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* Historical, outdated term: preferred terminology- wild-type TTR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

Surv

ival (%

)

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

Surv

ival (%

)

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

Treatments

CP1251932-94


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.


TTE


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.

http://www.ncbi.nlm.nih.gov/pubmed/23088948









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!

[email protected]

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

Healthcare

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