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...

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