Chapter 22: Radionuclide Angiography: Equilibrium and First Pass

The noninvasive assessment of resting left ventricular (LV) performance is an integral part of the evaluation of patients with known or suspected cardiac disease, having important diagnostic, therapeutic, and prognostic significance.^1–11 Although scintigraphic measures of cardiac function historically included measurement of ejection fraction (EF), estimation of cardiac output, valvular regurgitant fraction, and detection of intracardiac shunts have also been successfully performed. Other than EF, these potential applications for nuclear cardiology techniques have been largely supplanted by echocardiography, cardiac computed tomography, and magnetic resonance imaging (MRI) techniques over the past two decades.

Gated equilibrium radionuclide angiography (ERNA, often called multiple-gated acquisition [MUGA] and equilibrium radionuclide ventriculography [RNV]) were introduced nearly 30 years ago. These techniques were routinely utilized in the evaluation of patients with known or suspected LV dysfunction, postmyocardial infarction (MI), and valvular disease, and for monitoring the cardiotoxic effects of chemotherapeutic drugs. Exercise radionuclide angiography (RNA), particularly with the first-pass radionuclide angiographic (FPRNA) technique, was widely used to diagnose or evaluate known coronary artery disease (CAD),^5–9 competing favorably with and often complementing planar myocardial perfusion imaging (MPI). However, since its introduction, RNA has evolved little, while other noninvasive methods, such as gated single-photon emission computed tomography (SPECT) MPI, echocardiography, and cardiac magnetic resonance, have been introduced and become increasingly sophisticated and cost effective.

Red Blood Cell Labeling

For FPRNA alone, Tc-99m DTPA is often used if no equilibrium images are required. For ERNA, red blood cell labeling can be performed via multiple methods. The in vitro method, usually using a commercial kit, is preferred, and offers the highest level of labeling efficiency (>97%). Blood is withdrawn from the patient, mixed into a "reaction vial" containing stannous pyrophosphate. After 5 minutes it is mixed with sodium hypochlorite to destroy extracellular stannous ion, and then with citrate buffer. After shaking lightly, 25mCi Tc-99m is added, incubated for 20 minutes and then reinjected back into the patient. The in vivo method, although simple, cheap and fast, is no longer recommended as it provides the lowest labeling efficiency (80–85%). It involves giving stannous pyrophosphate directly to the patient, followed by Tc-99m 15 to 20 minutes later (which can be given as a rapid bolus if for FPRNA). Finally, a modified in vivo/in vitro method can be used with labeling efficiency of 92% to 95%. Perfusion imaging can also be performed if desired.^12–14

First-Pass Radionuclide Angiography

FPRNA images are usually obtained using a single- or multicrystal high-count rate gamma camera fitted with a high-sensitivity parallel hole collimator (e.g., SIM 400, Scinticor, Milwaukee, WI; or ElGems CardiaL [formerly Elscint], Haifa, Israel). Images are acquired in the anterior or the right anterior oblique (RAO) projection using 25 (±4) frames per cardiac cycle. Preliminary work suggests that FPRNA can also be performed with positron emission tomography (PET) using images acquired during a bolus of radiolabeled water (H₂¹⁵O), but this has not yet achieved widespread utilization or validation.¹⁵

FPRNA data are analyzed using the frame method for LVEF using commercially available computer software,^16–18 as shown in Figures 22-1, 22-2, 22-3. This software creates a representative LV volume curve by summing frames of several (usually 5–10) cardiac cycles, which are aligned by matching their end diastoles (histogram peaks) and end systoles (histogram valleys) during the operator-defined levophase of radioactive tracer transit. The pulmonary-frame background-corrected representative cycle is then examined with a fixed region of interest (ROI) in order to obtain the final first-pass LV time–activity curve. This ROI is drawn over the LV as defined by a first harmonic Fourier transformation phase image, which distinguishes clearly the LV from the aortic counts. End diastole is taken as the first frame of the representative cycle, and end systole is defined as the frame with the minimum counts in the histogram. Historically, the LVEF was taken as the end-diastolic counts minus the end-systolic counts, divided by the background-subtracted end-diastolic counts.

