Chapter 9. Nuclear Cardiology Applied to Electrophysiology

The electrophysiologist needs precise electromechanical investigation tools to quantify the electrical propagation and its impact through the heart muscle. Analysis of the timing of the myocardial contraction based on Fourier phase histograms allows mapping of the kinetics of the different ventricular segments from functional phase pictures and, by extrapolation, mapping of the electrical activity of the heart. Nuclear cardiology combines mechanical and electrical analysis in real time. In this chapter, we report on our experience of gated blood pool scintigraphy combined with phase analysis and myocardial innervation imaging in various diseases with electrical disorders.

Radionuclide functional imaging of the heart addresses multiple aspects of cardiac function.1 Although most applications of nuclear cardiology are focused on coronary artery disease, in which the combination of stress/rest myocardial perfusion and/or viability imaging plays a major clinical role, many other less common cardiac diseases may benefit from this noninvasive diagnostic approach.

Perfusion and viability imaging modalities are based on cellular uptake of a radioactive molecule such as thallium-201 (201Tl), which presents an active transport comparable to that of potassium cation (K+), or sestamibi or tetrofosmin labeled with technetium 99m (99mTc), which are larger cations whose cellular penetration is passive due to concentration gradient.

Imaging is usually performed in tomographic mode (SPECT) and is a two-step procedure that combines stress imaging (shortly after physical exercise or pharmacologic coronary vasodilation) with resting imaging after stress-injected tracer redistribution with time (thallium) or a second resting administration (technetium-labeled molecules). The first set of images describes coronary perfusion reserve at stress, whereas the second set reflects cellular viability.

In addition to single photon (gamma ray) methods, positron emission tomography (PET) may also be a choice for a comparable approach, but PET uses specific positron-emitting radiopharmaceuticals such as the generator-produced rubidium-82 for perfusion and fluorine 18–labeled fluorodeoxyglucose.

Myocardial sympathetic innervation imaging is based on the presynaptic uptake of catecholamines. The gamma-emitting tracer is meta-iodobenzyl guanidine (MIBG) labeled with iodine 123. Comparable positron-emitting tracers are used as well. Image acquisition can be planar or SPECT. Innervation defects appear as hypoactive areas, which have to be compared with perfusion defects using an adequate perfusion agent.

Imaging the mechanical contraction of the heart needs a dynamic acquisition of the periodic motion of the myocardium. Electrocardiographically (R wave) triggered acquisitions can be performed on myocardial perfusion SPECT images. Another option consists of blood pool labeling using an intravascular tracer such as albumin or red blood cells, both labeled with 99mTc. Gated blood pool pictures can be acquired in planar mode as well as in SPECT, but in any case, one single cardiac cycle is unable to provide a sufficient number of counts. Therefore, a high number of successive cardiac cycles (≥100) have to be superimposed for an adequate image (Fig. 9–1). Measurement of left ventricular ejection fraction is the most common variable obtained by these studies, but as will be shown later in this chapter, several other variables can be of special interest in the context of arrhythmias.

The reliability of gating is the key to adequate imaging of cardiac contraction. In patients with a stable heart rate, superimposition of multiple cardiac cycles in electrocardiogram (ECG)-triggered synchronism is not a crucial problem. However, this is far from true in a patient population with cardiac rhythm abnormalities. More or less sophisticated technical approaches may be able to at least partially solve this problem. Their common principle consists in selecting the acquired cardiac cycles based on the R-R interval duration.

Cycle selection can be made a priori after acquiring for a given time a series of successive cardiac cycles and construction of the R-R histogram. By defining a temporal window on the desired part of the histogram, only the cycles matching inside the window will be accepted for final image acquisition. The R-R histogram may present a continuous variation around an average value (eg, in atrial fibrillation) or may show distinct peaks (eg, in extrasystoles where the average peak of sinusal cycles can be surrounded by a peak of shorter cycles—extrasystoles—and a second peak of longer cycles—postextrasystoles).

The option of "a posteriori" gating is more flexible because cardiac cycles are then acquired in "list mode," which means without immediate superimposition. Cycle combination is performed in a second time, when acquisition has been completed, which allows changes in R-R windowing as well as multiple window acquisitions.

Diagnosis of coronary artery disease is mainly focused on the left ventricle. Perfusion tracers, as well as thallium and technetium-labeled molecules, show a very low uptake in the right ventricular wall, which is difficult to see on the images. Only in right ventricular hypertrophy can the right ventricle be clearly visualized, but it is always visualized with a lower intensity than the left ventricle. Therefore, myocardial SPECT is a limited tool for assessment of right ventricular diseases.

