Echocardiography of Cardiac Amyloidosis Frederick L. Ruberg

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Echocardiography of Cardiac Amyloidosis

• Frederick L. Ruberg, MD
• Boston University Medical Center
• May 25, 2005

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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

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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

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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

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Manifestations of AL
Merlini, G. et al. N Engl J Med 2003349583-596
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Diagnosis of Amyloidosis
Falk, R. H. et al. N Engl J Med 1997
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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

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Echo Features
Rehman, JACC 2004
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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

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Advanced Amyloid
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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

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Diastolic dysfunction

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

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Early Cardiac Amyloid
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Early Cardiac Amyloid
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After cardiac arrest
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Hypertension vs. Amyloid
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HTN vs Amyloid Doppler
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HTN vs. Amyloid TDI
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Moderate disease
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Restrictive inflow, Absent A
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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

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Depressed E prime
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Low stroke volume
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Evidence of congestion
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Advanced Amyloid
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Restrictive filling
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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

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Restrictive?
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Grade I Dysfunction
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LVOT obstruction
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LVOT Obstruction
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SSA (Senile Cardiac)
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SSA Doppler
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SSA Clinical Features

• Onset age greater than 60 years
• Often exclusively cardiomyopathy
• More benign clinical course than AL
• Often tolerate medications that AL patients wont
• TTR amyloid, must exclude AL as well as known
  mutations in TTR to diagnose

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Familial TTR
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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

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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 lt 40 or decompensated CHF
• Lower dose, marrow sparing regimens
• Oral therapy, investigative drug regimens

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Survival after HDM/SCT
Skinner, et al. Ann Int Med 2004
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Post-BMT changes?
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Post BMT

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

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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

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CMR vs. echo
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CMR vs. echo
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Diffuse Delayed Enhancement
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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

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Applications of echo/CMR

• Early diagnosis
• Predict outcomes with treatment
• Monitor response to treatment