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)

Cardiac Amyloidosis Update

• Thank you

• Questions/comments?

• nmfine@ucalgary.ca