1. Senile cardiac amyloid (ATTRwt) is an under-appreciated cause of HFpEF that is often overlooked. 2. Non-invasive bone scintigraphy is highly specific for diagnosing ATTR cardiac amyloid. 3. Emerging investigational therapies like tafamidis and revusiran aim to stabilize or reduce amyloid deposits and may provide effective treatment for ATTRwt amyloidosis.

1. Heart Failure with a Preserved
Ejection Fraction and Senile
Amyloidosis:
Under Appreciated and Often Overlooked
Mat Maurer, MD
Columbia University Medical Center
March 15, 2015

2. Disclosures
• I have research support from several
pharmaceutical companies and device
companies that are working on TTR amyloid:
–Foldrx Pharmaceuticals, Inc.
–Pfizer, Inc.
–ISIS Pharmaceuticals
–Alnylam Pharmaceuticals
• I will discuss unapproved investigational
therapies for TTR amyloidosis.

3. 5 Things we know about
Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most
common form of cardiac amyloidosis.
2. ATTRwt cardiac amyloid is an under-appreciated
cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific
for ATTR cardiac amyloid

4. 5 Things we know about
Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most
common form of cardiac amyloidosis.
2. ATTRwt cardiac amyloid is an under-appreciated
cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific
for ATTR cardiac amyloid

5. Cardiac Amyloid: A Rare Condition?
Incidence/Prevalence
Type Incidence/Prevalence
1◦ AL Amyloid ~2500 Cases per year
50% have cardiac involvement
ATTRmutant 4% of African Americans are carriers
25,000-120,000 US patients
ATTRwt (SCA) ~10-25% of adults >80 years
~1 million

6. TTR (Prealbumin)
Transthyretin - TTR
• Tetramer of subunits of 127 amino
acids each
• TTR is a plasma transport protein for
thyroxine (T4) and for retinol.

7. ATTR Amyloidosis in United States:
THAOS Registry
• Most common type is ATTRwt
• 76±7 years
• 97% Males
• Echo;
– IVS = 18±3 mm
– EF = 51±12%
• Survival: 58.5% at 3 years
N= 390

8. 5 Things we know about
Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most
common form of CA.
2. ATTRwt cardiac amyloid is an under-appreciated
cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific
for ATTR cardiac amyloid

9. TTR Cardiac Amyloidosis:
A underappreciated cause of HFpEF
JACC Heart Fail. 2014;2(2):113-22.
8%
92%
< 75 years
Amyloid No Amyloid
32%
68%
> 75 years
Amyloid No Amyloid

10. Transthyretin Cardiac Amyloid in
Afro-Caribbean Patients with ADHF
• 1,142 ADHF patients
• 170 (14.9%) Afro-
Caribbean patients
– 17 (10%) were confirmed to
have cardiac ATTR V122I.
• Survival worse in amyloid
compared to non-amyloid
cardiomyopathy
– 34 vs 59 months,
p<0.01.
JACC 2012; 59 (13): E993
Black
Patients
(n=170)
All Other
Patients
(n=972)
P
value
Age (years) 71 (53-77) 73 (63-81) <0.01
Male 64.7% 67.1% <0.01
Non-ischemic 87.1% 58.2% <0.01
ATTR V122I 10% 0.4% <0.01
HTN disease 18.8% 7% <0.01

11. TTR cardiac amyloidosis among elderly
patients with HFpEF (=120)
Parameter Result
Age (years) 83±9
% Female 61%
NT-proBNP (pg/L) 3524
LVH by EKG 13%
MWT (mm) 14
EF (%) 61±8
European Heart Journal (2014) 35: S1025

12. 5 Things we know about
Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most
common form of CA.
2. ATTRwt cardiac amyloid is an under-appreciated
cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific
for ATTR cardiac amyloid

13. Both of them
Which patient has
Cardiac Amyloid?

14. ECG is Relatively Insensitive
0%
25%
50%
75%
100%
Atrial
Fibrillation
Pseudoinfarct PPWRP Low Limb Lead
Voltage
Low Precordial
Lead Voltage
Sokolow Criteria Abnormal
Voltage to
Masss Ratio
Overall (n=210) AL (n=110)
ATTRmt (n=45) ATTRwt (n=45)
Am J Cardiol. 2014;114(7):1089-93

