Review Article
Quantification of myocardial blood flow and flow reserve: Technical aspects

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Introduction

Myocardial perfusion imaging (MPI) is a powerful tool for detection of impaired myocardial blood supply due to atherosclerotic lesions in the epicardial arteries. MPI is commonly conducted using single photon emission computed tomography (SPECT) with 201Tl- or 99mTc-based tracers, under conditions of rest and hyperemic stress. Regions of high tracer uptake are assumed to be normally perfused, while regions with relatively low uptake (perfusion defects) typically reflect stenosis of the upstream arteries. Regions of reversible myocardial ischemia are identified as stress perfusion defects that normalize at rest.

In recent years, positron emission tomography (PET) has been utilized increasingly for MPI due to its superior image quality. PET images can be corrected accurately for attenuation losses and may have higher diagnostic accuracy than SPECT.1, 2, 3 Attenuation effects are particularly important in overweight patients, women with large or dense breast tissue and men with high abdominal fat. Thus, PET MPI is generally accepted to have improved specificity (fewer false-positives) compared to SPECT MPI, and fewer inconclusive exams, especially in obese patients and in women.4 Furthermore PET images provide quantitative measurements of activity concentration, and dynamic imaging can be used to quantify myocardial blood flow (MBF) in absolute terms of mL/minute/g.5,6 This provides an added quantitative dimension to routine MPI, and is sensitive to disease in both the epicardial conduit vessels as well as the resistance vessels of the microvasculature.7 MBF quantification has been shown to be beneficial in detecting multivessel disease that can cause a global reduction in flow, producing false-negative results with standard relative MPI.8, 9, 10, 11, 12 In addition, MBF has been shown to detect subclinical or presymptomatic disease in the microvasculature13, 14, 15 in diabetes, hypertension, hyperlipidemia, and obesity.16, 17, 18

Routine perfusion imaging uses radio-labeled tracers that are extracted from the blood and retained by the myocardium, ideally in proportion to blood flow. The net tracer concentration (uptake) in the tissue is therefore related to the rate of blood supply. As opposed to MPI which uses static images of the relative tracer distribution following blood clearance, MBF quantification uses dynamic sequences of images measured during the entire tracer uptake and clearance phases. Time-activity-curves (TAC) are measured in arterial blood and in regions of myocardial tissue. A tracer kinetic model is used to describe the exchange of tracer between arterial blood and myocardium during the course of the scan. In particular, the rate of tracer uptake (transport) from blood to tissue is closely related to MBF, depending only on the tracer extraction fraction.

This article describes the technical considerations associated with MBF quantification with PET, mainly using the MPI tracers 82Rb and 13N-ammonia, and quality assurance methods needed to ensure clinical measurements of high quality.

Section snippets

Perfusion Tracers

The properties of clinically applicable perfusion tracers are shown in Table 1. 15O-water is considered to be the most accurate PET flow tracer. Because it is freely diffusible across capillary and cell membranes, extraction is near unity and independent of flow. However, it is not used widely in the clinical routine due to the need for a dedicated cyclotron for continuous production, and the rapid equilibration between blood and tissue prevents acquisition of a myocardial perfusion image for

Imaging Protocols

As shown in Figure 2,36 a complete MPI exam consists of two scans: one at physiologic rest followed by one at hyperemic stress. Quantification of MBF requires dynamic PET imaging from the start of tracer injection for at least 2 minutes. The short half-life of 82Rb enables repeat imaging of the same patient after only 6 minutes, since the background activity from the previous scan is decayed to below 5%. Longer-lived tracers may require additional time for tracer decay between rest and stress

PET Instrumentation

Several recent advances in PET instrumentation are well suited for high-throughput MBF imaging.

Repeatable Tracer Infusion

The infused activity should be adjusted for patient size to compensate for tracer distribution volume in the body and increased attenuation. This ensures sufficient tracer activity in the myocardium during the uptake phase for high-quality MPI. However, for dynamic image acquisition in 3D-mode, the activity must be limited to avoid saturation of the detectors and/or electronics during the first-pass transit through the heart, when the tracer has not had time to decay or to be distributed

Image Analysis

Cardiac images are commonly reoriented to the left ventricle (LV) myocardium reference frame for reporting. Images are viewed as short axis slices (SA), vertical long axis (VLA), and horizontal long axis (HLA). The LV myocardium is segmented and the mid-myocardial activity represented in a polar-map format as demonstrated in Figure 6. Likewise, a blood region of interest (ROI) is defined in the center of the left ventricular and/or atrial cavity. The myocardium and blood ROIs can be sampled in

Myocardial Blood Flow Quantification

The dynamic exchange of activity between arterial blood and myocardial tissue can be described using the general compartmental model illustrated in Figure 7, where Ca(t) and Ct(t) are the activity concentrations (Bq/cc) as a function of time in the arterial blood and myocardial tissue, respectively. The uptake rate K1 (mL/minute/g) describes the transfer of tracer from blood to tissue, while k2 (min−1) is the washout rate in the opposite direction. While the myocardial tissue may be modeled

Partial Volume Effects

The limited resolution of PET as well as cardiac motion results in partial volume averaging that reduce the accuracy of MBF quantification. Partial volume effects reduce the measured activity concentration in the myocardial wall as the resolution decreases, wall thickness decreases, and/or wall motion increases. The apical myocardium, which is thinnest and moves the most, can suffer more severe PV loss and therefore usually has a smaller recovery coefficient (RC) as illustrated in Figure 11.

Attenuation Image Misalignment

Misalignment of PET and attenuation images has been shown to introduce artifacts,57 particularly at the interface of the myocardium and lung regions (antero-lateral wall), which will also be translated directly into the quantitative MBF measurements. These artifacts can be resolved through careful AC quality assurance (ACQC) to confirm or correct alignment prior to image reconstruction. CT-based attenuation images are more susceptible to misalignment since they can be acquired very quickly and

Summary of Requirements

  • Tracer with uptake and retention directly proportional to flow.

    • Low radiation dose, high resolution, and high throughput.

  • PET scanner with wide dynamic range.

    • Single injection for MPI (late) and MBF (early) imaging.

    • Combined ECG-gated and dynamic scans with list-mode.

  • Validated tracer kinetic model.

    • Regional correction for partial volume effects (PVE).

    • Tracer extraction/retention function.

  • Reproducible dynamic image analysis.

    • Low operator variability (automated processing).

    • Quality assurance (CTAC and

Conclusion

82Rb PET imaging enables PET centers without access to a cyclotron to perform high-quality ECG-gated MPI and dynamic MBF exams. Since the tracer cost-per-scan decreases with increasing patient volume, the 82Sr/82Rb generator cost is best recovered using a dedicated cardiac PET imaging service. The development of accurate 3D cardiac PET scanners with list-mode capabilities and optimized 82Rb elution systems has made routine MPI and MBF quantification feasible in the clinical setting with reduced

Acknowledgments

This work was supported by CIHR grants MOP-79311 and MIS-100935, and Ontario Research Fund Grant RE-02-038. We would like to thank Astellas Pharma US, Inc., Covidien, and GE Healthcare for corporate support to publish and distribute this article. Corporate supporters were not involved in the creation or review of information contained in this article. RK, RB, and RdK receive consulting fees and royalties from DraxImage for the sale of Rb generators. RK and RdK receive profit shares from the

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