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