Principles of myocardial blood flow quantification with SPECT and PET imaging

Introduction

Absolute myocardial blood flow (MBF) assessments for nuclear cardiology add unique information that is difficult, if not impossible, to acquire using other modalities. Specifically, the assessment of absolute MBF with cardiac positron emission tomography (PET) improves the determination of normalcy, ^, detection of multivessel disease, and assessment of patient prognosis. An absolute MBF assessment has recently been demonstrated in a large study of 12,594 patients to be effective in assessing which patients may benefit from revascularization. An MBF assessment using single photon emission computed tomography (SPECT) has also demonstrated potential for absolute MBF assessment. Nevertheless, these benefits can only be obtained if the quantitative values are accurate.

The assessment of MBF uses measurements of the concentration of radiotracer in the blood as a function of time and the uptake of that tracer and also uses a model that describes the kinetics of the tracer. This measurement uses a set of dynamic tomographic images beginning at the time of tracer infusion and following the transport of the tracer into the myocytes. Because of the rapidly changing tracer concentration during the initial infusion, these dynamic tomographic images must be acquired in short intervals. In addition, these dynamic images must be quantitatively accurate. This can be challenging owing to differences in scanner sensitivity and the wide range of count rates that may be present at the beginning, middle, and end of the acquisition. For many PET blood flow protocols, the count rate can be 10 times higher during the initial bolus of activity than the count rate during the perfusion scan. Also, in the case of ⁸² Rubidium ( ⁸² Rb), the activity will decay to near background levels during the course of the study. This complex, kinematically dynamic and quantitative study must be accomplished without adding to the radiation dose or compromising the quality of the clinical myocardial perfusion study. ^,

The choice of the radiotracer used to measure blood flow, in principle, should not have an impact on coronary blood flow; thus, blood flow measurements should be independent of the radiotracer used. In practice, the radiotracer’s first-pass extraction fraction plays a vital role in determining the accuracy and precision of blood flow measurements. Therefore, protocols and models for measuring MBF are specific to the radiotracer used. Radiotracers with higher first-pass extraction fractions tend to create a greater contrast between normal and abnormal regions. Quality control and data processing steps depend heavily on the choice of radiotracer.

MBF assessment with SPECT is even more challenging than with PET. Conventional Anger SPECT systems cannot acquire the rapid dynamic studies necessary for quantitation of the arterial input function. There have been some studies that have attempted to use a fast rotation scanning protocol to acquire the dynamic data sets ^, ; however, most conventional SPECT camera gantries are unable to scan at the necessary rotation rates. An alternate approach is to use either a set of small cadmium-zinc-telluride (CZT) scanners capable of a fast sweeping acquisition ^, or a multipinhole dynamic acquisition that does not require rotation.

Ultimately, the assessment of MBF greatly increases the diagnostic information available to the cardiologist. As discussed throughout this textbook in patient-centered applications of radionuclide imaging, this new information complements the visual assessment of the study; however, the utility of an absolute blood flow assessment requires an understanding of the entire acquisition, processing, and quality control procedures to ensure that the measurements are accurate and reliable.

Myocardial blood flow measurements with PET and SPECT

PET tracers for measuring myocardial blood flow

In principle, with an accurate model of a PET tracer’s extraction and retention properties and a high-quality dynamic acquisition, all PET tracers would produce equivalent results. Nevertheless, variations in each tracer uptake and retention introduces both systematic and random errors into the measurement of MBF.

One of the most important considerations for the accuracy of absolute blood flow determination is the linearity of tracer extraction relative to MBF. The better the extraction of the tracer at high flow rates, the more sensitive the tracer is at detecting small changes in absolute blood flow. Fig. 3.1 illustrates the relationship between the extraction rate ( K ₁ ) and MBF for several SPECT and PET tracers.

¹⁵ O-water

The gold standard for the estimation of MBF is oxygen-15-labeled water ( ¹⁵ O-water). This tracer has particularly favorable characteristics by freely diffusing across the cell boundary. This property gives ¹⁵ O-water a linear 1-1 relationship between K ₁ and blood flow. A major challenge with ¹⁵ O-water is the very short half-life of ¹⁵ O-water (122 seconds). This makes delivery of the radiotracer very difficult. In addition, ¹⁵ O-water is not retained in the cell and is best imaged parametrically, making traditional assessment of wall-motion thickening and visual interpretation challenging, if not impossible.

⁸² Rubidium

⁸² Rb is the most commonly used PET perfusion agent in the world. It is most commonly delivered using an infusion system as rubidium chloride solution. As a potassium analog, rubidium is absorbed into myocytes via the sodium potassium pump. Once inside the cell, rubidium is not bound and will slowly wash out (k ₂ < 0.14/minutes at rest). ⁸² Rb properties are similar to ²⁰¹ thallium.

Because of the efficient uptake and slow wash-out rate, ⁸² Rb can be modeled well with a net retention, single-tissue compartment model (1TCM) or a two-tissue compartment model (2TCM). For the net retention model, a short (<3 minutes) dynamic acquisition is necessary to avoid errors from tracer washout. For longer acquisitions, either the 1TCM or 2TCM is recommended. ^,

¹³ N-ammonia

¹³ N-ammonia is a cyclotron-produced tracer with a 9.93-minute half-life. This radiotracer has excellent first-pass extraction and a relatively long half-life and produces high-quality perfusion and functional images. Quantitative measurements of MBF are complicated by the fact that ¹³ N-ammonia is only partially retained in the cell. Upon first extraction from the blood pool, a portion of the ammonia is converted to glutamine and retained in the cell. A smaller fraction is then converted into a ¹³ N metabolite and washes out into the blood pool. This metabolite cannot be re-extracted from the blood pool and can artifactually increase the estimate of the arterial input function. For an accurate measurement of MBF with ammonia, a 2TCM that includes corrections for the metabolite must be used. ^,

¹⁸ F flurpiridaz

A new ¹⁸ F-labeled tracer, ¹⁸ F flurpiridaz, is currently under Phase III investigation as a myocardial perfusion agent. Preliminary studies of this agent demonstrate a high signal to background, high extraction fraction, and excellent resolution properties. ^, In addition, this agent has the advantage of unit dose delivery, thereby opening opportunities for cardiac PET without the challenge of owning a generator or cyclotron. More recently, quantitative blood flow modeling has indicated that ¹⁸ F flurpiridaz has superior flow characteristics than ⁸² Rb comparable flow characteristics to ¹³ N-ammonia with a high extraction fraction (0.94) that is constant up to flows of 5.06 mL/g/minute.