Blood pool imaging does not present the same limitations, and the labeling of the circulating blood allows adequate visualization of all of the heart chambers and thoracic vessels. The drawback of this global imaging of cardiac structures is the risk of superimposition of different cavities, and technical solutions have to be found in order to minimize these overlaps.

For planar imaging, the projection must be performed in the anterior oblique view with optimization of the angle for each individual patient with regard to the orientation of the interventricular septum in order to obtain the best separation between the right and left ventricles (Fig. 9–2).

The gated blood pool SPECT approach is another option for selection of the right ventricle and evaluation of its functional variables. Measurements of ejection fractions, whether left or right, presuppose proportionality of labeled blood volumes with collected gamma counts in selected regions of interest. After adequate correction for extracardiac background activity, the end-diastolic and end-systolic counts are representative of the corresponding blood volumes.

The ECG gating process provides a series of images covering an average cardiac cycle over the R-R interval. The temporal course of the blood contents within the ventricles (ie, the corresponding radioactive counts) evolves from end-diastole to end-systole during the contraction phase and from end-systole again to end-diastole during the filling phase. This periodic change can be approximated by a single sinus function (Fig. 9–3); a better model of the real time/volume curve, including the faster and slower parts of the filling phase, may require more sinus functions (eg, three harmonics).

Temporal Fourier analysis, mostly limited to the first harmonic only, consists of mapping pixel by pixel the two variables, amplitude and phase, that characterize the sinus function, which describes the time course of the pixel activity during the R-R interval. The phases are expressed either in time units or in angular degrees. When phases are in milliseconds, they correspond to the time between the cardiac cycle origin (R wave) and the time of end-systole. The total cycle length is highly dependent on the heart rate (1000 ms for 60 beats per minute).

The use of degrees allows some independence with regard to the heart rate because a cardiac cycle is always scaled between 0° and 360° (a complete "turn") regardless of its duration. The value of the phase is somewhere in the middle of the cycle (180°), with a value usually lower because the systolic part of the cycle is shorter than the diastolic part. Nevertheless, a correction (like the Bazett correction for the QT interval) is possible to take into account the heart rate changes. Amplitude images show the amplitude of the diastolic-systolic activity change and indicate the contraction intensity.

Phase images present for every pixel the time when the sinus function is at its minimum (nadir of the curve), which is a good approximation of the time of end-systole. A color scale gives the correspondence with the phase values and displays the time of mechanical contraction from the earliest area to the latest area. It is important to note that the phase picture is a pattern of contraction and not an activation map, even if in many cases, in absence of contraction abnormalities or delays, the contraction pattern is close to the activation map (eg, in Wolff-Parkinson-White syndrome with normal contraction and ejection fraction).

Two characteristic values describe the phase histograms: the mean value of the phase distribution and the standard deviation of the distribution. From the phase mapping, the statistics of the phase distribution within a given ventricle (separately for left and right) can be displayed and quantified as phase histograms. The colors of the histogram bars match the colors of the phase display (green is early and red is delayed; Figs. 9–4 and 9–5).

Normal limits acquired from our personal experience with a given methodology are as follows:

• Left ventricular ejection fraction (LVEF) >55%
• Right ventricular ejection fraction (RVEF) >26%
• Left ventricular phase standard deviation (LVSD) <28°
• Right ventricular phase standard deviation (RVSD) <36°
• Interventricular asynchronism (phase difference) (IVA) <14°

Values can vary substantially between scintigraphy centers due to changes in acquisition or processing modalities.

MIBG images can be acquired in planar mode or in SPECT mode. From planar pictures, the relative myocardial tracer uptake can be quantified as the ratio between cardiac uptake and mediastinal activity (Fig. 9–6). Normal ratios are in the range of 1.8 to 2.0. SPECT data have to be analyzed by comparing perfusion and innervation. When both studies show a concordant defect (same localization, extent, and severity), the conclusion should be the presence of a fixed myocardial lesion (probably necrosis) without any particular sign suggesting a special risk for arrhythmias. On the contrary, finding a perfusion/innervation mismatch (normal perfusion in the area of decreased MIBG uptake) indicates a significant abnormality related to risk of arrhythmias and bad prognosis (Fig. 9–7).