A second ROI (end diastolic) can be derived from a Fourier transformation amplitude image with masking of the lower 10% of image intensity, which extends the ROI in a basal direction, usually one to four pixels, depending on the vigor of ventricular contraction, up to the amplitude signal of the aortic root. The remainder of this ROI is drawn to match the first ROI (end systolic). The dual ROI LVEF is determined as the end-diastolic ROI counts minus the end-systolic ROI counts, divided by the background-subtracted end-diastolic ROI counts. This results in an accounting for valve plane motion during the cardiac cycle, using Fourier-guided dual ROI analysis of FPRNA, giving EFs that are highly reproducible and similar in value to ERNA.¹⁸

Gated Planar Equilibrium Blood Pool Imaging

Electrocardiogram (ECG)-gated planar equilibrium blood pool images (Fig. 22-4) can be performed with any of the several blood pool agents, such as Tc-99m–labeled red blood cells (described above and the standard) and Tc-99m–labeled human serum albumin. These images are best when acquired using high-resolution collimation. Images for planar LVEF calculation are obtained in the best septal (shallow) left anterior oblique (LAO) view. For regional wall motion assessment, the best septal view ±45 degrees should be obtained (approximately "anterior" and "lateral" views). Each of these planar-gated images should be acquired for 6- to 10-minute duration, dividing each cardiac cycle into a minimum of 32 frames. A smaller number of frames (e.g., 16) are adequate for assessment of EF due to the usual length of the isovolumic ejection period (at end diastole) and relaxation period (at end systole). However, more frames are desirable if quantitative assessment of diastolic performance is needed.

For LVEF, automated regions of interest are generated on the planar-gated equilibrium blood pool data throughout the cardiac cycle using the commercially available software. An automated periventricular background ROI must be adjusted routinely in order to avoid inclusion of high-count structures (e.g., spleen and descending aorta), which would artifactually increase the LVEF if included.

Gated Tomographic Equilibrium Blood Pool Imaging

ECG-gated projections for SPECT reconstruction are usually obtained using high-resolution collimation in a fashion similar to gated SPECT perfusion imaging (Fig. 22-5), scanning from RAO 45 degrees to left posterior oblique (LPO) 45 degrees projections. A total of 45 to 60 projections of 20- to 30-second duration, at 4-degree or 3-degree steps, respectively, should give adequate count density. At each projection, either 8 or 16 frames per cardiac cycle should be acquired. After collimator sensitivity and center of rotation correction, projections are reconstructed into transaxial slices of the blood pool for each of the 8 or 16 frames of the cardiac cycle. The transaxial slice sets can then be reoriented in cardiac planes (i.e., short axis, horizontal long axis, and vertical long axis) for each of the eight frames of the cardiac cycle.

Multiple methods of quantifying blood pool SPECT images have been published using either three-dimensional images or midventricular horizontal and vertical long-axis slices, which can be analyzed for wall motion or EF.^19–25 The LVEF and RVEF can be calculated for each long axis as the end-diastolic counts minus the end-systolic counts, divided by the end-diastolic counts, combining them for a biplane EF.

The three-dimensional techniques are useful for blood pool volume rendering, which is used for delineation of myocardial (actually endocardial) topography. This technique is limited by the accuracy of automated valve plane definition since there is often little count density change at the mitral or tricuspid valve planes. However, this method has been validated against standard approaches, such as cardiac magnetic resonance.²⁵ Due to the uniformly high contrast and lack of overlap between cardiac blood pool and extracardiac structures, no background subtraction algorithm should be employed for these analyses.

Gated SPECT Myocardial Perfusion Imaging

Gated SPECT MPI (Fig. 22-6) has become one of the most powerful tools available in nuclear cardiology and is discussed in detail in Chapter 11. Acquisition of SPECT data, synchronized with the electrocardiographic R wave, is generally performed using 8 or 16 gating intervals and allows evaluation of both global (EF) and regional (myocardial wall motion and wall thickening) cardiac function. Gated SPECT acquisition is now recommended for all perfusion studies whenever possible. It is estimated that over 90% of all SPECT studies in the United States are currently performed using the gated acquisition technique.²⁶ Gated SPECT MPI is most often performed with poststress ECG gating. Ungated SPECT perfusion imaging is usually reserved for resting images in some institutions or for patients with cardiac arrhythmias.

