Cardiovascular nuclear medicine examinations

22. Nuclear Cardiology

Author: Oszkár Pártos

 

Aim of the chapter:

This chapter aims to describe the cardiac imaging modalities used in nuclear medicine. It provides an overview of the administered radiopharmaceuticals, examination methods, their indications and diagnostic value particularly in respect of ischemic heart disease.

22.1 Examinations

The methods used in nuclear cardiology give us a chance to image some of the functional characteristics of the heart and central circulation (including myocardial tissue perfusion, pump function, the metabolic processes of the heart and molecular level imaging of the distribution of myocardial receptors). In the diagnostics of ischemic heart disease (IHD), nuclear cardiologic methods are cutting edge techniques of cardiac clinical practice used to evaluate the severity of the disease, estimate risks, determine therapeutic principles, and to follow up patients.

1. Basic cardiologic examinations (routine clinical exams)
   1. Myocardial perfusion studies
   2. Myocardial viability assessment
   3. Central circulation examination
   4. Hybrid imaging (SPECT/CT, PET/CT)
2. Further examination possibilities
   1. Metabolic tests: glucose, lipid, amino acid, oxidative metabolism
   2. Receptor examinations: adrenergic, cholinergic, muscarinic, angiotensin, endothelin, opiate etc.
   3. Apoptosis, molecular level imaging

22.1.1 Myocardial perfusion studies (SPECT / Gated SPECT, in special cases PET)

This is one of the most commonly performed routine examinations in clinical nuclear medicine for suspected or known cases of IHD. The method is based on the imaging of perfusion radiotracers as they are taken up by the normal myocytes. The rate of accumulation is determined by regional perfusion and tissue extraction. Hence, it shows a homogenous distribution in normal circumstances. In stress tests the work and oxygen consumption of the myocardium elevates. The correspondingly increased tissue perfusion is ensured by the dilatation of the coronary arteriolar system – called the coronary reserve capacity. If tissue perfusion needs are unmatched with the perfusion increase perfusion disturbances /ischemia occur. This is the first stage of the ischemic cascade (stages include: regional perfusion disturbances, metabolic disorders, diastolic dysfunction followed by systolic dysfunction, ECG abnormalities, typical angina pectoris). The most common etiologic factor is IHD related stenosis in the epicardial coronary system. In order to assess perfusion abnormalities, the radiotracer is injected at the peak of the stress test and its result is compared to the resting state. The examination gives valuable information about the perfusion defects of the left ventricle, their extension, ratio, distribution and type, which in turn will be relevant for prognostics and therapeutic planning. If the required level of physical exercise is unachievable, corresponding coronary vasodilation can be induced pharmacologically (intravenous direct acting vasodilators: Dipyridamol, Adenosine or Regadenoson, in case of bronchial asthma, beta agonist Dobutamine stress can be used).

Perfusion radiotracers:

Gamma ray emitters (SPECT imaging – clinical routine)

²⁰¹Thallium : ²⁰¹Tl ( K analogue ion )

It is actively transported into the cell by Na/K ATP-ase enzyme. When injected at the peak of the stress test, it reflects tissue perfusion rates under stress in the first 20 minutes. This is followed by a redistribution between the myocytes and the blood pool. TI is washed out of the tissues. There is less uptake in regions with decreased perfusion or ischemia (perfusion defect). Since in these regions wash-out is also decreased, this leads to a gradual equalization, and the level of activity becomes consistent with normal regions. From a clinical diagnostic viewpoint, redistribution in the ischemic region may be considered complete 3-4 hours following injection (reversible perfusion defect). In case of necrosis no equilibrium is seen (fix defect).

^99mTc – labeled : sestaMIBI (Methoxyisobutyl Isonitrile) and Tetrofosmin

It accumulates in the mitochondria, for which intact myocardial metabolism is required. After injection, its distribution reflects the current state of perfusion permanently, there is no significant redistribution. For the stress test and for resting state examination, two separate doses of radiopharmaceutical are needed. It is suitable for the use of ECG gated SPECT examination (see further). It is used according to diagnostic protocols, its diagnostic and prognostic value is equal to the examination carried out with 201Thallium. The different properties of each gamma-emitting perfusion radiotracer are diagnostically exploitable.

