Download Amyloid Cardiomyopathy

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)
• Systemic amyloidoses
The Systemic Amyloidoses
• Primary (AL) or light chain disease
 Plasma cell dyscrasia (clonal proliferation)
 12-15% patients with myeloma have AL
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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 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
Merlini, G. et al.
N Engl J Med 2003;349:583-596
Diagnosis of Amyloidosis
Falk, R. H. et al. N Engl J Med 1997
Amyloid Cardiomyopathy
• Very poor prognosis (6 mo survival)
• Restrictive cardiomyopathy with profound
abnormalities of diastolic function
 Systolic dysfunction late manifestation
• Classic teaching
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biventricular thickening in a small ventricle
valvular thickening, “speckled pattern”
Atrial enlargement
Pericardial effusion/evidence of elevated filling
pressures
Echo Features
Rehman, JACC 2004
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
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
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
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
HTN vs. Amyloid TDI
Moderate disease
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Restrictive inflow, Absent A
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
Depressed E prime
Low stroke volume
Evidence of congestion
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Advanced Amyloid
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Restrictive filling
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
Restrictive?
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Grade I Dysfunction
LVOT obstruction
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LVOT Obstruction
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SSA (Senile Cardiac)
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SSA Doppler
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 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
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
Skinner, et al. Ann Int Med 2004
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
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
CMR vs. echo
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CMR vs. echo
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Diffuse Delayed Enhancement
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
• Early diagnosis
• Predict outcomes with treatment
• Monitor response to treatment