Download Cardiac Amyloidosis

Cardiac Amyloidosis
Sehrish Memon MD
Case Presentation
• 77 y.o M with PMHx of Diastolic CHF, moderate MVR, HLP, HTN,
Mortons neuroma, Peyronie’s disease presented with progressive
DOE and orthopnea
• Diagnosed with Diastolic CHF about one year prior on demadex 20mg
daily
• Reports compliancy with medications, diet and exercise
• Echo 11/13/15
• Overall left ventricular ejection fraction is estimated at 55 to 60%.
• Normal global left ventricular systolic function.
• (Grade 3) Severely abnormal left ventricular diastolic filling.
• Moderate concentric left ventricular hypertrophy.
• Severely dilated left atrium.
Cardiac MRI
• Referral to Cleveland Clinic
• Underwent RV endomyocardial Bx: Tissue Dx of amyloidosis faintly
positive for lamba light chains
• BMB: Mildy Hypocellular BM (20%) with lambda predominant plasma
cells (<5%)
• Pro-BNP: 11477, TN-T: 0.042
• Serum Free lambda Chain: 48.4( 5.7-26.3), Free Serum Kappa Chain
39.6 (6.5 – 29.9)
• CMT: Bortezomib + cyclophosphamide + Dexamethasone
Definition
• Deposition of extracellular
misfolded proteinaceous material
affecting multi-organ system
• Cardiac manifestation maybe the
predominant feature or found
when investigating other major
organ involvement
• Amyloid deposition occurs in
ventricles, atria, perivascularly,
valves and the conduction system.
• Amyloid deposits leads to
increased myocardial stiffness and
reduced contractility causing
diastolic and progressing to systolic
dysfunction
B, Staining of the tissue using sulfated Alcian blue. The
amyloid stains turquoise green and the myocytes stain
yellow, characteristic of amyloid
Rodney H. Falk Circulation. 2005;112:2047-2060
Congo Red staining of myocardial tissue from a patient with amyloid cardiomyopathy.
Congo Red staining of myocardial tissue from a patient with amyloid cardiomyopathy. A, Light
microscopy; B, polarized light microscopy, 400× magnification.
Frederick L. Ruberg, and John L. Berk Circulation.
2012;126:1286-1300
Copyright © American Heart Association, Inc. All rights reserved.
Figure 2. Myocardial biopsy in cardiac amyloidosis viewed under electron microscopy.
Rodney H. Falk Circulation. 2005;112:2047-2060
Copyright © American Heart Association, Inc. All rights reserved.
Type of Cardiac Amyloidosis
1) AL Amyloidosis: Acquired monoclonal light-chain
2) Senile Systemic Amyloidosis (Wild-Type ATTR)
3) Hereditary Amyloidosis (ATTR)
AL Amyloidosis
• estimated 2000 to 2500 new cases annually in the United States
• Plasma cell clone produce a light chain prone to misfold into betapleated sheets
• These light chains circulate in the bloodstream and deposit in one or
more tissues
• Monoclonal kappa or lambda LCs
• Commonest plasma cell dyscrasia is multiple myeloma, can overlap
with AL amyloidosis
• Only a minority of myeloma patients develop amyloidosis, and most
patients with AL amyloidosis do not have multiple myeloma
Cardiac Involvement AL Amyloidosis
• 50% of cases, underdiagnosed
• Congestive heart failure is the presenting clinical manifestation in
about half of these patients
• Presence of cardiac amyloidosis is the worst prognostic factor
• Once congestive heart failure occurs, the median survival is <6
months in untreated patients
Pathogenesis and presentation of AL amyloidosis.
Shameem Mahmood et al. Haematologica 2014;99:209-221
©2014 by Ferrata Storti Foundation
TTR Amyloidosis
• Transthyretin (TTR), tetrameric protein with physiologic function of transporting thyroxine and retinolbinding protein
• Synthesized by the liver
• Able to aggregate into insoluble amyloid fibers depositing into variety of tissues
• Familial form from mutated or variant TTR
• Wild type, sporadic, nongenetic due to misaggregation of wild-type transthyretin (SSA)
Diagnosis and Evaluation
Electrocardiography
• Low QRS voltages: <5mm in all limb
leads with poor R-wave progression
in chest leads (pseudoinfarction
pattern)
• Low ECG voltage with concentrically
increased LV wall thickness
• First-degree AV block (21%)
• Nonspecific IVCD (16%)
• Second- or third-degree AV block
(3%)
• Atrial fibrillation/flutter (20%)
• Ventricular tachycardia (5%)
• LBBB seen in 40% of wild-type ATTR,
4% AL type
Echocardiography
• Increased LV wall
thickness ≥ 12 mm with
‘brilliant’ speckled appearance
of the myocardium
• Amyloid fibrils deposits are
more echogenic than normal
myocardium
• Mean LV wall
thickness > 15 mm was
independently associated with
worse outcome
• normal or small LV cavity
Early Stage Cardiac Amyloidosis
Imaired relaxation
with reversal of
E/A ratio
Late Stage Cardiac Amyloidosis
Severe Restrictive Filling
Pattern
-E/A ratio > 2, increased
E/E’ and small A wave
due to atrial dysfunction
-Short DT <150ms
-Short IVRT <60ms
• elevated LV filling pressure may lead
progressively to left atrial enlargement
(diameter > 23 mm/m2, area > 20 cm2 or
maximal volume > 28 mL/m2),
independently associated with worse
outcome in AL
• right atrial enlargement and dilated vena
cave reflecting right ventricular (RV) filling
pressure
• increased interatrial septal thickness
• increased RV free wall thickness (> 7 mm)
with RV systolic and diastolic dysfunctions
associated with worse survival
• Left and right valve thickening, usually
responsible for mild regurgitation
The right ventricle in cardiac amyloidosis.