Positron emitters (PET) imaging

¹³N Ammonium, ¹⁵O Water, ⁸²Rb (Rubidium: K analogue ion)
Their significance lies in the quantitative characterization of perfusion: ml/gram of tissue/minute. Their use allows for the measurement of coronary reserve capacity regionally, as well as the detection of early perfusion abnormalities, endothelial dysfunction or a certain drug effect. They provide extra information in case of “balanced multi-vessel coronary artery disease”. The increasing number of PET imaging systems allows cardiac PET exams to become widespread. The short half-life of perfusion radiotracers impedes their more extensive use (on-site cyclotron is needed). Due to the limited accessibility and higher cost of PET exams, when SPECT provides equally relevant clinical information, the latter should be chosen in routine diagnostics.

Imaging modalities: SPECT, PET, hybrid machines: SPECT/CT, PET /CT

Development directions: specially optimized and built SPECT machines for cardiologic examinations. SPECT scanners are available with traditional detectors, but recently semiconductor detectors are also used. Their recently developed hybrid systems are with a joined CT machine. The role and significance of hybrid imaging are further mentioned.

Imaging and analyzing methods

Both SPECT and PET measure the spatial (3D) distribution of the isotope. If the left ventricle is being investigated, the heart can be depicted in its “own geometry” short-axis, vertical and horizontal cross-sections. Identical imaging planes are comparable with each other. Short-axis slices of the heart of an actual patient can be represented in a polar coordinate system as a sum image and it is possible to compare that to a normal reference database (expert systems) (Fig. 2.) The severity of ischemia either according to a score system or according to the percentage ratio of the ischemic myocardial mass of the left ventricle can be evaluated and used to determine the diagnosis and the prognosis of the disease. Then further therapeutic options can be decided according to the gained results. (Fig. 1.)

Combined myocardium perfusion + function assessment: ECG gated SPECT and PET

^99mTc labeled radiotracers can be used in ECG gated SPECT examinations. The ECG gated data acquisition makes the differentiation of the phases of the cardiac cycle possible. In this procedure global and regional left ventricle ejection fraction (EF), end-systolic-, end-diastolic volumes, ventricular wall motion and wall thickening can be determined. (Fig. 4.) Ventricular functional parameters provide independent prognostic information about IHD. By co-evaluating perfusion and functional parameters, all components of the ischemic process (transient ischemia, myocardial stunning, hibernation, necrosis) may be determined. Further differentiation is possible based on regional glucose metabolism and the effect of positive inotropic stimulation. (See table below.)

	transient ischemia	stunned	hibernated	necrosis
perfusion	normalizes after ischemia	normalizes after ischemia	decreased	decreased
function	decreased during ischemia	remains decreased after ischemia (hours-days)	decreased (improvement is only seen weeks-months after revascularization)	decreased, no improvement
glucose(18FDG) uptake	normal	preserved	preserved ("mismatch")	decreased
inotropic reserve	present	present	present	none

 

22.1.2 Myocardial viability assessment

In case of decreased left ventricular function (left ventricle EF <35 % - most commonly after myocardial infarct) the high risk of IHD can be lowered if there is a possibility for the revascularization of a considerable volume of hibernated myocardium while eliminating residual ischemia. Hibernated myocardium can be identified by PET through parallel imaging of perfusion and glucose metabolism (decreased perfusion + sustained glucose metabolism), by SPECT through the use of both types of perfusion radiotracers. The principle of imaging is that perfusion radiotracers only accumulate in living myocytes. In routine diagnostics SPECT method is recommended. In uncertain cases, PET is the gold standard taking into account other cardiac imaging modalities as well (Echocardiography, MRI).

22.1.3 Central circulation examinations - Radionuclide angiography ( RNA )

First-pass examination: FP-RNA

is carried out with planar imaging. The activity of iv. injected bolus of gamma emitting ^99mTc is measured as it travels with the central circulation (central veins-right atrium-right ventricle-pulmonary flow-left atrium- left ventricle –aorta). Time-activity curves can be created to determine cardiac output and stroke volume indices and transit times. Global and regional right and left ventricular functions and volumetric assessment can all be made in resting state or in a stress examination (physical exercise or pharmacologic stress).

