1. NUCLEAR REPORT:
Imaging of Cardiac Innervation,
Amyloidosis,
Sarcoidosis
DINA CARISSA M. LUNA
Cardiology Fellow Level II

2. REFERENCE

3. CARDIAC
INNERVATION

4. Cardiac autonomic innervation
• may play an important role in the regulation of
myocardial perfusion, heart rate, and contractile
function
• Abnormal neuronal function is often seen in
various heart diseases, such as heart failure (HF),
myocardial ischemia, infarction, and arrhythmias.
• The cardiac autonomic nervous system is controlled
by circulating chemicals and by both sympathetic
and parasympathetic innervations
• Their major transmitters are norepinephrine (NE)
and acetylcholine

5. Cardiac autonomic innervation
• Sympathetic innervation
• originates from the right and left stellate ganglia, which
provide the sympathetic nerves to form the cardiac plexus of
the heart.
• The sympathetic nerve fibers travel parallel to the vascular
structures on the epicardial surface of the heart and
penetrate the underlying myocardium in a manner similar to
the coronary vessels
• Parasympathetic innervation
• originates from the medulla and passes through the right and
left vagal nerves, which further divide into the superior and
inferior cardiac nerves.
• Parasympathetic nerve fibers primarily modulate sinoatrial
nodal and atrioventricular nodal functions and innervate the
atria

6. Cardiac autonomic innervation
• Radionuclide imaging is
suitable for assessing global
LV and regional myocardial
autonomic neuronal system in
vivo with use of suitable
radiopharmaceuticals
• Among the tracers,
sympathetic
neurotransmission imaging
using the I-123-labeled NE
analog
metaiodobenzylguanidine
(MIBG) has been widely used
in experimental and clinical

7. Radiotracers Used for the Evaluation of
Autonomic Nervous System Functions
Sympathetic Nerves
• Presynaptic
• 123I-metaiodobenzylguanidine (MIBG)
• 11C-hydroxyephedrine (HED)
• 18F-metaraminol
18F-dopamine 11C-threohydroxyepinephrine 11C-
epinephrine
• Postsynaptic
• 123I-iodocyanopindolol (ICYP) 11C-practolol
11C-propranolol
11C-CGP 12177
• 11C-CGP 12388 11C-prazocin

8. Basic Aspects of I-123-Labeled
MIBG
• MIBG - meta-positioned-iodolabeled
analog of the adrenergic blocking
antiarrhythmic drug guanetidine
• After intravenous administration,
MIBG is taken up by sympathetic
nerves in a similar manner to NE but
is not metabolized
• Most of the MIBG is actively taken up
into neuronal vesicles in an Na-
dependent specific process (uptake
1), and the remaining MIBG goes into
the neuron terminals by passive
diffusion (uptake 2)
• the ability of sympathetic nerve
terminals to take up catecholamine
is a more sensitive index of nerve
function and viability than the
catecholamine content.

9. MIBG Data Acquisition
• Administration of 111 to 148 MBq (3–4 mCi) of I-123- labeled MIBG at
rest
• Myocardial images are usually obtained at 10 to 15 minutes (early phase)
and 3 to 4 hours (late phase) to calculate the myocardial uptake and
washout
• To obtain satisfactory SPECT images, particularly for patients with severe
HF and/or obese patients, some investigators have recently used up to
370 MBq (10 mCi)

10. MIBG Data Analysis
• Planar imaging is used to assess
the global LV tracer uptake.
• Two regions of interest (ROIs)—
one irregular region in the whole
LV myocardium, and the other a
rectangular region in the upper
third of the mediastinum—are
used to calculate the heart-to-
mediastinum count ratio (H/M
ratio)
• H/M ratio - used as an index of
the myocardial MIBG uptake

