Increasing Awareness and Improving Care for TTR Cardiac Amyloidosis

Farooq Sheikh, MD, FACCDirector, Infiltrative Cardiomyopathy ProgramMedStar Heart and Vascular InstituteGeorgetown University

Course Speaker Disclosure Information

Farooq Sheikh, MD, FACC

Disclosures

Consultant Fees/Honoraria: Abbott; Alnylam; Pfizer

Institutional Research Support: Abbott

Travel Fee: Medtronic

A Case Based Lecture

• Case 1: Who to suspect (red flag signs and symptoms)

• Case 2: How to evaluate for cardiac amyloidosis

• Case 3: Treatment of TTR cardiac amyloidosis

Which of the following is the most common form of cardiac amyloidosis in the United States?

A. AL.

B. hATTR (Val122Ile).

C. ATTR wild type.

D. hATTR (Val30Met).

Amyloidosis

• Systemic process resulting in extracellular deposition of abnormal insoluble fibrils

• Derived from a variety of serum proteins (“protein folding disorder”)

• Can affect one or more organs

• Results in organ dysfunction due to tissue infiltration

Falk RH, Circulation 2005, 2011

Causes of Cardiac Amyloidosis (CA)

Sperry BW et al., JACC 2018

Mutant TTR

monomers misfold

Formation of insoluble

amyloid fibrils and

amyloid deposition Mutant TTR

monomers

aggregateTTR gene mutation

destabilizes the

tetramer → dissociation

Identical TTR

monomers are

synthesized in the

liver and form

tetramers

TTR tetramers

ATTR Amyloidosis

1. Hawkins et al. Ann Med 2015;47:625–38; 2. Hanna. Curr Heart Fail Rep 2014;11:50–7; 3. Damy et al. J

Cardiovasc Transl Res 2015;8:117–27

TTR amyloidosis leads to “irreversible” organ/tissue damage1–3

Disease Course and Prognosis in ATTR Cardiac Amyloidosis

Ruberg FL et al., JACC 2019

Distribution of ATTR Disease

Maurer MS et al., Circulation 2017

hATTR Amyloidosis: >100 AmyloidogenicMutations

Rapezzi C et al.,

European Heart Journal

2013

Which of the following is a “red flag” for possible cardiac amyloidosis?

A. Heart Failure with Preserved EF (HFpEF) in a patient >60 years of age.

B. History of stroke.

C. Mitral valve disease.

D. Intolerance to digoxin.

Case # 1

69 year old African American man with diagnosis of hypertrophic cardiomyopathy and HFpEF presents for a 2nd opinion.

Reports worsening dyspnea and fluid retention.

Past Medical History:

Family history of heart failure

Coronary angiogram: no significant CAD

Bilateral carpal tunnel release

Lumbar spinal stenosis

Case # 1

Objective data:

ECG: sinus rhythm at 68 bpm with 1st degree AV block, prior anterior infarct age undetermined. Low voltage ECG noted.

Echo: LVEF 40%, Severe “concentric LVH” with IVS thickness of 2.2 cm. Mild MR and TR. Mild aortic stenosis. Mild RV systolic dysfunction.

Physical exam: +JVD, 1/6 HSM, 1+ LE edema.

Labs: Cr 1.7, NT-proBNP 2800, Troponin T 0.06

Cardiac amyloidosis is suspected.

Case # 1

What are the red flag signs?

CNS Manifestations

• Progressive dementia• Headache• Ataxia• Seizures• Spastic paresis• Stroke-like episodes

GI Manifestations

• Nausea and vomiting• Changes in GI motility

(i.e., diarrhea, constipation, gastroparesis, early satiety)

• Unintentional weight loss

Renal Disease

• Proteinuria• Renal failure

Carpal Tunnel Syndrome

Ocular Manifestations

• Vitreous opacification• Glaucoma• Abnormal conjunctival vessels• Papillary abnormalities

CV Manifestations

• Conduction blocks• Cardiomyopathy• Palpitations and arrhythmia• Mild regurgitation• Shortness of breath• Edema

Peripheral Sensory Motor Neuropathy

• Neuropathic pain• Altered sensation (i.e., change

in sensitivity to pain and temperature)• Numbness and tingling• Muscle weakness• Impaired balance• Difficulty walking

Autonomic Neuropathy

• Orthostatic hypotension• Recurrent UTI (due to urinary retention)• Sexual dysfunction• Sweating abnormalities

TTR Amyloidosis is a Multisystem Disease: Signs and Symptoms

Clues for Cardiac Amyloidosis

Shah KB et al., Circ HF 2016

Diagnosis Requires Pattern Recognition

Hanna M, Cleveland Clinic Journal of Medicine, 2017

“Red Flags” for TTR Amyloidosis

Witteles RM et al., JACC 2019

TTR Amyloidosis and Aortic Stenosis

Castano A et al., European

Heart Journal 2017

TTR Amyloidosis and HFpEF

Mohammed SF et al., JACC HF

2014

Delay from Symptom Onset to Diagnosis

Early and common manifestation

Papoutsidakis et al. J Card Fail 2018

Biceps Tendon Rupture and ATTRwt Disease

Geller HI et al., JAMA 2017

A 68-year-old woman presents with signs and symptoms concerning for cardiac amyloidosis. Echocardiogram reveals moderate concentric LV hypertrophy (wall thickness 1.6 cm). Lab tests reveal a monoclonal gammopathy of undetermined significance (MGUS).