ECG gated blood-pool scintigraphy

PLANAR: ECG gated RNA – ERNA

SPECT: ECG gated blood-pool SPECT or G-SPECT - ( 3D ERNA )

After adequate preparation, the iv. injected gamma emitting 99mTc remains in the bloodstream (e.g. red blood cell labeling), with which cardiac chambers and the main vessels (aorta, pulmonary arteries) can all be depicted.
Planar imaging is used for the ventricles. Left ventricle is imaged with multi-planar ECG gated acquisition. During acquisition, several hundred cardiac cycles can be acquired and their average gives a representative cardiac cycle. Besides the calculation of the left ventricular EF, visual assessment of the wall motion and further global and regional left and right ventricular functional data can be computed. (Planar images of ventricular activity represent volumes!) (Fig. 5)
Through parametric imaging (imaging of various calculated parameters of the function e.g. phase and amplitude imaging) it’s possible to depict dysfunctional regions accurately and numerically characterize them. ECG gated SPECT technique makes the real-time, spatial representations of all these parameters possible, with a better imaging quality of the right ventricle. (Fig. 6, Fig. 7) Combined with stress examination, the technique is used to assess regional dysfunctions due to ischemia (ischemic cascade). By parametric imaging, the degree of inter and intra ventricular asynchrony is also computable.

Myocardial infarct detection

The detection of myocardial infarct in its late, chronic phase is possible with perfusion radiotracers (fix defect) or with functional examination, with the detection of wall motion and thickening abnormalities. ECG gated SPECT techniques with perfusion radiotracers can depict both abnormalities simultaneously during the same examination.
Acute myocardial infarct: rarely investigated with nuclear medicine techniques, only in special cases with perfusion radiopharmaceuticals or with radiopharmaceuticals accumulating in the necrotic tissue.

Indications of nuclear cardiologic exams in IHD

I

• In case of stable angina to determine the extent and severity of ischemia, or if symptoms of ischemia/silent ischemia are present with medium risk IHD
• Prognostic evaluation after myocardial infarcts
• Ischemia assessment in unstable angina in stabilized acute coronary syndrome
• Percutaneous coronary intervention (PCI) planning – identification of the ischemic lesion
• Perioperative risk assessment before high risk (non-cardiac) surgeries
• Ischemia – restenosis – identification in symptomatic cases after PCI/CABG
• Examination of certain symptom free patients after PCI/CABG, if there is suspicion for myocardial ischemia (e.g. ECG)
• Ventricular function assessment (not solely in IHD)

 
II/A

• Pharmacologically treated (stable) patients for the assessment of ischemia
• Coronary – circulatory anomaly detection in adult congenital heart diseases
• In valvular heart diseases to assess accompanying coronary disease and functional assessment

 
II/B

• Pharmacological therapy effectiveness measurements for myocardium –perfusion
• Coronary arteriopathy verification after heart transplant

 
III

• Low risk, non-symptomatic IHD patients – not recommended

 

22.1.4. Hybrid imaging ( SPECT/CT, PET/CT, recently PET/MR)

Calcium score: CT imaging allows for the detection of calcification caused by atherosclerosis in the epicardial coronary arteries. The extent and localization of the calcified plaques can be assessed with scoring systems (e.g. Agatston score). Co-evaluation of perfusion conditions and the calcium score makes the risk assessment of IHD more accurate.

Coronary CT angiography: It is a method to image the morphology of epicardial coronary arteries and plaques. Co-evaluation of the coronary artery conditions and tissue perfusion makes assessment of the disease more accurate, and the necessary revascularization can be planned non-invasively (according to the severity of perfusion disturbance caused by stenosis). The order of the examinations may vary according to the patient’s condition. Co-evaluation is significantly more informative in 20-30 % of patients (see examples below in Chapter 22.3 Appendix: Fig.8.1., 8.2., 8.3.). Modern imaging techniques make it possible to acquire these more detailed, multi-modality images with lower radiation exposure.

22.2.1 Myocardial metabolic tests (used in clinical practice)

Glucose: 18-FDG (PET)
Fat metabolism: 123 I labeled fatty acids. The fatty-acid chain determines the possible functional examination (partially suitable for the assessment of perfusion parameters - SPECT)

22.2.2 Myocardial receptor imaging (used in clinical practice)

Adrenergic receptors: 123I MIBG (meta-iodo-benzyl-guanidine) presynaptic receptor density assessment with SPECT. In case of decreased left ventricular function, the amount of tracer uptake (heart-mediastinum ratio), the kinetics of enrichment and wash-out (planar imaging), the regional distribution of the left ventricle (SPECT) correlate with the prognosis of the disease and the incidence of malignant arrhythmic disorders.
The previously described radiotracers/methods are used in clinical cardiology practice. The most commonly performed examination is the ECG gated myocardium perfusion stress test with SPECT in connection with IHD, for determining diagnosis, prognosis, therapeutic interventions and the follow-up of IHD. There are several radiotracers in their experimental phase that could be used to depict molecular level processes. Further myocardial receptors, cell-level metabolic processes and genetic markers are also in their research phase. The development of imaging technologies and methods (semiconductor detector cameras, hybrid systems) and the results of radiopharmacological research are aiming to provide earlier detection, genetic background assessment and the understanding of molecular origin of the cardiologic diseases, as well as the lowering of patient radiation burden.

