18 radionuclide imaging in heart failure

CHAPTER

18Radionuclide Imaging

in Heart Failure

Gautam V. Ramani and Prem Soman

to determine success of therapies, and potential necessity for devices. However, some clinically important concepts of ventricular function as-sessment have received insuffi cient emphasis in the literature. With multiple imaging modali-ties available for EF assessment, it is important to recognize that the lower limit of normality is modality-specifi c (Table 18-1).2 Furthermore, the intermodality variability is exaggerated in patients with LV systolic dysfunction.3 Thus, in the commonly encountered situation where pa-tients have had EF assessed by gated SPECT and echocardiography, the absolute numbers are likely to be different, with SPECT-derived EF gener-ally higher than echocardiography-derived EF. It is noteworthy that this intermodality variability in EF assessment was not taken into account even in

INTRODUCTION

Heart failure (HF) is highly prevalent, with an es-timated 5.7 million Americans living with the con-dition, and 670,000 new patients diagnosed each year.1 Despite many advances in pharmacotherapy and device therapy, the mortality of HF still ex-ceeds that of common cancers. It is anticipated that 80% of men and 70% of women <65 years of age who have HF die within 8 years.1 Several aspects of the pathophysiology of HF are gainfully evaluated by radionuclide imaging. The ubiqui-tous presence of myocardial single photon emis-sion computed tomography (SPECT) imaging in the academic hospital and community settings makes it potentially well suited for application to this highly prevalent condition. This chapter will discuss the established applications of radionu-clide cardiac imaging in HF, and also highlight some of its evolving applications in this area.

ASSESSMENT OF LV FUNCTION

The use of scintigraphic techniques for the as-sessment of ventricular function is discussed in Chaps. 7 and 10. In the context of the HF pa-tient, several management decisions including invasive device therapy with implantable defi bril-lators and biventricular pacing are predicated by accurate and absolute measurements of ejection fraction (EF). Since reproducibility is high, as-sessment of LV function over time can be used

Table 18-1

Normal Ranges for LVEF by Imaging Modality

MethodMean LVEF ± SD (%)

Lower Limit of Normal (%)

Gated SPECT 63 ± 10 44

Echocardiography 60 ± 5 48

MRI 65 ± 5 57

Angiography 67 ± 8 51

Values shown are derived from samples containing both genders. Data adapted from Rozanski et al.2

Heller_Ch18_253-266.indd 253Heller_Ch18_253-266.indd 253 6/8/10 1:42:10 PM6/8/10 1:42:10 PM

254 Section 4 Applications and Indications of Nuclear Cardiology

the design of large multicenter trials with specifi c EF requirements for inclusion criteria, such as the implantable cardioverter defi brillator (ICD) tri-als in HF. A powerful advantage of gated SPECT over echocardiography is that automated quanti-fi cation reduces the variability and error involved in subjective reader interpretation and eliminates the need for manual border tracing that is time consuming, and greatly infl uenced by the pa-tient’s body habitus.4 The two standard deviation limit of variability in the serial assessment of EF by high-dose, rest-gated Tc-99m SPECT studies is estimated to be approximately ±5%.5,6 The vari-ability in EF by different modalities suggests that serial imaging should be confi ned to the same im-aging modality.

DETERMINATION OF HF ETIOLOGY (DIAGNOSIS OF ISCHEMIC CARDIOMYOPATHY)

Coronary artery disease (CAD) is the underlying etiology for 60–70% of HF in the United States.7 Patients with ischemic HF have a worse progno-sis than those with non-ischemic cardiomyopathy, but the former may improve cardiac function dra-matically with revascularization, highlighting the critical importance of an accurate diagnosis. The literature regarding the use of SPECT for the di-agnosis of underlying CAD in LV dysfunction has primarily focused on patients with chronic HF, with only one recent study addressing the diagno-sis of CAD in new-onset HF.

