To amyloid and beyond

©2013 MFMER | slide-1
Cardiac Amyloid – And Beyond!
Presenter:
Kyle W. Klarich, MD
Professor of Medicine, Mayo Clinic, College of Medicine
ACC March 15, 2015

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

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?

37 Year-Old Female
Class IV CHF

37 Year-Old Female, HFpEF

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

Cardiac Amyloidosis
Establish the
Diagnosis

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

• 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

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.

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%

Cardiac Amyloidosis
What Is Amyloid?

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* Historical, outdated term: preferred terminology- wild-type TTR

AL Amyloid
TTR Amyloid

Cardiac Amyloid: Infiltrative Disorder

Extracellular deposition of amyloid fibrils

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

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

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

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

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

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

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

Determine Amyloid Type
Mass Spectrometry
Halt Production or
Stabilize Protein

Why Should A
Cardiologist Care?
CP1251932-94

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

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

Diagnostic Delay
Worsens Prognosis

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

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

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

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

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

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

MOC Question #9
CP1251932-94

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

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

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

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.

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

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

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

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

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

To amyloid and beyond

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