15. 5 Things we know about
Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most
common form of CA.
2. ATTRwt cardiac amyloid is an under-appreciated
cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific
for ATTR cardiac amyloid

16. You’ve Got to Think of IT
to Diagnose IT!!!
History/ Exam Clues
• HFPEF without hypertension,
particularly in men
• Evidence of right-sided heart
failure (e.g. hepatomegaly, ascites,
and lower extremity edema)
• Intolerance of ACE, Beta-blockers.
• Bilateral carpal tunnel syndrome
Imaging Clues
• Thick septum and granular
sparkling on 2D TTE
• Low voltage to mass ratio
• Low tissue Doppler velocities,
strain, or strain rate
• Apical sparring on strain rate
imaging
• Delayed gadolinium enhancement
on CMRI

17. Preserved Apical Strain
Echocardiographic Clue

18. Delayed Enhancement in Amyloid

19. 5 Things we know about
TTR Cardiac Amyloidosis
1. TTR amyloid is the most common form of CA.
2. TTR cardiac amyloid is an under-appreciated cause
of HFpEF
3. An EKG is not a good screening test for TTR
amyloidosis
4. Clues to TTR Cardiac Amyloidosis are available
5. Non-invasive bone scintigraphy is highly specific
for TTR amyloid

20. Noninvasive Diagnosis of TTR Cardiac
Amyloidosis Using 99mTc-DPD Scintigraphy
J Am Coll Cardiol 2005;46:1076–84

21. Differences in Cardiac Retention with Tc-99
in Controls, AL and ATTR Amyloid
Circ Cardiovasc Imaging. 2013;6(2):195-201.

22. PYP Scanning for Cardiac Amyloid
Sensitivity and Specificity
Semi-Quantitative
Sensitivity Specificity
91% 90%
Positive
Predictive
Value
Negative
Predictive
Value
95% 82%
Scoring
0 = absent cardiac uptake and
normal bone uptake
1 = mild cardiac uptake,
inferior to bone uptake
2 = moderate cardiac uptake
equal to bone or attenuated
bone uptake;
3 = strong cardiac uptake
greater than bone or with
mild/absent bone uptake

23. PYP Scanning for Cardiac Amyloid
Sensitivity and Specificity
Quantitative
Sensitivity Specificity
91% 90%
Positive
Predictive
Value
Negative
Predictive
Value
95% 82%
Methods
• Heart: Whole body
• Heart: CL Ratio
• Heart: Blood Pool

24. What we don’t know about
Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related
cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt
amyloid?

25. What we don’t know about
Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related
cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt
amyloid?

26. Age Dependent Penetrance
Journal of Cardiac Failure, 2011; 17 (8), S69

27. What we don’t know about
Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related
cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt
amyloid?

28. TTR Amyloid as a Cause of Age Related
Cardiac and Non-Cardiac Disorder
• HFpEF (aka DHF)
• Atrial fibrillation
• Conduction disease
• Subdural hematoma
• Lumbar Spinal Stenosis
Ups J Med Sci. 2014 Aug;119(3):223-8,
JACC Heart Fail. 2014;2(2):113-22

29. What we don’t know about
Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related
cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt
amyloid?

30. Biomarkers for TTR Cardiac Amyloid

31. What we don’t know about
Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related
cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt
amyloid?

32. Disease modifying therapeutic
opportunities for TTR amyloidosis

33. Tafamidis Open Label Study:
Baseline Demographics / Medical History
Parameter
Overall
N=35 V122I
N=4
Wild-Type
N=31
Mean age, years (SD) 76.4 (4.65) 72.8 (3.38) 76.9 (4.62)
Gender (% male) 32 (91.4) 3 (75.0) 29 (93.5)
Black 4 (11.4) 4 (100.0) 0
NYHA (I / II / III ) 5 / 28/ 2 0 / 3 / 1 5 / 25/ 1
Duration of TTR-CM symptoms, months (SD) 92.5 (92.34) 74.5 (34.24) 94.8 (97.46)
NT-proBNP, pg/mL 4934.2 (4324.9) 5317.5 (343.0) 4909.5 (4465.1)
Troponin I, ng/mL 0.135 (0.080) 0.140 (0.000) 0.134 (0.082)
Atrial fibrillation*, n (%) 21 (60.0) 1 (25.0) 20 (64.5)
Cardiac pacemaker/ ICD. n (%) 14 (40.0%) 1 (25.0%) 13 (41.9%)
Circ Heart Failure: Accepted for publication