11. MIBG Data Analysis
• High liver activity may superimpose myocardial
activity in the planar images and thus affect the
interpretation of MIBG myocardial distribution,
particularly in the inferior region.
• To minimize such superimposition, SPECT is preferred
for the assessment of regional MIBG distribution
• Prone data acquisition may improve the MIBG SPECT
image quality, similar to myocardial perfusion SPECT.
• For SPECT image analysis, the MIBG defect score has
been applied to estimate the severity of the myocardial
MIBG defect.
• The MIBG SPECT may also be compared either visually
or quantitatively to perfusion SPECT images to assess
perfusion–innervation match/mismatch patterns

12. the normal H/M ratio
ranged from 2.0 to 2.7 for
the early image and 2.1 to
2.9 for the delayed image.

13. Treatment Monitoring
• Adrenergic neuronal dysfunction seems to be one
of the major targets for HF therapy to improve
cardiac function and patient outcome.
• A number of studies suggested that cardiac MIBG
uptake improves after beta-blocker or other
therapies
• Fukuoka et al. showed improvement of MIBG
uptake and washout after beta-blocker therapy in
patients with dilated cardiomyopathy
• The H/M ratio on the delayed images was a good
predictor of the response to the beta-blocker
therapy

14. Predicting Life-Threatening
Arrhythmias
• MIBG may identify the areas of denervation
hypersensitivity, which may likely cause ventricular
arrhythmias.
• In a prospective study using both MIBG and resting
myocardial perfusion imaging in patients who
received ICD treatment
• a low H/M ratio on MIBG and a large perfusion defect were the
most powerful predictors of ICD discharge
• Used for risk stratification of patients who may need prophylactic
ICD therapy.
• Denervation and myocardial scar were both important predictors
for ICD discharge and fatal arrhythmias as well

15. Predicting Life-Threatening
Arrhythmias
• ADMIRE-HF substudies
• analyzed SCD events; reported that LV mechanical
dyssynchrony was associated with SCD in patients with
HF.
• patients who had high H/M ratio (≥1.6) were less likely
to suffer SCD
• a low H/M ratio (<1.6) and a high summed stress score
(>8) evaluated by myocardial perfusion SPECT were
independent predictors of arrhythmic events among
nonischemic cardiomyopathy patients

16. Diabetes Mellitus and Other
Disorders
• Cardiac autonomic neuropathy has most frequently
been studied in patients with diabetes mellitus
• Both early and late H/M ratios were significantly
reduced in patients with diabetes compared with
control subjects
• Cardiac autonomic dysfunction was demonstrated in
Brugada syndrome, essential hypertension, and
hypertrophic cardiomyopathy using MIBG
• Abnormal adrenergic nerve function was noted in
ischemic heart disease. The degree of coronary artery
disease was associated with MIBG uptake and inversely
related to MIBG washout.
• chronic renal failure was associated with high MIBG
washout

17. Sympathetic Neuronal Imaging
Using PET
• PET has great advantages in terms of higher spatial
resolution and higher sensitivity with better
quantification of tracer concentration than SPECT
• Sympathetic neuronal PET tracers - allow more detailed
analyses of neuronal signaling compared to MIBG
• C-11 epinephrine
• C-11 phenylephrine
• HED - most widely used PET tracer for cardiac neuronal
imaging; has high affinity for presynaptic neuronal
catecholamine transporter (uptake 1) without being
metabolized by monoamine oxidase or catechol-O-methyl-
transferase (COMT)
• HED-PET distribution in the myocardium is quite
homogenous compared to MIBG-SPECT, mainly due to
suitable attenuation and scatter correction by PET

19. Key Points
• I-123-labeled metaiodobenzylguanidine (MIBG) is an
analog of the false neurotransmitter guanetidine that
reflects sympathetic nervous function
• The semiquantitative parameters heart-to-
mediastinum ratio (H/M ratio) and washout rate are
used to evaluate cardiac sympathetic nervous function
in MIBG imaging
• Impaired cardiac sympathetic nervous function is
potently associated with a poor prognosis in patients
with heart failure (HF)
• Beta-blocker therapy for HF improves cardiac
sympathetic nervous function
• MIBG imaging and C-11 hydroxyephedrine positron
emission tomography (HED PET) can predict fatal
arrhythmia and sudden cardiac death