Two- and three-dimensional techniques for display of gated perfusion SPECT have been well validated for EF.^26–31 Gated SPECT has been utilized extensively for determination of EF and wall motion, adding incremental diagnostic and prognostic information. The addition of wall motion has improved the specificity of myocardial perfusion SPECT by distinguishing myocardial scarring from attenuation artifacts, both of which may result in "fixed" defects.³²

The exponential increase in the use of gated SPECT perfusion has been fueled by the increased availability of automatic and semiautomatic algorithms for the quantification of cardiac function. DePuey et al.²⁹ described a method based on the automated detection of endocardial borders. Williams and Taillon²⁸ developed a method based on digitally subtracting and inverting the perfusion images and analyzing the change in counts occurring in the ventricular chamber, using an edge-detection method identical to that commonly used in gated ERNA. Germano et al.^27,30 developed a totally automated method of fitting geometric shapes to the endocardial borders to obtain systolic and diastolic volumes and EFs. Smith et al.³¹ have used partial volume effect to quantitate regional thickening and estimate LVEF, without need for any edge-detection algorithm. Each of these techniques has been well "correlated" with standard methods of performing EF, but each demonstrating varying degrees of "substitutability."²⁸

For these reasons, the gated SPECT policy statement of the American Society of Nuclear Cardiology encourages the use of gated SPECT with every perfusion study in which gating is feasible. This reflects the improved quality control and diagnostic accuracy of interpreting perfusion images in light of regional and global LV performance, as well as the incremental value of gated SPECT over perfusion imaging alone for prognosis.^32–35

Functional Images

Each of the scintigraphic modalities described above, whether planar or gated SPECT ERNA, FPRNA, or gated SPECT MPI, consists of a series of digital images. These series can be evaluated by computer techniques, which allow automated analyses and aid image interpretation, particularly for the assessment of regional function. The resultant images are the so-called functional images.

Functional images may be as simple as a subtraction (e.g., end-diastole image − end-systole image = stroke volume image) or more complex computer calculations (e.g., Fourier transformation phase and amplitude images).^36–39 The Fourier transformation process fits the changes that occur in each pixel (picture element) to a cosine wave, which is characterized by the height of change throughout the cycle (amplitude) and the relative timing of the wave (phase).

The amplitude images may be used to detect regions of decreased wall motion (hypokinesis) on blood pool or FPRNA images or to quantitate myocardial wall thickening on gated SPECT perfusion images. The presence of amplitude on Fourier transformation of perfusion polar maps has been shown to correlate with perfusion residual myocardial perfusion defect reversibility.³⁶

The phase images are used to detect alterations in regional timing, such as the dyskinesis (outward wall motion) of an aneurysmal myocardial segment, or the often subtle degrees of late contraction (tardokinesis), typical of myocardial ischemia or prior infarction. They have also been utilized to detect the location of ventricular tachycardia or insertion of an accessory conduction bypass tract in Wolff–Parkinson–White syndrome.^36,37 In fact, a delay in segmental right ventricular (RV) activation compared with the LV detected on Fourier phase images of gated blood pool RNA is consistent with arrhythmogenic RV dysplasia and has been correlated with a poor prognosis.^37–39

The assessment of LV size, systolic function, diastolic function, regional wall motion, and timing of mechanical activation remain diagnostically and prognostically important uses of radionuclide imaging. The exercise FPRNA LVEF has particularly greater prognostic value in patients with ischemic heart disease than many other clinical, noninvasive, and invasively derived variables.^5–9 An exercise LVEF of 0.50 (50%) has been identified as the inflection point below which patients with CAD demonstrate a probability of cardiac death, which increases as the EF decreases.⁷ However, the direct applicability of these numerical data when the EF is obtained with other protocols or techniques, such as the more widely utilized ERNA technique, is uncertain.

