Positron emission tomography i. cardiology

Positron emission tomography (PET) is undergoing evaluation as a new diagnostic technique with the potential to provide unique information about cardiac metabolism and blood flow. PET can be used to measure myocardial blood flow, study glucose metabolism in areas of jeopardised ischaemic myocardium and measure oxidative metabolism of the heart. The principal clinical application of PET is in the detection of ischaemic, but viable, myocardium which may benefit from revascularisation. The possible future applications of PET include study of autonomic innervation of the heart in patients with heart failure or after cardiac transplantation. Since late 1992, two PET centres in Australia have become operational at the Royal Prince Alfred Hospital, Sydney and at the Austin Hospital, Melbourne.

The radionuclide tracers used in positron emission tomography (PET) are usually produced in a cyclotron. These tracers have short half lives (1.3-110 minutes) and decay by emission of a positron (positively charged electron). When this positron collides with an electron, annihilation occurs and two photons are emitted, travelling in opposite directions. These two photons can be detected by a PET camera which accurately localises the site of annihilation within the heart. A unique characteristic of PET radiotracers is that principal positron emitters, including ¹³N, ¹⁵O and ¹¹C, are isotopes of important biological atoms, allowing labelling and study of normal biochemical processes in the heart. The short physical half lives of PET tracers facilitate sequential studies of myocardial perfusion and metabolism on the same day.

The principal current applications of PET in cardiology are the measurement of regional myocardial blood flow and the investigation of the viability of ischaemic myocardium.

Table 1

Until the advent of PET, there was no reliable noninvasive method for the measurement of absolute myocardial blood flow. Techniques such as thallium scanning provide only a relative index of regional blood flow. Routine diagnosis of coronary artery disease does not require quantification of absolute myocardial blood flow, but in some cases, measurement of coronary flow reserve is indicated. These indications include:

• assessment of interventions such as balloon angioplasty or atherectomy
• evaluation of the functional consequences of progression of atherosclerosis
• documentation of flow reserve in patients with diffuse coronary disease or after cardiac transplantation.

Several PET tracers are available for measuring blood flow, including ¹³Nammonia, ¹⁵Owater and ⁸²Rubidium (Table 1). They are extracted by the myocardium in nonlinear proportion to blood flow. Application of appropriate tracer kinetic models permits calculation of absolute myocardial blood flow (mL/min/g) from PET using ¹³Nammonia or ¹⁵Owater. Coronary flow reserve can then be measured by comparing myocardial blood flow during resting conditions and during maximal vasodilatation with dipyridamole or adenosine.

Fig. 1 Example of a 'matched' perfusion and metabolism defect in a patient with completed infarction of the anterior free wall and septum of the left ventricle. The short axis images show concordant reduction in 13N blood flow and FDG metabolism in the anterior wall (visible at top of each image).	Fig. 2 Example of a 'mismatched' perfusion defect in the inter ventricular septum in a patient with ischaemic, but viable, myocardium. There is a perfusion defect on the 13N image, but retained FDG metabolism in the septum. A small area of infarction, with absent perfusion and metabolism, is evident in the posterolateral wall of the left ventricle. Image orientation is as for Fig. 1.

However, PET is not indicated for the routine diagnosis of coronary artery disease, for which exercise testing and/or thallium scanning remain the appropriate avenues of investigation.

The major current application of PET is the detection of ischaemic but viable myocardium which may benefit from revascularisation. Ischaemic myocardium may exhibit persistent contractile dysfunction, but remain viable for prolonged periods (myocardial hibernation). Measurements of regional contractile function (e.g. gated heart pool scan) cannot distinguish dysfunctional viable myocardium from necrotic or scarred myocardium. Similarly, measurements of blood flow alone may not distinguish severely ischaemic, viable myocardium from scar tissue. The key is definition of retained myocardial metabolic activity in an ischaemic region. Most importantly, restoration of blood flow to dysfunctional, hibernating myocardium is associated with restoration of contractile function.