22.3 Appendix

22.3.1.

 
Interpretation
Moderate to severe reduction of perfusion in the inferolateral-basal and apical regions. Moderate reduction in the anterior, anterolateral segments and mild reduction in the lateral wall. Reversibility in the anterior wall and partial reversibility in the lateral, anterolateral and apical region. The size of the left ventricle’s cavity and its wall thickness shows no significant difference compared to the normal state. No transient left ventricular dilation is seen on the images following stress test. (On the image following stress test, the cavity of the left ventricle is not larger compared to the image taken at rest.)

Diagnostic Impression
Inferolateral-basal necrosis with moderate to severe perfusion defect. Extensive moderate transient ischemia is present in the apical two-thirds of the anterior and anterolateral regions and mild ischemia in the basal third of the lateral region. Mild necrotic defect in the apical region cannot be excluded.

Summary:
Multivessel disease is demonstrated. Prognostically there is a high risk of IHD. Coronarography and possible complete revascularization is recommended.

22.3.2.

 
Interpretation:
There is no significant (stable or reversible) perfusion defect.

Stable defect:
Identically lower activity may be detected in the same localization both on the stress-test and on the resting myocardial scans. It is characteristic for myocardial necrosis. (Although, a similar finding can be noted due to radiation attenuation in specific regions – in females radiation attenuation caused by larger breasts is commonly seen in the anterior region, while in males the diaphragm can cause attenuation seen on the inferior wall.) In case of necrosis there’s also a functional defect, which can be verified by the ECG gated imaging.

Reversible defect:
On the stress-test scan a significantly lower activity is detected in the affected areas that is totally or partially reversed on the resting scan. It is characteristic for transient ischemia.

Diagnostic impression:
Myocardial necrosis and transient ischemia can be excluded.

Summary:
The probability of ischemic event is low. Further invasive evaluation is not indicated.

22.3.3.

a b

 
Interpretation
a.: Perfusion: Severe stable apical, apical-inferior, apical-inferolateral perfusion defect. Severe to moderate inferior-inferolateral perfusion defect. Minimal reversible lateral perfusion defect.
b.: Function: Medium degree reduction of global LV function. EF: 0.
Akinesis in the apical and inferior-apical, inferolateral-apical segments without wall thickening. Moderate hipokinesis and wall thickening is detectable in the basal-inferior, basal-inferolateral region, in the zone of the moderate necrosis.

Diagnostic Impression
Extensive apical, inferior and inferolateral necrosis. Minimal transient ischemia in the lateral segments. Moderate reduction of global systolic LV function. The presence of viable myocardium is likely in the basal-inferior and basal-inferolateral segments (based on functional data and on the extent of perfusion defect).

Summary:
High risk IHD. Revascularisation is recommended.

22.3.4.

::Fig. 4. One vessel disease: anterior ischemia + small apical necrosis.

Interpretation:
Perfusion: Moderate reversible perfusion defect is shown in the apical and anterior regions. Reversibility in the apical region is not complete, there is a defined residual defect in the section images of the resting scan. (The stable defect that can be detected in the basal-inferoseptal region is most likely caused by gamma ray absorption by the diaphragm, so it does not indicate necrosis.) The volume of the left ventricle is a bit larger after stress: transient ischemic dilatation (TID).
Function: Good global left ventricular systolic function, ejection fraction (EF): 0. Moderate hypokinesis in the apical region and localized decreased wall thickening referring to necrosis is seen. (There is no functional deficit in the basal-inferoseptal region, which demonstrates radiation attenuation)

Diagnostic impression:
Moderate transient ischemia in the anterior region and in the apex. There is a defined mild necrosis causing defect in the apical region. Good global systolic LV function.

Summary:
Ischemic heart disease verified. The probability of ischemic events is moderate. Revascularization is indicated.

22.3.5

 
Planar projection movies + quantitative evaluation
Apical-inferior + inferior necrosis, enlarged left ventricle, decreased left ventricular function
a, LAO 70 projection
b, LAO OPT projection (as it is perpendicular to the septum, the left ventricle can be separated from the other cavities, making this projection suitable for quantitative evaluation.)
c, Quantitative evaluation: besides calculated functional parameters in the apical-inferior region there is amplitude reduction and phase shift according to parametric evaluation.

