A diagnostic algorithm

1. Cardiac Amyloidosis:
A Diagnostic Algorithm
Mazen Hanna, M.D.
Director, Heart Failure Intensive Care Unit
Co-Director, Amyloid Program
Cleveland Clinic
March 15,2015

2. Disclosures
• Prothena
– Served on scientific advisory board 2015

3. Protein misfolding disorder

4. Over 25 Amyloidogenic Proteins

5. Amyloidosis Type Precursor protein Cardiac
involvement
Prognosis
AL (Primary) Light chain 30-50% Poor if
untreated
SSA (“Senile cardiac ) TTR
(Transthyretin)
100% 5-7 yrs
ATTR (hereditary) Mutant TTR Mutation
dependent
variable
AA (Reactive) Amyloid A < 5-10% 2 yrs
AANF (Isolated Atrial) Atrial natiuretic
factor
Limited to atria …..
Cardiac amyloid

6. 2 Types of Amyloid that Affect the Heart
AL TTR
Wild type = SSA
Mutant = FAC

7. Production Circulation
Deposition
ATTR _ TherapyTransthyretin (TTR)
“Prealbumin”

8. How common is TTR-CM?
• In the US, V122I is believed to occur heterogeneously
in 3.5% of the African–American population
• SSA is not uncommon in the elderly population
– ~ 25% pts > 80 yrs have wild type TTR amyloid deposits in
myocardium
– ~ 20% HFPEF in the elderly population
Ruberg FL, Maurer MS, Judge DP, et al. Am Heart J 2012;164:222–228; Buxbaum JN and Tagoe. Ann Rev Med 2000;51:543–569; Dungu JN,
Andersen LJ, Whelan CJ et al. J Heart 2012;98:1146–1154.

11. Normal

13. 55 year old male

14. 55 year old male

15. 55 year old male
AL Amyloid

16. 72 yr old white female

17. 72 yr old white female
AL Amyloid

18. Biventricular Thickening

19. Atrial septal thickening

20. Diastolic filling abnormalities

21. Classic ECG
Pseudoinfarction pattern about 50% in AL
Low voltage 50% in AL
Low voltage 25% of ATTR

22. Presentation
• CHF with predominant
R sided sx’s
• Heart failure with
preserved EF (HFPEF)
• Atrial fibrillation /
cardioembolic stroke
• Pacemaker / Complete
heart block
• Angina w normal cors
• Nephrotic syndrome
• Orthostasis
• Neuropathy
• Macroglossia or
periorbital purpura (AL)
• Bilateral carpal tunnel
syndrome (TTR)

25. Suggestive Echo + Suggestive ECG
Clinical Findings
Fat pad biopsy?
Bone marrow
biopsy?

30. Shah et al. Amyloidosis and the Heart. Arch Intern Med. 2006;166:1805-1813

31. Congo red – Apple green birefringence

32. Thioflavin S
What we use at our institution

33. TTR κ,λ

35. Diagnostic Approach
Clinical + Echo + ECG
Endomyocardial biopsy
Serum free light chains
Serum immunofixation
Urine immunofixation
SPEP/UPEP
ĸ or ‫תּ‬ light chains
Heme/Onc Consult
Transthyretin
Genetic testing
Mutant TTRWild Type
Cardiac MRI
Technetium
pyrophosphate scan
Echo w/ Strain

36. Laboratory Testing
• SPEP and UPEP
• Serum free light chain assay
(Kappa/Lambda)
• Serum immunofixation
• Urine immunofixation

37. The Serum Free-Light Chain Assay
- An Abnormal Ratio Proves a Clonal Plasma Cell Disorder
- Useful for Diagnosis, Prognosis, Response Assessment
Dispenzieri et al. Leukemia 23, 215–224, 2009
Principle Immune - Nephelopmetry

38. Diagnosis Cardiac Amyloid by MRI
– There is accumulation of Gadolinium in areas of extracellular
fibrosis/protein infiltration, due to increased volume of distribution and
slower washout kinetics

39. Vogelsburg et al. JACC 2008;51:1022-30
80 % sensitivity
90% specificity
85% negative predictive value

40. 55 yr old AA female w/ angina & normal coronaries
Lambda Kappa

41. Heart 2012 ; 98: 1442-8

42. Apical sparing pattern

43. Apical Sparing Pattern: “Relative strain”

44. Technetium pyrophosphate
(dipyrophosphate) scan

45. Technetium pyrophosphate scan
Bokhari, Circ Cardiovasc Imaging. 2013;6:195-201.)
Specificity is very good
Sensitivity for earlier disease is unknown

46. HCM
HTN heart w/ renal failure Lysosomal storage disease
Amyloid

47. 63 yr old AA male
Recurrent CHF

48. (-) fat pad bx (-) renal bx
63 yr old AA male
Recurrent CHF
Endomyocadial Bx c/w TTR Amyloid

49. TTR allele 1:
Sequence alteration detected: transition G ---> A
Nucleotide position:
7356
Codon position:
122
Amino acid change:
valine --> isoleucine
V122I
Genetic testing for TTR mutation
Heart transplant 2008
Doing well 7 years out

50. Onset of Disease in Patients with Cardiac Mutations or Wild
Type TTR Amyloidosis
Ile68Leu N = 11
Leu111Met
N = 10
Thr60Ala
N = 11
WT
N = 74
Val122Ile
N = 29

51. 78 yo AA female h/o HTN & EF 45%
Referred for shortness of breath

52. Echocardiogram

53. Technetium pyrophosphate scan
Genetic testing for
Transthyretin mutation
+ for Val 122 Ile

54. RED FLAGS
• White age > 70 yrs with
– “LVH” +/ - relative low voltage ECG
– Conduction disease/ pacemaker
– h/o Bilateral carpal tunnel syndrome
• AA > 65 yrs
– “LVH”
• +/- relative low voltage ECG
• Out of proportion to valve disease/ HTN
– Family history CHF

55. RED FLAGS
• Elderly patient with HOCM (white male)
– Echo with strain may help
– Need high index of suspicion TTR - CM
• Elderly patient with aortic stenosis or HTN
– LVH “out of proportion”
– Gradient or clinical picture doesn’t entirely fit
– ECG may or may not help
– Need high index of suspicion

56. Pearls
• High index of suspcion
– ECG and ECHO
• Noninvasive testing can be helpful (strain,
technetium pyrophosphate scan)
• DO NOT ORDER SPEP/UPEP!!!!!!!!!!!
• Wild type TTR (“senile”)
– h/o carpal tunnel syndrome, bilateral
• African Americans, TTR, V122I variant

57. AL TTR
Serum free light chains
Serum immunofixation
Urine immunofixation
Technetium pyrophosphate scan
ECHO with strain
Endomyocardial biopsy
Cardiac MRI
ECG

58. THANK YOU

59. λ-light chain antibody