Copyright © American Heart Association, Inc. All rights reserved.
Rodney H. Falk et al. Circ Cardiovasc Imaging. 2014;7:552562
Left ventricular strain imaging in cardiac amyloidosis.
• Well preserved apical
straining, with significant
mid and basal ventricle
may help distinguish
cardiac amyloid from LVH
from other causes
Rodney H. Falk et al. Circ Cardiovasc Imaging. 2014;7:552562
Copyright © American Heart Association, Inc. All rights reserved.
Loss of atrial function in cardiac amyloidosis.
Rodney H. Falk et al. Circ Cardiovasc Imaging. 2014;7:552562
Copyright © American Heart Association, Inc. All rights reserved.
Depressed E’
Low Stroke Volume
Figure 3. A. Typical echocardiography findings in cardiac amyloidosis: thickened and sparkled left ventricular (LV) walls, thickened
interatrial septum, mitral and tricuspid valves, thickened right ventricular free wall, small pericardial effusion, normal LV c...
Dania Mohty, Thibaud Damy, Pierre Cosnay, Najmeddine Echahidi, Danielle Casset-Senon, Patrice Virot, Arnaud Jaccard
Cardiac amyloidosis: Updates in diagnosis and management
Archives of Cardiovascular Diseases, Volume 106, Issue 10, 2013, 528–540
http://dx.doi.org/10.1016/j.acvd.2013.06.051
Definitive Dx
Stanfordhealthcare.org
Positive for amyloid deposits in >70% of patients with AL amyloid
Figure 7. Simultaneous right and left ventricular pressure tracings in a patient with AL
amyloidosis and atrial fibrillation.
Rodney H. Falk Circulation. 2005;112:2047-2060
Copyright © American Heart Association, Inc. All rights reserved.
Cardiac Biomarkers
• BNP, NT-pro BNP and Troponins T prognostic importance in AL amyloidosis
• Elevated NT-proBNP in AL amyloisis sensitive marker for cardiac
involvement, >152 pmol/L associated with higher mortality rate (72% vs
7/6% per year)
• High filling pressures, however local affect of amyloid deposits, BNP
granules found in higher quantities in myocytes adajcent to amyloid
deposits
• Elevated TNI marker of poor prognosis
• Combination of BNP/NT-proBNP plus troponin measurements is used to
stage and risk-stratify patient and follow response to treatment in pts
with AL amyloidosis at diagnosis
CMR with the classic amyloid global, subendocardial late gadolinium enhancement pattern in
the left ventricle with blood and mid-/epimyocardium nulling together.
• Global, subendocardial late
gadolinium enhancement is highly
characteristic of cardiac amyloid
• and correlates with prognosis.
• Faster washout of gadolinium from
myocardium and blood pool
compared to non-amyloid control
subjects
Sanjay M. Banypersad et al. J Am Heart Assoc
2012;1:e000364
© 2012 Sanjay M. Banypersad et al.
Cardiac Amyloidosis
Biatrial enlargement, moderate concentric LVH, small pleural
effusion, large bilateral pleural effusions and moderate global
left ventricle (LV) and right ventricle (RV) systolic dysfunction Late gadolinium diffuse subendocardial involvement of the LV
and left atrium with sparing of the RV
T1 scout images demonstrate nulling of the blood
pool (dark) before the myocardium (bright). This
is a characteristic finding, with the myocardium
having shorter T1 values than blood due to
extensive extracellular space expansion and rapid
myocardial gadolinium uptake.
Iron Overload Cardiomyopathy
Severe left ventricular (LV) enlargement
with moderate global biventricular
dysfunction (LV ejection fraction 32%, right
ventricular ejection fraction 36%) with
definite iron overload in the liver (T2* 4
msec) and borderline iron overload in the
myocardium (T2* 18 msec).
Cardiac Sarcoidosis
-Localized areas of wall thinning
and regional WMA due to
inflammation on T2 weighted
images
–LGE may help guide the site for
endomyocardial biopsy.
