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Echocardiography of Cardiac Amyloidosis. Frederick L. Ruberg, MD Boston University Medical Center May 25, 2005. What is amyloid. Any misfolded protein that aggregates as a  -sheet stains with Congo Red (birefringence) Implication in pathogensis of alzheimers disease (  amyloid)

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echocardiography of cardiac amyloidosis

Echocardiography of Cardiac Amyloidosis

Frederick L. Ruberg, MD

Boston University Medical Center

May 25, 2005

what is amyloid
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
the systemic amyloidoses
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
the systemic amyloidoses1
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
manifestations of al
Manifestations of AL

Merlini, G. et al.

N Engl J Med 2003;349:583-596

diagnosis of amyloidosis
Diagnosis of Amyloidosis

Falk, R. H. et al. N Engl J Med 1997

amyloid cardiomyopathy
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
echo features
Echo Features

Rehman, JACC 2004

amyloid cardiomyopathy1
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
continuum of amyloid
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
diastolic dysfunction
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
atrial arrest
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
treatment of al
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
ssa clinical features
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
familial amyloid cmp
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
stem cell transplant
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
survival after hdm sct
Survival after HDM/SCT

Skinner, et al. Ann Int Med 2004

post bmt
Post BMT
  • Symptomatic improvement without obvious change in echo appearance
    • Hemodynamic recovery (A wave)
    • Improvement in TDI
    • BNP normalization
    • Mass regression
    • Chamber remodeling
role of cmr
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
new echo approaches
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
applications of echo cmr
Applications of echo/CMR
  • Early diagnosis
  • Predict outcomes with treatment
  • Monitor response to treatment