In the setting of newly diagnosed LV systolic dysfunction, the identifi cation of underlying CAD and potential “at-risk” dysfunctional myocardium that might recover with coronary revasculariza-tion is critical. Although current practice guide-lines specifi cally mandate coronary angiography only in HF patients with angina, chest pain is of-ten absent in patients with ischemic cardiomyopa-thy, even those with signifi cant amounts of viable myocardium.8,9 Furthermore, the mere presence of CAD in the setting of a cardiomyopathy does not imply an ischemic etiology to the LV dysfunc-tion. What is traditionally referred to as signifi -cant CAD in the literature, that is, ≥50% luminal

stenosis, may be encountered in 15–30% of patients with a dilated cardiomyopathy, and thus may not be suffi ciently sensitive for accurate risk stratifi cation of the HF population. Felker et al. addressed this question, and tested a more strin-gent defi nition of ischemic cardiomyopathy for characterization of HF patients.10 The authors de-fi ned ischemic cardiomyopathy as LV dysfunction with one or more of the following angiographic criteria: signifi cant left main or proximal left ante-rior descending coronary artery stenosis, at least two-vessel disease with ≥70% stenosis or single-vessel disease with prior myocardial infarction, or prior coronary revascularization. For example, a patient with LV dysfunction and 70% stenoses of one major epicardial vessel without antecedent myocardial infarction or revascularization would be adjudicated to the non-ischemic cardiomyopa-thy group. Using these more restrictive criteria, patients with LV dysfunction and single-vessel CAD had a prognosis comparable to those with non-ischemic cardiomyopathy.

The recently published Investigation of Myo-cardial Gated SPECT Imaging (IMAGING) in Heart Failure trial specifi cally addressed the utility of gated SPECT as an initial diagnostic modality in the de novo acute HF setting.11 Two hundred and one patients hospitalized with new-onset HF were prospectively enrolled, and underwent exercise or pharmacologic SPECT during the index hospitalization. At the physician’s discre-tion, approximately one third of the patients un-derwent coronary angiography. Using a summed stress score (SSS) >3 to defi ne an abnormal study, SPECT had a sensitivity of 96% and a negative predictive value of 96% for the diagnosis of isch-emic cardiomyopathy using the criteria proposed by Felker, but was less accurate in detecting lim-ited-extent CAD (Table 18-2). Thus, this study provides proof of concept of the utility of myo-cardial SPECT for the initial characterization of patients presenting with severe new-onset HF. Such patients who have normal stress myocardial SPECT are very unlikely to have underlying ex-tensive CAD that is etiologically related to their HF (Fig. 18-1).

Several previous studies have established the utility of myocardial perfusion imaging for the


255Chapter 18 Radionuclide Imaging in Heart Failure

FIGURE 18-1 Categorization of HF etiology using technetium-99m sestamibi MPI. (A) Left ventricular (LV) dilation (abnormal LV systolic function by gated SPECT not shown) with large, fixed perfusion defects in the septum, anterior wall, apex, and inferior wall suggestive of CAD-related (“ischemic”) cardiomyopathy. (B) Normal stress–rest perfusion and LV size (normal LV EF on gated SPECT not shown) indicative of HF likely related to diastolic mechanisms. (C) LV dilation (with abnormal LV systolic function on gated SPECT, not shown) and normal perfusion suggestive of non-CAD related (“non-ischemic”).

Table 18-2

Performance Characteristics of Gated SPECT Tc-99m Sestamibi for CAD Diagnosis in Patientswith New-onset Heart Failure from the IMAGING in Heart Failure Study

CAD definition Any CAD: ≥70% stenosis in any coronary artery

Extensive CAD: stenosis ≥70% in the LM or proximal LAD, ≥70% in ≥2 major epicardial coronary arteries or any stenosis ≥70% with a prior MI or coronary revascularization

CAD prevalence by angiography 51% (n = 38) 36% (n = 27)

Sensitivity (95% CI) 82% (66–92) 96% (81–99)

Specificity (95% CI) 57% (40–72) 56% (41–71)

PPV 67% 55%

NPV 75% 96%

CAD: coronary artery disease; LM: left main coronary artery; LAD: left anterior descending coronary artery; NPV: negative predictive value; PPV: positive predictive value. Criteria for positive SPECT were summed stress score >3. Adapted from Ref 11 with permission.