Which of the following is the preferred next step in the diagnostic algorithm?

A. Technetium pyrophosphate scan.

B. Hematology consultation for bone marrow biopsy.

C. Fat pad biopsy.

D. Endomyocardial biopsy.

E. Cardiac MRI with and without gadolinium.

Case # 2

63 year old African American man presents with exertional dyspnea and fatigue.

Past Medical History:

HTN, T2DM with peripheral neuropathy, obesity, chronic back pain, history of bilateral carpal tunnel release, family history of “heart problems”.

Recently diagnosed with “bone marrow problem”.

Objective data:

ECG: Atrial fibrillation with slow ventricular response 60 bpm.Computer states “low voltage ECG”. Possible inferior MI.

Case # 2

Objective data (continued):

Echo: LVEF 45%, moderate to severe concentric LVH with IVS thickness of 1.5-1.6 cm. Mild MR and TR. Mild RV systolic dysfunction.

Physical exam: +JVD, 1/6 HSM, 1+ LE edema. +Popeye sign

Labs: Sodium 133, Cr 1.5, Free light chain assay K/L ratio 2.6. Serum immunofixation: kappa “spike” detected.

Cardiac amyloidosis is suspected.

How do you evaluate?

Diagnostic Tools: Electrocardiogram

Falk RH, Circulation, 2011

Echocardiogram

Falk RH, Circulation, 2011

Falk RH, Prog Cardiovasc Dis, 2010

Echocardiogram

Strain Imaging

Falk RH et al., JACC 2016

Cardiac MRI

Esplin BL, Curr Probl Cardiol, 2013

Technetium Pyrophosphate Imaging (PYP)

Technetium Pyrophosphate Imaging (PYP)

Dorbala S et al., JACC Img, 2019

Proteomic Analysis of Biopsy Tissue

Vrana JA et al, Blood 2009

Imaging Clues for Cardiac Amyloidosis

Shah KB et al., Circ HF 2016

Imaging Cardiac Amyloidosis: A Summary

Dorbala S et al., JACC Imaging, 2019

How to Evaluate Cardiac Amyloid

Falk RH et al., JACC 2016

How to Evaluate Cardiac Amyloid

Hanna M, Cleveland Clinic Journal

of Medicine, 2017

A 68-year-old woman presents with signs and symptoms concerning for cardiac amyloidosis. Echocardiogram reveals moderate concentric LV hypertrophy (wall thickness 1.6 cm). Lab tests reveal a monoclonal gammopathy of undetermined significance (MGUS).

Which of the following is the preferred next step in the diagnostic algorithm?

A. Referral to a neurologist.

B. Gene sequencing of the TTR gene.

C. Initiation of diflunisal for treatment of ATTR wild type disease.

D. Palliative care consultation.

Genetic Sequencing of TTR Gene is Essential

• Retrospective analysis of 153 biopsy-proven ATTR patients

• 56 with both genetic testing and proteomic analysis by mass spectrometry

• Proteomics identified the mutant peptide in 47/56 (84%) of cases

Brown EE et al., Amyloid 2017

“Red Flags” for TTR Amyloidosis

Witteles RM et al., JACC 2019

Who to Screen for ATTR-CM

Witteles RM et al., JACC 2019

Case # 3

72 year old African American woman is referred for treatment of hATTR amyloidosis.

Past Medical History:

hATTR amyloidosis (cardiac and nerve involvement)Val122Ile heterozygous mutationHFpEF (LVEF 50%), NYHA class I or II symptomsAtrial fibrillation

What treatment options is she eligible for?

• Treatment depends on the identification of the precursor protein

• Diuretics/sodium restriction

• Surveillance for and treatment of atrial/ventricular arrhythmias

• Monitoring for conduction disease

• Avoidance of negative inotropic/chronotropic drugs (beta blockers, calcium channel blockers)

• Avoidance of vasodilator therapy

General Principles for Treatment of Cardiac Amyloidosis

Multidisciplinary Team Approach

Treatment Strategies in TTR Disease

Ruberg FL et al., JACC 2019

Therapeutic Targets in ATTR Disease

Buxbaum JN, NEJM 2018

Tafamidis (ATTR-ACT Trial)

Tafamidis

Maurer MS et al, NEJM 2018

Tafamidis

Maurer MS et al, NEJM 2018

NNT to prevent 1 death=7.5

NNT to prevent 1 hospitalization per year=4.5

Tafamidis

Maurer MS et al, NEJM 2018

AG-10 (ATTRibute-CM Trial)

Current and Emerging Therapies for hATTRAmyloidosis

Buxbaum JN, NEJM 2018

Patisiran (APOLLO Trial)

FDA-approved for treatment of hATTR polyneuropathy

Adams D et al, NEJM 2018

Patisiran:Effects on Cardiac Parameters

Solomon SD et al, Circulation 2018

Inotersen: NEURO-TTR Trial

Benson M.D. et al, NEJM 2018

Biomarker Staging System in ATTRwt(TnT and NT-proBNP)

Grogan M et al., JACC 2016