one of the form of restrictive cardiomyopathy usually missed in diagnosis. correct diagnosis can make N different outcome.

1. CARDIAC AMYLOIDOSIS
DR MAHENDRA
CARDIOLOGY, JIPMER

2. Amyloidosis
• Systemic process
• Extracellular tissue infiltration of aberrantly folded
insoluble β-pleated sheets of protein aggregates
• Apple-green birefringence in Congo red stain
• Deposition - parenchymal stiffening and dysfunction of
affected organs
2

3. • Myocardial amyloid deposition - cardiomyocyte distortion,
cardiomyocyte separation, tissue stiffening, and organ
dysfunction
• Disruption of mechanical and electrochemical cardiac
function
• Most apparent in the ventricles –
* Progressive myocardial thickening,
* Restrictive cardiomyopathy, and
* Diastolic dysfunction
• Conduction abnormalities, valvular malfunction, and
vascular infiltration
3

4. Cardiac specimen exhibiting amyloid deposition. Amyloid deposits
show as light-pink infiltrative material with concentric left ventricular
and interventricular septal thickening. Right ventricular amyloid
deposition is also apparent
4

5. Precursors that may affect the heart
• Light-chain (LC) immunoglobulin
• Mutant hereditary transthyretin (TTR)
• Wild-type TTR
• Mutant apolipoprotein AI
• Amyloid atrial natriuretic peptide localized to the atrium
• Fibrinogen alpha type
• Serum amyloid A protein
Organs involved
• Liver, kidney, gastrointestinal tract,nervous tissue and
heart
5

6. Heart involvement
• AL amyloidosis – 50 %
• Systemic senile amyloidosis (SSA) and some forms of
hereditary TTR-related amyloidosis (ATTR) affect the
heart almost invariably
• Secondary amyloidosis - Cardiac involvement is rare or
minimal or clinically non-significant
6

7. Key “red flags” to possible systemic
amyloidosis
• Nephrotic syndrome
• Autonomic neuropathy (eg postural
hypotension, diarrhea)
• Soft-tissue infiltrations (eg
macroglossia, carpal tunnel syndrome,
respiratory disease),
• Bleeding (eg cutaneous, such as
periorbital, gastrointestinal)
• Malnutrition/cachexia and
• Genetic predisposition (eg, family
history, ethnicity).
7

8. • Secondary amyloidosis- consequence of chronic
inflammatory conditions
* Rheumatoid arthritis
* Crohn’s disease
* Chronic inflammatory/infectious diseases
* Familial Mediterranean fever
* Idiopathic amyloid A amyloidosis
8

9. Survival
• AL amyloidosis- Median survival of <1 year without
treatment
• Median survival 6-9 months in those with heart failure
• 1.1 years in those with any sign of cardiac involvement
• Transthyretin amyloidosis (familial or wild-type) and
secondary amyloidosis –
Myocardial infiltration can be severe with
minimal symptoms and a median survival of several
years, even if untreated
9

10. 10

11. 11

12. Monoclonal Paraprotein
• SPEP
• Monoclonal Lambda or Kappa
Light chain spike
• Free serum light chains
• The presence of a serum or
urine monoclonal paraprotein
is suggestive of AL
amyloidosis, but it alone does
not firmly establish the
diagnosis.
• Pt may have senile cardiac
amyloid and unrelated MGUS
with these clinical findings
12

13. Light-chain amyloidosis
• Extracellular deposition of fibril-forming monoclonal
immunoglobulin LCs, secreted by a small plasma cell clone
• Detectable by Immunofixation and/or immunoelectrophoresis in
80—90% of patients
• Non-invasive biopsies of abdominal fat and minor salivary
glands should be performed initially (usually positive in 80% of
patients)
• If necessary, biopsy of a clinically affected organ (kidney,
gastrointestinal tract or endomyocardial tissue) should be
considered
• Electron microscopy : ultrastructural appearance of randomly
arranged fibrils (7—10 nm in external diameter)
13

14. 14

15. Diagnostic criteria for cardiac involvement
• An increase in mean wall thickness in end-ventricular
diastole of ≥ 12 mm by echocardiography, with no other
obvious cardiac cause,
• An increase in the concentrationof NT-proBNP to > 332
ng/L (in absence of renal failure). (may fall dramatically
within weeks after chemotherapy
15