diagnosis of CAD in chronic HF.12 Although many of these studies predated contemporary myocardial perfusion imaging, they uniformly demonstrated a very high negative predictive val-ue for excluding CAD. Using more contemporary imaging with gated Tc-99m SPECT, Danias et al. reported a sum stress score (SSS) >8 as 87% sensi-tive for detection of CAD, and that incorporating the sum difference score (SDS) with fi ndings of ischemia and regional wall motion abnormalities increased this to 94%.13 Thus, in the setting of both new-onset and established HF, and global dysfunction, a normal stress myocardial perfusion scan virtually excludes a diagnosis of ischemic LV dysfunction.12

One important issue remains: whether SPECT MPI can replace coronary angiography as the di-agnostic test for important underlying CAD in patients with new-onset HF. A major concern is that of balanced ischemia due to extensive CAD that might be missed or underestimated due to the fact that the MPI assessment of regional myo-cardial perfusion is relative. While it is unlikely that a patient with severe and extensive CAD will have no angina and a normal and rest/stress ECG and MPI, given the critical importance of exclud-ing CAD in this population and the lack of sub-stantive clinical trial data with MPI, patients with new-onset HF continue to undergo diagnostic coronary angiography for this purpose. Therefore, although evolving data increasingly suggest that this might be the case, only a large prospective clinical trial can defi nitively answer this question.

From a practical perspective, new-onset HF patients with angina and/or an intermediate to high probability of CAD (based on age, symp-toms, and risk factors) should undergo diagnos-tic coronary angiography. HF patients with a low probability of CAD, with clinical circumstances suggestive of non-ischemic LV dysfunction, can safely have a rest/stress MPI as the initial diagnos-tic test. In patients with known CAD being evalu-ated for new-onset or established HF, a rest/stress MPI provides invaluable information on ischemia, viability, and quantitative LV function that can be used to drive important management decisions such as the choice between targeted percutaneous and surgical revascularization.

It is important to recognize that mild perfusion defects are common in non-ischemic cardiomyo-pathy, may refl ect true physiological phenomena such as myocardial fi brosis or abnormal coronary vasodilator reserve, and have prognostic signifi -cance.14 Inferior defects may also be caused by diaphragmatic attenuation and attenuation from LV dilatation. Attenuation correction is helpful in identifying soft tissue artifacts in SPECT imaging, but its effect on diagnostic accuracy for CAD has not been specifi cally tested in the HF population.

ASSESSMENT OF VIABILITY AND PREDICTING RESPONSE TO REVASCULARIZATION

Regional LV dysfunction in ischemic cardio-myopathy is caused by one or more specifi c pathophysiological processes: myocardial infarc-tion and related remodeling, repetitive stunning, or hibernation. Stunned myocardium refers to regional dysfunction that persists following reso-lution of acute ischemia. Prolonged periods of severe ischemia may result in prolonged dysfunc-tion. Thus, repetitive ischemic attacks may induce chronic myocardial dysfunction in the setting of normal or mildly reduced resting perfusion (re-petitive stunning). Importantly, although resting fl ow may be preserved in myocardial stunning, coronary fl ow reserve is always abnormal. There maybe a temporal progression from stunning, with near-normal fl ow, to a state of hibernation, with impaired resting perfusion. Hibernating myocardium refers to chronically hypoperfused myocardial segments that reduce their metabolic and contractile function as a protective and adap-tive mechanism against irreversible cellular injury. There is energy depletion and downregulation of energy turnover in hibernating myocardium, which may trigger tissue degradation and myo-cyte loss. Histopathologic changes are evident at the level of the cardiac myocyte.15

The recognition that dysfunctional but vi-able myocardium recovers function following revascularization was a major breakthrough in the treatment of ischemic cardiomyopathy.16,17 In HF patients with LV systolic dysfunction and



signifi cant amounts of residual myocardial vi-ability, prompt revascularization may lead to improvement in quality of life,18,19 regional and global LV function,20 and survival.21,22 Allman et al. performed a meta-analysis of 24 studies in-volving 3088 patients investigating late survival in patients with ischemic cardiomyopathy treated with revascularization or medical therapy.23 Vi-ability testing was performed using positron emis-sion tomography (PET), SPECT, or dobutamine stress echocardiography (DSE). In patients with myocardial viability (42% patients), there was a marked 79% reduction in annual mortality (16% vs. 3%), and the greatest benefi t was seen in pa-tients with the poorest LV function and preserved viability. Furthermore, patients without viability demonstrated no incremental benefi t with revas-cularization (Fig. 18-2).18