A number of PET tracers of myocardial metabolism are available to study glucose, fatty acid and oxidative metabolism (Table 1). The tracer usually used to study myocardial viability is 18Fdeoxyglucose (FDG), as ischaemic myocardium preferentially metabolises glucose instead of free fatty acids. The FDG tracer is taken up and phosphorylated by hexokinase in the myocyte in the same manner as glucose. However, the phosphorylated FDG is not a substrate for further glycolytic metabolism and the tracer is therefore trapped within the myocyte as a marker of viability. Necrotic myocytes are unable to phosphorylate and therefore do not accumulate the FDG tracer.

Studies of myocardial viability require paired PET scans of regional myocardial blood flow and glucose uptake. Comparison of these paired scans reveals 3 main patterns of tracer uptake (Table 2). In normal myocardium, there is a match of perfusion and glucose uptake, while in necrotic myocardium, reduced perfusion is matched by absent glucose uptake (Fig. 1). However, ischaemic but viable myocardium exhibits a mismatch with reduced or absent perfusion, but retained glucose uptake and phosphorylation (Fig. 2). The extent of matched and mismatched regions of perfusion and metabolism allow the clinician to determine the possible benefit of revascularisation to the patient.

Current evidence indicates that many patients with heart failure and coronary artery disease have significant areas of viable myocardium that may benefit from revascularisation. These viable areas may not be detected by thallium scanning. Therefore, PET is indicated for detection of myocardial viability in patients with coronary artery disease and impaired left ventricular function, where evidence of retained myocardial viability would influence clinical management of the patient.

The future

A number of new cardiac applications of PET are currently under investigation, including study of myocardial oxidative metabolism in ischaemic heart disease and cardiomyopathy, and study of cardiac autonomic innervation in patients with heart failure and after transplantation.

At first, PET investigations of myocardial oxidative metabolism used tracers of fatty acid metabolism, such as ¹¹Cpalmitate. However, the associated processes of fatty acid transport, betaoxidation and interchange with the intracellular triglyceride pool confounded these investigations. More recently, ¹¹Cacetate has been used as a tracer of oxidative metabolism, as acetate is a direct substrate for the tricarboxylic acid cycle. Application of dynamic scanning and kinetic modelling allows characterisation of myocardial oxidative metabolism under different workloads. At present, such studies are not in routine clinical use, although there is increasing evidence that ¹¹Cacetate may provide useful information in assessing the myocardial response to revascularisation, as well as evaluating the metabolic efficiency of the heart in patients with dilated cardiomyopathy or valvular heart disease.

Autonomic innervation of the heart

The study of myocardial autonomic activity is presently an area of vigorous investigation, using tracers such as ¹¹Chydroxyephedrine and ¹⁸Fdopa. Characterisation of myocardial autonomic activity may yield important prognostic information in patients with dilated cardiomyopathy, who are at increased risk of sudden death.

Conclusion

PET can provide unique diagnostic information, but it is a sophisticated and costly technology which requires considerable supporting infrastructure. As new tracers of cardiac metabolism and autonomic function are developed, it is likely that the diagnostic utility of PET will expand. An important role for PET will also be the validation of new, less costly, tracers for single photon emission computed tomography (SPECT) (see 'Thallium scanning' Aust Prescr 1994;17:57-61). Clinical and research PET studies are being carried out at the Austin Hospital, Melbourne and the Royal Prince Alfred Hospital, Sydney. Currently, the accepted clinical indications for PET scanning are documentation of myocardial viability and measurement of coronary flow reserve, according to specific protocols.

Further reading

Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps M, et al. Reversibility of cardiac wall motion abnormalities predicted by positron tomography. N Engl J Med 1986;314:884-8.

Bergmann SR, Herrero P, Markham J, Weinheimer CJ, Walsh MN. Noninvasive quantitation of myocardial blood flow in human subjects with oxygen15labelled water and positron emission tomography. J Am Coll Cardiol 1989;14:639-52.

Nienaber CA, Brunken RC, Sherman CT, Yeatman LA, Gambhir SS, Krivokapich J, et al. Metabolic and functional recovery of ischaemic human myocardium after coronary angioplasty [see comments]. J Am Coll Cardiol 1991;18:966-78. Comment in: J Am Coll Cardiol 1991;18:979-81.

Rahimtoola SH. The hibernating myocardium [see comments]. Am Heart J 1989;117:211-21. Comment in: Am Heart J 1989;118:1361.