Wolff-Parkinson-White Syndrome

For over 20 years, radionuclide ventriculography has been used to localize the atrioventricular accessory pathways associated with Wolff-Parkinson-White syndrome. So far, studies in this field have only included a limited number of patients. Moreover, the phenomenon of successful radiofrequency ablation accessory pathways is not fully understood, and the exact mechanisms leading to disappearance of pre-excitation still have not been worked out. Using scintigraphic imaging techniques, we have assessed the effects of atrioventricular accessory pathways radiofrequency ablation2 and found that the concordance of scintigraphy and endocardial mapping for localizing accessory pathways was broadly confirmed (Fig. 9–8). In addition, the ipsilateral ventricular ejection fraction could be improved following radiofrequency ablation, particularly in patients with left-sided accessory pathways. However, the main finding was that, despite successful ablation of the accessory pathways, unexpected persistence of local ventricular pre-excitation was occasionally unveiled by scintigraphy. The persistence of a zone of premature ventricular contraction as shown by scintigraphy, despite the disappearance of the delta wave on the surface ECG, has never been described. Such a phenomenon may indicate a persisting aborted conduction via the accessory pathway. One must postulate that the atrial insertion of the accessory connection is, at least partly, undamaged. However, it is apparent that the site of anterograde block as a result of ablation occurred near the ventricular interface.

Arrhythmogenic Right Ventricular Dysplasia

Recent clinical studies demonstrated that sudden death may be the first manifestation of arrhythmogenic right ventricular dysplasia (ARVD) and underscored the need for early diagnosis of this genetically determined heart muscle disease. The diagnosis of ARVD is based on the presence of mixed criteria established by the International Society and Federation of Cardiology (task force criteria).3 Most of the functional parameters used to diagnose ARVD can be measured by planar radionuclide angiography.4,5 In our hospital, we routinely use scintigraphy in patients with suspicion of ARVD (Figs. 9–9 and 9–10).

Resynchronization in Cardiac Heart Failure

The criteria for selection of heart failure patients for cardiac resynchronization therapy (CRT) (ie, ejection fraction, New York Heart Association class, and QRS width) have been validated by large-scale randomized studies. However, identification of the precise determinants of the resynchronization reserve (ie, the extent and the origin of the response to biventricular pacing) is lacking. Despite thorough investigation of electrical and mechanical dyssynchrony, identification of good candidates for biventricular therapy is still unsatisfactory. In addition, the confusion caused by the multiple Doppler measurement technique is increased by the use of different end points for defining response to CRT. Invasive and noninvasive electroanatomic investigations (mapping) are very informative in patients with intramyocardiac conductive disorders.6,7 We have used planar radionuclide ventriculography with phase analysis to identify the scintigraphic markers of improved cardiac function after triple-chamber stimulation. Another goal was to improve understanding of the electromechanical mechanisms underlying the effect of biventricular pacing. We found that all of the radionuclide cardiac dyssynchronism and contraction parameters improved following implantation in responder patients. In the nonresponder group, phase standard deviation, a marker of left ventricular dyssynchronism (Fig. 9–11), did not change during follow-up despite an improvement in interventricular dyssynchrony. Interventricular dyssynchrony was identified as an independent predictive factor of good clinical response with a practical cutoff value of 25.5°, a sensitivity of 91.4%, and a specificity of 84.4%. New scintigraphic markers of cardiac dyssynchrony for tailored therapy in heart failure patients and a better comprehension of how resynchronization works may be acquired in the future using high-resolution and high-sensitivity SPECT imaging with the most recent cameras for multiple slice analysis.

A regional disparity in myocardial sympathetic innervation has been found in patients with congenital long QT syndrome (LQTS), using iodine 123–MIBG.8 We have also used MIBG scintigraphy in patients with acquired LQTS.9 The heart/mediastinum activity ratio was calculated using an anterior view, 4 hours after injection of the isotope. In this way, we were able to demonstrate that patients with acquired LQTS had a reduction in sympathetic innervation (see Fig. 9–6). Indeed, much clinical and experimental evidence has proven that ventricular electrical stability may be threatened by an imbalance in the autonomic nervous system. Heterogeneous sympathetic activity could act by amplifying existing differences in transmural dispersion of repolarization in LQTS. In this way, heterogeneous sympathetic activity could be considered as having an amplifier role able to raise the propensity toward life-threatening arrhythmia and could partially explain the distinct severity of the disease within a family.

In the near future, new technical developments in nuclear imaging may help to improve the understanding of most of the heart electrical disorders. Further clinical studies are needed to evaluate the exact interest of gated blood pool SPECT global and local systolic measurements, compared with more traditional planar imaging, in the long-term follow-up of patients.