22.3.6.

 
Sectional images, parametric evaluation, 3D movie, quantitative data (the method separates the left end right ventricles, so the functional data can be calculated for both ventricles properly)

22.3.7.

 
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD)
Segmental movement, parametric images, 3D movie, functional parameters (dilated right ventricle, decreased right ventricular function, regional dysfunction in the anteroseptal region of the right ventricle with phase delay)

22.3.8

Fig. 8.1 Hybrid methods: myocardial perfusion SPECT + CT + CTCA

a: left ventricle longitudinal section image on myocardial perfusion SPECT
b: left ventricle longitudinal section image identically on CT
c: SPECT + CT fusion image (function + morphology)
d: myocardial perfusion SPECT + CTCA (CT Coronary Angiography) 3D fusion

Normal conditions.
Based on tissue density data provided by the CT, SPECT data can be corrected in order to estimate actual myocardial perfusion activity (attenuation correction, scattering, depth dependent correction) and in case of PET even quantitative perfusion data can be calculated (ml/gr tissue/minute)
Coronary Calcium Score (CCS) assessment is possible with the CT scan
3D reconstruction of CTCA and perfusion conditions facilitates combined evaluation of the actual coronary status and perfusion in the region of a specific vessel.

Fig. 8.2 Hybrid methods: Coronarography + CTCA + myocardial perfusion SPECT

• a, b, c (upper line): invasive coronarography
  • a: significant right coronary stenosis
  • b: revascularization by stent implantation
  • c: 50 % non-significant stenosis of the circumflex branch (CX)
• d: CTCA measuring 50 % non-significant stenosis of a specific CX region (intense white spots indicate calcified coronary plaques (confer Ca score))
• e: stress phase of myocardial perfusion SPECT + 3D reconstruction of CTCA demonstrating significant perfusion disturbance in the region of CX: Revascularization is indicated.

 

Fig. 8.3 Hybrid methods coronary calcium score (CCS)

The score calculated based on the CT scan - which was taken at the time of the myocardial perfusion SPECT for correction - provides further information about the prognosis of IHD. A higher score indicates higher cardiac risk even if the severity of the perfusion disturbance is the same. (CCS can be assessed when taking a CTCA, but can be done so by itself with low dose radiation for screening.)

22.4 Message:

Nuclear cardiology studies provide functional information about the condition of the central circulation, molecular information about myocardial tissue perfusion, metabolic parameters and innervation. In addition to perfusion, the ventricles’, primarily the left ventricle’s global and regional function can be determined. In case of ischemic heart disease, ischemia, myocardial necrosis, hibernated and stunned myocardium condition can be analyzed in order to diagnose the disease, establish prognosis, and choose the accurate therapy. Nuclear cardiology alongside with other imaging techniques is an integrated component of cardiologic diagnostic and therapeutic protocols.

22.5 References

• Nukleáris Medicina Tankönyv, Kiadó: Medicina Könyvkiadó Zrt. Budapest, 2010
• Guidelines on myocardial revascularisation. The task force on myocardial revascularisationof the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS ) Eur. Journal of Cardio-Thoracic Surgery 38,51 (2010 )S1-S52
• EANM/ ESC gudelines for radionuclid imaging of cardiac function - Eur.J.Nucl.Med .Mol.Imaging 208, 35 851-885
• ACCF/ASCN/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 Appropriate use Criteria for Cardiac Radionuclide imaging: A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force , the Am.Society of Nuclear Cardiology, the Am.College of Radiol., the Am. Heart Association, the Am. Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance And the Society of Nuclear Medicine Circulation 2009 119, e561-e587
• Hybrid cardiac imaging: Insights in the dilemma of the appropriate clinical management of patients with suspected coronary artery disease; S. Koukouraki^{a, ∗}, K. Pagonidis^{b, 1}, K. Perisinakis^{c, 2}, I. Klinaki^{a, 3}, M. Stathaki^{a, 3}, J. Damilakis^{c, 4}, A. Karantanas^{b, 1}, N. Karkavitsas^{a, 3} (a: Department of Nuclear Medicine, Faculty of Medicine, University of Crete, Greece; b: Department of Radiology, Faculty of Medicine, University of Crete, Greece; c: Department of Medical Physics, Faculty of Medicine, University of Crete, Greece); European Journal of Radiology 82 (2013) 281– 287

 
Translated by Balázs Futácsi

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