Quantifying Myocardial Blood Flow: An Expanding Role for PET?

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 - PET-Myocardial Bloodflow
Transverse, coronal and sagittal slices and short-, long-vertical-and horizontal-axis images of Rb-18
Source: J Nucl Med 2009; 50:1062–1071
The possibility of quantifying myocardial blood flow (MBF) with PET imaging has existed for decades, but its clinical use has been limited. MBF is assessed more often in relative terms, with visible differences in flow between regions of myocardium, used as an indicator of problems. Now, new developments in tracers could make cardiac PET the more precise approach for absolute quantification.

Current methods of visually assessing MBF with SPECT have several limitations and can lead to an underestimation of the magnitude of a patient's coronary artery disease (CAD). There is low spatial resolution and high levels of soft tissue attenuation hindering image quality, and SPECT also is unable to quantify MBF in absolute terms. Relative assessment of MBF has certain weaknesses, according to Vasken Dilsizian, MD, chief of the division of nuclear medicine at the University of Maryland Medical Center in Baltimore.

Relative assessment involves visually evaluating the homogeneity of radiotracer distribution across the three coronary vascular territories. If the pattern of uptake is different between a normal reference region and the other territories, it could be an indication of CAD. The problem, Dilsizian says, is blood flow in the reference region also could be abnormally decreased, causing the physician to underestimate the reduction of blood flow in the other regions.

"When reading these images, we are always comparing it to a normal reference region, where in some patients, there is no normal reference region. Everything is abnormal," says Dilsizian.

What's more, if all regions are similarly occluded, the physician could misinterpret the exam as normal.

PET, with its higher image quality and robust attenuation algorithm, can measure MBF in absolute terms, thus avoiding the problems of relative assessment. Kajander et al studied the benefit of absolute quantification using PET over relative assessment using conventional angiography. They found that absolute quantification had a positive predictive value, negative predictive value and accuracy of detecting obstructive CAD of 86 percent, 97 percent and 92 percent, respectively (Circ Cardiovasc Imaging 2011;6:678-684). This is compared with values of 61 percent, 83 percent and 73 percent, respectively, for relative assessment.

However, the application of absolute MBF quantification by PET has been limited clinically. Part of this is due to limitations of PET tracers, as well as the restricted availability of PET cameras for cardiac studies conducted in academic centers.

Searching for the perfect tracer

Absolute blood flow measurements have been conducted with Rb-82, N-13 ammonia and O-15 water tracers, though each has its own set of drawbacks:
  • O-15 water: Typically, this tracer is used only in research as it is not FDA approved and not reimbursed by the Centers for Medicare & Medicaid Services (CMS), according to Dilsizian. It requires an onsite cyclotron, a cost most facilities would like to avoid, and with a two-minute half-life, unit dose orders are impractical. Also, the myocardium cannot be visualized with O-15 water.
  • N-13 ammonia: This tracer is both FDA approved and reimbursed by CMS. Like O-15 water, though, N-13 ammonia is cyclotron produced with a half-life of 10 minutes, which restricts its use to clinics equipped with cyclotrons, according to Georges El Fakhri, PhD, of the department of radiology at Massachusetts General Hospital in Boston.
  • Rb-82: Rubidium tracers have only a 72 second half-life, but are produced by a column generator, not a cyclotron. El Fakhri says while there are high costs for a generator— approximately $30,000 for a month's use—it is still a more accessible piece of equipment than a cyclotron.

While the current crop of tracers is held back by costly equipment, a new F-18-based flow agent could shake up the nuclear cardiology space, says El Fakhri. F-18 labeled flow agents, such as flurpiridaz, have a half-life of 110 minutes, which means a dose order could be manufactured and shipped rather than having to be produced onsite. While still undergoing clinical trials, preliminary results are spreading optimism about its potential future clinical use.

The results have demonstrated that the extraction fraction of F-18 perfusion "is much better than that of ammonia," and if F-18 flow agents get FDA clearance, El Fakhri predicts it "could have a major impact on cardiac PET imaging."

Studies, such as one by Sherif et al, have shown the usefulness of F-18 flurpiridaz in quantifying blood flow, and demonstrated favorable results when compared with other PET and SPECT agents. High extraction of a tracer improves reliability of flow quantification and F-18 flurpiridaz was shown to have an extraction fraction of 0.94. This is compared with extraction fractions of 0.38 for 99mTc-sestamibi, a SPECT tracer, and 0.42 for Rb-82 (J Nucl Med 2011;52:617-624).

SPECT marches on

While a new radiotracer to quantify blood flow could help PET make inroads in cardiac use, advancements in SPECT—such as CZT crystal high-speed SPECT, semiconductor detectors and multi-pinhole SPECT with circular orbit—could eventually allow SPECT to perform absolute quantification, says El Fakhri.

Ritt et al outlined these advancements toward absolute quantification in SPECT (Eur J Nucl Med Mol Imaging 2011;38Suppl 1:S69-S77) and other researchers have demonstrated the feasibility of absolute quantification of regional MBF using SPECT in animal test subjects (Eur J Nucl Med Mol Imaging 2008;35:896-905).

Advancements in SPECT might help, but the modality will still be held back by its imaging agents, predicts Gary D. Hutchins, PhD, of the department of radiology at the Indiana University School of Medicine in Indianapolis.

"The agents that are used currently still have some limitations in terms of their pharmacokinetic properties as blood flow tracers, so a better scanner is not going to help you overcome those limitations," says Hutchins. Current SPECT agents aren't valid across the same range of blood flow values and the detection specificity between SPECT and PET is a factor of 100, he says.

Hutchins believes that regulatory agencies ultimately will drive the future of MBF quantification. PET is used very heavily in oncology, where it is FDA approved and nets CMS reimbursement, and even if the number of PET scanners expands, adoption will come only with regulatory approval.

The success of PET in oncology could facilitate its use in cardiology, says Dilsizian. The superior resolution of PET allows it to detect tumors mere millimeters in size, and most PET labs across the U.S. have been dedicated to oncology, with cardiac PET competing for utilization. As the number of PET scanners increases for use in cancer studies, however, there may be more opportunities for cardiac PET procedures.

"What is happening currently, given that PET represents a quantum leap advancement over SPECT, just like the SPECT era represented a quantum leap advancement over planar technology of the 1970s, there is no doubt that PET will steadily and slowly replace SPECT systems in the coming years because of its technological advancement and extremely high quality images," says Dilsizian.

As the different technologies evolve—tracer development, the growth of cardiac PET, improvements to SPECT—the role of quantifying MBF remains unclear, though with further study and regulatory approval, the full clinical potential of quantification may be realized in the not too distant future.