34. TTR Stabilization*
with Tafamidis 20 mg QD
Visit
Wild-Type
N=31
Week 6* Patients evaluated, n
Patients stabilized, n (%)
95% CI
31
30 (96.8)
83.3–99.9
Month 6 Patients evaluated, n
Patients stabilized, n (%)
95% CI
30
27 (90.0)
73.5–97.9
Month 12 Patients evaluated, n
Patients stabilized, n (%)
95% CI
28
25 (89.3)
71.8–97.7
*Primary endpoint.

35. Clinical Stabilization with Tafamidis*
Considered stabilized if:
• Alive and
• Did not have 2 of the
following parameters
– TTR not stabilized
– Increase in NT-proBNP ≥1000
pg/mL from baseline
– Increase in troponin I ≥0.1 ng/mL
from baseline
– ≥10% unit decrease in EF from
baseline
– >2 mm increase in IVS thickness
from baseline
74%
26%
Stabilization Clinically
with Tafamidis
Stabilized
Not
Stabilized
* Investigational - not approved

36. Tafamidis* in Patients With Transthyretin
Cardiomyopathy (ATTR-ACT)
• Safety and Efficacy of Tafamidis in Patients With
Transthyretin Cardiomyopathy (ATTR-ACT)
– NCT01994889
– Phase III study in 400 subjects randomized to 80 mg (n=160),
20 mg (n=80) or placebo (n=160).
– 30 Months duration
– Primary endpoint is all-cause mortality and frequency of
cardiovascular-related hospitalization
– Analysis: hierarchical combination of the endpoints for a
pooled analysis of the tafamidis treatment groups in
comparison to placebo
* Investigational - not approved

37. Personalized Medicine for Adopting
Dose of Tafamidis
Biochemistry. 2014;53(12):1993-2006. Amyloid – under review

38. Revusiran (ALN-TTRSC) in Patients With
Transthyretin (TTR) Cardiac Amyloidosis
• Phase 2, Open-Label Trial
• Evaluate the Safety, Pharmacokinetics, Pharmacodynamics
and Exploratory Clinical Activity of ALN-TTRSC in Patients
With Transthyretin (TTR) Cardiac Amyloidosis
– N= 26
– 35 day duration – 10 doses
• Primary Outcome
– % experiencing adverse events (AEs), serious adverse events
(SAEs) and study drug discontinuation.
• Secondary Outcome:
– Pharmacokinetics (PK) of ALN-TTRSC (revusiran)
– Effect of ALN-TTRSC (revusiran) on transthyretin (TTR)

39. Therapeutic Hypothesis for Revusiran
in TTR Cardiac Amyloid
Production of mutant
and wild type TTR
Neuropathy,
cardiomyopathy
Organ deposition of
monomers, amyloid
(β-pleated) fibril
Unstable circulating
TTR tetramers
Stabilization of
cardiomyopathy/neuropathy
(and potential recovery)
Prevention of organ deposition of
TTR monomers and amyloid fibrils
(and potential clearance)
Reduction of
unstable circulating
TTR tetramers
Revusiran acts to knock
down hepatic mutant and
wild-type TTR production

40. Revusiran Phase 2 Study Results
Serum TTR Lowering at 5.0 mg/kg by TTR Type

41. Summary
• ATTRwt cardiac amyloid is an unrecognized and
potentially modifiable cause of HFpEF.
• Early identification is essential and facilitated by
–Non-invasive imaging (echo and MRI)
–Bone Scintigraphy
• Emerging novel therapies are entering into early
and late phase clinical trials.