The evaluation of LV systolic function has become one of the most common applications of nuclear imaging, using FPRNA, planar ERNA, and, more recently, gated SPECT perfusion and SPECT ERNA. Each noninvasive imaging technique has unique strengths and limitations. Detection of regional global ventricular dysfunction can be performed with many noninvasive methods, but the nuclear imaging techniques are inherently quantitative, rather than relying on visual estimation of ventricular size and function. Factors to consider upon test selection include local expertise, local access, cost, and the need for reproducible quantitative measurements. The ability to distinguish systolic from diastolic dysfunction should also be considered. The RNA techniques can be used to compute quantitative estimates of LV, as well as RV EFs, and absolute volumes with geometric or count-based methods.

FPRNA has some distinct advantages over ERNA. These include (1) the acquisition of data in <30 seconds; (2) the evaluation of RV function with less overlap of the activity from other chambers⁴⁰; (3) the use of multiple radiopharmaceuticals, including bone, renal, and myocardial scintigraphic agents¹³; (4) a proven robust measurement of stress ventricular function at the true point of peak exercise^5,7,9; and (5) the presence of a wealth of prognostic information available for management of patients with ischemic heart disease based on stratification by FPRNA exercise LVEFs.^5,7,9 Despite these advantages, widespread use of FPRNA has been limited by the need for large-bore intravenous access, absence of significant tricuspid regurgitation,⁴⁰ impeccable bolus technique,²⁸ and a high-count rate-capable, often dedicated, gamma camera.^16–18 Currently, ERNA use is far more widespread than FPRNA and allows for multiple views of imaging.

In terms of feasibility, quantitation of LV chamber volume and EFs are obtainable in essentially 100% of patients. If venous access is poor, FPRNA cannot be performed, but ERNA requires no bolus, and therefore can be performed with a minimally sized intravenous catheter or direct venous punctures. If ERNA is difficult due to poor tagging of red cells (e.g., with heparin infusion), a Tc-99m–labeled perfusion agent may be employed for gated SPECT perfusion imaging. As noted earlier, the latter test has become the most commonly performed scintigraphic ejection EF, as a diagnostically and prognostically important addition to myocardial perfusion SPECT. The high degree of reproducibility in the EF makes RNA an ideal choice for the assessment of medical interventions on LV function, such as in oncology patients receiving chemotherapy. In particular, this is an ideal choice for serial imaging to assess for cardiotoxicity in patients receiving anthracycline-based drugs such as daunorubicin, discussed further below.

Assessment of Systolic Function

Left Ventricle

The assessment of systolic function is an important component of the initial evaluation of all patients with the clinical symptoms of right- or left-sided congestive heart failure (CHF), ischemic heart disease, and in patients who are undergoing potentially cardiotoxic treatments, such as doxorubicin. Systolic dysfunction is usually defined by the presence of an LVEF <50%, while a normal RVEF is 10 to 15 units lower than that of the LV. However, it should be recalled that the EF is an ejection phase index, which is dependent on loading conditions of the ventricle. Preload (i.e., fiber stretch) deficiency or inappropriate afterload (e.g., severe hypertension) may result in lowering of the EF in the absence of any real decrease in inotropic state or contractile reserve. Compensatory dilatation of the ventricle is present in most patients with systolic dysfunction. Assessment of ventricular volume indices has both diagnostic and therapeutic implications. The presence of ventricular enlargement in the absence of systolic dysfunction in the patient with clinical symptoms of heart failure raises the possibility of heart failure secondary to high-output states, such as anemia or valvular heart disease. For example, when systolic function deteriorates in the RV or LV, this is an indicator of the need to proceed with mitral or aortic (respectively) valvular replacement surgery.^11,41 In the absence of dilatation or systolic dysfunction, heart failure symptoms suggest the presence of pulmonary disease (RV dysfunction), pericardial disease (biventricular dysfunction), or predominant diastolic dysfunction.

