To amyloid and beyond

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Cardiac Amyloid – And Beyond!
Presenter:
Kyle W. Klarich, MD
Professor of Medicine, Mayo Clinic, College of Medicine
ACC March 15, 2015

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DISCLOSURE
No relevant financial relationship(s) with industry
Core Curriculum – ACC 2015

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Objectives
Cardiac Amyloid
Three Questions every Cardiologist
needs to be able answer in 2015:
1. How does one diagnosis it?
2. What is it?
3. Why does it matter?

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37 Year-Old Female
Class IV CHF

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37 Year-Old Female, HFpEF

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37 Year-Old Female with Class IV CHF
What next test will likely make the diagnosis?
1. SPEP
2. UPEP
3. Free Light Chains
4. Iron and Ferritin

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37 Year-Old Female with Class IV CHF
What next test will likely make the diagnosis?
1. SPEP
2. UPEP
3. Free Light Chains
4. Iron and Ferritin

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Cardiac Amyloidosis
Establish the
Diagnosis

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Cardiac Amyloidosis
Clues to Diagnosis – When to Suspect
Dyspnea or heart failure with:
• Unexplained weight loss
• Peripheral or autonomic neuropathy
• Nephrotic syndrome
• Unexplained hepatomegaly

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• Mild Multi-valvular
regurgitation
• Thickened walls & Low or
normal voltage ECG
• Pericardial effusion
• Diastolic dysfunction
• Abnormal Strain
• Intracardiac thrombi
even in NSR
Cardiac Amyloidosis
Clues to Diagnosis – When to Suspect

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ECG in Cardiac Amyloid
ECG
AL
Primary
(n=12)
TTR- Senile
Wild Type
(177)
TTR-Fam
Mutant
(82)
Low voltage
(%)
45 22 26
Pseudo-
infarct
47 24 14
AF 10 34 10
LVH 16 3 10
Murtagh B. AJC 2005; Submitted - Mayo Data.

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Cardiac MR in Amyloid
Pattern of Delayed Enhancement
• Diffuse late gadolinium
enhancement
• Difficult to “null” the
myocardium
Described by Maceira et al: JACC, 2005
~ 90 % sensitive
and specific
... Not 100%

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Cardiac Amyloidosis
What Is Amyloid?

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Cardiac Amyloid Types
Familial (ATTR)
Mutant
Transthyretin (TTR)
Unstable
DNA mutation
(liver)
AL (primary) Monoclonal light
chains
Plasma cell
disorder
(bone marrow)
Wild type TTR Liver
“Senile” (SSA)*
Wild Type
* Historical, outdated term: preferred terminology- wild-type TTR

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AL Amyloid
TTR Amyloid

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AL Amyloid
TTR Amyloid

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Cardiac Amyloid: Infiltrative Disorder

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Extracellular deposition of amyloid fibrils

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Direct Toxicity
Light Chains (AL), Pre-Fibrillar Proteins, Oxidative Stress

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The TTR Amyloid Cascade
Image of 3TCT (Bulawa, C.E. et al. PNAS 2012;109:9629-9634) created with Chimera
Tetramer kinetically
stabilized by tafamidis
Free tetramer
Folded dimers
Folded monomer
Misfolded
amyloidogenic
monomer
Spherical
oligomers Amorphous
oligomers
Fibrils
Functional Forms of TTR
Aggregates

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0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100
Survival in Wild-Type TTR vs AL Amyloid
Arch Intern Med 165(12):1425, 2005
Survival(%)
Survival (mo)
Wild type TTR
AL amyloidosis

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Amyloidosis – Clinical Differences
• Primary AL
• multi-organ involvement heart, kidney, nervous system
• Survival after onset of heart failure – 6 mo if no Rx
Familial - TTR age of onset – 20-90 years
• Wide variation from neuropathy to cardiac depending
on genotype, population
• Wild type TTR “Senile”
• mostly males, > 60 years old
• Mean duration onset of symptoms to death ~ 10 years
• highly variable

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Is Amyloidosis Rare?
• All types are under-diagnosed
• AL is uncommon: ~ 3000 new cases per year in US
• Hereditary TTR – most forms are rare
• Val 122 Ile mutation present in 3-4% of Blacks
and Cubans
• Under-recognized cause of heart failure, often
mis-diagnosed as hypertensive heart disease
• Senile (wild-type TTR) - much more common than
previously thought – important cause of AF and HF
in men

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Cardiac Amyloidosis
Diagnosis
• Tissue diagnosis – mandatory
• Fat aspirate – 85% in AL, 15% TTR
• Bone marrow
• Cardiac Biopsy – often required in TTR
Prove: Amyloid organ involvement
Determine type: AL or TTR