The literature on the interaction between myo-cardial viability and outcome of therapy is charac-terized by a conspicuous lack of randomized con-trol trial data, and consists mostly of observational data and meta-analyses. The clinical issue in ques-tion however is one of profound relevance. On the one hand, the perioperative mortality is high in patients with severe LV systolic dysfunction, ranging from 1.6% to 37% in clinical series.24,25 On the other hand, patients with the lowest EF appear to derive the greatest survival benefi t when a substantial amount of residual myocardial via-

bility is present.24 Thus, appropriate selection for revascularization is critical among patient with severely depressed LV function where periopera-tive mortality and potential for benefi t are both high. The probable mechanistic basis of the inter-action between myocardial viability and outcome of therapy in HF was demonstrated in a study by Senior et al. who showed that revascularization of viable myocardium results in an improvement in the sphericity index of the LV, and a reduc-tion in end-systolic volume, changes which are indicative of reverse remodeling and associated with improved survival.26 However, other studies have failed to demonstrate a mechanistic role for viability in the interaction between therapy and outcome in HF.27,28 It is important to note that prognostic benefi t from revascularization may ac-crue in the absence of improvement in global LV function.29

Viability exits along a continuum of extent and severity, and not all dysfunctional segments with viability improve function after revasculariza-tion. In a study by Schinkel et al., one third of dysfunctional segments improved regional func-tion and 40% of patients demonstrated improved LVEF following revascularization.30 A large meta-analysis of patients with ischemic cardiomyopathy who underwent DSE identifi ed 53% of segments that improved with revascularization, with 84% of these showing evidence of viability pre-revascular-ization.31 Ragosta et al. showed that post-revas-cularization functional improvement was related to the number of viable segments, and that the presence of viability in 7 of 15 myocardial seg-ments in patients with LV systolic dysfunction was predictive of an improvement in EF follow-ing revascularization (Fig. 18-3).32 Thus, it ap-pears that the presence of a critical threshold mass of viable myocardium will predict improved pa-tient outcome following revascularization, and that a determination of the extent and severity of myocardial viability in dysfunctional segments in addition to the underlying coronary anatomy is essential for making decisions regarding revas-cularization. Furthermore, the absence of angina is a poor surrogate of the absence of myocardial viability9 and the ECG is highly non-specifi c for viability determination, as Q waves on the ECG

3.2%

0Viable

Mor

talit

y

Non-viable

2468

1012141618

16%

7.7%6.2%

RevascularizationMedical

FIGURE 18-2 Death rates for patients with and without myocardial viability treated by revascularization or medical therapy. There is 79.6% reduction in mortality for patients with viability treated by revascularization (P = .0001). In patients without myocardial viability, there was no significant difference in mortality with revascularization vs. medical therapy. (From Allman et al.23 with permission.)



predicted irreversibility in only 43% of patients compared to PET.33

Radionuclide techniques for the assessment of myocardial viability include SPECT and PET (Table 18-3). The property of redistribution may confer a unique advantage for thallium-201 for viability detection with SPECT since the contin-ued active uptake of tracer in areas of initial severe hypoperfusion is an indication that the myocyte is alive. The simplest protocol involves detec-tion of a perfusion defect on rest imaging, with evidence of redistribution on delayed imaging at 4 h.34 This protocol has high specifi city, but low sensitivity, and several modifi cations have been proposed that allow more time for redistribution (rest-24-h redistribution imaging) or supplement blood levels of thallium-201 with a reinjection at 4 h to facilitate tracer uptake into hypoperfused but viable areas (rest-redistribution reinjection imaging).35 Tl-201 markers of viability in dys-functional segments include normal rest perfu-sion, rest defects with redistribution on delayed

imaging with or without reinjection of additional tracer, and stress-induced ischemia. In addition, fi xed defects with signifi cant thallium-201 uptake (>50% of maximum) are also considered viable.