16. The Mayo Clinic staging
• A current staging system—the Mayo Clinic staging (based
on NT-proBNP (cut-offvalue = 332 ng/L; BNP = 100 ng/L)
and cardiac troponin (cut-off value = 0.035 g/L)
• High risk (stage III: both biomarkers are increased)
• Intermediate risk (stage II: at least one biomarker is
abovethe cut-off value)
• Low risk (stage I: both biomarkers are below the cut-
offvalues).
16

17. ECG
• Abnormal in 90% of cases with cardiac involvement
• Low voltage QRS complex (defined as all limb leads < 5 mm in
height) and a pseudoinfarct pattern on the precordial leads (50%
of patients with cardiac AL amyloidosis)
17

18. Echo
• Infiltrative/restrictive cardiomyopathy
• Increased LV wall thickness ≥ 12 mm with ‘brilliant’ speck-
led appearance of the myocardium (amyloid fibrils
deposits are more echogenic than normal myocardium)
• Sparkling pattern is not sensitive because only a minority
(26%) has it
• Normal or small LV cavity
• Preserved LVEF > 50% (at least in the early stage of the
disease), but reduced S and E’ waves Abnormal mitral
filling pattern
18

19. Absent A wave in setting of NSR (Atrial arrest)
19

20. 20

21. • Typical echo findings in cardiac amyloidosis: thickened
and sparkled LV walls, thickened inter-atrial septum, mitral
and tricuspid valves, thickened right ventricular free wall,
small pericardial effusion, normal LV cavity size and atrial
enlargement
21

22. Other echo findings
• LAE (diameter > 23 mm/m2,area > 20 cm2 or maximal volume
> 28 mL/m2)
• RAE and dilated IVC reflecting elevated RV filling pressure
• Increased interatrial septal thickness
• Increased RV free wall thickness (> 7 mm) with RV systolic and
diastolic dysfunctions
• Left and right valve thickening
• Reduced aortic ejection time (< 273 ms), described as a
prognostic factor
• Small pericardial effusion in 50% of cases
• Atrial thrombi may be seen, despite the presence of
sinusrhythm
22

23. Buss et al, JAm Coll Cardiol 2012;60:1067—76.
Longitudinal strain (LS) and
2D global LS (2D-GLS)
* Strongly correlates with NT-proBNP in patients with AL
* Independently associated with prognosis in AL, including
overall survival
* Incremental value over NT-proBNP, cardiac troponin and
all otherclinical variables assessed
23

24. 2D speckle-tracking
• Differentiating cardiac amyloidosis from othercauses of LV
hypertrophy
• Reduced basal strain and regional variations inLS from
base to apex
• A relative ‘apical sparing’ (average apical LS/[average
basal LS + mid LS]) pattern of LS is an easily
recognizable, accurate and reproducible means of
differentiating cardiac amyloidosis from other causes of
LVH
Phelan D, Collier P, Thavendiranathan P, et al.. Heart
2012;98:1442—8.
24

25. • TTE with speckle tracking.The red and yellow lines represent
longitudinal motion in the basal segments, whereas the purple and
green lines represent apical motion. This shows loss of longitudinal
ventricular contraction at the base compared to apex
25

26. Cardiac magnetic resonance imaging
• Excellent spatial resolution for tissue characterization
• Very sensitive for detecting the presence of infiltrative
cardiomyopathy, even in cases of normal LV wall
thickness
• Precise measurement of the LV walls, the inter atrial and
RV free walls, biatrial enlargement and pericardial
effusion
• Transmural late gadolinium enhancement(LGE) or patchy
LGE.
26

27. Cardiac MRI in patient with AL amyloidosis.
• SSFP images in short axis at the base,mid and apex
demonstrate thickened biventricular walls,with circumferential
PE of increased signal intensity. 4-chamber view also
demonstrates the pericardial effusion, and mildly thickened
atrial walls and interatrial septum
27

28. • CMR with the classic amyloid global,subendocardial LGE
pattern in the LV with blood and mid-epi myocardium
nulling together
28

29. Nuclear imaging
29

30. 99mTC-PYP imaging in TTR cardiac amyloidosis. A positive
99mTc-PYP SPECT-only ,fused SPECT/CT and maximal
intensity projection image are illustrated demonstrating
increased cardiac uptake in a patient with familial TTR cardiac
amyloidosis.
30

31. 99mTc-3-3-diphosphono-1-2-propanodicarboxylic acid
(99mTc-DPD) nuclear imaging.
A.Patient with cardiac
systemic senile amy-
loidosis showing
important99mTc-DPD
uptake in the heart.
B. Cardiac99mTc-DPD
tomoscintigraphy in the
same patient (the red
colourcorresponds to
amyloid deposition).
C. Patient with cardiac light-
chain amyloidosis
without heart uptake
of99mTc-DPD
31

