Transcript Amyloidosis

Cardiac Amyloidosis
Ann Isaksen
Morning Report
November 10, 2009
Causes of Non-Ischemic Cardiomyopathy









Infiltrative (Sarcoidosis, Amyloidosis, Hemocromatosis)
Viral (HIV, lyme, coxsackie, etc)
Endocrine (Thyroid, pheo, cushing’s)
SLE
Drug/toxin induced (EtOH, cocaine, arsenic,chemo)
Nutritional deficiencies (thiamine, selenium)
Malignancy
Pregnancy
?Celiac disease
Amyloidosis
 Rudolph Virchow in 1854 adopted
the term "amyloid“ to refer to
tissue deposits of material that
stained in a similar manner to
cellulose when exposed to iodine
 Amyloidosis is a generic term that
refers to the extracellular tissue
deposition of fibrils composed of
low molecular weight subunits
(most of which are in the
molecular weight range of 5 to 25
kD) of a variety of proteins.
 At least 25 different human and
eight different animal protein
precursors of amyloid fibrils are
now known
 “Apple-green birefringence”
Many kinds of Amyloidosis
Primary (AL amyloidosis)
 = plasma cell dyscrasia leading to overproduction of
Immunoglobulin light chains
 Clinical evidence of cardiac involvement occurs in up to 50
percent of patients
Secondary (AA amyloidosis)
 Deposition of fragments of serum amyloid A protein, an acute
phase reactant
 Associated with chronic inflammatory disorders (eg RA).
 Almost never produces clinically apparent heart disease (< 5%)
Senile systemic and Heritable amyloidosis
 = Transthyretin deposits
 + Cardiac involvement, but much slower time course than AL
Many kinds of amyloidosis
 Primary (AL amyloidosis)
 = plasma cell dyscrasia leading to overproduction of
Immunoglobulin light chains
 Clinical evidence of cardiac involvement occurs in up to 50
percent of patients
 Secondary (AA amyloidosis)
 Deposition of fragments of serum amyloid A protein, an acute
phase reactant
 Associated with chronic inflammatory disorders (eg RA).
 Almost never produces clinically apparent heart disease (< 5%)
 Senile systemic and Heritable amyloidosis
 = Transthyretin deposits
 +Cardiac involvement, but much slower time course than AL
Clinical Manifestations of AL amyloidosis
 Nephrotic syndrome with or without renal
insufficiency
 Peripheral neuropathy, typically axonal, which
can be associated with autonomic neuropathy.
Carpal tunnel syndrome is commonly seen
 Hepatomegaly, with elevated liver enzyme levels
 Macroglossia
 Purpura, characteristically elicited in a periorbital
distribution (raccoon eyes) by a valsalva
maneuver or minor trauma, is present in only a
minority of patients, but is highly characteristic of
AL amyloidosis
Cardiac exam findings
 Elevation of the jugular venous pressure,
sometimes with a low-volume pulse.
 Right sided heart failure hepatomegaly and LE
edema
 A right-sided third heart sound is occasionally
heard
 Fourth heart sound, which coincides with atrial systole,
argues against the diagnosis since atrial infiltration
causes atrial dysfunction
 Amyloidosis rarely causes significant valve
disease, but a murmur of tricuspid or mitral
regurgitation is occasionally heard.
Diagnostic Evaluation
ECG
TTE
Cardiac MRI
Tissue biopsy
SPEP/UPEP
ECG Findings
 The most common abnormality = low voltage in
the limb leads
 Occurs in approximately 50 percent of patients
 Other changes that can occur include
1st degree AV block (21%)
atrial fibrillation or flutter (20%)
Non-specific intraventricular conduction delay (16%)
VTach (5%)
2nd or 3rd degree AV block (3%)
Echocardiography
 Left ventricular wall thickening with evidence of diastolic
dysfunction is the earliest echocardiographic
abnormality,
 In more advanced disease, wall thickening progresses
resulting in a restrictive cardiomyopathy with a
nondilated or small LV cavity, biatrial enlargement
 Amyloid infiltration of the heart results in increased
echogenicity.
 "granular, sparkling" appearance of the myocardium, 
unusually high quality myocardial visualization
 Only a minority of patients has this pattern 26% = low sensitivity
Two-dimensional (2D) echocardiographic image (parasternal long-axis view) from a
patient with AL cardiac amyloidosis showing normal biventricular dimensions, granular
"sparkling" ventricular wall appearance, concentric left ventricular wall thickening, and
thickened mitral valve leaflets suggesting infiltration
Voltage-to-mass ratio
 Left ventricular thickening due to amyloid infiltration may
be misdiagnosed as left ventricular hypertrophy.
 However, unlike true left ventricular hypertrophy, left
ventricular thickening in cardiac amyloidosis is
associated with a decrease in electrocardiographic
voltage.
 This combination of increased ventricular mass with
reduced electrocardiographic voltage is unique to
infiltrative cardiomyopathy.