20. Key Points
• Cardiac autonomic dysfunction is often observed in
patients with diabetes mellitus
• HED is a PET tracer that has excellent image
resolution and can be used to quantitatively assess
regional presynaptic sympathetic nervous function
• More clinical experience is warranted to confirm
the clinical impact of sympathetic nervous function
imaging for the management of HF and arrhythmia
patients

21. AMYLOIDOSIS

22. Amyloidosis
• caused by deposition of insoluble nonbranching protein
aggregated as amyloid fibrils in the extracellular space
of different organs.
• Cardiac amyloidosis - increased thickness of the left
ventricle (LV)  heart failure (HF)
• Treatment of cardiac amyloidosis: symptomatic HF
therapy combined with specific therapy and
chemotherapeutic regimens to curtail light- chain
production.
• When the heart is involved, overall mortality and
treatment-related mortality are increased (10–15% risk
of major complications during stem cell mobilization
and a 2–10% risk of mortality).

23. Diagnosing Amyloidosis
• ECG and echocardiographic features can be
nonspecific.
• Endomyocardial biopsy with
immunohistochemistry and/or mass spectroscopy
for precursor protein identification
• Definitive diagnosis
• Invasive; does not provide sufficient information about
the extent or distribution of amyloid in the heart
• prone to sampling error (false-negative results)
• cannot be used to assess response to therapy.
Therefore, a noninvasive test that can diagnose cardiac amyloid, differentiate the
different subtypes, quantify the extent of myocardial amyloid infiltration, and
monitor disease progression and response to treatment is essential.

24. Radiotracers
• Cardiac ATTR amyloidosis has been imaged clinically since the 1980s
using bone-seeking radiotracers (99mTc pyrophosphate [PYP]15 or
99mTc 3,3-diphosphono-1,2-propanodicarboxylic acid [DPD])2
• Bone-seeking radiotracers are taken up by the myocardium via a
calcium-mediated mechanism and are widely used in clinical practice.
• 123I- metaiodobenzylguanidine [MIBG]) have been used in familial
amyloidosis
• used to image cardiac denervation in familial amyloid polyneuropathy
(characterized by sensorimotor and autonomic neuropathy, cardiac conduction
defects, and infiltrative cardiomyopathy).
• Amyloid binding radiotracers
• 99mTc-aprotinin,18,19 123I-labeled serum amyloid P component (SAP),
(Pittsburgh B compound),22 18F-florbetapir,23 18F-flumetamol, and 18F-
florbetaben
• Amyloid binding PET radiotracers
• (11C PiB,22 18F-florbetapir,23 18F- flumetamol, and 18F-florbetaben) approved
by the U.S. Food and Drug Administration (FDA) to image beta-amyloid in the
brain (Alzheimer’s disease)

25. Protocols
• Cardiac amyloid imaging
• performed using 20 to 25 mCi 99mTc PYP or 99mTc DPD imaging
with whole-body or cardiac imaging 60 minutes to 2.5 hours after
injection of radiotracer using chest SPECT imaging protocols
• Images are reconstructed using standard 99mTc protocols and
displayed using standard short-axis (SA), vertical long-axis (VLA),
and horizontal long-axis (HLA) views
• 123I MIBG imaging
• Planar and SPECT images are obtained early (15–30 minutes) and
late (3 hours) after injection of 3 to 10 mCi of 123I MIBG
• Radiotracer is injected with the patient supine and images are
acquired
• Patients are typically imaged NPO, with certain restrictions on
medications that may interfere with norepinephrine uptake
mechanisms, including opiates, tricyclic antidepressants,
sympathomimetic agents, and certain antihypertensive agents

