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Transthyretin(TTR) amyloidosis
1. 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
2. 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
3. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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