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 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 Figure 6. Distribution of Organ Involvement in 445 Patients with Light-Chain Amyloidosis. The light chains are predominantly {lambda} (ratio of {lambda} to {kappa} light chains, 4 to 1). Usually, a bone marrow plasma-cell clone, identified here by means of an immunofluorescence assay with rhodamine-labeled anti-lambda antibody (anti-{lambda}), synthesizes monoclonal light chains, which are best identified by immunofixation (IF) of serum and urine. The light chains can produce amyloid deposits in virtually every organ, with the exception of parenchymal brain tissue. Percentages indicate the frequency of dominant organ involvement. Only one quarter of the patients had involvement of a single organ at presentation; the remaining patients had involvement of two organs (36 percent) or three or more organs (39 percent). The heart mass can be markedly increased, and the interventricular septum is thickened. Involvement of the gastrointestinal tract may cause life-threatening bleeding. Shown is one example of peripheral nervous system involvement: infiltration of the carpal tunnel by amyloid, which may damage the median nerve, with consequent marked hypotrophy of the hand muscles. Soft tissues that may be infiltrated by amyloid include the tongue and the submandibular regions; bruising is typical and is caused by vascular fragility resulting from the infiltration of the vessel walls by amyloid (as indicated by the apple-green birefringence on polarized light microscopy). Merlini, G. et al. N Engl J Med 2003;349:583-596

Diagnosis of Amyloidosis Figure 3. Diagnostic Algorithm for Amyloidosis. A biopsy of tissue that shows amyloid deposits on Congo-red staining is the first step. If there is no family history of amyloidosis, the next step is to examine the patient for a plasma-cell dyscrasia by immunofixation electrophoresis of the serum and urine (Beckman Instruments, Fullerton, Calif.) and by a bone marrow biopsy with immunohistochemical staining of plasma cells for {kappa} and {lambda} light chains. If these are negative, the next step is to look for a mutant transthyretin (TTR) protein in serum, a mutant TTR gene in genomic DNA, or both, even if there is no family history of amyloidosis. Panel A shows an abdominal-fat aspirate stained with Congo red (amyloid deposits appear red) and viewed microscopically in normal light (x100), and Panel B shows the specimen under polarized light, demonstrating green birefringence of the amyloid deposits in the connective tissue surrounding the fat cells (x100). Immunofixation electrophoresis of serum shows a free {lambda} light chain (Panel C). A bone marrow-biopsy specimen stained with antibody to {lambda} light chain shows preferential staining of plasma cells as well as staining of an amyloid deposit around a blood vessel (Panel D, x400). In Panel E, isoelectric focusing of serum samples shows bands of both variant and wild-type TTR protein (arrow) from a patient with ATTR (lane 2) and a single band of wild-type TTR in normal subjects (lanes 1 and 3). Panel F shows a restriction-fragment-length polymorphism (RFLP) of DNA from amplified exon 2 of TTR after digestion with the restriction enzyme NsiI and polyacrylamide-gel electrophoresis. There are extra fragments of 4.9 and 1.5 kb in samples from patients with ATTR and the transthyretin Met 30 alleles (lanes 1 and 3) rather than the expected fragments of 6.4 and 3.2 kb (lane 2). Lane 4 shows the gel markers. 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 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

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

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

CMR vs. echo

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