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Cardiac Amyloidosis
Screening for Amyloid
Serum and urine immunofixation
Not serum protein electrophoresis
(SPEP & UPEP)
Serum-free light chains & fat aspirate
95-100% of AL amyloid

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Determine Amyloid Type
Mass Spectrometry
Halt Production or
Stabilize Protein

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Why Should A
Cardiologist Care?
CP1251932-94

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Back to our patient: 37 Year-Old Female Class IV
HF Primary AL Cardiac Amyloid
Baseline Post stem cell Tx
NYHA class IV
Septum = 13mm
Post wall = 14 mm
RV wall thickened
Pericardial Effusion
Grade 3 Diastolic
NYHA class I
Septum = 10 mm
Post wall = 10 mm
RV wall normal
Effusion Resolved
Normal Diastology

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Recent Improvements in Survival in Primary Systemic
Amyloidosis and Importance of an Early Diagnosis
0
20
40
60
80
100
0 1 2 3 4
Kumar et al: Mayo Clin Proc 83:297, 2008
Survival(%)
Follow-up diagnosis (year)
Group A (1987-1996; n=49)
Group B (1996-2004; n=61)
Group C (2004-2006; n=72

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Diagnostic Delay
Worsens Prognosis

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58 Year-Old Woman with
GI Amyloid, New Neurologic Signs

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What is the abnormality seen by
TTE likely to be?
1.Artifact
2.Cardiac myxoma
3.Amyloid deposit
4.Thrombus

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What is the abnormality seen by
TTE likely to be?
1.Artifact
2.Cardiac myxoma
3.Amyloid deposit
4.Thrombus

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Cardiac Amyloid – Autopsy Study
% of AL patients with intra-cardiac thrombus?
1. 5
2. 15
3. 30
4. 50

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Cardiac Amyloid – Autopsy Study
% of AL patients with intra-cardiac thrombus?
1. 5
2. 15
3. 30
4. 50
Many Amyloid Patients with AF
Extreme Caution With
Cardioversion

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108 Autopsy Hearts with Amyloid
AL
• 17% Atrial Fibrillation
• 51% Intracardiac
thrombus
Non-AL
• 40% AF
• 17% had thrombus
Elective Cardioversion: Always with TEE and anticoagulation
Feng DL Circ 2007

42. Treatments
CP1251932-94

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Cardiac Amyloid
Expanding treatment options
• AL– autologous stem cell transplant,
chemotherapy
• TTR (wild type and familial) – Trials starting
pharmacotherapy to stabilize TTR or prevent
formation
• Familial TTR – liver transplant
• All - Cardiac transplant, VAD, TAH in
selected cases

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MOC Question #9
CP1251932-94

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MOC Question #9
A 63-year-old man presents
with fatigue, exertional
dyspnea, nausea, dizziness,
and orthostatic hypotension.

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TTE

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Subsequent to this, a cardiac MRI with
gadolinium is obtained:

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Based on these imaging studies, which of
the following is the most likely diagnosis?
1. Hypertrophic obstructive cardiomyopathy
2. Viral myocarditis
3. Constrictive pericarditis
4. Amyloidosis
5. Ischemic cardiomyopathy

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Based on these imaging studies, which of
the following is the most likely diagnosis?
1. Hypertrophic obstructive cardiomyopathy
2. Viral myocarditis
3. Constrictive pericarditis
4. Amyloidosis
5. Ischemic cardiomyopathy
References:Syed IS, Glockner JF, Feng D, et al. JACC Cardiovasc Imaging
2010;3:155-64Restrepo CS, Tavakoli S, Marmol-Velez A. Contrast-enhanced
cardiac magnetic resonance imaging. Magn Reson Imaging Clin N Am
2012;20:739-60.

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Objectives: Cardiac Amyloid
Three Questions every Cardiologist needs to answer -
1. How does one diagnosis it?
Must have tissue - AL & TTR
2. What is it?
Miss folded proteins AL and TTR → HF
3. Why does it matter?
Therapies are available

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Cardiac Amyloid
We Need to make the
Diagnosis
Earlier
Delayed Diagnosis
A major factor in poor prognosis
The Challenge – Each clinician to
diagnose one patient in the next year

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Thank you!
klarich.kyle@mayo.edu
Acknowledge
Martha Grogan, MD
Director of Mayo Cardiac Amyloid Clinic

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Treatment TTR Amyloid
• TTR stabilizer
Diflunisal, Tafamidis
• RNA interference
Block production
• Fibril Disruption
Doxycycline and TUDCA or URSO

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Differences in cardiac retention of a
technetium-pyrophosphate-99 radiotracer
Dharmarajan K & Maurer M JAGS 2012