a diagnostic algorithm

Cardiac Amyloidosis: A Diagnostic Algorithm

Mazen Hanna, M.D.

Director, Heart Failure Intensive Care Unit Co-Director, Amyloid Program

Cleveland Clinic

March 15,2015

Disclosures

• Prothena

– Served on scientific advisory board 2015

Protein misfolding disorder

Over 25 Amyloidogenic Proteins

Amyloidosis Type Precursor protein Cardiac involvement

Prognosis

AL (Primary) Light chain 30-50% Poor if untreated

SSA (“Senile cardiac ) TTR (Transthyretin)

100% 5-7 yrs

ATTR (hereditary) Mutant TTR Mutation dependent

variable

AA (Reactive) Amyloid A < 5-10% 2 yrs

AANF (Isolated Atrial) Atrial natiuretic factor

Limited to atria …..

Cardiac amyloid

2 Types of Amyloid that Affect the Heart

AL TTR

Wild type = SSA Mutant = FAC

Production Circulation

Deposition

ATTR _ Therapy Transthyretin (TTR) “Prealbumin”

How common is TTR-CM?

• In the US, V122I is believed to occur heterogeneously in 3.5% of the African–American population

• SSA is not uncommon in the elderly population – ~ 25% pts > 80 yrs have wild type TTR amyloid deposits in

myocardium

– ~ 20% HFPEF in the elderly population

Ruberg FL, Maurer MS, Judge DP, et al. Am Heart J 2012;164:222–228; Buxbaum JN and Tagoe. Ann Rev Med 2000;51:543–569; Dungu JN, Andersen LJ, Whelan CJ et al. J Heart 2012;98:1146–1154.

Normal

55 year old male

55 year old male

AL Amyloid

72 yr old white female

72 yr old white female

AL Amyloid

Biventricular Thickening

Atrial septal thickening

Diastolic filling abnormalities

Classic ECG

Pseudoinfarction pattern about 50% in AL

Low voltage 50% in AL

Low voltage 25% of ATTR

Presentation

• CHF with predominant R sided sx’s

• Heart failure with preserved EF (HFPEF)

• Atrial fibrillation / cardioembolic stroke

• Pacemaker / Complete heart block

• Angina w normal cors

• Nephrotic syndrome

• Orthostasis

• Neuropathy

• Macroglossia or periorbital purpura (AL)

• Bilateral carpal tunnel syndrome (TTR)

Suggestive Echo + Suggestive ECG Clinical Findings

Fat pad biopsy?

Bone marrow

biopsy?

Shah et al. Amyloidosis and the Heart. Arch Intern Med. 2006;166:1805-1813

Congo red – Apple green birefringence

Thioflavin S What we use at our institution

TTR κ,λ

Diagnostic Approach

Clinical + Echo + ECG

Endomyocardial biopsy

Serum free light chains

Serum immunofixation

Urine immunofixation

SPEP/UPEP

ĸ or ּת light chains

Heme/Onc Consult

Transthyretin

Genetic testing

Mutant TTR Wild Type

Cardiac MRI

Technetium

pyrophosphate scan

Echo w/ Strain

Laboratory Testing

• SPEP and UPEP

• Serum free light chain assay (Kappa/Lambda)

• Serum immunofixation

• Urine immunofixation

The Serum Free-Light Chain Assay - An Abnormal Ratio Proves a Clonal Plasma Cell Disorder - Useful for Diagnosis, Prognosis, Response Assessment

Dispenzieri et al. Leukemia 23, 215–224, 2009

Principle Immune - Nephelopmetry

Diagnosis Cardiac Amyloid by MRI

– There is accumulation of Gadolinium in areas of extracellular fibrosis/protein infiltration, due to increased volume of distribution and slower washout kinetics

Vogelsburg et al. JACC 2008;51:1022-30

80 % sensitivity

90% specificity

85% negative predictive value

55 yr old AA female w/ angina & normal coronaries

Lambda Kappa

Heart 2012 ; 98: 1442-8

Apical sparing pattern

Apical Sparing Pattern: “Relative strain”

Technetium pyrophosphate (dipyrophosphate) scan

Technetium pyrophosphate scan

Bokhari, Circ Cardiovasc Imaging. 2013;6:195-201.)

Specificity is very good Sensitivity for earlier disease is unknown

HCM

HTN heart w/ renal failure Lysosomal storage disease

Amyloid

63 yr old AA male Recurrent CHF

(-) fat pad bx (-) renal bx

63 yr old AA male Recurrent CHF

Endomyocadial Bx c/w TTR Amyloid

TTR allele 1: Sequence alteration detected: transition G ---> A Nucleotide position: 7356 Codon position: 122 Amino acid change: valine --> isoleucine

V122I

Genetic testing for TTR mutation

Heart transplant 2008 Doing well 7 years out

Onset of Disease in Patients with Cardiac Mutations or Wild Type TTR Amyloidosis

50

Ile68Leu N = 11

Leu111Met N = 10

Thr60Ala N = 11

WT N = 74

Val122Ile N = 29

78 yo AA female h/o HTN & EF 45% Referred for shortness of breath

Echocardiogram


Genetic testing for

Transthyretin mutation + for Val 122 Ile

RED FLAGS

• White age > 70 yrs with – “LVH” +/ - relative low voltage ECG

– Conduction disease/ pacemaker

– h/o Bilateral carpal tunnel syndrome

• AA > 65 yrs – “LVH”

• +/- relative low voltage ECG

• Out of proportion to valve disease/ HTN

– Family history CHF

RED FLAGS

• Elderly patient with HOCM (white male) – Echo with strain may help

– Need high index of suspicion TTR - CM

• Elderly patient with aortic stenosis or HTN – LVH “out of proportion”

– Gradient or clinical picture doesn’t entirely fit

– ECG may or may not help

– Need high index of suspicion

Pearls

• High index of suspcion

– ECG and ECHO

• Noninvasive testing can be helpful (strain, technetium pyrophosphate scan)

• DO NOT ORDER SPEP/UPEP!!!!!!!!!!!

• Wild type TTR (“senile”)

– h/o carpal tunnel syndrome, bilateral

• African Americans, TTR, V122I variant

AL TTR

Serum free light chains

Serum immunofixation

Urine immunofixation


ECHO with strain

Endomyocardial biopsy

Cardiac MRI

ECG

THANK YOU

λ-light chain antibody

a diagnostic algorithm

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