26. Image Interpretation
• 99mTc PYP and 99mTc DPD images
• reported visually as positive or negative with a comparison to
bone/sternal uptake
• no uptake (Grade 0)
• less than sternal uptake (Grade 1)
• equal to sternal uptake (Grade 2)
• greater than sternal uptake (Grade 3)
• Grade 2 or greater Tc99 PYP or Tc99m DPD uptake is considered a
positive scan
• A quantitative analysis can be performed with a region of interest
(ROI) on the heart and another ROI in the contralateral lung field
to compute a heart-to-contralateral- lung ratio
• Myocardial uptake of 123I MIBG
• assessed visually (planar or SPECT) and using a heart-to-
mediastinal ratio
• The early and late images are compared to derive the
washout rate from the myocardium to assess myocardial
retention of norepinephrine

27. Diagnosis
• Imaging with 99mTc DPD and PYP is helpful
distinguish Al from ATTR Amyloidosis
• A heart-to-contralateral-lung ratio of at least 1.5
had 97% sensitivity and 100% specificity for
identifying ATTR cardiac amyloidosis.
• 99mTc PYP shows promise in discerning ATTR from
AL amyloid.

29. Diagnosis
• Myocardial denervation has been studied as an early
marker of cardiac involvement in patients with familial
amyloid polyneuropathy
• Cardiac 123I-MIBG uptake was significantly decreased
in familial amyloid polyneuropathy patients with no
difference in washout rates despite preserved LV
systolic function and cardiac perfusion.
• These findings suggest that subjects with familial
amyloid polyneuropathy can be identified early by
imaging myocardial innervation using 123I-MIBG before
clinical heart disease and echocardiographic changes
occur.
• Myocardial infiltration with amyloid may result in
coronary microvascular dysfunction.

30. Prognosis
• Radionuclide imaging offers prognostic value in
patients with TTR- mediated amyloidosis—familial
amyloid cardiomyopathy and familial autonomic
neuropathy
• Heart-to-whole-body ratio (>7.5) combined with LV
wall thickness (>12 mm) was associated with the
highest rate of major adverse cardiac events
(cardiovascular death or hospitalization or stroke)

31. Strengths and Limitations of
Noninvasive Imaging Tests
• Echocardiography
• universally available and widely used
• Increased myocardial wall thickness, restrictive physiology, and
characteristic strain patterns (apical sparing) are typical for
amyloidosis
• CMR
• shows characteristic patterns of late gadolinium enhancement
(LGE) in amyloidosis.
• The myocardial native T-1 is increased, and extracellular volume
fraction is significantly expanded even in myocardial segments
without apparent LGE, allowing for an early diagnosis
• None of these echocardiographic or CMR characteristics
definitively distinguishes amyloid heart disease from other
types of hypertrophic diseases
• atrial fibrillation limits CMR image quality, and certain
cardiac devices and renal dysfunction contraindicate CMR

32. Strengths and Limitations of
Noninvasive Imaging Tests
• Radionuclide imaging of cardiac amyloidosis has several
advantages
• widely available and easy to perform with almost no
contraindications
• Myocardial uptake of bone-imaging agents is diagnostic to
identify ATTR amyloidosis
• Amyloid-binding radiotracers may allow imaging of amyloid
deposits, and absolute quantitation of radiotracer uptake is
feasible with PET tracers for the assessment of response to
therapy
• Radionuclide techniques may also useful for patients who
cannot undergo a CMR for any reason.
• 18F-florbetapir PET is one of the very few targeted
molecular imaging tracers that is FDA approved and can
specifically image amyloidosis

