Echocardiography of Cardiac Amyloidosis

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 Merlini, G. et al. N Engl J Med 2003;349:583-596

6. Diagnosis of Amyloidosis 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