1. Echocardiography of Cardiac Amyloidosis
Frederick L. Ruberg, MD
Boston University Medical Center
May 25, 2005

2. What is amyloid Any misfolded protein that aggregates as a -sheet
stains with Congo Red (birefringence)
Implication in pathogensis of alzheimers disease ( amyloid)
Systemic amyloidoses

3. The Systemic Amyloidoses
Primary (AL) or light chain disease
Plasma cell dyscrasia (clonal proliferation)
12-15% patients with myeloma have AL
Immunoglobulin light chains
12 month survival without treatment
6 month survival with cardiac disease
Incidence is 1 in 100,000 in Western countries
Familial (AF)
Mutations in transthyretin (TTR)
Ile 122 of particular interest

4. The Systemic Amyloidoses
Senile systemic amyloid (SSA)
TTR-based non-genetic (ie, TTR normal)
Cardiac predilection
Male gender, onset after age 60
Secondary amyloidosis (AA)
Chronic inflammatory states
Other specific protein abnormalities
apolipoprotein A-I and A-II, lysozyme

5. Manifestations of AL
Figure 6. Distribution of Organ Involvement in 445 Patients with Light-Chain Amyloidosis. The light chains are predominantly {lambda} (ratio of {lambda} to {kappa} light chains, 4 to 1). Usually, a bone marrow plasma-cell clone, identified here by means of an immunofluorescence assay with rhodamine-labeled anti-lambda antibody (anti-{lambda}), synthesizes monoclonal light chains, which are best identified by immunofixation (IF) of serum and urine. The light chains can produce amyloid deposits in virtually every organ, with the exception of parenchymal brain tissue. Percentages indicate the frequency of dominant organ involvement. Only one quarter of the patients had involvement of a single organ at presentation; the remaining patients had involvement of two organs (36 percent) or three or more organs (39 percent). The heart mass can be markedly increased, and the interventricular septum is thickened. Involvement of the gastrointestinal tract may cause life-threatening bleeding. Shown is one example of peripheral nervous system involvement: infiltration of the carpal tunnel by amyloid, which may damage the median nerve, with consequent marked hypotrophy of the hand muscles. Soft tissues that may be infiltrated by amyloid include the tongue and the submandibular regions; bruising is typical and is caused by vascular fragility resulting from the infiltration of the vessel walls by amyloid (as indicated by the apple-green birefringence on polarized light microscopy).
Merlini, G. et al.
N Engl J Med 2003;349:

6. Diagnosis of Amyloidosis
Figure 3. Diagnostic Algorithm for Amyloidosis. A biopsy of tissue that shows amyloid deposits on Congo-red staining is the first step. If there is no family history of amyloidosis, the next step is to examine the patient for a plasma-cell dyscrasia by immunofixation electrophoresis of the serum and urine (Beckman Instruments, Fullerton, Calif.) and by a bone marrow biopsy with immunohistochemical staining of plasma cells for {kappa} and {lambda} light chains. If these are negative, the next step is to look for a mutant transthyretin (TTR) protein in serum, a mutant TTR gene in genomic DNA, or both, even if there is no family history of amyloidosis. Panel A shows an abdominal-fat aspirate stained with Congo red (amyloid deposits appear red) and viewed microscopically in normal light (x100), and Panel B shows the specimen under polarized light, demonstrating green birefringence of the amyloid deposits in the connective tissue surrounding the fat cells (x100). Immunofixation electrophoresis of serum shows a free {lambda} light chain (Panel C). A bone marrow-biopsy specimen stained with antibody to {lambda} light chain shows preferential staining of plasma cells as well as staining of an amyloid deposit around a blood vessel (Panel D, x400). In Panel E, isoelectric focusing of serum samples shows bands of both variant and wild-type TTR protein (arrow) from a patient with ATTR (lane 2) and a single band of wild-type TTR in normal subjects (lanes 1 and 3). Panel F shows a restriction-fragment-length polymorphism (RFLP) of DNA from amplified exon 2 of TTR after digestion with the restriction enzyme NsiI and polyacrylamide-gel electrophoresis. There are extra fragments of 4.9 and 1.5 kb in samples from patients with ATTR and the transthyretin Met 30 alleles (lanes 1 and 3) rather than the expected fragments of 6.4 and 3.2 kb (lane 2). Lane 4 shows the gel markers.
Falk, R. H. et al. N Engl J Med 1997