33. SARCOIDOSIS

34. Sarcoidosis
• a complex, multisystem, inflammatory disease of uncertain etiology;
typically occurs before the age of 50 years and more commonly afflicts
women and blacks
• The basic pathophysiologic abnormality in sarcoidosis is the
accumulation of foci of noncaseating granulomas, comprising
organized collections of macrophages, epithelioid cells, and
lymphocytes.
• Once formed in response to a variety of inciting antigens (pathogens,
organic or inorganic matter), the granulomas may resolve, persist, or
become scarred, leading to organ damage
• In the heart the granulomas may involve the pericardium, myocardium,
and endocardium of both the ventricles and the atria
• The most commonly affected part of the myocardium is the LV free wall,
particularly at the base of the heart, followed by the basal
interventricular septum
• Granulomas in the ventricular myocardium may lead to abnormal
automaticity and re- entrant tachyarrhythmias manifesting as
palpitations or syncope

35. Sarcoidosis
• The diagnosis of cardiac sarcoidosis remains
challenging
• variety of nonspecific signs and symptoms ranging from
asymptomatic ECG findings to sudden death and
progressively worsening HF and arrhythmias.
• Only about 25% of all patients with sarcoidosis have
clinical manifestations of cardiac involvement
• Endomyocardial biopsy
• definitive but invasive
• has low sensitivity from sampling error related to the focal
nature of the disease process
• Due to the low yield of histologic diagnosis, imaging
plays a critical role in the diagnosis of cardiac
sarcoidosis

38. Imaging Protocols: Perfusion
Imaging
• Typical imaging protocols for cardiac sarcoid imaging include
perfusion imaging combined with inflammation imaging
• Perfusion imaging is performed using standard protocols
and 99mTc, 201Thallium, 13N-ammonia, or
82Rubidium.48,49
67Gallium Imaging
• Inflammation imaging is performed with 67Gallium SPECT or
18F-FDG PET
• 67Gallium (6–10 mCi) is injected intravenously at rest with
imaging 24 to 72 hours later (to improve interference from
hepatic uptake).
• Whole-body images are acquired for 10 minutes as planar
or SPECT, using a medium-energy parallel-hole collimator
with imaging at two (93, 184 KeV) or three energy window
photopeaks (93, 184, 296 KeV)

39. Imaging Protocols: Perfusion
Imaging
18F-FDG Imaging
• 18F-FDG (10–15 mCi) is administered intravenously at rest,
and images are acquired 90 minutes later (a minimum of 60
minutes after 18F-FDG injection) for 10 minutes to 20
minutes (3D or 2D, respectively).
• Dedicated imaging of the heart and a limited whole-body
scan (from the base of the skull to mid-thigh) is performed
• 18F-FDG PET imaging requires special dietary preparation.
Prolonged fasting, dietary modification, and intravenous
administration of unfractionated heparin have been tried to
suppress physiologic 18F-FDG uptake in the heart.
• The goal of dietary preparation is to shift normal myocardial
metabolism to fatty acid use and thereby suppress glucose
utilization (and 18F-FDG uptake) by the normal myocardium

40. Interpretation of Perfusion and
18F-FDG PET Images
• The RV and the atria are evaluated as well as the
extracardiac organs for abnormal 18F-FDG uptake.
• Comparison of the perfusion images with 18F-FDG
PET images may reveal
• normal myocardium (normal perfusion and no
myocardial FDG uptake)
• focal inflammation (normal or reduced perfusion with
focally increased FDG uptake, a mismatch pattern)
• scar tissue (reduced perfusion with reduced
metabolism, a match pattern)

41. Interpretation of Perfusion and
18F-FDG PET Images
• exclude epicardial CAD in patients with either
invasive or CT-based coronary angiography, since
patterns of perfusion metabolism mismatch in
patients with LV systolic dysfunction may reflect
either hibernating myocardium or myocardial
inflammation based on the clinical context
• The whole-body 18F-FDG PET findings might
support a diagnosis of extracardiac sarcoid disease
activity and also guide a biopsy from an
extracardiac location of 18F-FDG uptake, such as
mediastinal lymph nodes.