-patchy, midwall, subepicardial,
or even subendocardial, LGE
with a predilection to involve
the basal and mid-septal
segments
Radionuclide imaging
• Single photon emission computed tomography (SPECT) or positron
emission tomography (PET) based radiotracers
• SPECT tracers:
1) I-123 labeled serum amyloid P component, SAP- Direct amyloid
imaging agent
-non-cardiac amyloid affected organs, calcium mediated mechanism
2) Tc-99m pyrophosphate (PYP) or Tc-99m 3,3-diphosphono-1,2propanodicarboxylic acid (DPD)- bone imaging agent
3)I-123 Metaiodobenzylguanidine(MIBG )- agent to image cardiac
sympathetic innervation
-Norepi analog taken up by cardiac sympathetic nerve
Tc-99m pyrophosphate (PYP) SPECT
in cardiac ATTR amyloidosis
• Tc-99m PYP or Tc-99m DPD helpful to
distinguis ALL from ATTR amyloidosis
• In one study, Tc-99m DPD was able to
noninvasively differentiate between AL
and ATTR amyloidosis, all ATTR
patients showing DPD uptake and none
of the AL patients showing DPD uptake
• Tc-99m PYP/DPD scan may be
preferable to a CMR study for ATTRAmyloid; however a negative Tc-99m
PYP/DPD scan does not rule out AL
cardiac amyloid
Circ Cardiovasc Imaging. 2014 May; 7(3): 552–562
PET Scans - F-18 florbetapir
• PET tracers of C-11 Pittsburgh B
compound and F-18 florbetapir
under investigation
• Direct amyloid imaging agents
quantitation of amyloid burden
and early cardiac involvement
before overt cardiac structural
changes
General Treatment Principles
• Volume management (diuretics/salt restriction) and arrhythmia management
• Standard HF medications, B-blocker, Ace-i/ARB poorly tolerated due to hypotension from ANS
dysfunction, small LV cavity and inability to augment SV in response to vasodilation
• B-blocker can exacerbate arrhythmias
• Digoxin bind to amyloid fibrils leading to potential Digoxin toxicity with normal circulating levels
• Pacemaker often indicated due to conduction disease
• Atrial fibrillation common and poorly tolerated req DCCV/anti-arrhythmics (amiodarone
preferred)
• Ventricular arrhythmias and SCD common
• ICDS in past were discouraged due to poor prognosis, but can be effective with reasonable
prognosis (>1 year)
• Cardiac transplantation given irreversible nature, severe Sx’s high mortality rates
Tx AL Amyloidosis
• Goal achieve reduction and normalization of pathologic light chains
• CMT agents:
-Combination of multiple classes of antineoplastics, including alkylators
(e.g., melphalan or cyclophosphamide), steroids (e.g., dexamethasone),
proteasome inhibitors (e.g., bortezomib or carfilzomib), and/or
immunomodulators (e.g., lenalidomide or pomalidomide)
• Alternative strategy: auto-stem-cell transplant utilizing high-dose
chemotherapy with an alkylating agent
Pathway for a patient with suspected AL amyloidosis.
Giampaolo Merlini et al. Blood 2013;121:5124-5130
©2013 by American Society of Hematology
ATTR amyloidosis
• No role for CMT, not a malignant process
• Diflunisal: nonsteroidal anti-inflammatory drug approved for arthritis pain stabilizes tetrameric
form of transthyretin
-A randomized trial demonstrated slowing of disease progression among patients with
polyneuropathy due to mutant ATTR amyloidosis
- nonsteroidal anti-inflammatory drugs are relatively contraindicated in HF, not likely to be
a good option for ATTR cardiomyopathy.
• Tafamidis:
-Approved in Europe and Japan for mutant ATTR amyloidosis causing polyneuropathy
-Binds thyroxine binding site to stabilize tetramer and block amyloid cascade
- A Phase 3 study investigating its utility in ATTR cardiomyopathy (both wild-type ATTR and
mutant ATTR) has finished enrollment, with results expected in 2018
• RNA interference approaches: Two agents that work via small-interfering RNA or RNA
interference (decreasing production of transthyretin by the liver) are in Phase 3 trials for ATTR
amyloidosis, including both polyneuropathy and cardiomyopathy form
Prognosis
• Dependent primarily on the degree of cardiac involvement and, in AL
amyloidosis, on circulating light-chain levels
• Prognosis for AL amyloidosis has markedly improved with life
expectancy of most patients measured in years rather than months
due to expanded CMT options
• Prognosis in ATTR amyloidosis is generally better than in AL
amyloidosis
References
• Falk, Rodney. Diagnosis and Management of Cardiac Amyloidosis.
Contemporary Reviews in Cardiovascular Medicine. Sept, 2005. Vol 112:13.
• Banypersad, Sanjay MRCP; Moon, James MRCP; Whelan, Carol MD et al.
Updates in Cardiac Amyloidosis: A Review. JAHA. April 23, 2012: 10.1161
• Falk, Rodney MD, Quarta, Candida MD, Dorbala, Sharmila MD. How to
Image Cardiac Amyloidosis. Circulation: Cardiovascular Imaging. 2014;
7:552-562
• Kassi, Mahwash MD, Nabi, Faisal. Role of Cardiac MRI in the Assessment of
Nonischemic Cardiomyopathies. Debakeyheartcenter.com/journal. 2013 IX
(3).