32. Endomyocardial Biopsy
• Gold standard for demonstrating cardiac amyloid
deposition
• In practice endomyocardial biopsies are most commonly
required to differentiate between AL and ATTR in older
patients, some 5% of whom have a MGUS
• Should be considered in patients with a thickened left
ventricle by echocardiography where hypertension,
valvular disease, and a family history of hypertrophic
cardiomyopathy have been excluded, particularly if the
patient is young
• Perforation remain a small but real risk and may not be
well tolerated in restrictive cardiomyopathy
32

33. Light microscopy :
33

34. Cardiac complications of myocardial
amyloid fibril deposition
• Severe CHF ,initially preserved LVEF and decreased LV
compliance  advanced diastolic dysfunction
• Decreased LVEF may follow diastolic dysfunction  terminal
and fatal heart failure
• Chronic elevated LV filling pressure  LAA  AF  atrial
thrombi (frequent in cardiac amyloidosis,even in patients with
sinus rhythm)  systemic embolic events
• Non-sustained or sustained ventricular arrhythmias
• Conduction disturbances (cardiac ATTR)
• Autonomic dysfunction  orthostatic hypotensive episodes
• Amyloid deposits  microcoronary circulation  chest pain
(The macrocoronary vessels are usually free of
significantstenosis )
34

35. Management and treatment of light-chain
amyloidosis
• Chemotherapy directed against the underlying B-cell
clone secreting amyloid forming LCs
• Supportive measures to sustain organ function.
• Goal of treatment  achievement of a haematological
response
35

36. Conventional chemotherapy
• Melphalan-dexamethasone
• Impressive efficacy with > 60% haematological response
has been reported
• ASCT remains restricted to selected patients who are
generally without advanced cardiac amyloidosis
• Compared with ASCT, melphalan-dexamethasone had
similar efficacy with less toxicity
Jaccard A, Moreau P, Leblond V, et al , NEngl J Med
2007;357:1083—93
36

37. Novel agents
• Thalidomide, lenalidomide & bortezomib
• Melphalan + bortezomib + dexamethasone
• Bortezomib + cyclophosphamide + dexamethasone
37

38. Cardiac supportive treatment
• Most drugs commonly used for the treatment of CHF are
inefficient or appear to be dangerous in patients with AL,
ATTR or SSA
• Digitalis has been shown to accumulate in cardiac
amyloid deposits
• Beta-blockers- decrease heart rate, which is the only
mechanism that can maintain cardiac output in
amyloidosis, also aggravate autonomic dysfunction like
ACEI.
• Loop diuretics,given at high dosage in patients with
severe fluid retention,are the mainstay of management
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39. • Amiodarone - first-line therapy for arrhythmia
• Anticoagulation therapy is mandatory in patients with
supraventricular arrhythmia
• Pacemaker implantation may be indicated in patients who
develop symptoms of bradycardia or conduction disorders
• A heart transplant should be considered in selected young
patientswith advanced amyloid cardiomyopathy free from
other comorbidities.
39

40. Hereditary transthyretin-related amyloidosis
• Specific treatment of ATTR is a liver transplant with or
without a heart transplant
• Tafamidis
Systemic senile amyloidosis
• Similar to ATTR; however because patients don’t have
symptomatic neuropathy, as seen in ATTR, ACEI and beta
blockers are better tolerated than in other types of
amyloidosis
40

41. There are three main questions that the
clinician should be aware of:
1) How to detect cardiac amyloidosis
2) When to think about it
3) Whom to refer the patient?
41

42. • A patient with dyspnoea, unexplained fatigue and LVH on
TTE contrasting with the microvoltage of QRS amplitude
should alert the clinician to an infiltrative process rather
than a classical sarcomeric hypertrophic or hypertensive
cardiomyopathy
• It is important to refer the patient to a specialist in internal
medicine and/or a haematologist to perform more specific
biological and/or genetic testing
42

43. 43

44. Take home :
• Cardiac involvement in amyloidosis remains difficult
todiagnose and treat
• Extracardiac signs, in addition to unex-plained LV
thickening on echocardiography in the absence
ofincreased voltage on ECG, favour amyloid
cardiomyopathy
• Confirmation of amyloid type is possible in most cases
• The cMRI pattern of LGE appears to be very
characteristic.
• Unlike other causes of heart failure, supportive treatment
is usually very limited and can be dangerous
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45. THANK YOU !!
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