Boston Medical Center is the primary teaching affiliate

of the Boston University School of Medicine.

Transthyretin (TTR) Amyloidosis

Frederick L. Ruberg, MD

Amyloidosis Center and Section of Cardiovascular Medicine

Boston University School of Medicine

Boston Medical Center

Boston, MA

OVERVIEW OF TTR AMYLOIDOSIS

• Amyloidosis is a disorder of protein folding

• Classification of amyloid type by precursor protein

• Transthyretin (TTR) aka prealbumin 55 k-Da protein

synthesized by liver > 100 known SNPs

• Mutations alter thermodynamic properties of protein to favor

mis-folding and aggregation as amyloid fibrils

– Variant TTR amyloidosis

– Autosomal dominant inheritance pattern (50% likelihood of

transmission)

Connors, Amyloid 2003

KEY POINTS TO REMEMBER 1. Variant TTR amyloidosis results from single nucleotide

polymorphisms (SNPs) that cause nerve, cardiac, and soft tissue amyloid fibril deposition (alone or in combination)

2. Mutations vary by geographic distribution thus ancestry can predict mutation

3. Penetrance is incompletely understood however there are clear gender and age associations with phenotypic expression

4. Clinically it can be difficult to distinguish variant TTR from ATTRwt, but easier to differentiate from AL

5. Novel approaches using TTR stabilization or suppression agents hold great promise to treat variant TTR disease

TTR STRUCTURE AND FIBRIL FORMATION

Bulawa et al. PNAS 2012

CLINICAL MANIFESTATIONS OF VARIANT TTR

AMYLOIDOSIS

Variant TTR amyloidosis

Restrictive Cardiomyopathy

(FAC)

V122I

T60A

Autonomic and peripheral

Neuropathy (FAP) V30M

Mutation

Ruberg, Circulation 2012

FEATURES OF TTR CARDIAC AMYLOIDOSIS

DIAGNOSIS OF VARIANT TTR CARDIAC

AMYLOIDOSIS 1. Clinical suspicion and recognition!

2. Tissue biopsy to identify amyloid by Congo red stain – Abdominal fat aspirate (20-25% sensitive for ATTRwt, 50-75%

sensitive for ATTRvariant)

– Endomyocardial biopsy (virtually 100% sensitive/specific)

3. Typing of amyloid by analysis of biopsy specimen – Immunohistochemistry (problematic high background)

– Mass spectrometry (Mayo Medical Labs send out)

4. Genetic testing to establish TTR genotype – Blood test - PCR

5. Exclusion of plasma cell dyscrasia

Connors Amyloid 2009

CLASSIC ECHO FINDINGS IN VARIANT TTR

AMYLOIDOSIS

Can non-invasive testing conclusively differentiate amyloid type?

ECG IN DIFFERENT AMYLOID TYPES

Rapezzi Circulation 2009

ECHOCARDIOGRAPHY IN DIFFERENT AMYLOID TYPES

Rapezzi Circulation 2009

ECHOCARDIOGRAPHY – LONGITUDINAL

SYSTOLIC STRAIN

Normal Cardiac Amyloidosis

Useful for differentiation of amyloid from non-amyloid

CMR: DIFFERENTIATION OF TTR VS. AL

Dungu JACC Img 2014

ICC = 0.66 (only fair agreement)

QALE score sensitivity 87%, specificity 96%

CMR: NATIVE (NON-CONTRAST) T1 MAPPING

Fontana JACC Img 2014

NUCLEAR IMAGING: SELECTIVE FOR TTR • Tc-99m Bone avid compounds

– Pyrophosphate (PYP) and DPD

– May preferentially identify TTR amyloid cardiomyopathy

Rapezzi Eur J Nuc Med Mol Imag 2011, JACC Img 2011: Banypersad, JAHA 2012

Bokhari Circ CV Imaging 2013: Longhi JACC Img 2014

PROGNOSIS: VARIANT TTR DUE TO V122I

• Mutation seen in 4% African Americans

– 1 million African Americans with mutation

– Approximately 100,000 over age 65y at risk

• Increased risk of CHF in cohort studies

• Median survival is 24-27 months following diagnosis

– Prospective multi-center TRACS (Transthyretin Amyloidosis Cardiac Study)

Jacobson NEJM 1997: Buxbaum AHJ 2010: Connors AHJ 2009: Ruberg AHJ 2012

LONGITUDINAL ASSESSMENT OFV122I ALLELE

STATUS, SURVIVAL AND HEART FAILURE • ARIC study of roughly 3850 African Americans

• V122I found in 3%, carriers vs. non-carriers compared after

25 years for survival, heart failure, and echo findings

Quarta et al, NEJM 2015

CHF curves diverge at 70 years

Limited # of older male carriers

MANAGEMENT OF VARIANT TTR AMYLOID • Medical treatments for heart failure

– Midodrine for orthostasis from autonomic neuropathy

• Liver transplant alone in TTR variant amyloid cardiomyopathy

is ineffective owing to continued progression despite wild-type

TTR

• Emerging medical treatments for TTR amyloid

– Stabilization

– Suppression

MANAGEMENT OF TTR AMYLOID: DIFLUNISAL • Currently available, FDA approved, but off-label usage

• Non-steroidal, inexpensive, oral, reversible inhibitor of TTR aggregation

• Efficacy dramatically demonstrated in neuropathic symptoms in TTR polyneuropathy, data regarding efficacy in TTR cardiomyopathy not yet reported

• Can be safely administered in patients with TTR (wt and variant) cardiomyopathy

• Limited by GI bleeding risk, heart failure risk, and nephrotoxicity

Berk et al, JAMA 2013: Castano, Congest Heart Fail 2012

INVESTIGATIONAL THERAPEUTICS FOR

VARIANT TTR AMYLOID CARDIOMYOPATHY Agent Mechanism Trial Identifier Design Endpoint Comments

Tafamidis stabilization ATTR-

ACT/Pfizer

NCT

01994889

20 mg vs. 80

mg vs.

placebo

All-cause

mortality +

cardiovasc.

hospitalization

PO daily for

30 months

Revusiran Suppression

(RNAi)

ENDEAVOR/A

lnylam

NCT

02319005

500 mg vs.

placebo

6 min walk

duration

SC weekly for

18 months

Patisiran Suppression

(RNAi)

APOLLO/Alnyl

am

NCT

01960348

Active drug

vs. placebo

NIS+7 score IV weekly for

18 months

ISIS-TTR-Rx Suppression

(Antisense

ODN)

ISIS NCT

01737398

300 mg vs.

placebo

NIS+7 score SC weekly for

65 weeks

SUMMARY • While sharing precursor protein with TTRwt, variant TTR

amyloidosis has a dramatically different and variable

phenotypic expression (heart/nerve) and disease course

– V122I may substantively contribute to heart failure in African

Americans

• Medical treatments overlap and may be equally effective

• Diagnosis involves genetic testing AND tissue identification,

though robustness of PYP/DPD nuclear scan data is altering

perception

– Biomarker discovery ongoing