Table 18-3Imaging Modalities Used and Mechanisms for Viability Detection

Imaging Modality Indicator of Viability

Gated SPECT Myocardial perfusion, regional function

Positron emission tomography (F-18 FDG)

Metabolism (glucose)

Dobutamine echocardiography Contractile reserve

Myocardial contrast echocardiography

Microvascular integrity

Delayed-enhancement MRI Absence of scar

CT Myocardial perfusion, regional function

FIGURE 18-3 Relationship between number of viable asynergic segments and improvement in function post-revascularization. (Adapted from Ragosta et al.32 with permission.)

Change in TI-201 uptake8 weeks after CABG

−.20

−.15

−.10

−.05

0

.05

.10

.15

.20

.25

.30

0 2 4 6 8 10 12

Number of viable, asynergic segments

p < 0.01 (all data)

Cha

nge

in e

ject

ion

frac

tion

Improved

No change or worse

No late thallium



Overall, thallium-201 imaging has a reported 90% and 54% sensitivity and specifi city, respectively, for detecting viable myocardium. The recovery of function after revascularization is linearly re-lated to the amount of preoperative thallium-201 uptake. When compared to myocardial segments that fulfi ll the rest-redistribution criteria for via-bility, those that demonstrate stress-induced isch-emia are most likely to recover function following revascularization.36

Technetium-99m tracers diffuse across the cellular membrane passively, but their retention within the myocyte is dependent on sequestra-tion within the mitochondria. Thus, the uptake and retention of these agents is an indicator of myocyte viability.37,38 The absence of redistribu-tion of Tc-99m ligands was initially thought to be a disadvantage for viability assessment, especially in myocardial segments subtended by a severely stenosed coronary artery and thus severely hy-poperfused. However, comparative studies sug-gest that increased extraction of Tc-99m sestamibi

in low-fl ow areas results in tracer uptake compa-rable to redistribution Tl-201 images, and that rest Tc-99m imaging appears to have comparable accuracy to rest-24-h redistribution Tl-201 for detection of myocardial viability.39–41 Areas with uptake ≥60% of maximum are considered viable. Nitrate enhancement with oral or sublingual ni-troglycerin 5 min prior to Tc-99m injection and the quantifi cation of perfusion optimizes viability detection with Tc-99m.42 Improved count statis-tics with Tc-99m compared to Tl-201 allow high-quality gated acquisitions more readily with the former. Adding data on regional function to the perfusion data signifi cantly improved the accuracy of viability detection in a study by Levine et al. (Fig. 18-4).43

PET has the advantage of being able to mea-sure both myocardial perfusion (using 13N am-monia, 15O water, or 82Rubidium) and cellular metabolic activity (using F-18-labeled deoxyg-lucose, FDG, and C-11-labeled fatty acids, such as palmitate and acetate). Areas that demonstrate

Sen

sitiv

ity

Spe

cific

ity

NP

V

Acc

urac

y

Per

cent

p < 0.05 p < 0.05

p = NS p = NS

0

20

40

60

80

100

PerfusionPerfusion + WM

FIGURE 18-4 Combined assessment of perfusion and function with Tc-99m sestamibi ECG-gated SPECT myocardial perfusion imaging improves the sensitivity and accuracy for determining viability. (Adapted from Levine et al.43 with permission. Copyright © Elsevier.)



normal perfusion on PET (or SPECT) are viable. However, in presence of ischemia, there is a shift in myocyte metabolism away from free fatty ac-ids to glucose. Thus, evidence of normal or in-creased glucose metabolism in a hypoperfused region of the myocardium indicates viability (“mismatch”).44 Distinct patterns of perfusion and metabolism have been described in the vari-ous pathophysiological states underlying ischemic LV dysfunction:

