretation without anatomical information very challenging.27
Summary and Future Developments
Quantification of myocardial perfusion will likely become standard technique also in clinical studies while more information and clinical evidence becomes available. Even the current limited experience demonstrates potential benefits in several patient groups.
To become standard technique the access to tracers that enable accurate quantification needs to be improved. Whether quantification of 82Rb kinetics will be accurate enough for clinical use remains to be seen. New 18Fluoride-labeled tracers with high extraction fraction are very promising.
The concept of hybrid imaging to deliver comprehensive integrated morphological and functional information is particularly appealing.26 In addition to being intuitively convincing, these images provide a panoramic view of the myocardium, the regional myocardial perfusion, or viability and the coronary artery tree, thus eliminating uncertainties in the relationship of perfusion defects, scar regions, and diseased coronary arteries.
More studies assessing the prognostic value and cost-effectiveness are warranted. The current bottleneck which slows the increase of cardiac PET/CT is the limited access to tracers. The clinical value of quantification is under research and in the near future more solid information will become available. The cost-effectiveness of this technique also needs to be studied although additional costs over the standard PET imaging are minimal.