echocardiography of cardiac amyloidosis frederick l. ruberg, md boston university medical center may...

Echocardiography of Cardiac Amyloidosis

Frederick L. Ruberg, MDBoston University Medical

CenterMay 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

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

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

Manifestations of AL

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

Diagnosis of Amyloidosis

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

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


After cardiac arrest


Hypertension vs. Amyloid


HTN vs Amyloid Doppler

HTN vs. Amyloid TDI

Moderate disease


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


Advanced Amyloid


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?


Grade I Dysfunction

LVOT obstruction


LVOT Obstruction


SSA (Senile Cardiac)


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


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?


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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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

echocardiography of cardiac amyloidosis frederick l. ruberg, md boston university medical center may...

Documents

dysfunction slide

echo slide

lysozyme slide

amyloid tdi slide

advanced amyloid slide

familial ttr slide

manifestations of al

restrictive filling