1. Stunned: Abnormal regional function, with normal perfusion and metabolism (fl ow/ function match).

2. Hibernating: Abnormal regional function, with reduced perfusion and normal metabo-lism (fl ow/function mismatch).

3. Scar: Abnormal regional function, perfusion, and metabolism (fl ow/function match).

4. Normal: Normal regional function, perfusion, and metabolism.

The extent of FDG uptake in patients with ischemic cardiomyopathy is predictive of im-provement in LVEF following revascularization.45 Similarly, the degree of scar burden identifi ed by FDG–PET is predictive of a lack response to revascularization, with larger scar burdens associ-ated with less functional improvement.27 A meta-analysis involving 598 patients who underwent FDG–PET reported a sensitivity of 93% and spec-ifi city of 58% in predicting regional improvement in contractile function; when only studies that included both perfusion and metabolism were in-cluded, sensitivity was reduced to 88%, but speci-fi city was increased to 76%.46

Despite minor differences in the sensitivity and specifi city of viability detection of these mo-dalities, there is a lack of comparative data on pa-tient outcome. A prospective, randomized, clini-cal study failed to demonstrate any difference in patient outcome when the decision to perform coronary revascularization in ischemic cardiomyo-pathy was made based on blinded PET or SPECT-derived viability data.47 A recently published study evaluating SPECT in patients with ischemic car-diomyopathy identifi ed three features associated with increased mortality: stress-induced ischemia, abnormal functional capacity, and evidence of

viability. Importantly, there were no differences in coronary angiographic criteria between the groups that impacted survival.48

There is marked institutional variability in the modalities used for viability testing. As a gener-al rule, test availability and operator experience are most important when choosing among spe-cifi c imaging tests. In many laboratories, SPECT MPI is the fi rst approach. In patients who have dual-isotope rest Tl-201/stress Tc-99m MPI, the presence of a large resting Tl-201 defect is an indication for delayed imaging to assess viability. In patients undergoing low-dose rest/high-dose stress Tc-99m MPI, the presence of viability in areas of resting defect is inferred if the quantita-tive uptake of Tc-99m is >60% of maximum, or if there is preserved regional function. When the indication for MPI is solely the assessment of vi-ability, a rest-delayed redistribution Tl-201 is usu-ally preferred. Delayed-enhancement MRI may have an advantage in detecting residual viability in areas that appear scarred by echocardiography or SPECT, and should be used preferentially when information on viability is the driving force be-hind the decision to revascularize a patient with severe LV dysfunction.

ASSESSMENT OF SYNCHRONY OF LV CONTRACTION

There are ongoing efforts to optimize patient selection for cardiac resynchronization therapy (CRT) that has been shown to improve mortality and morbidity in selected patients with HF.49–51 There are evolving data for the use of phase analy-sis (PA) of gated SPECT MPI for the assessment of LV mechanical synchrony.52 The approach is based on performing a Fourier transform of time–activity curves of myocardial counts obtained three-dimensionally from each myocardial voxel. Since myocardial brightening is a surrogate for thickening (partial volume effect), these curves can be used to determine the onset of mechani-cal contraction (OMC) for each myocardial voxel and, thereby, the synchrony of LV contraction. Typical parameters are shown in Fig. 18-5. Prelim-inary data indicate high reproducibility,53 which



Gated SPECTor PET data

First fourier harmonicapproximation

200

100

Cou

nts

00 1 2 3

Cardiac cycle (frame)4

Phase = 46.3°

5 6 7 8

Gated short-axisimages

Regional wallthickening curve

Reconstructionand reorientation

3D sampling forregional maximum

counts

FIGURE 18-5 First-harmonic Fourier analysis of regional myocardial thickening. The points in the plot represent counts from one myocardial voxel at each frame of the cardiac cycle. The curve represents the Fourier transform of the individual points. The horizontal line represents the average count intensity of the voxel over one cardiac cycle. The point at which the upslope of the curve intersects the horizontal line represents the onset of mechanical contraction (OMC) of this particular myocardial voxel. In this way, the phase of OMC of each myocardial voxel can be determined.