43. Challenges in Image Interpretation
• image interpretation can be challenging when there is
incomplete suppression of glucose utilization by normal
myocardium with diffuse myocardial 18F-FDG uptake,
focal on diffuse uptake, or increased nonspecific uptake
in the lateral wall.
• Diffuse myocardial 18F-FDG uptake, particularly with
normal perfusion, is typically a nonspecific finding that
is not diagnostic for sarcoidosis
• Interpretation of the perfusion and metabolism
patterns may not be diagnostic for cardiac sarcoidosis
in the regions corresponding to significant CAD (i.e.,
mismatch in the basal inferior wall in a patient with an
occluded right coronary artery).

44. Challenges in Image Interpretation
Interpretation of Follow-up Imaging
• A decrease in myocardial 18F-FDG uptake could
mean either a resolution of inflammation (normal
myocardium) or a progression of disease process to
fibrosis (scar)
• Perfusion imaging is therefore important even on
the follow-up to distinguish these two entities, as it
would improve in normal myocardium and worsen
in scar.

45. Diagnosis
• An early diagnosis of cardiac sarcoidosis is crucial, as data
suggest that steroid therapy can be administered to patients
with active inflammation before a decline in LV systolic
function
• 67Gallium imaging, in combination with myocardial
perfusion imaging, was used for the assessment of cardiac
sarcoidosis
• Compared to 18F-FDG PET, 67Gallium has a low sensitivity (0–36%)
and a high specificity (~100%) for diagnosing cardiac sarcoidosis
• its spatial resolution is limited (Fig. 26.5) and fewer extrapulmonary
lesions are identified
• Resolution of 67Gallium uptake after successful therapy with high-
dose steroids has been demonstrated.
• 18F-FDG PET has replaced 67Gallium as the test of choice
for imaging cardiac sarcoidosis.

47. Baseline
EF 34%
25 months after
EF 39%
8 months after
EF 37%

48. Diagnosis
• 18F-FDG has a characteristic heterogeneous uptake
pattern in the myocardium in patients with cardiac
sarcoidosis
• This appearance should help distinguish cardiac
sarcoidosis from other diseases such as dilated
cardiomyopathy with diffuse uptake and thus
decrease false-positive rates

49. When to Consider Cardiac Imaging in
Patients with Extracardiac Sarcoidosis
• Due to the lack of large-scale clinical trial data, no definitive
guidelines exist on evaluation or screening of patients with
extracardiac sarcoidosis for cardiac involvement.
• A recent heart rhythm society expert consensus statement
on the diagnosis and management of arrhythmias
associated with cardiac sarcoidosis recommends
questioning patients with extracardiac sarcoidosis for
significant palpitations (lasting >2 weeks), presyncope, and
syncope
• A screening CMR or 18F-FDG PET imaging is recommended
only in patients with symptoms or abnormalities on ECG or
echocardiogram
• CMR or 18F-FDG PET imaging can be considered (with CMR)
in patients with unexplained Mobitz type II or third-degree
atrioventricular block in adults aged less than 60 years

50. Strengths and Limitations of
Noninvasive Imaging
• Echocardiography
• first-line imaging technique for most cardiac diseases
• neither sensitive nor specific, and wall motion abnormalities related to cardiac
sarcoidosis cannot be easily distinguished from CAD or other etiologies
• CMR with LGE
• highly sensitive to diagnose cardiac sarcoidosis and may be used as the initial
test in patients with suspected cardiac sarcoidosis
• LGE (representing fibrosis or inflammation) - not specific for sarcoidosis;
changes in LGE in response to therapy may not be easily assessed with CMR
• 18F- FDG PET imaging
• could be performed to confirm the diagnosis and aid in guiding biopsy for a
definitive diagnosis (e.g., mediastinal node lymph node with 18F-FDG uptake)
• assess the need for initiation of medical therapy by distinguishing scar from
inflamed myocardium (both would demonstrate delayed enhancement on
CMR) and to monitor response to treatment over time
• CMR may be contraindicated in patients with certain types of intracardiac
devices; in those instances,18F-FDG PET could be used as a first-line imaging
test