Update On Cardiac Amyloidosis Nowell M. Fine, MD SM FRCPC ACC Rockies 2020
Update On Cardiac Amyloidosis
Nowell M. Fine, MD SM FRCPC
ACC Rockies 2020
Disclosures
• Grants/Research Support: Pfizer, Akcea, Servier, Takeda, Sanofi-Genzyme
• Speakers Bureau/Honoraria: Pfizer, Akcea, Alnylam, Amgen, Sanofi-Genzyme
Learning Objectives
• Briefly discuss the pathophysiology and subtyping of cardiac amyloidosis
• To review the clinical manifestations and diagnostic evaluation of cardiac amyloidosis
• To discuss management of cardiac amyloidosis, including novel disease-modifying therapies
What method do you usually use to diagnose transthyretin (ATTR) cardiomyopathy?
• Cardiac biopsy
• 99-Tc-pyrophosphate nuclear scintigraphy
• Echo and/or cardiac MRI and cardiac biomarkers
• Referral to another center
• More than one of the above
What Is Amyloidosis?
• Group of disorders caused by extracellular deposition of insoluble abnormal fibrils composed of misfolded proteins
• 2 main types cause cardiac infiltration
Merlini 2013. NEJM 213;7:583THAOS Registry
Light chain (AL) Transthyretin (ATTR)
• Renal > Cardiac > 50% involvement
• Transports thyroxin and retinol-binding protein
Cardiac Amyloidosis
Falk. JACC 2016;68:1323
Transthyretin Amyloidosis
• 2 subtypes
HereditaryTTR gene mutation, cardiac and/or neuro phenotype, relatively rare with certain endemic areas and populations
Age-related, no gene mutation, male predominance, aka systemic senile amyloidosis
Wild-type
Transthyretin Amyloidosis
F64L
V30M
V30M
W41L
S23N
T60A
L111M
I68L
V122I
H88R
T49AG47A
A36PR34T
F33L
C10R
S50R
E89Q
Neurologic Cardiac
Early onset
Late onset
Rapezzi. Eur Heart J 2013;34:520
Incidence >1:500 in Portugal
Mutation prevalence 3-4% African-Americans
Prevalence of wild-type unknown but likely under-diagnosed
Heart failure - frequently biventricular, typically preserved LVEF
Atrial fibrillation
Conduction system disease
Ventricular arrhythmia - may be asymptomatic
Aortic stenosis - low-flow low-gradient for wtATTR,
typically with preserved LVEF
Cardiac Manifestations
Fine. Cdn J Cardiol 2020;In press
ATTR – Hiding in Plain Site As Common CV Disorders
13% pts >60 with ↑ LV wall thickness hospitalized with HFpEF
16% pts receiving TAVR, especially low-flow low-gradient AS
5% of pts previously thought to have HCM
HFpEF Aortic Stenosis
Gonzalez-Lopez. Eur Heart J 2015;36:2585Castano. Eur Heart J 2017;38:2879
Damy. Eur Heart J 2016;27:1826
HCM
A Challenging Disease to Diagnose and Manage
Fine. Cdn J Cardiol 2020;In press
Index of Suspicion – Key Features
Sekijima. Orph J of Rare Dis 2018;13:6
SUSPECT CARDIAC AMYLOIDOSIS WHEN
NEW ONSET HEART FAILURE WITH ≥1 OF THE FOLLOWING
Established AL or ATTR in
non-cardiac organ/system
(i.e., renal AL amyloidosis
causing nephrotic syndrome)
Peripheral sensorimotor
neuropathy and/or
dysautonomia
Unexplained increased
LV wall thickness
Low-flow low-gradient
aortic stenosis
with preserved LVEF
(>60 years-of-age)
Carpal tunnel
syndrome (bilateral)
Fine. Cdn J Cardiol 2020;In press
AL Amyloidosis Screening
• Monoclonal protein screening is critical
• Serum and urine protein electrophoresis• Low sensitivity for AL, need immunofixation
• Serum free light chain assay• Elevation in Kappa or Lambda levels causing high/low ratio
ECG Echo
CMR PYPFine. Cdn J Cardiol 2020;In press
Cardiac amyloidosis suspected based on standard heart failure work-up, including
cardiac imaging with either echocardiography and/or CMR, troponin and BNP/NTproBNP
Screen for plasma cell dyscrasia – serum and urine protein electrophoresis
with immunofixation, serum free light chain assay
AL amyloidosis suspected –
monoclonal protein present
Hematology referral – biopsy of
involved organ, typically EMB, renal,
BMB or fat pad (which cannot exclude systemic
amyloidosis) with MS or IHC if positive†
ATTR amyloidosis suspected –
monoclonal protein absent
Tc-99m-PYP scan –
if unavailable perform
EMB with MS or IHC
if positive†
ATTR cardiac
amyloidosis –
perform TTR
genetic testing
Cardiac amyloidosis
excluded – if
equivocal results
consider EMB*
Cardiac
amyloidosis
excluded*
Positive -
hATTR
AL cardiac
amyloidosis –
(or other type by EMB
with MS or IHC)‡
Negative -
wtATTRFine. Cdn J Cardiol 2020;In press
Parallel Management Pathways
Cardiac Amyloidosis
Cardiovascular manifestations
Disease-modifying therapy
TTR Silencers- Reduce hepatic production
- Slow progression of hereditary ATTR polyneuropathy
Inotersen• Antisense oligonucleotide, SC dosing
Patisiran• Micro-RNA inhibitor, IV dosing
Left Ventricle Mass
LV
Ma
ss
(g
)
Cha
ng
e fro
m B
ase
line
(L
SM
±S
E)
-30
-20
-10
0
10
20
Benson. NEJM 2018;379:22Adams. NEJM 2018;379:11
Solomon. Circ 2019;139:431
CV hospitalizations and all-cause mortality
Tafamidis
Maurer. NEJM 2018;379(11):1007
• TTR Stabilizer, oral dosing
• ATTRACT trial• wtATTR + hATTR
• Significant ↓ all-cause mortality
• Reduced decline in 6WMD, QoL
• Safety events similar b/w groups
All-cause mortality
Fine. Cdn J Cardiol 2020;In press
Summary
• Cardiac amyloidosis is a challenging disease to recognize because it often has nonspecific signs, symptoms and investigation findings
• Pyrophosphate nuclear scintigraphy is the standard test to confirm the diagnosis of ATTR cardiomyopathy, ocne AL amyloidosis is excluded
• Tafamidis (TTR stabilizer) is recommended for the treatment of ATTR cardiomyopathy (NYHA class I-III)