FIGURE 18-6 Example of serial assessment of dyssynchrony before (A, left panel) and immediately after (B, right panel) CRT. The top panel shows a phase polar map (left) and a phase histogram (right). The left image in the bottom panel shows the site of initial contraction of the LV as a blackout area(s) on a perfusion polar map, corresponding to the position of the cursor on the histogram (arrows). The bottom panel also shows the quantitative results of dyssynchrony assessment. This patient has a right ventricular pacemaker at baseline. The pre-CRT image shows a heterogeneous phase polar map, with the onset of contraction at the LV apex. The histogram and quantitative indices indicate the presence of LV dyssynchrony. Following CRT, the phase polar map is more homogenous, and LV contraction is initiated almost simultaneously at the apex and posterolateral wall, as would be expected with biventricular pacing. The histogram and quantitative measure indicate significant improvement in LV synchrony. In this patient, LV ejection fraction improved from 34% pre-CRT to 44% post-CRT.

is an advantage over echocardiography-based ap-proaches.54 A PA approach has also been applied to radionuclide ventriculography.55 Examples of imaging synchrony are shown in Fig. 18-6.

EVOLVING APPLICATIONS AND FUTURE DIRECTIONS

Risk stratifi cation with 123I-metaiodobenzylguani-dine (MIBG): The HF syndrome is characterized by autonomic dysregulation, which is thought to underlie pathophysiological processes such as sudden death.56 MIBG is a norepinephrine analog that is taken up by myocardial presynaptic nerve terminals by mechanisms identical to norepineph-rine, but is retained largely unmetabolized, and can therefore be used for scintigraphic imaging, as discussed in some detail in Chap. 12.57 Sym-pathetic downregulation in HF results in de-creased myocardial uptake of MIBG. The heart/ mediastinum (H/M) ratio on early (5 min) planar imaging and the washout rate calculated from the H/M ratio as well as regional perturbations in



sympathetic activity identifi ed by SPECT imag-ing with MIBG may be useful markers of disease and therapeutic response in the setting of HF (Fig. 18-7).58 Early studies of MIBG indicated powerful prognostic capability in HF, beyond that provided by LVEF.59 An exciting and poten-tially clinically useful attribute of MIBG imaging is its potential ability to identify the specifi c risk of arrhythmia-related mortality as opposed to total mortality, and thus drive device therapy. Prelimi-nary results from the recent Adreview Myocardial Imaging for Risk Evaluation in HF (ADMIRE-HF study)60 of 964 patients with NYHA class II/III HF, LVEF <35%, and contemporary medical therapy demonstrated 18-month survival free of NYHA class progression, life-threatening arrhyth-mia, or cardiac death that was signifi cantly higher in patients with normal scans (85% vs. 63%), and a negative predictive value of 98% for cardiac death at 2 years. Thus, MIBG scintigraphy may be use-ful for identifying a low-risk subgroup of patients among those who currently fulfi ll criteria for de-vice therapy.

123I-(p-iodophenyl)-3-(R,S)-methylpentade-canoic acid (BMIPP) imaging of myocardial metabolism: As described previously, ischemia is associated with a shift in myocardial metabolism away from free fatty acids and toward glucose me-tabolism. The methyl-branched fatty acid tracer BMIPP has been the subject of recent research. In dysfunctional myocardium, a disproportionately

greater decrease in BMIPP relative to a standard perfusion tracer suggests ischemia from repetitive stunning, and correlates with recovery of function following revascularization. Conversely, a reduc-tion in both BMIPP uptake and perfusion sug-gests scar. Additional information about BMIPP imaging is contained in Chap. 12.

LV shape indices: The LV sphericity index (ratio of LV diastolic short and long axes) is a quantita-tive measure of LV deformation. Adverse remod-eling is typically refl ected in the transformation of the elliptical left ventricle into more spherical structure and is associated with a poorer prog-nosis.61 While traditionally assessed by echocar-diography, emerging data suggest that SPECT assessments of sphericity index are accurate, and correlate well with durable outcomes such as HF-related hospitalizations.61

