This document discusses imaging techniques for cardiac innervation, amyloidosis, and sarcoidosis. It summarizes imaging of cardiac autonomic innervation using radiotracers like MIBG and discusses their uptake and analysis. It then discusses diagnosing and imaging cardiac amyloidosis using bone-seeking radiotracers like PYP and DPD as well as amyloid-binding tracers. Positive cardiac uptake on PYP/DPD scans can diagnose ATTR amyloidosis. Imaging also provides prognostic value. Finally, it briefly mentions strengths and limitations of echocardiography, CMR, and radionuclide imaging for cardiac amyloidosis.

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