©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

©2013 MFMER | slide-2

DISCLOSURE

No relevant financial relationship(s) with industry

Core Curriculum – ACC 2015

©2013 MFMER | slide-3

©2013 MFMER | slide-4

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?

©2013 MFMER | slide-5

37 Year-Old Female Class IV CHF

©2013 MFMER | slide-6

37 Year-Old Female, HFpEF

©2013 MFMER | slide-7

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

©2013 MFMER | slide-8

©2013 MFMER | slide-9

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

©2013 MFMER | slide-10

Cardiac Amyloidosis

Establish the

Diagnosis

©2013 MFMER | slide-11

Cardiac Amyloidosis Clues to Diagnosis – When to Suspect

Dyspnea or heart failure with:

• Unexplained weight loss

• Peripheral or autonomic neuropathy

• Nephrotic syndrome

• Unexplained hepatomegaly

©2013 MFMER | slide-12

• 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

©2013 MFMER | slide-13

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.

©2013 MFMER | slide-14

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%

©2013 MFMER | slide-15

Cardiac Amyloidosis

What Is Amyloid?

©2013 MFMER | slide-16

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* Historical, outdated term: preferred terminology- wild-type TTR

©2013 MFMER | slide-17

AL Amyloid

TTR Amyloid

©2013 MFMER | slide-18

AL Amyloid

TTR Amyloid

©2013 MFMER | slide-19

©2013 MFMER | slide-20

Cardiac Amyloid: Infiltrative Disorder

©2013 MFMER | slide-21

Extracellular deposition of amyloid fibrils

©2013 MFMER | slide-22

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

©2013 MFMER | slide-23

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

©2013 MFMER | slide-24

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

Surv

ival (%

)

Survival (mo)

Wild type TTR

AL amyloidosis

©2013 MFMER | slide-25

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

©2013 MFMER | slide-26

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

©2013 MFMER | slide-27

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

©2013 MFMER | slide-28

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

©2013 MFMER | slide-29

Determine Amyloid Type

Mass Spectrometry

Halt Production or

Stabilize Protein

©2013 MFMER | slide-30

Why Should A

Cardiologist Care?

CP1251932-94

©2013 MFMER | slide-31

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

©2013 MFMER | slide-32

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

Surv

ival (%

)

Follow-up diagnosis (year)

Group A (1987-1996; n=49)

Group B (1996-2004; n=61)

Group C (2004-2006; n=72

©2013 MFMER | slide-33

Diagnostic Delay

Worsens Prognosis

©2013 MFMER | slide-34

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

©2013 MFMER | slide-35

What is the abnormality seen by TTE likely to be?

1.Artifact

2.Cardiac myxoma

3.Amyloid deposit

4.Thrombus

©2013 MFMER | slide-36

©2013 MFMER | slide-37

What is the abnormality seen by TTE likely to be?

1.Artifact

2.Cardiac myxoma

3.Amyloid deposit

4.Thrombus

©2013 MFMER | slide-38

Cardiac Amyloid – Autopsy Study

% of AL patients with intra-cardiac thrombus?

1. 5

2. 15

3. 30

4. 50

©2013 MFMER | slide-39

©2013 MFMER | slide-40

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

©2013 MFMER | slide-41

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

Treatments

CP1251932-94

©2013 MFMER | slide-43

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

©2013 MFMER | slide-44

MOC Question #9

CP1251932-94

©2013 MFMER | slide-45

MOC Question #9

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

©2013 MFMER | slide-46

TTE

©2013 MFMER | slide-47

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

©2013 MFMER | slide-48

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

©2013 MFMER | slide-49

©2013 MFMER | slide-50

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.

©2013 MFMER | slide-51

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

©2013 MFMER | slide-52

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

©2013 MFMER | slide-53

Thank you!

klarich.kyle@mayo.edu

Acknowledge

Martha Grogan, MD

Director of Mayo Cardiac Amyloid Clinic

©2013 MFMER | slide-54

©2013 MFMER | slide-55

Treatment TTR Amyloid

• TTR stabilizer

Diflunisal, Tafamidis

• RNA interference

Block production

• Fibril Disruption

Doxycycline and TUDCA or URSO

©2013 MFMER | slide-56

Differences in cardiac retention of a technetium-pyrophosphate-99 radiotracer

Dharmarajan K & Maurer M JAGS 2012