 In another report, the combination of low voltage on ECG
and an interventricular septal thickness >1.98 cm
detected amyloidosis with a sensitivity and specificity of
72 and 91 percent, respectively
Cardiac MRI
 Amyloidosis  global and subendocardial
late gadolinium enhancement (LGE) of the
myocardium.
Replacing Echo as imaging modality of
choice in pt’s whom you have high clinical
suspicion for amyloid cardiomyopathy
Monoclonal Paraprotein
 SPEP
 Monoclonal Lambda or
Kappa Light chain spike
 Free serum light chains
 The presence of a serum
or urine monoclonal
paraprotein is suggestive
of AL amyloidosis, but it
alone does not firmly
establish the diagnosis.
 Pt may have senile
cardiac amyloid and
unrelated MGUS with
these clinical findings.
Tissue biopsy = Gold standard
 The diagnosis of cardiac amyloidosis is
confirmed either by
1. demonstrating amyloid deposits on
endomyocardial biopsy
2. or, in patients with appropriate cardiac
findings, by demonstrating amyloid deposits on
histologic examination of a biopsy from other
tissues (eg, abdominal fat pad, rectum, or
kidney).
Medication Interaction
 Amyloid fibrils bind to both digoxin and
nifedipine
Increased susceptibility to digitalis toxicity and to
hemodynamic deterioration after nifedipine
 Angiotensin converting enzyme (ACE) inhibitors
often provoke profound hypotension in AL
amyloidosis, possibly by exposing a subclinical
autonomic neuropathy.
 Amiodarone seems to be relatively well tolerated
strategy for rate control in atrial fibrillation.
Treatment Options
Melphan + steroids
Cyclophosphamide + thalidomide
Autologous HCT
Heart Transplant
Prognosis
Untreated:
Median survival
 six to nine months in those with heart failure
1.1 years in those with any sign of cardiac
involvement
Hematopoietic Cell Transplant
 Melphalan therapy + autologous HCT has had a
significant impact on survival in AL amyloidosis
without cardiac involvement
 Cardiac amyloidosis is associated with
increased morbidity and mortality from HCT and
reduced post-therapy survival compared to
those without clinically apparent cardiac
involvement.
 The largest reported experience of HCT comes
from an eight-year study of 701 consecutive new
patients with AL amyloidosis
Hematopoietic Cell Transplant
 312 were eligible for high-dose melphalan and HCT
 Cardiac involvement, (137 patients - 43 %), was defined
by
 septal or posterior wall thickening ≥13 mm on echocardiography
 clinical syndrome of heart failure.
 The following observations were noted in the patients
with cardiac involvement:
 At one year, 21% had a cardiac response, defined as
 a decrease in intraventricular septal thickness (if initially increased)
of ≥2 mm or
 a decrease in NYHA functional class of at least one grade without
an increase in diuretic dose.
 Median survival was 1.6 years compared to 6.4 years in
patients without cardiac involvement.
 However, some cardiac patients had a prolonged
survival, with approximately one-third alive at five years.
Before & After HCT
Chemotherapy
 Regimens:
 melphalan + prednisone
 cyclophosphamide, thalidomide and dexamethasone
 In a report of 46 patients who were not eligible for HCT
(32 because of severe cardiac involvement), the
administration of up to nine courses of melphalan +
prednisone was associated with a hematologic response
in 67 % and complete hematologic remission in 33%.
 An organ response was noted in 22 pts (48%), including
six with a ≥2 mm reduction in interventricular septum
thickness that was associated with resolution of heart
failure.
Heart transplantation
 The majority with cardiac AL amyloidosis have significant
noncardiac amyloidosis and are not suitable candidates
for heart transplantation.
 In one series, only 4 percent had clinically isolated cardiac
disease
 Early cardiac transplantation did not address the
underlying plasma cell dyscrasia, which later progressed
in other organs and/or returned in the transplanted heart.
 Heart transplantation is followed by high–dose
chemotherapy and autologous HCT within a 12-month
period. Long-term follow-up data in these patients is not
yet available, but several appear to have had an good
results
Summary
 AL amyloid cardiomyopathy presents with
rapidly progressive symptoms of right-sided
heart failure
 SPEP, serum free light chains
 LV thickening/restrictive cardiomyopathy + lowvoltage ECG
 Characteristic appearance on TTE and cardiac
MRI
 Tissue biopsy if possible
 Poor prognosis, but some treatment response to
chemotherapy and HCT
References
 Mullens et al. Resolution of cardiac amyloidosis after
autologous blood stem cell transplantation.
European Heart Journal.
 Kyle, RA. "Amyloidosis: The Last Three Centuries."
Amyloid and Amyloidosis. Bely, M, Apathy, A (Eds),
2001; p10-13.
 Falk and Skinner. The systemic amyloidose: an
overview. Adv Intern Med 2000; 45:107.
 Maurer et al. Cardiac transplantation using extendeddonor criteria organs for systemic amyloidosis
complicated by heart failure. Transplantation 2007;
83:539.
 Up To Date. Amyloid Cardiomyopathy.