Molecular imaging of HF pathophysiology: Patients demonstrate a heterogeneous response to HF pharmacotherapy, including beta blockers and angiotensin-converting enzyme (ACE) in-hibitors. Molecular and metabolic imaging in HF helps identify specifi c processes that may predom-inate in individual patients or patient groups, and explain the heterogeneity in response to therapy. Small studies utilizing radiolabeled annexin-V, a phosphatidyl-binding protein that is translo-cated to the cell surface during apoptosis, have successfully demonstrated the capacity to image apoptosis, which has potential applications in

FIGURE 18-7 Serial planar imaging with 123I-MIBG showing improvement in heart to mediastinum ratio with heart failure therapy. (From Agostini et al.58 with permission.)



myocarditis, and acute rejection.62 Studies utiliz-ing radiolabeled 18F-captopril and 18F-lisinopril to detect paracrine ACE effects on the failing heart are ongoing.63

CONCLUSION

Nuclear cardiology techniques are well suited to answer several key clinical questions to assist in the diagnosis and management of HF patients. Established nuclear techniques provide an ac-curate assessment of LV EF, can reliably predict the presence or absence of underlying CAD, and detect viable myocardium to help drive decisions regarding coronary revascularization. Ongoing investigation into novel tracers, coupled with im-provements in image acquisition, processing, and software, promises to expand the indications for radionuclide imaging in HF.

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1. A 65-year-old male with a remote history of coronary artery disease presents to the hospital with chest pain. He rules out for myocardial infarction by serial enzymes, and undergoes pharmacologic stress SPECT im-aging utilizing a rest Th-201 and stress Tc-99m protocol. Perfusion images demonstrate fi xed anterior and inferior defects, with no ar-eas of reversible ischemia. There are associat-ed anterior and inferior regional wall motion

abnormalities on gated SPECT, and overall LVEF is reduced at 25%. The most appropri-ate next step is:a. referral for coronary angiography.b. in the absence of ischemia, optimization

of medical therapy.c. have the patient return for 24-h delayed

Th-201 imaging to assess for viability.d. contrast-enhanced MRI for assessment of

LV function and viability.

REVIEW QUESTIONS



2. A 50-year-old male presents to the emergen-cy room complaining of progressive dyspnea, fatigue, and edema. ECG demonstrates left bundle branch block (LBBB), and cardiac en-zymes are elevated. Urgent coronary angiog-raphy discloses severe three-vessel coronary artery disease with suitable targets for surgi-cal and percutaneous revascularization, and ventriculography demonstrates mild mitral regurgitation and severe LV systolic dysfunc-tion, with an LVEF of 15%. The most appro-priate next step in the management of this patient involves:a. consultation with surgery for CABG.b. staged percutaneous coronary interven-

tion (PCI).c. initiation of the process of heart transplant

evaluation.d. FDG/rubidium PET imaging for assess-

ment of myocardial viability.e. initiation of beta blockade and referral for

ICD placement.

3. All of the following statements are true except:a. LV dilatation commonly causes false-

positive anterior defects on SPECT imaging.

b. SPECT quantifi cation of LVEF is highly accurate and reproducible.

c. Mild perfusion defects are commonly en-countered in dilated cardiomyopathy.

d. SPECT imaging can reliably exclude un-derlying coronary artery disease as the eti-ology for newly diagnosed heart failure.

4. Which of the following statements is false re-garding rubidium–FDG PET imaging?a. A perfusion/metabolism mismatch sug-

gests viable myocardium.b. Myocardial stunning will demonstrate a

fl ow/function match pattern.c. Myocardial scar will demonstrate a fl ow/

function match pattern.d. Myocardial ischemia is associated with a

shift from metabolism from utilizing glu-cose to free fatty acids.

5. The following statements regarding heart failure and CAD are true except:a. Patients with HF and single-vessel ob-

structive CAD have a similar prognosis to HF patients with normal coronary arter-ies.

b. Mild perfusion defects commonly seen in patients with non-ischemic cardiomyopa-thy have prognostic signifi cance.

c. The addition of data on regional LV func-tion to perfusion data improves identifi ca-tion of extensive CAD.

d. A normal rest/stress SPECT MPI ex-cludes CAD in patients with heart failure.


18 radionuclide imaging in heart failure

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