Right Ventricle

Right ventricular function is less commonly assessed than LV function but can have diagnostic and prognostic implications in assessment of lung disease and lung transplantation patients, congestive heart failure, and assessment of arrhythmogenic RV dysplasia.^39,42–45 FPRNA offers the most accurate scintigraphic assessment of RVEF, but again, is rarely performed these days.

Assessment of Diastolic Function

The presence and severity of diastolic dysfunction should be assessed in every patient presenting with evidence for heart failure, since it is the predominant abnormality in as many as 30% to 40% of such patients.⁴⁶ Most often, this sways both the diagnostic considerations (e.g., hypertension, diabetes mellitus, hypertrophic myopathies, or myocardial infiltration) and the therapeutic options (e.g., antihypertensives and tight glucose control). This may indicate the need for further procedures, such as myocardial biopsy.

In RNA studies, the rate of change (first derivative) of counts in diastole can be analyzed to calculate indices of diastolic filling, including the peak LV filling rate, time to peak filling, and atrial contribution to filling.⁴⁷ In practice, Doppler blood flow velocity indices of transmitral flow are used much more commonly to assess LV diastolic filling parameters. For RNA, a peak diastolic filling rate of >2.5 end-diastolic volumes per second (EDV/s) is considered normal.^47,48 Age- and gender-specific criteria for diagnosing LV diastolic dysfunction using Doppler blood flow velocity from transmitral flow based on large population studies have been defined that are applicable to clinical practice.^49,50 However, large population-based criteria, adjusted for age and gender, for abnormal diastolic function have not yet been established for RNA.

Assessment of Ventricular Dyssynchrony

Recent advancements in the management of CHF include prevention of sudden death with implanted defibrillators and improvement of mechanical efficiency by synchronizing the timing of ventricular contraction. Ventricular dyssynchrony is typified by a wide QRS complex on electrocardiography, often with a left bundle branch block morphology,⁵¹ and is associated with a higher risk of sudden cardiac death.⁵² Various parameters have been looked at to help delineate which patients would be optimal candidates for cardiac resynchronization therapy, including LV dyssynchrony, scar burden, and site of late activation for placement of the LV lead.⁵³

Echocardiography has been highly touted as the method of choice for evaluation of ventricular dyssynchrony, but suffers from its two-dimensional nature, and lack of reproducibility.⁵⁴ Recent data have indicated that gated SPECT perfusion^55,56 and SPECT blood pool⁵⁷ imaging can be utilized as three-dimensional methods that easily evaluate regional timing of myocardial contraction in an automated operator-independent fashion (Fig. 22-7). SPECT phase analysis has been shown to be reproducible, validated using commercially available software and has been validated again dyssynchrony parameters measured by tissue Doppler imaging and speckle tracking echocardiography.^58–61 Phase analysis holds promise for improving the evaluation and selection of patients with CHF and QRS widening, but further randomized clinical trials are needed.

Monitoring the Effects of Chemotherapy

Monitoring for cardiotoxicity from chemotherapy is an important use of radionuclide angiography. The two main classes of chemotherapy that cause cardiac toxicity include anthracyclines and the newer tyrosine kinase inhibitors (TKIs).

Anthracyclines include daunorubicin (the most commonly used) and various analogs of anthracyclines (including doxorubicin, epirubicin, idarubicin, mitoxantrone, and others).⁶² They cause myocardial necrosis due to free radical formation, characterized by myocellular vacuolization. Risk factors for the development of more rapid deterioration in LV function with anthracyclines include cumulative anthracycline dose, extremes of age, female gender, cardiovascular comorbidities, adjuvant chemotherapies, and adjuvant thoracic radiation therapy.⁶³ Anthracyclines cause what is traditionally called type I cardiotoxicity, with irreversible injury from cardiomyocyte death.⁶⁴ This results in progressive lowering of the LVEF as the cumulative dose of the agent increases and is clearly dose related.