7. Amyloid Cardiomyopathy
Very poor prognosis (6 mo survival)
Restrictive cardiomyopathy with profound abnormalities of diastolic function
Systolic dysfunction late manifestation
Classic teaching
biventricular thickening in a small ventricle
valvular thickening, “speckled pattern”
Atrial enlargement
Pericardial effusion/evidence of elevated filling pressures

8. Echo Features
Rehman, JACC 2004

9. Amyloid Cardiomyopathy
Patients do NOT respond to normal medication for CHF
ACE inhibitors, beta-blockers, dig
There is a treatment for AL amyloid
Autologous bone marrow transplant
Patient selection critical
assessment of cardiac involvement

10. Advanced Amyloid

11. Continuum of Amyloid Advanced disease is too late
Initial changes are abnormalities of diastolic function
As wall thickness progresses restrictive physiology ensues
Loss of limb lead voltage on ECG
Systolic dysfunction late stage

12. Diastolic dysfunction
Transmitral inflow
E and A wave pattern
E wave deceleration time
IVRT
Tissue Doppler mitral annular velocities
E prime < 6 cm/s
LA enlargement, IVC dilation
Restrictive physiology a late manifestation

13. Early Cardiac Amyloid

14. Early Cardiac Amyloid

15. After cardiac arrest

16. Hypertension vs. Amyloid

17. HTN vs Amyloid Doppler

18. HTN vs. Amyloid TDI

19. Moderate disease

20. Restrictive inflow, Absent A

21. Atrial arrest Absent A wave in setting of NSR Restrictive pattern
Atrial amyloid infiltration and/or markedly elevated LV DP
Risk of stroke/TIA, anticoagulation
Recovery of A wave following successful BMT correlating to symptomatic improvement

22. Depressed E prime

23. Low stroke volume

24. Evidence of congestion

25. Advanced Amyloid

26. Restrictive filling

27. Treatment of AL Autonomic dysfunction, low stroke volumes
Dependent on HR
Beta blockers, ACEI poorly tolerated
Digoxin may bind to amyloid and promote toxicity
Can use diuretics
Loop diuretics
Aldactone/eplerenone
Amiodarone
Proamatine (Midodrine) for BP support

28. Restrictive?

29. Grade I Dysfunction

30. LVOT obstruction

31. LVOT Obstruction

32. SSA (Senile Cardiac)

33. SSA Doppler

34. SSA Clinical Features Onset age greater than 60 years
Often exclusively cardiomyopathy
More benign clinical course than AL
Often tolerate medications that AL patients won’t
TTR amyloid, must exclude AL as well as known mutations in TTR to diagnose

35. Familial TTR

36. Familial Amyloid CMP Over 80 mutations identified
Ile 122 in African Americans
2-4% heterozygotic allele frequency
Unclear penetrance
Unclear importance in setting of HTN
Onset of CMP after age 60 years
Stabilization of TTR tetramer to stop amyloidogensis by diflunisal
Other agents in development
Liver transplant/heart transplant

37. Stem Cell Transplant AL can respond to chemotherapy
High dose melphalan with autologous stem cell transplantation
8-year follow-up data (Skinner, et al. Ann Int Med 2004)
Median survival 1.6 yrs
Exclusion EF < 40% or decompensated CHF
Lower dose, marrow sparing regimens
Oral therapy, investigative drug regimens

38. Survival after HDM/SCT
Skinner, et al. Ann Int Med 2004

39. Post-BMT changes?

40. Post BMT
Symptomatic improvement without obvious change in echo appearance
Hemodynamic recovery (A wave)
Improvement in TDI
BNP normalization
Mass regression
Chamber remodeling

41. Role of CMR More sensitive than echo
Explore tissue-dependent changes through delayed enhancement
Demonstrated in 70% patients (Maceira, Pennell, et al. Circ 2005) associated with mass
Small LV size + increased wall thickness does not necessarily = increased mass

42. CMR vs. echo

43. CMR vs. echo

44. Diffuse Delayed Enhancement

45. New echo approaches
Strain imaging determines impaired longitudinal contraction (Koyama, Falk, et. al. Circ 2003)
In absence of fractional shortening abnormality
Preceded CHF symptoms
Utility of TDI with BNP to facilitate diagnosis in early disease

46. Applications of echo/CMR
Early diagnosis
Predict outcomes with treatment
Monitor response to treatment