The tyrosine kinase inhibitors include trastuzumab, lapatinib, imatinib, sorafenib, and sunitinib, among others.⁶⁵ They cause type 2 cardiotoxicity which is characterized by cardiomyocyte dysfunction, rather than cell death, which is felt to be reversible. For TKIs, the toxicity is not dose related and usually responds to standard medical treatment or discontinuation of drug.⁶⁶ Risk factors for the development of trastuzumab-induced cardiotoxicity include previous or concurrent anthracycline use and older age.

Noninvasive monitoring of LVEF during chemotherapy with anthracyclines or TKIs is recommended for the early assessment of cardiotoxicity; however there is no clear consensus on how to monitor. Both ECHO and ERNA techniques have been evaluated for chemotherapy monitoring. FPRNA has been found to be more sensitive than echocardiography for the detection of anthracycline-induced LV dysfunction,⁶⁷ but is no longer readily available. ERNA is well established and is still commonly used. It has extensive data regarding its accuracy and reproducibility with long-term follow-up and is widely available.⁶⁸ However, there are concerns about its cumulative radiation exposure. As such, echocardiography is used commonly these days, and certain protocols intersperse ECHO with RNA to provide reduced radiation and still have the improved accuracy of RNA. ECHO evaluation during chemotherapy should include assessment of LVEF (ideally by 3D echo, else by 2D echo using modified biplane Simpson's technique), assessment of wall motion score index, and global longitudinal strain.⁶⁹ Other echocardiogram parameters being assessed for the early detection of cardiotoxicity include fractional shortening, and newer tissue Doppler and speckle tracking indices (strain).⁶⁷ Although ECHO is used commonly these days, concerns do exist regarding the reproducibility of LVEF by ECHO. Regardless of which imaging technique is used, the LVEFs are likely not interchangeable, and it is recommended that a single technique be used in an individual patient for serial monitoring of LVEF.

There are no definitive guidelines on the optimal timing and duration of cardiac monitoring for patients receiving anthracycline-based chemotherapy. All patients that are at high risk for cardiotoxicity should receive a baseline evaluation of LVEF. The newest guidelines by the European Society of Medical Oncology and the American Society of Echocardiography recommend: a baseline evaluation of LV function with ECHO and Troponin levels.^69,70 For asymptomatic patients, serial evaluation should be considered at 6 months after completion of treatment, annually for 2 to 3 years thereafter, and then at 3- to 5-year intervals for life. High-risk patients may be monitored more frequently. Assessment of subclinical LV dysfunction should be considered with evaluation of global longitudinal strain on ECHO. American Society of Clinical Oncology (ASCO) guidelines include: (1) an evaluation of EF prior to each planned course of doxorubicin (per the labeling guidelines of the drug), (2) monitoring after a cumulative dose of 400 mg/m² is reached, (3) repeated after 500 mg/m² cumulative dose, and (4) thereafter after every 50 mg/m² dose.⁷¹ Traditional ERNA assessment has included EF assessment at baseline, measurement at 250 to 300 mg/m², at 450 mg/m² and measurement before each dose above 450 mg/m². If the baseline EF is >50%, then therapy should be discontinued once it decreases by >10% from baseline and LVEF is <50%. If EF is <50% at baseline, serial measurements should be obtained before each dose, with discontinuation of therapy once LVEF <30% or drops by >10%.⁷² It has been advocated that keeping a table of RNA/EF results along with cumulative doses may be helpful for proper monitoring.

In general, if test results indicate deterioration in cardiac function associated with an anthracycline, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.

For tyrosine kinase inhibitors, especially trastuzumab, baseline cardiac function and troponin should be assessed prior to treatment.^69,70 Optimal surveillance with these agents has also not been established, but higher-risk patients should be followed more closely. Both ERNA and ECHO are being used for monitoring of LV function. Serial assessment in an individual patient should be performed by a consistent method.

This chapter details the technical aspects and the wide range of clinical diagnostic possibilities available by dynamic imaging of myocardial function using scintigraphic techniques. These principles are now finding new applications in the realm of myocardial timing and mechanics and for the monitoring of chemotherapy-induced cardiomyopathy.